Synthetic studies on macrolactin A: Construction of C4-C24 fragment

Article abstract of DOI:10.1021/jo0701942

(Chemical Equation Presented) The preparation of the C4-C24 fragment of the macrolactin A is described. The adopted synthetic strategy involves two isomerizations to selectively construct the (8E,10Z) and (16E,18E) dienes, using a sequential Claisen rearrangement/allene isomerization and a Ph ₃P-catalyzed isomerization of an yne-one, respectively.

Full text of DOI:10.1021/jo0701942

Synthetic Studies on Macrolactin A:
Construction of C4-C24 Fragment
Marie Georgy,† Philippe Lesot,‡ and Jean-Marc Campagne*,§
ICSN-CNRS AVenue de la Terrasse, 91198 Gif-sur-YVette, France, Laboratoire de Chimie Structurale
Organique, RMN en Milieu Oriente´, ICMMO, CNRS UMR 8182, Baˆt 410, UniVersite´ Paris-Sud (XI),
91405 Orsay, France, and Institut Charles Gerhardt Montpellier, UMR 5253, Ecole Nationale Supe´rieure
de Chimie (laboratoire AM2N), 8 Rue de l’Ecole Normale, 34296 Montpellier, France
jean-marc.campagne@enscm.fr
ReceiVed January 31, 2007
The preparation of the C4-C24 fragment of the macrolactin A is described. The adopted synthetic strategy
involves two isomerizations to selectively construct the (8E,10Z) and (16E,18E) dienes, using a sequential
Claisen rearrangement/allene isomerization and a Ph3P-catalyzed isomerization of an yne-one, respectively.
Introduction
replication.1 Owing to its original macrocyclic structure, potent
biological activities, and some unreliability in the cell culture,
macrolactin A appeared to be an attractive target for total
synthesis. Indeed, starting from the seminal work initiated by
Rychnovsky establishing the relative and absolute stereochem-
istry of the chiral centers,2 considerable synthetic efforts have
been undertaken culminating in three total syntheses by Smith,
Carreira, and Marino,3-5 a great number of different synthetic
approaches,6-13 and the synthesis of a simplified analogue.14
In these works, palladium-catalyzed Stille cross-coupling and
The macrolactin family was discovered in 1989 by Fenical
et al. from a taxonomically undefined deep sea marine
bacterium.1a More recently, macrolactins have been re-isolated
from other biological sources.1b-h The parent aglycone, mac-
rolactin A 1, is a 24-membered polyene macrolide possessing
three stereodefined (Z,E-, E,Z-, and E,E-) 1,3-dienes systems
and four chiral hydroxy groups. Macrolactin A displays a broad
spectrum of biological activity: a strong cytotoxicity on B16-
F10 murine melanoma cell (IC50 ) 3.5 µg/mL) and antiviral
activity against Herpes simplex types I and II and HIV virus
(2) Rychnovsky, S. D.; Skalitzky, D. J.; Pathirana, C.; Jensen, P. R.;
Fenical, W. J. Am. Chem. Soc. 1992, 114, 671.
(3) (a) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1996, 118, 13095.
(b) Smith, A. B., III; Ott, G. R. J. Am. Chem. Soc. 1998, 120, 3935.
(4) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int. Ed. 1998,
37, 1261.
* To whom correspondence should be addressed. Tel: +33 4 67 14 72 21.
Fax: +33 4 67 14 43 22.
† ICSN.
‡ ICMMO.
§ Institut Charles Gerhardt Montpellier.
(1) (a) Gustafson, K.; Roman, M.; Fenical, W. J. Am. Chem. Soc. 1989,
111, 7519. (b) Hyeon-Ho, K.; 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. (c) Jaruchoktaweechai, C.; Suwanborirux, K.; Tanasupawatt, S.;
Kittakoop, P.; Menasveta, P. J. Nat. Prod. 2000, 63, 984. (d) Nagao, T.;
Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J. Antibiot. (Tokyo) 2001,
54, 333. (e) Choi, S. W.; Bai, D. H.; Yu, J. H.; Shin, C. S. Can. J. Microbiol.
2003, 49, 663. (f) Seung-Je, L.; Cho, J. Y.; Cho, J. I.; Moon, J. H.; Park,
K. D.; Lee, Y. J.; Park, K. H. J. Microbiol. Biotechnol. 2004, 14, 525. (g)
Han, J. S.; Cheng, J. H.; Yoon, T. M.; Song, J.; Rajkarnikar, A.; Kim, W.
G.; Yoo, I. D.; Yang, Y. Y.; Suh, J. W. J. Appl. Microbiol. 2005, 99, 213.
(h) Romero-Tabarez, M.; Jansen, R.; Sylla, M.; Lunsdorf, H.; Haussler, S.;
Santosa, D. A.; Timmis, K. N.; Molinari, G. Antimicrob. Agents Chemother.
2006, 50, 1701.
(5) Marino, J. P.; McClure, M. S.; Holub, D. P.; Comasseto, J. V.; Tucci,
F. C. J. Am. Chem. Soc. 2002, 124, 1664.
(6) Benvegnu, T. J.; Schio, L.; Gre´e, R. L. Synlett 1994, 505. (b)
Benvegnu, T. J.; Toupet, L.; Gre´e, R. L. Tetrahedron 1996, 52, 11811.
(7) (a) Godula, K.; Ba¨rmann, H.; Donaldson, W. A. J. Org. Chem. 2001,
66, 3590. (b) Li, S.; Donaldson, W. A. Synthesis 2003, 2064. (c) Prahlad,
V.; Donaldson, W. A. Tetrahedron Lett. 1996, 37, 9169. (d) Ba¨rmann, H.;
Prahlad, V.; Tao, C.; Yun, K. Y.; Whang, Z.; Donaldson, W. A. Tetrahedron
2000, 56, 2283.
(8) (a) Takemoto, Y.; Yoshikawa, N.; Baba, Y.; Iwata, C.; Tanaka, M.;
Ibuka, T.; Ohishi, H. J. Am. Chem. Soc. 1999, 121, 9143. (b) Fukuda, A.;
Kobayashi, Y.; Kimachi, T.; Takemoto, Y. Tetrahedron 2003, 59, 9305.
(9) Tanimori, A.; Morita, Y.; Tsubota, M.; Nakayama, M. Synth.
Commun. 1996, 26, 559.
10.1021/jo0701942 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/03/2007
J. Org. Chem. 2007, 72, 3543-3549
3543

Georgy et al.
SCHEME 2. Fragment A Synthesis of Macrolactin A
SCHEME 1. Retrosynthetic Analysis of Macrolactin A
Wittig-type reactions have been mainly used to stereoselectively
construct the 1,3 diene subunits. In our retrosynthetic approach,
we planned to construct these 1,3 dienes using different
strategies: (i) a sequential Claisen rearrangement/allene isomer-
ization to construct the C8-C11 (E,Z) diene,15-17 (ii) a Ph3P-
catalyzed isomerization of an ynone precursor for building the
C16-C19 (E,E) diene,18-20 and (iii) an intramolecular Heck
reaction to obtain C2-C5 (Z,E) conjugated diene. In this paper,
we would like to disclose our route to the C4-C24 fragment
of macrolactin A.
fragment B could be synthesized by the asymmetric Noyori’s
hydrogenation of â-keto ester 4, and the (E,Z) 1,3 diene could
be then obtained by a sequential Claisen rearrangement/allene
isomerization starting from propargylic alcohol 3.15 Fragment
D has been previously described,23 and C is a precursor for an
asymmetric allylation.24 In a second step, these molecular
fragments could then be joined by (i) an asymmetric allylation
(B + C), (ii) the alkynylation of an aldehyde (B + A), (iii) an
esterification or a macrolactonisation (A + D), and (iv) an (inter-
or intramolecular) Heck reaction (D + C).
