A concise and efficient stereoselective synthesis of the C1-C11 fragment of macrolactin A

Article abstract of DOI:10.1055/s-2006-950424

A stereoselective synthesis of the C1-C11 fragment of macrolactin A, using original approaches for the introduction of the Z,E-diene stereochemistry and the C-7 stereogenic center, is reported. The adopted strategy has allowed us to build up the fragment

Full text of DOI:10.1055/s-2006-950424

LETTER
2427
A Concise and Efficient Stereoselective Synthesis of the C1–C11 Fragment of
Macrolactin A
S
ynthesis of C1–C
a
11 Fragm
r
ent of
M
l
acrolac
o
tin A Bonini,*a Lucia Chiummiento,a Valeria Videtta,a Françoise Colobert,b Guy Solladiéb
a
Dipartimento di Chimica, Università degli Studi della Basilicata, via N. Sauro 85, 85100 Potenza, Italy
Fax +39(971)202223; E-mail: bonini@unibas.it
b
Laboratoire de Stéréochemie associé au CNRS, Université Louis Pasteur (ECPM), rue Bacquerel, 67087 Strasbourg, France
Received 4 July 2006
macrolactin A into its upper and lower parts, fragments 3
and 2, is shown in Scheme 1. We have recently reported
an efficient synthesis of the C12–C24 subunit 2.5
Abstract: A stereoselective synthesis of the C1–C11 fragment of
macrolactin A, using original approaches for the introduction of the
Z,E-diene stereochemistry and the C-7 stereogenic center, is report-
ed. The adopted strategy has allowed us to build up the fragment by
the assembly of three key intermediates via cross-metathesis, Still–
Gennari, and Wittig olefinations. Opening of the commercially
available chiral benzyl glycidol epoxide to the corresponding
homoallylic alcohol introduced the C-7 chiral center. A cross-meta-
thesis reaction was used to create the C5–C4 E double bond. The
Still–Gennari reaction introduced the 2Z,4E-diene moiety and
finally the Wittig reaction with a propargylic triphenylphosphorane
introduced directly the 1,3-enyne unit in a highly efficient stereo-
selective fashion.
In our strategy, the prepared fragment 2 will be assembled
with the upper C1–C11 fragment 3, through alkylation
(C11–C12 bond formation) and macrolactonization reac-
tions, followed by the final reduction of the triple bond to
the Z olefin on C10–C11.
In our first projected route we planned to synthesize seg-
ment 3 from precursor 4, a compound containing two 1,3-
enynes. With the novel propargylic benzothiazolyl (BT)-
sulfone 66 in hand, we decided to investigate the one-pot
Julia olefination7 in the construction of trans double
bonds.8 This approach has never been used in the con-
struction of the C1–C11 segment of macrolactin A
(Scheme 2).
Key words: macrolactin A, cross-metathesis, Still–Gennari reac-
tion, Wittig olefination, dienes
Macrolactin A (1), a 24-membered polyene macrolide,
isolated in 1989 by Fenical and co-workers from a deep-
sea bacterium of unclassified taxonomy along the coast of
California,1 belongs to the class of macrolactins whose
other members have been more recently isolated.2 Macro-
lactin A displays strong cytotoxic activity in vitro on B16-
F10 murine melanoma cells (IC50 = 3.5 mg/mL) as well as
powerful antiviral activity against Herpes simplex types I
and II and against human HIV-1 virus replication.1 Its
complex structure and potent antiviral action, combined
with an extremely low natural supply, has provided the
impetus for a number of synthetic efforts.3,4 In many of the
synthetic approaches, a step-by-step addition of suitable
synthons was applied to build up the stereogenic centers
and the diene units.3,4 Our retrosynthetic disconnection of
As shown in Scheme 3, ring-opening of the known (R)-p-
methoxybenzyl glycidyl ether (5) with methyl phenyl sul-
fone in THF afforded the g-hydroxy sulfone 8 in 60%
yield. Thus, protection as its cyclic acetal led to 9 in 70%
yield. The subsequent classical Julia reaction with propar-
gylic aldehyde 7, prepared from the corresponding alco-
hol 11, did not furnish the corresponding b-hydroxy
sulfone but only many by-products. A similar trend was
also observed in the Julia olefination when sulfone 10,
prepared by derivatization of compound 8, was used.
