Stereoselective synthesis of the C14-C26 fragment of the cytotoxic macrolide FD-891

Article abstract of DOI:10.1016/j.tetlet.2004.08.013

A stereoselective synthesis of compound B, which contains the C ₁₄-C₂₆ fragment and seven stereocenters of the naturally occurring, cytotoxic macrolide FD-891, is described. Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis. A stereoselective synthesis of the C₁₄-C₂₆ fragment of the naturally occurring, cytotoxic macrolide FD-891, is described. Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis.

Full text of DOI:10.1016/j.tetlet.2004.08.013

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7499–7501
Stereoselective synthesis of the C14–C26 fragment of the cytotoxic
macrolide FD-891
a
a
b,
*
Juan Murga,a, Jorge Garcıa-Fortanet, Miguel Carda and J. Alberto Marco
*
´
a
´
´
´
´
Depart. de Q. Inorganica y Organica, Univ. Jaume I, Castellon, E-12080 Castellon, Spain
b
´
Depart. de Q. Organica, Univ. de Valencia, E-46100 Burjassot, Valencia, Spain
Received 9 July 2004; revised 30 July 2004; accepted 3 August 2004
Available online 26 August 2004
Abstract—A stereoselective synthesis of the C14–C26 fragment of the naturally occurring, cytotoxic macrolide FD-891, is described.
Asymmetric Evans aldol reactions and aldehyde Brown allylations are key steps of the synthesis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The cytotoxic metabolite FD-891 was isolated from the
fermentation broth of Streptomyces graminofaciens A-
8890 and was found active against several tumor cell
lines. In addition, it was found to potently prevent both
perforin- and FasL-dependent CTL-mediated killing
pathways. In contrast to the structurally related concan-
amycin A, however, it was unable to inhibit vacuolar
acidification.1 We have now faced the problem of syn-
thesizing this bioactive metabolite and have chosen the
convergent retrosynthesis shown in Scheme 1. Accord-
ing to it, the molecule of FD-891 is disconnected to frag-
ments A (C1–C13) and B (C14–C26) via an esterification
and a Heck coupling. Which one of these two reactions
will be the final macrocyclization process still remains an
open issue to be decided at a later stage. Indeed, both
macrolactonizations2 and intramolecular Heck reac-
tions3 are amply represented in the literature.
In the present communication, we will describe the syn-
thetic work performed to achieve the preparation of
fragment B, which carries the protecting groups
R = TBS (t-butyldimethylsilyl) and MOM (methoxy-
methyl).4 This fragment, which contains 7 of the 12 ster-
eocenters of the molecule, was further retrosynthetically
disconnected as shown in Scheme 2. One key structural
transformation in this retrosynthesis (B ! I) is the
Scheme 1. Structure of FD-891 and main retrosynthetic disconnection.
Keywords: Macrolides; Cytotoxicity; FD-891; Asymmetric allylbora-
tion; Boron aldol reactions.
*
Corresponding authors. Tel.: +34 96 3544337; fax: +34 96
3544328; e-mail: alberto.marco@uv.es
Scheme 2. Retrosynthetic disconnection of fragment B.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.013

