Relative stereochemical determination and synthesis of the C1-C17 fragment of a new natural polyketide

Article abstract of DOI:10.1021/jo9012833

(Chemical Equation Presented) The challenging determination of the relative stereochemistry of a complex natural polyketide portion was achieved. After careful NMR analysis, a concise synthesis of a set of possible relative diastereomers (only 6 diastereo

Full text of DOI:10.1021/jo9012833

pubs.acs.org/joc
Relative Stereochemical Determination and Synthesis of the C1-C17
Fragment of a New Natural Polyketide
Etienne Fleury,† Marie-Isabelle Lannou,† Olivia Bistri,† Franc-ois Sautel,‡
Georges Massiot,‡ Ange Pancrazi,*,† and Janick Ardisson*,†
†
ꢀ ꢀ
CNRS UMR 8638, Faculte de Pharmacie, Universite Paris Descartes, 4 avenue de l’observatoire, 75270
Paris cedex 06, France, and ‡CNRS/Pierre Fabre UMS 2597, Laboratoire Pierre Fabre, 3 rue des satellites,
BP 94244, 31402 Toulouse cedex 4, France
janick.ardisson@parisdescartes.fr; ange.pancrazi@parisdescartes.fr
Received June 19, 2009
The challenging determination of the relative stereochemistry of a complex natural polyketide
portion was achieved. After careful NMR analysis, a concise synthesis of a set of possible relative
diastereomers (only 6 diastereomers out of the 32 initially envisioned) has been carried out using
a common strategy based on enantioselective aldol reactions. With a high predictability, final NMR
comparison established the relative stereochemistry of the C1-C17 fragment of this natural product.
Introduction
nate motifs, reflecting their common biosynthesis from
propionates.2
For more than a century, polyketides have been of great
interest for the scientific community. Natural compounds of
this family are produced by various organisms (such as
bacteria, sponge invertebrates, fungi or plants) and exhibit
a wide range of biological activity (antibiotic, antitumoral,
antifungic, or immunomodulatory action) along with a great
molecular complexity.1 Many of them include polypropio-
In general, the low abundance of these natural polyketides
requires their total synthesis to deliver significant quantities
of pure material for extensive testing. Moreover, in numer-
ous cases, the stereochemistry of these natural products can
only be established by stereocontrolled synthesis of putative
structures, especially when analytical methods do not permit
full assignment.
(1) (a) Yeung, K.-S.; Paterson, I. Chem. Rev. 2005, 105, 4237–4313.
(b) Rohr, J. Angew. Chem., Int. Ed. 2000, 39, 2847–2849. (c) Paterson, I.;
Mansuri, M. M. Tetrahedron 1985, 41, 3569–3624. (d) Omura, S. Macrolide
Antibiotics; Academic Press Inc.: New York, 1984.
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493.
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Sheppard, G. S. J. Am. Chem. Soc. 1990, 112, 866–868. (b) Evans, D. A.;
Ng, H. P.; Clark, J. S.; Rieger, D. L. Tetrahedron 1992, 48, 2127–2142.
(c) Paterson, I. Pure Appl. Chem. 1992, 64, 1821–1830. (d) Paterson, I.;
Norcross, R. D.; Ward, R. A.; Romea, P.; Lister, M. A. J. Am. Chem. Soc.
1994, 116, 11287–11314. (e) For a recent review, see Schetter, B.; Mahrwald,
R. Angew. Chem., Int. Ed. 2006, 45, 7506–7525.
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3701–3702. (b) Brown, H. C.; Bhat, K. S.; Randad, R. S. J. Org. Chem. 1989,
54, 1570–1576. (c) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J. Am. Chem. Soc. 1990, 112, 6339–6348. (d) Roush, W. R.;
Palkowitz, A. D.; Ando, K. J. Am. Chem. Soc. 1990, 112, 6348–6359.
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F.; Takenaka, N.; Panek, J. S. J. Am. Chem. Soc. 1996, 118, 12475–12476.
(h) BouzBouz, S.; Cossy, J. Org. Lett. 2001, 3, 3995–3998. (i) BouzBouz, S.;
Cossy, J. Org. Lett. 2003, 5, 3029–3031. (j) Hoppe, D. Angew. Chem., Int. Ed.