Synthesis of C16-C24 Fragment A. Our route to C16-
C24 fragment A starts from 1-heptyne (Scheme 2). After
treatment of the lithium salt of heptyne with acetic anhydride,
the corresponding ketone 2 was then asymmetrically reduced
to the propargylic alcohol 6 under Noyori’s hydrogen transfer
conditions.21
At this stage, the enantiopurity of 6 was checked using proton-
decoupled carbon-13 (13C-{1H}) NMR spectroscopy in polypep-
tide chiral liquid crystals (CLCs).25a This original analytical
strategy proved to be very efficient for analyzing a large range
of chiral compounds, including alkyne compounds.25b-d As
illustration, the 13C-{1H} signals of C-3 and C-4 atoms for (()-6
and (R)-6 dissolved in the PBLG/chloroform system are shown
in Figure 1a and b. For this compound, the 13C chemical shift
anisotropy (CSA) of sp-hybridized carbons causes a sufficiently
large 13C chemical shift difference (at 100.6 MHz) to discrimi-
nate the NMR signals of each enantiomer (Ds ≈ 0.14 ppm (≈
14 Hz).25a This enables a direct and easy determination of the
ee value of enantioenriched 6 by peak integration or deconvo-
Results and Discussion
Our convergent synthetic strategy is outlined in Scheme 1.
In the light of constructing the 1,3 dienes subunits (vide supra),
macrolactin A was ultimately divided in four distinct fragments
denoted A, B, C, and D. Fragment A could be obtained by an
asymmetric Noyori’s hydrogen transfer21 on alkynone 2 fol-
lowed by an alkyne zipper reaction.22 The chiral alcohol in
(10) Li, S.; Xu, R.; Bai, D. Tetrahedron Lett. 2000, 41, 3463. (b) Xiao,
X.; Li, S.; X., Y.; Liu, X.; Xu, R.; Bai, D. H. Chem. Lett. 2005, 37, 906.
(c) Li, S.; Xiao, X.; Yan, X.; Liu, X.; Xu, R.; Bai, D. Tetrahedron 2005,
61, 11291.
(11) Bonini, C.; Chiummiento, L.; Pullez, M.; Solladie´, G.; Colobert, F.
J. Org. Chem. 2004, 69, 5015.
(12) Gonza´lez, A.; Aiguade´, J.; Urpi, F.; Vilarrasa, J. Tetrahedron Lett.
1996, 37, 8949.
(13) Vakalopoulos, A.; Hoffmann, H. M. R. Org. Lett. 2001, 3, 177.
(14) Kobayashi, Y.; Fukuda, A.; Kimachi, T.; Ju-ichi, M.; Takemoto,
Y. Tetrahedron Lett. 2004, 45, 677.
(15) For an original construction of the C16-C19 diene, based on a
double reductive elimination reaction, see ref 11.
(16) (a) Tsuboi, S.; Masuda, T.; Makino, H.; Takeda, A. Tetrahedron
Lett. 1982, 23, 209. (b) Tsuboi, S.; Masuda, T.; Takeda, A. J. Org.
Chem. 1982, 47, 4478. (c) Tsuboi, S.; Masuda, T.; Mimura, S.; Takeda, A.
Org. Synth. 1987, 66, 22. (d) Tsuboi, S.; Wu, X. H.; Maeda, S.; Ono, S.;
Kuroda, A.; Kawazu, K.; Takeda, A. Bull. Chem. Soc. Jpn. 1987, 60, 1103.
(17) (a) Passaro, L. C.; Webster, F. X. Synthesis 2003, 1187. (b) Mori,
K.; Maemoto, S. Liebigs Ann. Chem. 1987, 863.
(18) (a) Trost, B. M.; Kazmaier, U. J. Am. Chem. Soc. 1992, 114, 7933.
(b) Guo, C.; Lu, X. J. Chem. Soc., Perkin Trans. 1 1993, 1921. (c) Guo,
C.; Lu, X. J. Chem. Soc., Chem. Commun. 1993, 394. (d) Rychnovsky, S.
D.; Kim, J. J. Org. Chem. 1994, 59, 2659. (e) Kazmaier, U. J. Chem. Soc.,
Chem. Commun. 1997, 2305.
(19) For synthetic applications, see: (a) Matsuo, K.; Sakaguchi, Y. Chem.
Pharm. Bull. 1997, 45, 1620. (b) Bluet, G.; Campagne, J. M. Synlett 2000,
221. (c) Hunter, T. J.; O’Doherty, G. A. Org. Lett. 2001, 3, 1049.
(20) During the completion of this work, a related strategy has been
recently used in the synthesis of a macrolactin analog; see ref 14.
(21) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am. Chem.
Soc. 1997, 119, 8738.
(22) (a) Brown, C. A.; Yamashita, A. J. Am. Chem. Soc. 1975, 97, 891.
(b) Abrams, S. R.; Shaw, A. C. Org. Synth. 1993, 8, 146.
(23) Ma, S.; Lu, X.; Li, Z. J. Org. Chem. 1992, 57, 709.
(24) For, a comprehensive review: Denmark, S. E.; Fu, J. Chem. ReV.
2003, 103, 2763.
(25) (a) Sarfati, M.; Lesot, P.; Merlet, D.; Courtieu, J. J. Chem. Soc.,
Chem. Comm. 2000, 2069 and references therein. (b) Madiot, V.; Lesot P.,
Gre´e, D., Courtieu, J.; R. Gre´e, R. J. Chem. Soc., Chem. Commun. 2000,
169. (c) Parenty, A.; Campagne, J. M.; Aroulanda, C.; Lesot, P. Org. Lett.
2002, 4, 1663. (d) Manthati, V. L.; Murthy, A. S. K.; Caijo, F.; Drouin, D.;
Lesot, P.; Gre´e, D.; Gre´e, R.; Tetrahedron: Asymmetry 2006, 17, 2306.
3544 J. Org. Chem., Vol. 72, No. 9, 2007

Construction of C4-C24 Fragment of Macrolactin A
SCHEME 3. Fragment B Synthesis of Macrolactin A
FIGURE 1. 13C-{1H} NMR signals (100.6 MHz) for the acetylenic
carbons (C-3 and C-4) of (()-6 and (R)-6 both dissolved in the chiral
liquid-crystalline phase (PBLG/chloroform) at 310 K; 1700 scans were
recorded and added prior to Fourier transformation.
lution 13C-{1H} resonances. The ee experimentally measured
is over 95 ( 3% (averaged value on a series of measurements).
The (R) absolute configuration was confirmed by comparison
of the rotation with the same compound previously obtained in
68% ee.26
Propargylic alcohol 6 was then submitted to an alkyne zipper
reaction22b to give alcohol 7 in 73% yield. Note here that the
alkyne zipper reaction does not modify the enantiomeric purity
of chiral propargyl alcohols.25c Construction of fragment A was
finally achieved by the protection of the alcohol as a PMB ether,
in the presence of p-methoxybenzyltrichloroacetimidate, in 62%
yield. Fragment A (C16-C24) 8 was thus obtained in only four
steps, in 25% overall yield and an ee >95%.
the amount (25 equiv) of alumina (dried 2 h at 200 °C under
vacuum) proved to be essential in this reaction. Indeed after 15
min, at 110 °C, the conjugated diene 12 could be isolated in
80% yield and as a 9:1 (2E,4Z)/(2E,4E) mixture.29 The two-
step conversion of the ester to the corresponding aldehyde
ultimately led to the C7-C15 fragment B 13 (9 steps, 32%
overall yield from 4).