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J. Murga et al. / Tetrahedron Letters 45 (2004) 7499–7501
stereoselective allylation of a chiral a-methyl aldehyde
and was planned to be performed in an asymmetric
way using one of BrownÕs chiral allylboration reagents.5
The protecting group TPS (t-butyldiphenylsilyl) was se-
lected with the idea in mind of its later selective cleavage
in the presence of two TBS groups. The two other key
retrotransformations, II ! III and III ! IV, are aldol
reactions conceived to create the C22–C25 dipropionate
segment. In the actual synthesis, both aldol steps
were executed with the aid of the chiral oxazolid-
inones developed by Evans and his group.6 The ulti-
mate chirality source was the commercially available
ester 1.
Scheme 3 depicts the actual synthetic sequence, which
led to compound B. The chiral, commercially available
ester 1 was converted into the known primary alcohol
27 via a literature procedure. Swern oxidation of the
latter to aldehyde 3 was followed by Evans asymmetric
aldolization using the Z boron enolate of the chiral oxa-
zolidinone 16.6a This provided aldol adduct 4 as an
essentially single stereoisomer. Conversion of 4 into
the Weinreb amide8 and silylation afforded 5, which
was then reduced (DIBAL) to aldehyde 6. The latter
compound was submitted to a second aldolization
with Evans oxazolidinone 17,6a followed by silylation
and amidation. This yielded Weinreb amide 9,9 which
was converted into methyl ketone 10 by treatment with
methylmagnesium bromide. Stereoselective reduction of
the carbonyl group of 10 under chelation control10–13 to
alcohol 11 and subsequent O-methylation with methyl
triflate/2,6-di-tert-butylpyridine14 afforded compound
12. Selective cleavage of the OTPS group in 12 under
alkaline conditions15 provided the primary alcohol 13,
which was then oxidized to aldehyde 14. Asymmetric
allylation of the latter5 afforded secondary alcohol 15,
which, through protection of the secondary alcohol
group as its MOM derivative,16 afforded the desired
fragment B.17
In summary, a stereoselective synthesis of the C14–C26
fragment of the cytotoxic macrolide FD-891 has been
achieved. Studies toward the total synthesis of the natu-
ral product are underway and will be published in due
course.
Acknowledgements
Financial support has been granted by the Spanish
Ministry of Education (project BQU2002-00468), by
the AVCYT (project GRUPOS03/180) and by the
BANCAJA-UJI foundation (project P1B99-18). J.M.
and J.G.-F. thank the Spanish Ministry of Education
´
and Science for a Ramon y Cajal and for a pre-doctoral
fellowship, respectively.
Scheme 3. Stereoselective synthesis of compound B. Reagents and
conditions: (a) (COCl)2, DMSO, CH2Cl2, Et3N, 1h, 0ꢁC; (b) 16,
Bu2BOTf, Et3N, 0ꢁC, then 3, 2.5h, 0ꢁC, 89% overall from 2; (c)
MeNHOMe, AlMe3, THF, 3h, rt, 79%; (d) TBSOTf, 2,6-lutidine,
CH2Cl2, rt, 1h, 92%; (e) DIBAL, THF, ꢀ78ꢁC, 30min; (f) 17,
Bu2BOTf, Et3N, 0ꢁC, then 6, 3h, 0ꢁC, 75% overall from 5; (g)
TBSOTf, 2,6-lutidine, CH2Cl2, rt, 1h, 90%; (h) H2O2, aq LiOH, THF,
0ꢁC ! rt, overnight; (i) MeNHOMe, 1,10-carbonyldiimidazole,
CH2Cl2, rt, 12h, 80% overall from 8; (j) MeMgBr, THF, 0ꢁC, 1h,
70%; (k) Me2AlCl (2.5equiv), Bu3SnH, CH2Cl2, ꢀ90ꢁC, 1h, 91% (92:8
diastereoisomeric mixture); (l) MeOTf, 2,6-di-t-butylpyridine, CHCl3,
D, 4h, 84%; (m) 10% NaOH, MeOH, D, 30h, 84%; (n) (COCl)2,
DMSO, CH2Cl2, Et3N, 20min, 0ꢁC; (o) allylBIpc2 [from (ꢀ)-DIP-Cl
and allylmagnesium bromide], Et2O, 1h, ꢀ90ꢁC, 55% overall from 13
as a single stereoisomer; (p) MOMCl, EtNi-Pr2, CH2Cl2, rt, overnight,
79%.
References and notes
1. The structure of FD-891 was established with the aid of
X-ray diffraction analyses on degradation products. See:
Eguchi, T.; Kobayashi, K.; Uekusa, H.; Ohashi, Y.;
Mizoue, K.; Matsushima, Y.; Kakinuma, K. Org. Lett.
2002, 4, 3383–3386.
´
2. Bartra, M.; Urpı, F.; Vilarrasa, J. In Recent Progress in the
Chemical Synthesis of Antibiotics and Related Microbial
Products; Lukacs, G., Ed.; Springer: Berlin, 1993; Vol. 2,
pp 1–65.
3. Ojima, I.; Tzamarioudaki, M.; Li, Z.-Y.; Donovan, R.
J. Chem. Rev. 1996, 96, 635–662.