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Engl. 1984, 23, 932–948. (k) de Lemos, E.; Poree, F.-H.; Bourin, A.; Barbion,
J.; Agouridas, E.; Lannou, M.-I.; Commerc-on, A.; Betzer, J.-F.; Pancrazi,
A.; Ardisson, J. Chem.;Eur. J. 2008, 14, 11092–11112.
7034 J. Org. Chem. 2009, 74, 7034–7045
Published on Web 08/20/2009
DOI: 10.1021/jo9012833
r
2009 American Chemical Society

Fleury et al.
JOCArticle
syn-syn stereotriad, and the C9-C11 motif as a syn-anti,
anti-syn, or anti-anti stereotriad.
As a result of these considerations, only 6 relative dia-
stereomers (1a-f) out of the 32 initially envisioned could
potentially correspond to natural product A (Figure 2). We
set out to synthesize these 6 compounds (1a-f) to deter-
mine the correct relative stereochemistry of the natural product.
Results and Discussion
As outlined in Scheme 1, the deconvolution of target 1 into
three fragments 2, 3, and 4 has been envisaged.
FIGURE 1. Structure of natural product A and model compound 1.
Noteworthy, all the required stereovariations will occur in
the central fragment 4. This subunit presents five of the
six contiguous stereogenic centers of the C8-C13 hexad,
the C13 carbonyl group being subsequently reduced.
The final set up of the adjacent unsaturations will be
achieved through a nucleophilic addition and a Horner-
Wadsworth-Emmons olefination (Scheme 1).
Phosphonate 2 was readily accessible from sorbic acid 5
in three steps. The carboxylic acid function was protected as
a trimethylsilylethyl ester.9 Indeed, a fluorine-cleavable
protecting group proved to be necessary at this position
since classical saponification methods10 of the corresp-
onding ethyl ether failed to regenerate the acid in advanced
stages of the synthesis. A cross metathesis/Arbuzov se-
quence developed by Cossy11 was then applied to 6 to
yield phosphonate 2 with a high selectivity (95% de, esti-
mated by NMR analysis of the crude reaction mixture;
Scheme 2).
Compound 3was efficiently prepared, with a total selectivity,
from commercial 2,3-dihydrofuran 7 using a cuprate transposi-
tion developed by Kocienski12 and recently applied in total
synthesis in our laboratory.4k,13 The resulting vinyl tin species 8
was protected at the C17 position as a tert-butyldiphenylsilyl
ether and a Sn/Br or Sn/I exchange step was performed to lead
to vinyl bromide 3a or vinyl iodide 3b (Scheme 3).
The central fragment 4 features the polypropionate pat-
tern of 1 and therefore constitutes the portion where the
stereovariation must take place to access all diastereomers
4a-f (Figure 3) and, consequently, 1a-f. We designed a
straightforward strategy that could provide the six isomers
using common intermediates and featuring a minimum
number of steps.
Elaboration of these polypropionates is challenging, con-
sidering the number of contiguous stereogenic centers.
Therefore, numerous stereocontrolled approaches (such as
aldol3 and allylation/crotylation4 reactions) have been deve-
loped in the past three decades.
In this context, natural compound A, a complex polyke-
tide recently isolated by Pierre Fabre laboratories in associa-
ꢀ
tion with IRD (Institut de Recherche pour le Develop-
pement), has been subjected to extensive work in our group
(Figure 1).5 Its full structure elucidation is still under in-
vestigation, but the planar structure of the C1-C19 region
was well-characterized as a three-propionate subunit (hexad)
bordered with polyunsaturated chains. However, the
stereochemical information was limited since the very low
extraction yield prevented from any derivatization or degra-
dation. The relative configurations of the stereogenic centers in
the acyclic C8-C13 subunit were therefore not assigned (32
possible relative diastereomers). To solve this problem, a model
compound 1, close enough to the natural compound to enable
NMR comparison, was selected for synthesis (Figure 1).6
An extension of Kishi’s NMR database method based on a
statistical approach was first considered.7 However, the C9
methyl ether led to internal perturbations that could not be
circumvented. Fortunately, a careful NMR data analysis
provided an interesting indication. A surprisingly low 13C
NMR chemical shift (δ=7.6 ppm) was noticed for the sole
C12 methyl group and this characteristic value is consistent
with a syn-syn stereotriad, whether substituted or not.8
Consequently, the C11-C13 motif was assigned as a
(5) The C1-C19 portion represented in Figure 1 features approxima-
tively half of the actual natural molecule.