At this stage, due to tactics reasons, the introduction of
fragment C (an asymmetric allylation on the C7 aldehyde) was
first examined.
Synthesis of C7-C15 Fragment B. As described in Scheme
3, our synthesis starts from known â-keto ester 4,27 which was
first subjected to an asymmetric Noyori hydrogenation28 to give
alcohol 9 in 86% yield and 98% ee (HPLC). The alcohol was
next protected as TMBDS ether 10 in 93% yield. Reduction of
the ester to the aldehyde, followed by the alkynylation with
TMS-acetylene and further deprotection of the TMS group
led to compound 3 (in a 4:3 dr) in 78% overall yield. The
key Johnson-Claisen/allene isomerization was next investi-
gated.15 After some experimentation, we conclude that, in our
hands, the best conditions to obtain allene 11 are the follow-
ing: 140 °C in the presence of 10% of propionic acid during 8
h. Note that every 2 h, ethanol is removed in vacuo and ethyl
orthoacetate/propionic acid is re-added. Allene 11 was found
to be quite unstable under purification and/or storage. Conse-
quently, after evaporation of the reaction mixture, allene 11 was
found to be pure enough to be engaged in the next step without
any further purification (a 75% yield could be estimated by
NMR). The allene isomerization also required some optimiza-
tion: the source (Brockmann I, 150 mesh from Aldrich) and
Introduction of Fragment C: Asymmetric Allylation on
a Conjugated Diene. The catalytic enantioselective addition
of allyl-metal reagents to aldehydes has emerged as a key
transformation in the total synthesis of numerous natural
products.24 However, such asymmetric allylations on unsaturated
aldehydes have been scarcely reported so far. Consequently,
the asymmetric allylation was first investigated on a model
reaction in the presence of sorbaldehyde (Table 1). The original
Keck’s conditions30 were rather deceptive because they lead to
the allylated product 14 in low conversion and relatively poor
ee (Table 1, entry 1).
By increasing the amount of catalyst to 30%, the enantiose-
lectivity could be raised up to 68% but the conversion was still
very low (Table 1, entry 2). The use of additives in this
procedure has been reported by Yu31 but was unsuccessful when
applied in our case (Table 1, entry 3). We next moved to the
procedure described by Yamamoto32 in the presence of silver
salts and binap. Under these conditions, the conversion is still
low, but the enantioselectivity is 83% ee (Table 1, entry 4).
(29) At this stage the (2 E,4E) minor isomer could not be separated from
the (2 E,4Z) isomer. This separation was only possible at the aldehyde 13
stage.
(30) Keck, G. E.; Krishnamurthy, D. J. Org. Synth. 1998, 75, 12.
(31) Yu, C. M.; Choi, H. S.; Yoon, S. K.; Jung, W. H. Synlett 1997,
889.
(26) Helal, C. J.; Magriotis, P. A.; Corey, E. J. J. Am. Chem. Soc. 1996,
118, 10938.
(27) Herb, C.; Maier, M. E. J. Org. Chem. 2003, 68, 8129.
(28) Kitamura, M.; Tokunaga, M.; Ohkuma, T.; Noyori, R. Org. Synth.
1992, 71, 1.
J. Org. Chem, Vol. 72, No. 9, 2007 3545

Georgy et al.
SCHEME 4. C4-C15 Fragment of Macrolactin A
TABLE 1. Asymmetric Allylation of Sorbaldehyde
T
(°C)
time yield %
(h) (conv %) ee %
catalyst
additive
4 Å MS
(17)
4 Å MS
(25)
4 Å MS
B(OMe)3 50% (20)
-20
(50)
1
2
3
4
5
6
7
Ti(OiPr)4 10%
(S)-Binol 10%
Ti(OiPr)4 30%
(S)-Binol 30%
Ti(OiPr)4 10%
(S)-Binol 10%
AgOTf 5%
(R)-Binap 5%
AgOTf 30%
(S)-Binap 30%
AgF 20%
-20
-20
0
70
73
20
19
4
-
46 (S)
68 (S)
28 (S)
16
-
23
-20
-20
-78
83 (R)
72
87 (S)
63 (S)
44 (S)
3
43
(S)-Tol-Binap 5%
InCl3 20%
(S)-Binol 22%
4 Å MS
16
69
SCHEME 5. C4-C24 Fragment of Macrolactin A
TABLE 2. Optimization of the Asymmetric Allylation of
Sorbaldehyde
ligand
(S)-binap
(R)-difluorphos
(R)-SEGPHOS
(S)-Tol-binap
yield
ee %
1
2
3
4
72
(17)
64
87 (S)
63 (R)
67 (R)
89 (S)
76
Increasing the amount of catalyst to 30%, compound 14 was
isolated in an interesting 72% yield and 87% ee (Table 1, entry
5). Other procedures in the presence of silver or indium salts
led to rather disappointing results (Table 1, entries 6 and 7).33-34
Finally, we tried to further improve the enantioselectivity by
screening other phosphorus ligands in this reaction (Table 2).
As a consequence, among the several ligands tested, (S)-Tol-
binap was the most efficient, leading to 14 in slightly better
yield (76%) and higher enantioselectivity (89% ee).
Starting from this model reaction study, the asymmetric
allylation on aldehyde 13 was next tested (Scheme 4). Gratify-
ingly, under optimized reaction conditions (1 g scale, 15 h, -20
°C), the homoallylic compound 15 was obtained in 85% yield
and a 91:9 dr.35 The homoallylic alcohol was then transformed
into the TBDPS ether 16 in 96% yield.
the primary alcohol 17 was then carried out in 75% yield.
Introduction of the lithium acetylide of compound 7 (fragment
A) led to the propargylic alcohol, which was further oxidized
to the corresponding propargylic ketone 19 in 94% yield (over
2 steps). The yne-one isomerization of compound 19 was finally
carried out in the presence of triphenylphosphine at 80 °C18 to
give the expected C4-C24 fragment 20 of macrolactin A in a
nonoptimized 42% yield and as a single (16E,18E) isomer
(Scheme 5).
Synthesis of C4-C24 Fragment (A-B-C). Having secured
the C4-C15 (B-C fragment) skeleton of macrolactin A, the
introduction of fragment A was next undertaken. The PMB ether
was first removed in the presence of DDQ in buffered
dichloromethane in 53% yield (65% based on recovered starting
material). A Dess-Martin periodinane-mediated oxidation of
(32) Yanagisawa, A.; Nakashima, H.; Ishiba, A.; Yamamoto, H. J. Am.
Chem. Soc. 1996, 118, 4723.
(33) Yanagisawa, A.; Kageyama, H.; Nakatsuka, Y.; Asakawa, K.;
Matsumoto, Y.; Yamamoto, H. Angew. Chem., Int. Ed. 1999, 38, 3701.
(34) Teo, Y. C.; K. T., T.; Loh, T. P. J. Chem. Soc., Chem. Commun.
2005, 1318.
Conclusion
In summary, a convergent and efficient synthesis of the C4-
C24 fragment of macrolactin A is described. The synthesis was
(35) At this stage of the synthesis, the minor isomer could not be
separated from major isomer 15.