J. Murga et al. / Tetrahedron Letters 45 (2004) 7499–7501
7501
4. The synthesis of an intermediate related to fragment A has
been recently reported: Chng, S.-S.; Xu, J.; Loh, T.-P.
Tetrahedron Lett. 2003, 44, 4997–5000.
19ppm. This indicates that it is the acetonide of a syn-1,
3-diol13 and can only be that indicated below, as the
internal acetonide would necessarily be anti.
5. (a) Brown, H. C.; Ramachandran, P. V. J. Organomet.
Chem. 1995, 500, 1–19; (b) Ramachandran, P. V. Aldri-
chim. Acta 2002, 35, 23–35.
6. (a) Evans, D. A. Aldrichim. Acta 1982, 15, 23–32; (b) Kim,
B. M.; Williams, S. F.; Masamune, S. In Comprehensive
Organic Synthesis; Trost, B. M., Fleming, I., Winterfeldt,
E., Eds.; Pergamon: Oxford, 1993; Vol. 2, pp 239–276; See
also: Cowden, C. J.; Paterson, I. Org. React. 1997, 51,
1–200.
13. Rychnovsky, S. D.; Rogers, B. N.; Richardson, T. I. Acc.
Chem. Res. 1998, 31, 9–17.
´
14. Experimental procedure taken from: Walba, D. M.;
Thurmes, W. N.; Haltiwanger, R. C. J. Org. Chem.
1988, 53, 1046–1056. MeerweinÕs salt (trimethyloxo-
nium tetrafluoroborate) proved ineffective in the present
case.
15. Hatakeyama, S.; Irie, H.; Shintani, T.; Noguchi, Y.;
Yamada, H.; Nishizawa, M. Tetrahedron 1994, 50,
13369–13376.
7. Nicolaou, K. C.; Namoto, K.; Ritzen, A.; Ulven, T.; Shoji,
M.; Li, J.; DÕAmico, G.; Liotta, D.; French, C. T.;
Wartmann, M.; Altmann, K. H.; Giannakakou, P. J. Am.
Chem. Soc. 2001, 123, 9313–9323; However, we have
prepared 2 via an adaptation of one route described for
the TBS analogue: Chandrasekhar, S.; Reddy, C. R.
Tetrahedron: Asymmetry 2002, 13, 261–268.
8. Sibi, M. P. Org. Prep. Proc. Int. 1993, 25, 15–
40.
16. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, third ed.; John Wiley and Sons: New
York, 1999, pp 27–33.
9. Low yields and conversion rates were observed in all
attempts at direct formation of 9 from oxazolidinone 8
under standard conditions (MeNHOMe, AlMe3). There-
fore, we resorted to the alternative method described in
Scheme 3.
10. Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E.
J. Am. Chem. Soc. 2001, 123, 10840–10852; See also: Ooi,
T.; Morikawa, J.; Uraguchi, D.; Maruoka, K. Tetrahedron
Lett. 1999, 40, 2993–2996.
11. Prior to the use of Bu3SnH/Me2AlCl, we tested reductants
such as DIBAL and L-Selectride, which have proven
useful in closely related instances: Boger, D. L.; Curran, T.
T. J. Org. Chem. 1992, 57, 2235–2244. However, they
displayed a low stereoselectivity in the present case (about
2:1).
12. The configuration of the stereocenter created in this step
was established by total desilylation of 11 with TBAF and
treatment of the resulting tetraol with 2,2-dimethoxyprop-
ane and an acid catalyst. This gave a monoacetonide i,
which showed two methyl 13C NMR signals at ca. 30 and
17. Oil; [a]D ꢀ3.1 (c 0.86, CHCl3), 1H NMR (500MHz) d 5.82
(1H, m, H-2), 5.10 (1H, dd, J = 17, 1.5Hz, H-1t), 5.04 (1H,
dd, J = 10, 1Hz, H-1c), 4.65 (2H, AB system, J = 7Hz,
MOM), 3.81 (1H, dd, J = 5.8, 1.6Hz, H-10), 3.70 (1H, m,
H-8), 3.47 (1H, m, H-4), 3.37 (3H, s, OMe), 3.30 (3H, s,
OMe), 3.14 (1H, quint, J = 6.5Hz, H-12), 2.30 (2H, m, H-
3), 1.75–1.50 (5H, br m, H-5/H-6/H-9), 1.45–1.40 (2H, m,
H-7), 1.12 (3H, d, J = 6.5Hz, H-13), 0.94 (3H, d, J = 7Hz,
Me-C), 0.91 (3H, d, J = 7Hz, Me-C), 0.90 (9H, s, t-Bu),
0.89 (9H, s, t-Bu), 0.86 (3H, d, J = 7Hz, Me-C), 0.09 (3H,
s, Me-Si), 0.07 (3H, s, Me-Si), 0.06 (3H, s, Me-Si), 0.05
(3H, s, Me-Si). 13C NMR (125MHz) d 18.5, 18.3 (C),
135.6, 81.4, 79.9, 73.4, 72.6, 43.4, 41.2, 36.6 (CH), 116.7,
96.1, 36.0, 33.4, 27.2 (CH2), 56.4, 55.6, 26.1 (·3), 26.0 (·3),
16.5, 14.6, 11.1, 10.6, ꢀ3.3, ꢀ3.5, ꢀ4.0, ꢀ4.1 (CH3). HR
EIMS m/z (% rel. int.) 517.3756 (M+ ꢀ t-Bu, 3), 283 (20),
231 (55), 139 (34), 59 (100). Calcd for C31H66O5Si2-t-Bu,
517.3744.