Stereocontrolled installation of the C11-C12 and C9-C10
hydroxy-methyl patterns would arise from iterative boron-
mediated aldol reactions, involving aldehydes 9 and 10,
respectively. The C8 stereocenter would derive from Roche
ester 11, commercially available in its (R) or (S) configuration
(Scheme 4).
(6) The relevant choice of a vinyl C14-C15 motif instead of the C14-C17
diene (like in the natural compound A) was proved by preliminary NMR
studies: no significant NMR differences were observed for the C8-C13
sequence between the two products 28a and 29a shown below (see Support-
ing Information for synthesis and NMR data of these two compounds).
(9) Roush, W. R.; Blizzard, T. A. J. Org. Chem. 1984, 49, 1772–1783.
(10) Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau, L.; Lautens, M. J. Am.
Chem. Soc. 2005, 127, 15028–15029.
(11) (a) Amans, D.; Cossy, J. Angew. Chem., Int. Ed. 2006, 45, 5870–5874.
ꢀ
(b) Ferrie, L.; Amans, D.; Reymond, S.; Bellosta, V.; Capdevielle, P.; Cossy,
J. J. Organomet. Chem. 2006, 691, 5456–5465. (c) Hicks, J. D.; Flamme, E.
€
M.; Roush, W. R. Org. Lett. 2005, 7, 5509–5512. (d) Schoning, K.-U.;
Wittenberg, R.; Kirschning, A. Synlett 1999, 1624–1626.
(12) (a) Kocienski, P.; Wadman, S.; Cooper, K. J. Am. Chem. Soc. 1989,
111, 2363–2365. (b) Kocienski, P.; Barber, C. Pure Appl. Chem. 1990, 62,
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1933–1940. (c) Le Menez, P.; Fargeas, V.; Berque, I.; Poisson, J.; Ardisson, J.;
Lallemand, J.-Y.; Pancrazi, A. J. Org. Chem. 1995, 60, 3592–3599.
ꢀ
(d) Fargeas, V.; Le Menez, P.; Berque, I.; Ardisson, J.; Pancrazi, A.
Tetrahedron 1996, 52, 6613–6634.
(7) (a) Fleury, E.; Lannou, M.-I.; Bistri, O.; Sautel, F.; Massiot, G.; Pancrazi,
A.; Ardisson, J. Eur. J. Org. Chem. 2009, in press. (b) Kobayashi, Y.; Lee, J.;
Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2177–2180. (c) Lee, J.; Kobayashi, Y.;
Tezuka, K.; Kishi, Y. Org. Lett. 1999, 1, 2181–2184. (d) Kobayashi, Y.; Tan,
C.-H.; Kishi, Y. J. Am. Chem. Soc. 2001, 123, 2076–2078.
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(13) de Lemos, E.; Poree, F.-H.; Commerc-on, A.; Betzer, J.-F.; Pancrazi,
A.; Ardisson, J. Angew. Chem., Int. Ed. 2007, 46, 1917–1921.
(8) Hoffmann, R. W.; Weidmann, U. Chem. Ber. 1985, 118, 3980–3992.
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FIGURE 2. Structure of the six putative relative diasteromers 1a-f corresponding to natural product A.
SCHEME 1. Retrosynthetic Analysis of Target Compound 1
SCHEME 2. Synthesis of Fragment 2a
aReagents and conditions: (a) TMSCH2CH2OH, PPh3, DIAD, THF, 0 °C f r.t., 18 h, 83%; (b) allyl bromide, Grubbs-Hoveyda second generation
catalyst 3 mol %, CH2Cl2, r.t., 24 h, 62%; (c) P(OEt)3, 120 °C, 1 h, 96%.