3546 J. Org. Chem., Vol. 72, No. 9, 2007

Construction of C4-C24 Fragment of Macrolactin A
tography: Rf ) 0.65 and 0.70 (heptane/AcOEt 6:4). IR-FT (neat)
cm-1: 3412, 2954, 2928, 2896, 2855, 2170 (CtC). NMR 1H
(CDCl3, 300 MHz) δ ppm: first diastereoisomer 0.10 (s, 3H), 0.14
(s, 3H), 0.18 (s, 9H), 0.89 (s, 9H), 1.80-1.98 (m, 4H), 3.18 (d, J
) 5.1 Hz, 1H), 3.50 (t, J ) 6.3 Hz, 2H), 3.81 (s, 3H), 4.21-4.29
(m, 1H), 4.40 (d, J ) 11.5 Hz, 1H), 4.44 (d, J ) 11.5 Hz, 1H),
4.56-4.62 (m, 1H), 6.88 (d, J ) 8.6 Hz, 2H), 7.26 (d, J ) 8.6 Hz,
2H); second diastereosiomer 0.08 (s, 3H), 0.09 (s, 3H), 0.17 (s,
9H), 0.88 (s, 9H), 1.80-1.96 (m, 4H), 2.66 (d, J ) 4 Hz, 1H),
3.51 (t, J ) 6.3 Hz, 2H), 3.81 (s, 3H), 4.06-4.14 (m, 1H), 4.40 (d,
J ) 11.5 Hz, 1H), 4.44 (d, J ) 11.5 Hz, 1H), 4.50-4.56 (m, 1H),
6.88 (d, J ) 8.6 Hz, 2H), 7.26 (d, J ) 8.6 Hz, 2H). NMR 13C
(CDCl3, 75 MHz) δ ppm: first diastereisomer -4.4, 0.04, 18.1,
26.0, 37.0, 43.4, 55.4, 60.5, 66.3, 68.3, 72.8, 89.1, 106.8, 113.9,
129.4, 130.6, 159.3; second diastereosiomer -4.5, -4.3, 0.02, 18.1,
26.0, 37.7, 44.3, 55.4, 61.4, 66.3, 68.7, 72.8, 89.7, 106.7, 113.9,
129.4, 130.6, 159.3. MS (ESI) (m/z) 473.1 (100, [MNa]+); 474.2
(80, [MHNa]+). Anal. Calcd for C24H42O4Si2: C, 63.95, H, 9.39;
found: C, 63.95, H 9.43.
completed in 16 steps from â-keto ester 4. This synthesis
approach was highlighted by the stereoselective syntheses of
the C9-C11 (E,Z) and C16-C19 (E,E) dienes using the
isomerizations of an allene and an yne-one, respectively. C7,
C13, and C23 chiral centers have been obtained using a
Yamamoto asymmetric allylation, a Noyori aymmetric hydro-
genation, and a Noyori asymmetric hydrogen transfer respec-
tively.
Experimental Section
(R)-1-Methoxy-4-((non-8-yn-2-yloxy)methyl)benzene (R)-8. To
a solution of the alcohol 7 (130 mg, 0.91 mmol) and p-
methoxybenzyltrichloroacetimidate (450 mg, 1.6 mmol) in cyclo-
hexane (3 mL) and dichloromethane (1.5 mL) at 0 °C, was added
BF3‚Et2O (1 µL, 1 mol %). A white precipitate was formed. The
suspension was warmed up to room temperature and stirred for 2
h until the reaction was complete (TLC). The white solid was
filtrated on a pad of celite and washed with a 2:1 mixture of
cyclohexane and dichloromethane. The filtrate was concentrated
in vacuo, and the crude product was purified by flash chromatog-
raphy to afford the desired protected alcohol 8 (148 mg, 62%).
[R]D ) -13 (CHCl3, c 2, 28 °C); ee 96%. Rf ) 0.63 (heptane/
AcOEt 7:3). IR-FT (neat) cm-1: 3292, 2933, 2858, 2118. NMR
1H (CDCl3, 300 MHz) δ ppm: 1.18 (d, J ) 6.1 Hz, 3H),1.29-
1.47 (m, 6H), 1.51 - 1.62 (m, 2H), 1.95 (t, J ) 2.6 Hz, 1H), 2.19
(dd, J ) 2.6 Hz, J ) 7 Hz, 2H), 3.46-3.52 (m, 1H), 3.81 (s, 3H),
4.39 (d, J ) 11.4 Hz, 2H), 4.51 (d, J ) 11.4 Hz, 2H), 6.88 (d, J )
8.7 Hz, 2H), 7.28 (d, J ) 8.7 Hz, 2H). NMR 13C (CDCl3, 75 MHz)
δ ppm: 18.5, 19.8, 25.2, 28.6, 29.0, 36.7, 55.4, 68.3, 70.1, 74.6,
84.9, 113.9, 129.3, 131.4, 159.2. MS (ESI) (m/z): 283.2 (100,
[MNa]+); 284.2 (3, [MHNa]+). Anal. Calcd for C15H24O2: C, 78.42,
H, 9.29. Found: C, 78.21, H, 9.45.
(c) TMS Deprotection. To a solution of the TMS-protected
alkyne (12.3 g, 27.2 mmol) in methanol (200 mL) at 0 °C was
added K2CO3 (8.2 g, 59 mmol). The resulting suspension was
warmed up to room temperature and stirred for 19 h. After
quenching with saturated NH4Cl, the aqueous layer was extracted
with Et2O. The combined organic layers were washed with water
and brine, dried over MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography to afford
the terminal alkyne as a 3:4 mixture of two diastereoisomers. (8.4
g, 78% over 3 steps). Rf ) 0.52 and 0.54 (heptane/AcOEt 6:4).
IR-FT (neat) cm-1: 3406, 3307, 2952, 2928, 2884, 2855. NMR
1H (CDCl3, 300 MHz) δ ppm: first diastereoisomer 0.10 (s, 3H),
0.14 (s, 3H), 0.89 (s, 9H), 1.78-1.93 (m, 4H), 2.47 (d, J ) 2.4
Hz, 1H), 3.35 (d, J ) 5.2 Hz, 1H), 3.50 (t, J ) 6.4 Hz, 2H), 3.82
(s, 3H), 4.21-4.29 (m, 1H), 4.40 (d, J ) 11.6 Hz, 1H), 4.44 (d, J
) 11.6 Hz, 1H), 4.57-4.62 (m, 1H), 6.89 (d, J ) 8.6 Hz, 2H),
7.26 (d, J ) 8.6 Hz, 2H); second diastereoisomer 0.08 (s, 3H),
0.09 (s, 3H), 0.88 (s, 9H), 1.80-1.96 (m, 4H), 2.48 (d, J ) 2.2
Hz, 1H); 2.82 (d, J ) 3.4 Hz, 1H), 3.51 (t, J ) 6.4 Hz, 2H), 3.81
(s, 3H), 4.06-4.14 (m, 1H), 4.40 (d, J ) 11.6 Hz, 1H), 4.44 (d, J
) 11.6 Hz, 1H), 4.50-4.56 (m, 1H), 6.88 (d, J ) 8.6 Hz, 2H),
7.26 (d, J ) 8.6 Hz, 2H). NMR 13C (CDCl3, 75 MHz) δ ppm:
first diastereoisomer -4.5, -4.4, 18.1, 26.0, 38.8, 43.0, 55.4, 59.8,
66.2, 68.3, 72.6, 72.8, 85.1, 113.9, 129.4, 130.5, 159.3; second
diastereoisomer -4.6, -4.3, 18.1, 26.0, 37.6, 44.3, 55.4, 60.7, 66.2,
68.8, 72.8, 73.1, 85.0, 113.9, 129.4, 130.5, 159.3. MS (ESI) ) (m/
z) 401.2 (100, [MNa]+); 402.2 (30, [MHNa]+). HRMS (ESI) m/z
[MNa]+ calcd for C21H34O4SiNa 401.2124, found 401.2129.