As this approach was unsuccessful, we planned to change
the two partners of the Julia olefination and we decided to
use propargylic BT-sulfone 66 and aldehyde 14
(Scheme 3).
OH
OP
11
2
8
3
TMS
CO2Me
OC
11
O
+
BnO
O
23
12
HO
OTBS
23
HO
macrolactin A
1
O
2
Scheme 1 Retrosynthetic approach to the total synthesis of macrolactin A.
SYNLETT 2006, No. 15, pp 2427–2430
1
8
.0
9
.2
0
0
6
Advanced online publication: 08.09.2006
DOI: 10.1055/s-2006-950424; Art ID: G22206ST
© Georg Thieme Verlag Stuttgart · New York

2428
C. Bonini et al.
LETTER
OP
Since the failure of the previous approaches, a more suit-
able strategy was planned, as described in Scheme 4. Ho-
moallylic alcohol 12 (Scheme 4), was therefore subjected
to a cross-metathesis reaction10 with alkene 16 and, alter-
natively, with commercially available methyl acrylate 18.
While ester 19 was obtained with 87% yield and high ste-
reoisomeric ratio (E/Z, 99:1), olefin 17 was obtained in
50% yield and lower trans selectivity (E/Z, 71:29). Thus,
compound 19 represented the advanced fragment for the
preparation of 3.
11
7
TMS
CO2Me
R
3
OP
11
7
TMS
4
Julia olefination
R
a.
TBSO
OTBS
OH
O
11
SO2–BT
+
PMBO
16
X
PMBO
PMBO
7
+
7
OTBS
TMS
OH
5
7
X = CHO
or
6 X = CH2SO2–BT
6
PMBO
17 E/Z 71:29
7
12
b.
OH
CO2Me
18
CO2Me
E/Z 99:1
Scheme 2 First proposed route to the C1–C11 fragment.
7
19
Scheme 4 Reagents and conditions: a) 16, Grubbs II cat. (10
mol%), CH2Cl2, reflux, 1 h, 50%; b) 18, Grubbs II cat. (1 mol%),
CH2Cl2, reflux, 3 h, 87%.
OR
O
a
PMBO
R1O
7
7
SO2Ph
d
5
8: R = H, R1 = PMB
9: R–R1 = -CH(PMP)-
10: R = TBS, R1 = PMB
b
c
OR
OTBS
b
CO2Me
PMBO
PMBO
7
7
OR
OTBS
OTBS
e
19: R = H
20: R = TBS
21: R = H
22: R = TBS
O
HO
a
c
7
11
OTBS
OR
f, g
h
PMBO
PMBO
5
OTBS
7
OTBS
d
7
O
f
14
BT–SO2
7
12: R = H
13: R = TBS
7
OTBS
R
OTBS
TMS
TMS
23: R = CH2OH
24: R = CHO
i
25
8E/8Z 14:86
e
6
OTBS
Scheme 5 Reagents and conditions: a) TBSCl, imidazole, CH2Cl2,
r.t., 20 h (92%); b) DIBAL-H, toluene, 0 °C, 4 h (85%); c) TBSCl,
imidazole, CH2Cl2, r.t., 24 h (quant.); d) DDQ, pH buffer 7, CH2Cl2,
0 °C to r.t., 6 h, 73%; e) Dess–Martin periodinane, CH2Cl2, r.t., 3 h
(75%); f) 6, KHMDS, –67 to 0 °C to r.t., 4 h (76%).
PMBO
7
15
only Z
TMS
Scheme 3 Reagents and conditions: a) PhSO2Me, n-BuLi, HMPA,
THF, –65 °C to r.t., 30 min (60%); b) DDQ, MS, CH2Cl2, r.t., 5 h
(70%); c) TBSOTf, 2,6-lutidine, CH2Cl2, –78 °C, 30 min (63%); d) n-
BuLi, THF, –78 °C to r.t., 20 h; e) Dess–Martin periodinane, CH2Cl2,
r.t., 20 min (88%); f) vinylMgBr, CuI, THF, –20 °C, 10 min (quant);
g) TBSCl, imidazole, DMF, r.t., 16 h (88%); h) OsO4, NMO, NaIO4,
THF, H2O, r.t., 2 h (quant); i) KHMDS, 6, THF, –65 °C to r.t., 4 h
(56%).