SCHEME 3. Synthesis of Fragment 3a
aReagents and conditions: (a) (i) t-BuLi, THF, -78 °C f 0 °C, 50 min, (ii)
(Bu3Sn)2CuLi LiCN, Et2O, -78 °C f 0-5 °C, 90 min, (iii) MeI, -30 °C f
3
r.t., 5 h, 92%; (b) TBDPSCl, imidazole, DMF, r.t., 90 min, 99%; (c) (i) for
3a: NBS, CH2Cl2, 0 °C, 45 min, quant., (ii) for 3b: I2, CH2Cl2, 0 °C, quant.
The first goal was to synthesize aldehydes 9a-d. To this
aim, Paterson’s boron-mediated aldol reaction turned
out to be the most appropriate, because all of the four
FIGURE 3. Structure of the six diastereomers 4a-f.
(14) (a) Paterson, I. Synthesis 1998, 639–652. (b) Goodman, J. M.;
Paterson, I. Tetrahedron Lett. 1992, 33, 7223–7226. (c) Paterson, I.; Wallace,
possible relative configurations of the C8-C10 stereo-
triad were accessible from only two aldehydes (S)-10 and
(R)-10 and two known ketones 12 and 13 derived from ethyl
(S)-lactate 14 (Scheme 5).14 Noteworthy, Paterson’s boron-
mediated aldol reaction leads to the E- or Z-enolate for-
mation and consequently to the anti or syn aldol product
ꢀ
D. J.; Velazquez, S. M. Tetrahedron Lett. 1994, 35, 9083–9086. (d) Paterson,
I.; Wallace, D. J. Tetrahedron Lett. 1994, 35, 9087–9090. (e) Paterson, I.;
Wallace, D. J. Tetrahedron Lett. 1994, 35, 9477–9480. (f) Paterson, I.; Chen,
D. Y.-K.; Acena, J. L.; Franklin, A. S. Org. Lett. 2000, 2, 1513–1516. (g)
Paterson, I.; Collett, L. A. Tetrahedron Lett. 2001, 42, 1187–1191. (h)
Crossman, J. S.; Perkins, M. V. J. Org. Chem. 2006, 71, 117–124.
7036 J. Org. Chem. Vol. 74, No. 18, 2009

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SCHEME 4. Retrosynthetic Analysis of Fragment 4
the expected aldol product. Fortunately, Evans aldol reac-
tion, starting from (S)-17,17 successfully led to 18a (with over
95% de, estimated by NMR).18 After conversion of the
oxazolidine moiety into a Weinreb amide functionality,19
the C11 alcohol was protected as a trimethylsilyl ether 4a.
This synthetic pathway was performed in an identical
manner to afford diastereomers 4b-f, with similar selectiv-
ities (Scheme 8).
The synthesis of the six diastereomers 1a-f was now
possible through the coupling of fragments 2 and 3 with
4a-f (Scheme 9).
Vinyl bromide 3a was treated with tert-butyllithium to
generate the corresponding lithiated species, which could
successfully be coupled to Weinreb amide 4a.20 Surprisingly,
we found that lithiation of the vinyl iodide 3b only led to the
degradation of amide 4a.
15a-d according to the hydroxyl protecting group (Bz or
Bn) of the starting ketones (12 or 13) and the enolization
conditions.
The C11 alcohol function was then deprotected and the
C13 stereocenter was set up through a 1,3 diastereoselec-
tive reduction. The best result was obtained with zinc
borohydride, and the syn-syn C11-C12-C13 stereotriad
of 19a was generated in 91% yield and high diastereoselec-
tivity (over 90% de, NMR estimation).21 The C7 primary
alcohol function was then deprotected and the correspond-
ing triol was treated with triethylsilyl trifluoromethanesul-
fonate in the presence of 2,6-lutidine. Differentiation
between the triethylsilyl ethers was achieved by selective
oxidation of the protected primary alcohol function into
aldehyde 20a.22
This aldehyde was further involved in a Horner-
Wadsworth-Emmons olefination23 with phosphonate 1
to generate the C6-C7 double bond with over 95:5 E
stereoselectivity (1H NMR analysis). Final deprotection
was performed with tris(dimethylamino)sulfonium difluoro-
trimethylsilicate (TAS-F) to afford acid 1a.24
Commercially available (S)-Roche ester (S)-11 was
converted into aldehyde (S)-10 by silylation of the C7
alcohol function, ester reduction and subsequent Swern
oxidation of the C9 alcohol.4c This aldehyde was then
engaged in a substrate-controlled aldol coupling with the
E-dicyclohexylboroenolate derived from R-chiral ketone
12 to give the anti aldol product 15a with an excellent
diastereoselectivity (>95% de, estimated by NMR;
Scheme 6).15
The C9 hydroxyl group of the resulting R-keto alcohol 15a
was subsequently methylated to provide compound 16a. The
most efficient method consisted in the use of methyl trifluor-
omethanesulfonate with 2,6-di-tert-butyl-4-methylpyridine
in refluxing dichloromethane.16 The reduction of both ke-
tone and ester functionalities with lithium borohydride led to
the corresponding diol, which was then cleaved by treatment
with sodium periodate to yield aldehyde 9a.