(7S)-Ethyl 7-(tert-Butyldimethylsilyloxy)-9-(4-methoxyben-
zyloxy)nona-3,4-dienoate (11). To a solution of propargylic alcohol
3 (170 mg, 0.45 mmol) in triethyl orthoacetate (580 µL, 3 mmol)
was added one drop of propionic acid. The solution was stirred at
110 °C for 7 h. Every 2 h the ethanol produced by the reaction
was evaporated, and fresh triethyl orthoacetate (200 µL, 1 mmol)
and propionic acid (one drop) were added. When the reaction was
complete (TLC), the mixture was cooled down to room temperature
and concentrated in vacuo. The desired allene (125 mg) was used
without further purification. In order to carry out the analyses, part
of the crude product was purified by flash chromatography on
neutral alumina (heptane/AcOEt 95:5). [R]D ) +7 (CH2Cl2, c 1.03,
23 °C). Rf ) 0.68 (heptane/AcOEt 6:4). IR-FT (neat) cm-1: 2952,
2928, 2854, 1969 (CdCdC), 1736 (CdO). NMR 1H (CDCl3, 300
MHz) δ ppm: 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.27 (t, J )
7.1 Hz, 3H), 1.69-1.86 (m, 2H), 2.11-2.27 (m, 2H), 2.99-3.03
(m, 2H), 3.51 (t, J ) 6.4 Hz, 2H), 3.81 (s, 3H), 3.87-3.96 (m,
1H), 4.16 (q, J ) 7.2 Hz, 2H), 4.39 (d, J ) 11.4 Hz, 1H), 4.44 (d,
J ) 11.4 Hz, 1H), 5.14-5.25 (m, 2H), 6.89 (d, J ) 8.6 Hz, 2H),
7.26 (d, J ) 8.6 Hz, 2H). NMR 13C (CDCl3, 75 MHz) δ ppm:
-4.3, -4.6, 14.3, 18.2, 25.8, 35.0, 37.3, 37.3, 55.4, 60.9, 66.8,
69.1, 72.8, 83.7, 88.2, 113.9, 129.4, 130.8, 131.7, 159.3, 171.7.
(5R)-5-(tert-Butyldimethylsilyloxy)-7-(4-methoxybenzyloxy)-
hept-1-yn-3-ol (3). (a) Ester Reduction. To a solution of ester
1027 (11.3 g, 28.5 mmol) in dry dichloromethane (200 mL), at
-78 °C, was added dropwise diisobutylaluminium hydride (1 M
in hexanes, 31.3 mL, 31.3 mmol). The solution was stirred at
-78 °C for 1 h and warmed up to room temperature. It was then
treated with saturated potassium and sodium tartrate (Rochelle salt)
and stirred for 14 h. The aqueous layer was extracted with
dichloromethane. The combined organic layers were washed with
brine, dried over MgSO4, filtered, and concentrated in vacuo. The
crude aldehyde was used without further purification. [R]D ) +7
(CH2Cl2, c 1.04, 25 °C). Rf ) 0.64 (heptane/AcOEt 6:4). IR-FT
(neat) cm-1: 2954, 2929, 2895, 2856, 2725, 1725 (CdO). NMR
1H (CDCl3, 500 MHz) δ ppm: 0.07 (s, 3H), 0.08 (s, 3H), 0.88 (s,
9H), 1.79-1.90 (m, 2H), 2.53 (ddd, J ) 2.9 Hz, J ) 5.9 Hz, J )
15.7 Hz, 1H), 2.59 (ddd, J ) 2 Hz, J ) 5.2 Hz, J ) 15.7 Hz, 1H),
3.52 (t, J ) 5.9 Hz, 2H), 3.81 (s, 3H), 4.34-4.40 (m, 1H), 4.39 (d,
J ) 11.7 Hz, 1H), 4.44 (d, J ) 11.7 Hz, 1H), 6.89 (d, J ) 8.5 Hz,
2H), 7.26 (d, J ) 8.5 Hz, 2H), 9.80 (t, J ) 2.6 Hz, 1H). NMR 13
C
(CDCl3, 75 MHz) δ ppm: -4.5, 18.1, 25.8, 37.8, 51.2, 55.4, 65.8,
66.2, 72.8, 113.9, 129.4, 130.5, 159.3, 202.3. Data in accordance
with previously reported results.27
(b) TMS-Acetylene Addition. To a solution of trimethylsilyl-
acetylene (5 mL, 34 mmol) in THF (200 mL), at -78 °C, was
added dropwise n-butyllithium (1.6 M in hexanes, 27.2 mL, 34
mmol). After 1 h of stirring, a solution of the previously obtained
aldehyde (9.9 g, 28 mmol) in THF was added via cannula. The
resulting mixture was slowly warmed up to room temperature and
stirred for another 16 h. It was then quenched with saturated NH4-
Cl. The aqueous layer was extracted with Et2O (600 mL). The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The resulting oil was
used without further purification (12.3 g). The desired product came
as a 3:4 mixture of two diastereoisomers. In order to carry out the
analyses, part of the crude product was purified by flash chroma-
J. Org. Chem, Vol. 72, No. 9, 2007 3547

Georgy et al.
MS (ESI) (m/z) 471.2 (100, [MNa]+), 472.2 (30, [MHNa]+). HRMS
(ESI) m/z [MNa]+ calcd for C25H40O5SiNa 471.2543, found
471.2527.
(34 mg, 91%). [R]D ) +12 (CH2Cl2, c 1.03, 25 °C). Rf ) 0.47
(heptane/AcOEt 7:3). IR-FT (neat) cm-1: 2928, 2854, 1681 (Cd
O). NMR H (CDCl3, 300 MHz) δ ppm: 0.06 (s, 3H), 0.07 (s,
1
3H), 0.88 (s, 9H), 1.75 (q, J ) 6.2 Hz, 2H), 2.51 (t, J ) 7 Hz, 2H),
3.52 (t, J ) 6.2 Hz, 2H), 3.81 (s, 3H), 4.01 (quint., J ) 5.9 Hz,
1H), 4.38 (d, J ) 11.4 Hz, 1H), 4.46 (d, J ) 11.4 Hz, 1H), 6.07
(dt, J ) 7.9 Hz, J ) 10.9 Hz, 1H), 6.14 (dd, J ) 7.9 Hz, J ) 15.2
Hz, 1H), 6.35 (t, J ) 11 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 2H), 7.26
(d, J ) 8.6 Hz, 2H), 7.38 (dd, J ) 11.5 Hz, J ) 15.2 Hz, 2H),
9.55 (d, J ) 8 Hz, 1H). NMR 13C (CDCl3, 75 MHz) δ ppm: -4.6,
-4.3, 18.2, 25.9, 36.7, 37.3, 55.4, 66.5, 68.9, 72.8, 113.9, 128.5,
129.4, 130.5, 132.2, 139.9, 147.0, 159.2, 194,1. MS (ESI) (m/z)
427.2 (100, [MNa]+), 428.2 (30, [MHNa]+). HRMS (ESI) (m/z)
[MNa]+ calcd for C23H36O4NaSi 427.2281, found 427.2264.