Therefore, ester 20, obtained after silylation of 19 (92%
yield), was conveniently converted into the protected triol
22 by reduction to the corresponding alcohol 21 (DIBAL-
H, 85% yield) and quantitative protection of the hydroxyl
group with TBSCl. Subsequently, compound 22 was
selectively deprotected with DDQ (73% yield) affording
alcohol 23, which was oxidized with Dess–Martin perio-
dinane to furnish the desired aldehyde 24 in 75% yield.
The latter aldehyde was finally reacted with sulfone 6 via
Julia olefination, affording compound 25 in good yield
(76%) but still with high Z selectivity (E/Z, 14:86).11
Nucleophilic opening of epoxide 5 with vinylmagnesium-
bromide/CuI,9 and protection of the resulting homoallylic
alcohol 12, led to 13 in high yield (88% yield). The expo-
sure of 13 to OsO4 and NaIO4 resulted in the formation of
aldehyde 14 in quantitative yield. The latter compound
was then allowed to react with 6 according to the one-pot
Julia protocol, affording 15 in fair yield (56%), but with
very high Z selectivity.
Because of the failure of this route to introduce the correct
olefin stereochemistry, a second strategy for the synthesis
of the C1–C11 segment was planned as shown in the
retrosynthetic Scheme 6. In order to establish the appro-
priate double bond geometry in a simple short sequence,
Still–Gennari12 and final Wittig olefination were chosen,
Synlett 2006, No. 15, 2427–2430 © Thieme Stuttgart · New York

LETTER
Synthesis of C1–C11 Fragment of Macrolactin A
2429
cross-metathesis
in Scheme 5, was subjected to the Wittig olefination with
phosphorane 26. Compound 25 was obtained in 74% yield
and with 83:17 E/Z ratio. Considering that there were not
substantial improvements in the yield and selectivity in
the latter reaction, the shorter route to compound 3 re-
mained that reported in Scheme 7.
OP
11
7
TMS
CO2Me
Wittig
3
olefination
Still–Gennari
olefination
PPh3+Br–
OP
OTBS
OTBS
+
P'O
11
7
a
7
26
OTBS
27
TMS
OHC
OTBS
CO2Me
TMS
24
Still–Gennari
olefination
25
8E/8Z 83:17
1. desilylation of 1° alcohol
2. oxidation
3. Still–Gennari reaction
OTBS
PMBO
+
(CF3CH2O)2OP
28
CO2Me
7
OH
3
21
Scheme 8 Reagents and conditions: a) 26, n-BuLi, –78 °C to 0 °C,
3 h (74%).
Scheme 6 Second proposed route to the C1–C11 fragment.
starting from commercially available propargylic triphen-
ylphosphorane 26, phosphonate 28, and from alcohol 21
prepared, as described in Schemes 4 and 5, via the cross-
metathesis route.
In conclusion, after various attempts, an efficient prepara-
tion of a key C1–C11 intermediate toward the total syn-
thesis of macrolactin A (1) was described showing high
stereoselectivity in the introduction of the required three
double bonds.
Aldehyde 29 (Scheme 7), easily prepared from alcohol 21
via oxidation with Dess–Martin periodinane, was allowed
to react with phosphonate 28 affording (2Z,4E)-diene 27
with excellent stereoselectivity (Z,E/E,E, 95:5) in 70%
yield. Deprotection of 27 with DDQ afforded alcohol 30
in 73% yield, which was subsequently oxidized with
Dess–Martin periodinane to aldehyde 31 in 75% yield.
Preparation of the required compound 3 was finally
achieved by reacting the propargylic triphenylphos-
phorane 2613 with aldehyde 31 in the presence of n-BuLi
at –78 °C. This final Wittig reaction produced the target
C1–C11 fragment 314 of macrolactin A in 75% yield and
with a good level of stereoselectivity (E/Z, 79:21 ratio) at
the C8–C9 double bond.