Synthesis of diastereomer 9b was performed in an identical
manner, starting from (R)-Roche ester (R)-11 (Scheme 6). As
before, the aldol reaction was achieved with a high diaster-
eoselectivity.
Finally, the five other diastereomers 1b-f were synthe-
sized, following the same sequence as depicted in
Scheme 9.
Finally, for the synthesis of aldehyde 9c, the aldol
reaction starting from R-chiral ketone 13 generated the
syn aldol product 15c (over 90% de, estimated by NMR).
After reduction of the ketone, the benzyl ether was
cleaved by hydrogenolysis and subsequent oxidative clea-
vage with sodium periodate afforded aldehyde 9c. Synth-
esis of diastereomer 9d was performed in an identical
manner (similar de was obtained), starting from (R)-11
(Scheme 7).
Having the four possible relative diastereomers of the
C7-C11 segment in hand, the synthesis of the six diastere-
omers 1a-f was now possible through the setting up of the
syn C11-C12 hydroxy-methyl core. First studies showed
that Paterson’s boron-mediated aldol reaction failed to give
NMR Comparison
A direct comparison between natural product A and the
six synthesized diastereomers 1a-f was performed. Concerning
€
(18) Kangani, C. O.; Bruckner, A. M.; Curran, D. P. Org. Lett. 2005, 7,
379–382.
(19) Nicolaou, K. C.; Fylaktakidou, K. C.; Monenschein, H.; Li, Y.;
Weyershausen, B.; Mitchell, H. J.; Wei, H.-X.; Guntupalli, P.; Hepworth, D.;
Sugita, K. J. Am. Chem. Soc. 2003, 125, 15433–15442.
(20) (a) Raimundo, B. C.; Heathcock, C. H. Org. Lett. 2000, 2, 27–28.
(b) Marumoto, S.; Kogen, H.; Naruto, S. Tetrahedron 1999, 55, 7145–7156.
(c) Meyer, S. D.; Miwa, T.; Nakatsuka, M.; Schreiber, S. L. J. Org. Chem.
1992, 57, 5058–5060. (d) Hale, M. R.; Hoveyda, A. H. J. Org. Chem. 1992, 57,
1643–1645. (e) Schuppan, J.; Ziemer, B.; Koert, U. Tetrahedron Lett. 2000,
41, 621–624.
(21) This diol 19a was converted into the corresponding acetonide
compound 28a (see Supporting Information). 13C NMR analysis according
to the Rychnovsky method confirmed the presence of a C11-C12-C13 syn-
syn relationship.
(15) Aldol product 15a was already described, see (a) Paterson, I.;
Florence, G. J.; Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc.
2001, 123, 9535–9544. (b) Paterson, I.; Florence, G. J.; Gerlach, K.; Scott,
J. P. Angew. Chem., Int. Ed. 2000, 39, 377-380. The stereochemistry
assignment of other aldol products 15 was achieved through NOESY
experiments of corresponding δ-lactols 30 generated by cleavage of the silyl
ether (see Solsona, J. G.; Romea, P.; Urpi, F. Tetrahedron Lett. 2005, 45,
5379-5382 and Supporting Information).