(4S,5E,7Z,10S)-10-(tert-Butyldimethylsilyloxy)-12-(4-methoxy-
benzyloxy)dodeca-1,5,7-trien-4-ol (15). (S)-Tol-BINAP (126 mg,
0.2 mmol) and AgOTf (51 mg, 0.2 mmol) were sheltered from
light and stirred in dry THF (8 mL) for 20 min. A solution of
aldehyde 13 (410 mg, 1.01 mmol) in dry THF (0.5 mL) was then
added. The resulting mixture was cooled down to -20 °C, and
allyltributyltin (0.32 mL, 1.03 mmol) was added. The solution was
stirred at -20 °C for 20 h and then quenched with saturated
NaHCO3 and Et2O. The mixture was filtered on a pad of celite
and washed with Et2O (50 mL). The filtrate was dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography to afford 381 mg of the
desired alcohol (85%). Rf ) 0.41 (heptane/AcOEt 7:3). IR-FT (neat)
(S,2E,4Z)-Ethyl 7-(tert-Butyldimethylsilyloxy)-9-(4-methoxy-
benzyloxy)nona-2,4-dienoate (12). The weakly basic alumina
(Brockmann I type, Aldrich, 710 mg, 7 mmol) was placed in a
round-bottom flask connected to a vacuum pump and heated at
200 °C for 2 h to remove the water. It was then placed under argon
atmosphere and a solution of the allene (125 mg, 0.28 mmol) in
dry toluene (1.5 mL) was added. The resulting suspension was
vigorously stirred at 100 °C until the reaction was complete. This
was followed by FT-IR as the two products have different CdO
vibration wavelengths (1737 vs 1713 cm-1). The alumina was then
filtered and washed with dichloromethane. The filtrate was
concentrated in vacuo, and the crude product was purified by flash
chromatography to afford the desired diene as a 9:1 mixture of the
2E,4Z and 2E,4E isomers (99 mg, 60% over 2 steps). [R]D ) +7
(CH2Cl2, c 1.03, 23 °C). Rf ) 0.68 (heptane/AcOEt 6:4). IR-FT
(neat) cm-1: 2952, 2928, 2855, 2358, 1714 (CdO). NMR 1H (C6D6,
500 MHz) δ ppm: 0.04 (s, 3H), 0.05 (s, 3H), 0.95 (s, 9H), 0.99 (t,
J ) 7.1 Hz, 3H), 1.6 (t, J ) 6.1 Hz, 1H), 2.28 (dd, J ) 6.1 Hz, J
) 7 Hz, 2H), 3.31 (s, 3H), 3.34 (dt, J ) 5.7 Hz, J ) 9.2 Hz, 1H),
3.43 (dt, J ) 6.5 Hz, J ) 9.2 Hz, 1H),; 3.88 (quint, J ) 5.8 Hz,
1H), 4.05 (q, J ) 7.1 Hz, 2H), 4.28 (d, J ) 11.5 Hz, 1H), 4.34 (d,
J ) 11.5 Hz, 1H), 5.75 (dt, J ) 7.8 Hz, J ) 10.7 Hz, 1H), 5.94 (d,
J ) 15.3 Hz, 1H), 5.98 (t, J ) 11.3 Hz, 1H), 6.82 (d, J ) 8.7 Hz,
2H), 7.24 (d, J ) 8.7 Hz, 2H), 7.87 (dd, J ) 11.6 Hz, J ) 15.6
Hz, 1H). NMR 13C (CDCl3, 75 MHz) δ ppm; -4.3, -4.5, 14.5,
18.2, 26.0, 36.5, 37.2, 55.4, 60.4, 66.7, 68.9, 72.8, 113.9, 121.9,
128.5, 129.5, 130.7, 137.2, 139.5, 159.3, 167.3. MS (ESI) (m/z)
471.2 (100, [MNa]+), 472.2 (30, [MHNa]+). Anal. Calcd for
C25H40O5Si: C, 66.92, H, 8.99. Found: C, 66.96, H, 8.88.
(S,2E,4Z)-7-(tert-Butyldimethylsilyloxy)-9-(4-methoxybenzyl-
oxy)nona-2,4-dienal (13). (a) Reduction to the Alcohol. To a
solution of ester 12 (50 mg, 0.11 mmol) in dry dichloromethane (1
mL), at -78 °C, was added dropwise DIBALH (1 M in hexanes,
210 mL, 0.21 mmol). The reaction was followed by TLC and was
complete after 5 min. The mixture was quenched with saturated
potassium and sodium tartrate and stirred for 30 min. The aqueous
layer was extracted with dichloromethane. The combined organic
layers were washed with brine, dried over MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography to afford the desired alcohol (42 mg, 95%). [R]D
) +20.5 (CH2Cl2, c 1.51, 27 °C). Rf ) 0.33 (heptane/AcOEt 7:3).
IR-FT (neat) cm-1: 3401 (OH), 2951, 2926, 2854. NMR 1H
(CDCl3, 300 MHz) δ ppm: 0.06 (s, 3H), 0.07 (2 s, 3H), 0.89 (s,
9H), 1.44 (bs, 1H), 1.64-1.83 (m, 2H), 2.37 (ddd, J ) 1.2 Hz, J
) 6.1 Hz, J ) 7 Hz, 2H), 3.52 (dd, J ) 6.2 Hz, J ) 6.7 Hz, 2H),
3.82 (s, 3H), 3.88-3.96 (m, 1H), 4.19 (d, J ) 5.6 Hz, 2H), 4.39
(d, J ) 11.5 Hz, 1H), 4.46 (d, J ) 11.5 Hz, 1H), 5.51 (dt, J ) 7.8
Hz, J ) 10.8 Hz, 1H), 5.82 (dt, J ) 5.9 Hz, J ) 15.1 Hz, 1H),
6.09 (t, J ) 11 Hz, 1H), 6.49 (ddd, J ) 1.2 Hz, J ) 8.7 Hz, J )
15. Hz, 2H), 6.89 (d, J ) 8.7 Hz, 2H), 7.27 (d, J ) 8.7 Hz, 2H).
NMR 13C (CDCl3, 75 MHz) δ ppm: -4.3, -4.5, 18.2, 26.0, 36.1,
37.0, 55.4, 63.7, 66.9, 69.2, 72.7, 113.9, 127.0, 128.5, 129.4, 129.5,
130.7, 132.3, 159.2. MS (ESI) (m/z) 429.2 (100, [MNa]+), 430.2
(30, [MHNa]+). Anal. Calcd for C23H38O4Si: C, 67.94, H, 9.42.
Found: C, 67.57, H, 9.64.
1
cm-1: 3424 (OH), 2928, 2854. NMR H (CDCl3, 500 MHz) δ
ppm: 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s, 9H), 1.63 - 1.83 (m,
2H), 1.68 (bs, 1H), 2.22 - 2.41 (m, 4H), 3.51 (t, J ) 6.5 Hz, 2H),
3.81 (s, 3H), 3.87 - 3.95 (m, 1H), 4.17-4.25 (m, 1H), 4.39 (d, J
) 11,5 Hz, 1H), 4.45 (d, J ) 11.5 Hz, 1H), 5.15 (d, J ) 10.8 Hz,
1H), 5.16 (d, J ) 16.5 Hz, 1H), 5.50 (dt, J ) 7.7 Hz, J ) 10.8 Hz,
1H), 5.70 (dd, J ) 6.4 Hz, J ) 15.1 Hz, 1H), 5.82 (ddt, J ) 7.4
Hz, J ) 10.4 Hz, J ) 16.9 Hz, 1H), 6.06 (t, J ) 11 Hz, 1H), 6.48
(dd, J ) 11 Hz, J ) 15.2 Hz, 1H), 6.88 (d, J ) 8.6 Hz, 2H), 7.16
(d, J ) 8.6 Hz, 2H). NMR 13C (CDCl3, 75 MHz) δ ppm: -4.6,
-4.2, 18.2, 26.0, 36.2, 37.0, 42.1, 55.4, 66.9, 69.3, 71.6, 72.8,
113.9, 118.4, 126.1, 128.6, 129.4, 129.5, 130.8, 134.,3, 135.4, 159.2.