Acknowledgment
Thanks are due to the University of Basilicata and the MIUR
(FIRB-Progettazione, preparazione e valutazione biologica e far-
macologica di nuove molecole organiche quali potenziali farmaci
innovativi) for financial support.
References and Notes
(1) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc.
1989, 111, 7519.
(2) (a) Kim, H.-H.; Kim, W.-G.; Ryoo, I.-J.; Kim, C.-J.; Suk, J.-
E.; Han, K.-H.; Hwang, S.-Y.; Yoo, I.-D. J. Microbiol.
Biotechnol. 1997, 7, 429. (b) Jaruchoktaweechai, C.;
Suwanborirus, K.; Tanasupawatt, S.; Kittakoop, P.;
Menasveta, P. J. Nat. Prod. 2000, 63, 984. (c) Nagao, T.;
Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J. Antibiot.
2001, 54, 333. (d) Romero-Tabarez, M.; Jansen, R.; Sylla,
M.; Lünsdorf, H.; Häußler, S.; Santosa, D. A.; Timmis, K.
N.; Molinari, G. Antimicrob Agents Chemother. 2006, 50,
1701.
OTBS
OTBS
a
b
PMBO
PMBO
7
OH
7
O
21
29
OTBS
OTBS
e
c
PMBO
7
7
R
(3) For the total synthesis, see: (a) Smith, A. B. III.; Ott, G. R. J.
Am. Chem. Soc. 1996, 118, 13095. (b) Kim, Y.; Singer, R.
A.; Carreira, E. M. Angew. Chem. Int. Ed. 1998, 37, 1261.
(c) Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto,
J. V.; Tucci, F. C. J. Am. Chem. Soc. 2001, 124, 1664.
(4) For partial syntheses, see: (a) Benvegnu, T.; Schio, L.; Le
Floch, Y.; Grèe, R. Synlett 1994, 505. (b) Donaldson, W.
A.; Bell, P. T.; Wang, Z.; Bennett, D. W. Tetrahedron Lett.
1994, 35, 5829. (c) Boyce, R. J.; Pattenden, G. Tetrahedron
Lett. 1996, 37, 3501. (d) Benvegnu, T.; Toupet, L.; Greè, R.
Tetrahedron 1996, 52, 11811. (e) Benvegnu, T.; Greè, R.
Tetrahedron 1996, 52, 11821. (f) Prahlad, V.; Donaldson,
W. A. Tetrahedron Lett. 1996, 37, 9169. (g) Gonzàlez, A.;
Aiguadè, J.; Urp, F.; Villarasa, J. Tetrahedron Lett. 1996, 37,
8949. (h) Tanimori, S.; Morita, Y.; Tsubota, M.; Nakayama,
M. Synth. Commun. 1996, 26, 559. (i) Donaldason, W. A.;
Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y. K.; Wang, Z.
Tetrahedron 2000, 56, 2283. (j) Li, S.; Xu, R.; Bai, D.
27
CO2Me
30: R = CH2OH
31: R = CHO
CO2Me
d
2Z,4E/2E,4E 95:5
OTBS
4
7
2
11
3
TMS
CO2Me
8E/8Z 79:21
Scheme 7 Reagents and conditions: a) Dess–Martin periodinane,
CH2Cl2, r.t., 3 h (78%); b) 28, KHMDS, 18-crown-6, THF, –78 °C,
4 h (70%); c) DDQ, buffer pH 7, CH2Cl2, r.t., 5 h, 73%; d) Dess–
Martin periodinane, CH2Cl2, r.t., 6 h (75%); e) 26, n-BuLi, –78 °C to
0 °C, 3 h (75%).
In order to improve the selectivity of the Wittig reaction
additional experiments were performed. The aldehyde 24
(Scheme 8), prepared according to the conditions reported
Synlett 2006, No. 15, 2427–2430 © Thieme Stuttgart · New York

2430
C. Bonini et al.
LETTER
Tetrahedron Lett. 2000, 41, 3463. (k) Hoffmann, H. M. R.;
Vakalopoulos, A. Org. Lett. 2001, 3, 177. (l) Shukun, L.;
Donaldson, W. A. Synthesis 2003, 13, 2064. (m) Fukuda,
A.; Kobayashi, Y.; Kimachi, T.; Takemoto, Y. Tetrahedron
2003, 59, 9305. (n) Li, S.; Xiao, X.; Yan, X.; Xu, R.; Bai, D.