(22) (a) Rodrı
´
guez, A.; Nomen,M.; Spur, B. W.; Godfroid,J.J.Tetrahedron
guez, A.; Nomen, M.; Spur, B. W.;
Lett. 1999, 40, 5161–5164. (b) Rodrı
´
Godfroid, J. J.; Lee, T. H. Tetrahedron 2001, 57, 25–37. (c) Zanardi, F.;
Battistini, L.; Marzocchi, L.; Acquotti, D.; Rassu, G.; Pinna, L.; Auzzas, L.;
€
Zambrano, V.; Casiraghi, G. Eur. J. Org. Chem. 2002, 1956–1964. (d) Hubner,
J.; Liebscher, J.; Patzel, M. Tetrahedron 2002, 58, 10485–10500.
(23) (a) Evans, D. A.; Connell, B. T. J. Am. Chem. Soc. 2003, 125, 10899–
10905. (b) Nicolaou, K. C.; Daines, R. A.; Chakraborty, T. K.; Ogawa, Y.
J. Am. Chem. Soc. 1988, 110, 4685–4696.
(24) For all this sequence, the choice of hydroxyl and acid protecting
groups was imposed by problems of selectivity and stability of the different
synthetic intermediates.
€
(16) Nakamura, R.; Tanino, K.; Miyashita, M. Org. Lett. 2003, 5, 3583–
3586.
(17) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org. Chem. 2002, 67,
5176–5183.
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SCHEME 5. Retrosynthetic Analysis of Aldehydes 9a-d
SCHEME 6. Synthesis of Aldehydes 9a and 9ba
aReagents and conditions: (a) TBSCl, imidazole, DMF, r.t., 18 h; (b) DIBAL-H, CH2Cl2, -40 °C f -20 °C, 3 h, 98% over 2 steps; (c) (i)
(COCl)2, DMSO, CH2Cl2, -55 °C, 1 h, (ii) Et3N, r.t., 1 h, 100%; (d) (i) 12, ClB(Cy)2, Me2NEt, Et2O, 0 °C, 2 h, (ii) (S)-10, -78 °C f -25 °C,
16 h, 98%; (e) MeOTf, DTBMP, CH2Cl2, 45 °C, 24 h, 76%; (f) LiBH4, THF, -78 °C f r.t., 16 h; (g) NaIO4, MeOH, r.t., 20 min, 84% over
two steps.
SCHEME 7. Synthesis of Aldehydes 9c and 9da
aReagents and conditions: (a) (i) 13, ClB(Cy)2, Et3N, Et2O, -78 °C, 2 h, (ii) (S)-10, -78 °C f -25 °C, 16 h, 84%; (b) MeOTf, DTBMP, CH2Cl2,
45 °C, 24 h, 75%; (c) LiBH4, THF, -78 °C f r.t., 16 h; (d) Pd/C, H2 (1 atm), EtOH, r.t., 16 h; (e) NaIO4, MeOH, r.t., 20 min, 65% over three
steps.
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SCHEME 8. Synthesis of Weinreb Amides 4a-fa
aReagents and conditions: (a) (i) (S)-17, n-BuOTf, Et3N, CH2Cl2, 0 °C, 1 h, (ii) 9a, -78 °C f 0 °C, 90 min, 91%; (b) MeONHMe HCl, AlMe3, CH2Cl2, -
3
20 °C f r.t., 16 h, 75%; (c) TMSOTf, 2,6-lutidine, CH2Cl2, -30 °C, 1 h, 93%.
SCHEME 9. Synthesis of the Four Diastereomers 1a-fa
aReagents and conditions: (a) (i) 3, t-BuLi, Et2O, -90 °C, 10 min, (ii) 4a, -78 °C f -50 °C, 1 h; (b) Amberlyst-15, MeOH, r.t., 30 min, 85% over two
steps; (c) Zn(BH4)2, Et2O, CH2Cl2, -78 °C f -50 °C, 5 h, 91%; (d) AcOH, THF, H2O, r.t., 16 h, 88%; (e) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 45 min,
99%; (f) (i) (COCl)2, DMSO, CH2Cl2, -80 °C f -55 °C, 1 h, (ii) Et3N, -80 °C f r.t., 1 h; (g) (i) 2, LDA, THF, -78 °C, 15 min, (ii) 20a, -78 °C f 0 °C, 45
min, 59% over two steps; (h) TAS-F, DMF, 0 °C, r.t., 9 h, 67%.