MS (ESI) ) (m/z) 469.2 (100, [MNa]+), 470.3 (10, [MHNa]+).
Anal. Calcd for C26H42O4Si: C, 69.91, H, 9.48. Found: C, 69.89,
H, 9.55.
(5S,6E,8Z,11S)-5-Allyl-11-(2-(4-methoxybenzyloxy)ethyl)-2,2,-
13,13,14,14-hexamethyl-3,3-diphenyl-4,12-dioxa-3,13-disilapen-
tadeca-6,8-diene (16). To a solution of alcohol 15 (313 mg, 0.67
mmol) and imidazole (57 mg, 0.83 mmol) in dry DMF (3 mL)
was added TBDPSCl (390 µL, 1.5 mmol). The resulting mixture
was stirred at room temperature for 16 h and then quenched with
saturated NH4Cl. The aqueous layer was extracted with Et2O. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography to afford the desired protected
alcohol 16 (440 mg, 96%). Rf ) 0.77 (heptane/AcOEt 7:3). IR-FT
(neat) cm-1: 2957, 2928, 2896, 2855. NMR 1H (CDCl3, 500 MHz)
δ ppm: 0.03 (s, 6H), 0.88 (s, 9H), 1.08 (s, 9H), 1.58 - 1.78 (m,
2H), 2.20 - 2.28 (m, 4H), 3.46 - 3.53 (m, 2H1), 3.81 (s, 3H),
3.83 - 3.90 (m, 1H), 4.25 (q, J ) 6 Hz, 1H), 4.37 (d, J ) 11.7
Hz, 1H), 4.43 (d, J ) 11.4 Hz, 1H), 4.93 (d, J ) 14.1 Hz, 1H),
4.97 (d, J ) 9.4 Hz, 1H), 5.39 (dt, J ) 7.8 Hz, J ) 10.8 Hz, 1H),
5.61 (dd, J ) 6.9 Hz, J ) 15.3 Hz, 1H), 5.71 (ddt, J ) 7.2 Hz, J
) 9.9 Hz, J ) 16.8 Hz, 1H), 5.94 (t, J ) 11.1 Hz, 1H), 6.15 (dd,
J ) 11.1 Hz, J ) 14.7 Hz, 1H), 6.87 (d, J ) 8.7 Hz, 2H), 7.25 (d,
J ) 8.7 Hz, 2H), 7.33 - 7.42 (m, 6H), 7.63 - 7.75 (m, 4H). NMR
13C (CDCl3, 75 MHz) δ ppm: -4.6, -4.2, 18.2, 19.5, 26.0, 27.2,
36.2, 37.1, 42.8, 55.4, 66.9, 69.2, 72.7, 74.7, 113.9, 117.2, 125.8,
127.5, 127.6, 127.9, 129.4, 129.6, 129.7, 129.8, 130.9, 134.3, 134.5,-
135.0, 135.7, 136.1, 159.3. MS (ESI) m/z 707.4 (100, [MNa]+),
708.4 (30, [MHNa]+). Anal. Calcd for C42H60O4Si2: C, 73.63, H,
8.83. Found: C, 73.84, H, 9.01.
(b) Alcohol Oxidation. To a solution of DMSO (23 µL, 0.3
mmol) in dichloromethane (1 mL), at -78 °C, was added dropwise
oxalyl chloride (13 µL, 0.15 mmol). After 30 min of stirring, a
solution of the alcohol (38 mg, 0,09 mmol) in dichloromethane
(0.4 mL) was added via cannula. The resulting mixture was stirred
for 1 h, and triethylamine (41 µL, 0.3 mmol) was added. The
reaction was complete after 15 min (TLC). The mixture was
quenched with saturated NH4Cl. The aqueous layer was extracted
with dichloromethane. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography to afford the desired aldehyde
3548 J. Org. Chem., Vol. 72, No. 9, 2007

Construction of C4-C24 Fragment of Macrolactin A
1
(3S,5Z,7E,9S)-3-(tert-Butyldimethylsilyloxy)-9-(tert-butyldiphe-
nylsilyloxy)dodeca-5,7,11-trienal (18). To a solution of protected
alcohol (613 mg, 0.895 mmol) in dichloromethane (10 mL) and
borate buffer (pH ) 8, 10 mL) was added DDQ (305 mg, 1.34
mmol). The black suspension was stirred at room temperature for
1.5 h and became white. The precipitate was filtered on a pad of
celite and washed with dichloromethane. The filtrate was dried over
MgSO4, filtered, and concentrated in vacuo. The crude product was
purified by flash chromatography to afford a 1:1 unseparable
mixture of the desired unprotected alcohol (53% yield, NMR
estimation) and anisaldehyde, along with 122 mg of recovered
starting material.
cm-1: 2929, 2855, 2211 (CtC), 1673 (CdO). NMR H (CDCl3,
500 MHz) δ ppm: 0.05 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 1.08 (s,
9H), 1.18 (d, J ) 6 Hz, 3H), 1.30-1.46 (m, 6H), 1.55 - 1.61 (m,
2H), 2.24 - 2.28 (m, 4H), 2.34 (t, J ) 7.5 Hz, 2H), 2.49 (dd, J )
4 Hz, J ) 15 Hz, 1H), 2.65 (dd, J ) 4 Hz, J ) 15 Hz, 1H), 3.49
(sext, J ) 6 Hz, 1H), 3.81 (s, 3H), 4.24 - 4.27 (m, 1H), 4.27 -
4.31 (m, 1H), 4.38 (d, J ) 11.5 Hz, 1H), 4.50 (d, J ) 11.5 Hz),
4.94 (d, J ) 17 Hz, 1H), 4.98 (d, J ) 10.5 Hz, 1H), 5.36 (dt, J )
7.5 Hz, J ) 11 Hz, 1H), 5,64 (dd, J ) 7 Hz, J ) 15 Hz, 1H), 5.72
(ddt, J ) 7 Hz, J ) 10.5 Hz, J ) 17.5 Hz, 1H), 5.97 (t, J ) 11 Hz,
1H), 6.12 (dd, J ) 11 Hz, J ) 15 Hz, 1H), 6.88 (d, J ) 8.5 Hz,
2H), 7.27 (d, J ) 8.5 Hz, 2H), 7.33 - 7.44 (m, 6H), 7.65 (d, J )
6.5 Hz, 2H), 7.69 (d, J ) 6.5 Hz, 2H). MS (ESI) m/z 843.4 (100,
[MNa]+), 844.5 (45, [MHNa]+). HRMS (ESI) [MNa]+ calcd for
C51H72O5NaSi2 843.4816, found 843.4809.