Tetrahedron 2005, 61, 11291. For a total synthesis of an
analogue of macrolactin A, see: (o) Kobayashi, Y.; Fukuda,
A.; Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron
Lett. 2004, 45, 677. (p) Kobayashi, Y.; Fukuda, A.;
Kimachi, T.; Ju-ichi, M.; Takemoto, Y. Tetrahedron 2005,
61, 2607.
(9) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.;
Colobert, F.; Solladié, G. Tetrahedron Lett. 2003, 44, 2695.
(10) For recent reviews of the alkene metathesis reaction, see:
(a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.
Int. Ed. 2005, 44, 4490. (b) Schmidt, B.; Hermanns, J. Top.
Organomet. Chem. 2004, 7, 223. (c) Fürstner, A. Angew.
Chem. Int. Ed. 2000, 39, 3012. (d) Grubbs, R. H.; Chang, S.
Tetrahedron 1998, 54, 4413.
(11) These high Z selectivities prompted us to study the one-pot
Julia olefination with propargylic sulfone 6 and several
different aromatic and aliphatic aldehydes more extensively:
Bonini, C.; Chiummiento, L.; Videtta, V. Synlett 2006, 2079.
(12) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24,
4405. (b) Yu, W.; Su, M. Tetrahedron Lett. 1999, 40, 6725.
(13) Attempts were made to prepare the tributyl propargylic
phosphorane but we had some problems obtaining it pure.
(14) Compound 3: Rf 0.26 (PE–Et2O–CH2Cl2, 99:2:1). 1H NMR
(500 MHz, CDCl3): d = 7.40 (dd, J4,5 = 14.4 Hz, J4,3 = 11.9
(5) Bonini, C.; Chiummiento, L.; Pullez, M.; Solladié, G.;
Colobert, F. J. Org. Chem. 2004, 69, 5015.
(6) Extensive work on different propargylic alcohols led to a
general protocol for the preparation of aromatic and
heteroaromatic sulfones as reported in: Bonini, C.;
Chiummiento, L.; Videtta, V. Synlett 2005, 3067.
(7) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002,
2563. (b) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336. (c) Baudin, J.
B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull. Soc.
Chim. Fr. 1993, 130, 856. (d) Baudin, J. B.; Hareau, G.;
Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991, 32, 1175.
(8) The stereochemical outcome of the one-pot Julia olefination
is generally substrate (sulfone and aldehyde) controlled.
Moreover, there are some examples where b,g-unsaturated
BT-sulfones give high levels of E stereoselectivity (see ref.
7a).
Hz, 1 H), 6.55 (t, J3,2 = J3,4 = 11.0 Hz, 1 H), 6.18 (dd, J8,9
=
16.0 Hz, J8,7 = 5.0 Hz, 1 H), 6.03 (dt, J5,4 = 15.5 Hz, J5,6 = 8.0
Hz, 1 H), 5.72 (d, J9,8 = 16.0 Hz, 1 H), 5.61 (d, J2,3 = 11.5 Hz,
1 H), 4.26 (m, 1 H), 3.73 (s, 3 H), 2.41 (m, 2 H), 0.89 (s, 9
H), 0.19 (s, 9 H), 0.03 (s, 6 H). 13C NMR (125 MHz, CDCl3):
d = 166.9, 146.4, 145.0, 140.4, 129.2, 115.8, 109.2, 103.3,
95.0, 71.8, 51.1, 41.3, 25.8, 18.1, –0.1, –4.6, –4.9. EI-MS:
m/z (%) = 392 (100), 267 (100), 73 (50), 75 (20), 45. Anal.
Calcd for C21H36O3Si2: C, 64.23; H, 9.24. Found: C, 64.32;
H, 9.18.
Synlett 2006, No. 15, 2427–2430 © Thieme Stuttgart · New York