To a solution of the previous mixture of unprotected alcohol
and anisaldehyde in dichloromethane (1 mL) was added Dess-
Martin periodinane (15 wt % solution in dichloromethane, 1.2 mL,
0.57 mmol). A white precipitate formed, and the suspension was
stirred at room temperature for 20 min. The solid was filtered on
a pad of celite and washed with dichloromethane. The filtrate was
dried over MgSO4, filtered, and concentrated in vacuo. The crude
product was purified by flash chromatography to afford 160 mg of
the desired aldehyde (60%). Yield over 2 steps: 32%. Rf ) 0.72
(heptane/AcOEt 7:3). IR-FT (neat) cm-1: 3069, 2928, 2856, 2718,
(2R,6E,8E,12S,14Z,16E,18S)-12-(tert-Butyldimethylsilyloxy)-
18-(tert-butyldiphenylsilyloxy)-2-(4-methoxybenzyloxy)henicosa-
6,8,14,16,20-pentaen-10-one (20). To a solution of propargylic
ketone 19 (100 mg, 0.12 mmol) in dry toluene (0.5 mL) at 80 °C
was added triphenylphosphine (36 mg, 0.15 mmol). The mixture
was stirred at 80 °C for 48 h and then quenched with water. The
aqeous layer was extracted with Et2O. The organic layer was dried
over MgSO4, filtered, and concentrated in vacuo. The crude product
was purified by flash chromatography to afford 42 mg of the desired
1
1726 (CdO). NMR H (CDCl3, 500 MHz) δ ppm: 0.06 (s, 3H),
0.07 (s, 3H), 0.88 (s, 9H), 1.09 (s, 9H), 2.25 - 2.31 (m, 4H), 2.30
(ddd, J ) 2 Hz, J ) 4.6 Hz, J ) 15.7 Hz, 1H), 2.48 (ddd, J ) 2.7
Hz, J ) 7.3 Hz, J ) 15.7 Hz, 1H), 4.18 - 4.30 (m, 2H), 4.95 (d,
J ) 15.9 Hz, 1H), 4.99 (d, J ) 10.8 Hz, 1H), 5.35 (dt, J ) 7.8 Hz,
J ) 10.5 Hz, 1H), 5.66 (dd, J ) 6.6 Hz, J ) 14.7 Hz, 1H), 5.72
(ddt, J ) 7.2 Hz, J ) 10.2 Hz, J ) 17.4 Hz, 1H), 6.00 (t, J ) 10.8
Hz, 1H), 6.14 (dd, J ) 11 Hz, J ) 14;7 Hz, 1H), 7.35 - 7.44 (m,
6H), 7.64 - 7.75 (m, 4H), 9.75 (t, J ) 2,3 Hz, 1H). NMR 13C
(CDCl3, 75 MHz) δ ppm: -4.7, -4.3, 18.1, 19.5, 26.0, 26.7, 36.1,
42.7, 50.6, 68.0, 73.9, 117.3, 125.2, 126.2,127.5, 127.6, 129.7,
129.8, 130.8, 134.4, 134.4, 136.1, 136.7, 202.0. MS (ESI) m/z 585.3
(5, [MNa]+), 617.4 (100, [M + MeOH + Na]+). HRMS (ESI) m/z
[M + MeOH + Na]+ calcd for C34H50O3NaSi2 585.3196, found
585.3226.
dienone (42%). Rf ) 0.63 (heptane/AcOEt 7:3). IR-FT (neat) cm-1
:
1
2928, 2855, 1687 (CdO). NMR H (CDCl3, 500 MHz) δ ppm:
0.02 (s, 3H), 0.04 (s, 3H), 0.84 (s, 9H), 1.07 (s, 9H), 1.19 (d, J )
6.2 Hz, 3H), 1.42-1.50 (m, 2H), 1.53 - 1.62 (m, 2H), 2.15 -
2.19 (m, 2H), 2.25 - 2.33 (m, 4H), 2.43 (dd, J ) 4.4 Hz, J ) 14.9
Hz, 1H), 2.72 (dd, J ) 7.6 Hz, J ) 15 Hz, 1H), 3.50 (sext, J ) 5.7
Hz, 1H), 3.81 (s, 3H), 4.21 - 4.28 (m, 2H), 4.38 (d, J ) 11.4 Hz),
4.51 (d, J ) 11.4 Hz), 4.94 (d, J ) 17.4 Hz, 1H), 4.97 (d, J ) 11.2
Hz, 1H), 5.40 (dt, J ) 7.9 Hz, J ) 10.7 Hz, 1H), 5.63 (dd, J ) 6.9
Hz, J ) 15.2 Hz, 1H), 5.71 (ddt, J ) 7.3 Hz, J ) 10.3 Hz, J ) 17
Hz, 1H), 5.98 (t, J ) 11 Hz, 1H), 6.06 (d, J ) 15.6 Hz, 1H), 6.13
(dd, J ) 11 Hz, J ) 14.6 Hz, 1H), 6.17 - 6.16 (m, 2H), 6.88 (d,
J ) 8.2 Hz, 2H), 7.05 (m, 1H), 7.27 (d, J ) 8.2 Hz, 2H), 7.32 -
7.44 (m, 6H), 7.64 (d, J ) 6.4 Hz, 2H), 7.69 (d, J ) 6.4 Hz, 2H).
NMR 13C (CDCl3, 75 MHz) δ ppm: -4.8, -4.6, 18.0, 19.4, 19.6,
25.9, 27.0, 33.2, 36.1, 36.3, 42.6, 47.3, 55.3, 69.3, 70.0, 73.9, 74.1,
113.8, 117.1, 125.4, 126.9, 127.4, 127.5, 129.1, 129.2, 129.5, 129.6,
130.2, 131.1, 134.1, 134.3, 136.0, 136.0, 143.5, 145.5, 159.1, 199.7.
MS (ESI) m/z 843.5 (100, [MNa]+), 844.6 (35, [MHNa]+). HRMS
(ESI) [MNa]+ calcd for C51H72O5NaSi2 843.4816, found 843.4832.
(2R,12S,14Z,16E,18S)-12-(tert-Butyldimethylsilyloxy)-18-(tert-
butyldiphenylsilyloxy)-2-(4-methoxybenzyloxy)henicosa-14,16,-
20-trien-8-yn-10-one (19). To a solution of alkyne 7 (13 mg, 0.05
mmol) in dry THF (0.4 mL) at -78 °C was added dropwise
n-butyllithium (1.6 M in hexanes, 30 µL, 0.048 mmol). The reaction
mixture was stirred at -78 °C for 20 min. A solution of aldehyde
18 (15 mg, 0.034 mmol) in dry THF (0.3 mL) was added via
cannula, and the resulting mixture was stirred at -78 °C for 1.5 h.
The reaction was quenched with saturated NH4Cl (1 mL). The
aqeous layer was extracted with Et2O (5 mL). The organic layer
was dried over MgSO4, filtered, and concentrated in vacuo. The
resulting crude mixture (35 mg) was dissolved in dry dichlo-
romethane (1 mL), and Dess-Martin periodinane (15 wt % in
dichloromethane, 0.11 mL, 0.05 mmol) was added. After 10 min,
a white precipitate was formed and the reaction was complete
(TLC). The solvent was evaporated and the crude mixture was
purified by flash chromatography to afford the desired ketone (26
mg, 94% over 2 steps). Rf ) 0.63 (heptane/AcOEt 7:3). IR-FT (neat)
Acknowledgment. We are grateful to MENRT-France for
a grant (M. G.) and to CNRS (ICSN, Gif-sur-Yvette/ICMMO,
Orsay) for financial support. We also thank Prof. Webster for
sharing informations on the allene isomerization.
Supporting Information Available: Expiremental procedures
and characterizations for known compounds 2, 6, 7, 9, 10, and 14
and copies of the 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0701942
J. Org. Chem, Vol. 72, No. 9, 2007 3549