SCHEME 10. Synthesis of Model Compounds 21 and 22
the trienic portion, an inconsistency was immediately
noticed. Indeed, a large difference in 13C and 1H NMR
chemical shifts was observed between compound A and all
diastereomers with a decreasing impact from position 1 to 7
(Figure 4).
A dilution effect was first assumed to explain this differ-
ence, but subsequent experiences ruled out this hypothesis.
FIGURE 4. Δδ 13C (ppm) between A and 1a-f for carbons 1 to 7.
The observed chemical shift differences were then supposed
to be attributed to the presence of a carboxylate salt
in natural product A. To prove this assumption and to
determine whether this could affect the polypropionate
section or not, a model compound 21 was synthesized25
and converted into its corresponding sodium carboxylate
salt 22 (Scheme 10).
(25) Model compound 21 was prepared from the aldehyde (R)-10 and
phosphonate 2 (through the same sequence as the one described in Scheme 9).
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Fleury et al.
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FIGURE 7. Δδ 13C (ppm) between A and 1d-f for the C8-C13
subunit.
FIGURE 5. Δδ 13C (ppm) between 21 and 22 for carbons 1-10.
FIGURE 6. Δδ 13C (ppm) between A and 1a-c for the C8-C13
subunit.
FIGURE 8. Δδ 1H (ppm) between A and 1a and 1b for the C7-C13
subunit.
A chemical shift deviation profile was observed for car-
bons C1-C7 by 13C NMR data comparison between com-
pounds 21 and 22. Because this deviation was similar to that
observed between diastereomers 1a-f and A, natural com-
pound A was then deduced to be extracted as a carboxylate
salt, but the nature of the counterion could not be deter-
mined.
Unfortunately, the available quantity of natural com-
pound A did not allow its conversion into the corresponding
carboxylic acid. However, it is interesting to note that this
salt effect does not affect the saturated portion (see C8, C9,
and C10 in Figure 5). An NMR comparison of the central
polyketide portion C8-C13 of 1a-f with natural compound
A was therefore possible.
TABLE 1. Comparison of the 1H and 13C NMR Data for Natural
Compound A and Isomer 1a
compound A
δH, m, 3J [Hz]
isomer 1a
carbon No.
δC
δH, m, 3J [Hz]
δC
C8
C8-CH3
C9
C9-O-CH3
C10
C10-CH3
C11
C12
C12-CH3
C13
2.53, m
41.5
17.2
88.3
59.6
40.1
13.0
75.5
38.5
7.6
2.54, m
41.8
18.1
87.3
59.1
40.3
12.4
74.5
38.6
7.9
1.07, d, 6.7
3.27, dd, 6.7, 4.6
3.38, s
1.10, d, 6.7
3.32, dd, 7.4, 3.6
3.41, s
2.03, m
0.85, d, 7.0
3.57, dd, 9.6, 2.0
0.86, d, 6.9
3.49, dd, 10.1, 1.7
1.78, m
0.96, d, 7.0
3.97, d, 8.1
0.93, d, 7.0
3.99, d, 7.3
82.1
82.2
The differences in the 13C NMR spectra are highlighted in
Figures 6 and 7 by plotting the chemical shift difference
observed for each carbon of the C8-C13 portion between
natural product A and 1a-f.
There is a significant difference (Δδ > 1 ppm) in the
chemical shift of a number of peaks for compounds 1c-f,
most notably at positions C9, C9-O-CH3, and C10-CH3 for
1c and 1d and at positions C12, C12-CH3, and C13 for 1e and
1f. Consequently, these structures could not be correlated
with the natural product A.
For compounds 1a and 1b, the difference in 13C NMR
chemical shifts is low (Δδ < 1 ppm), except for the C8-CH3
position of 1b (Δδ = 2.8 ppm). We turned to 1H NMR
comparison to clearly distinguish the two compounds
(Figure 8).
In this case, a much closer correlation with natural pro-
duct A is observed for compound 1a, especially with regard
to protons H7, H8, C8-CH3, and C9-OCH3. The small
variations (Δδmax=0.08 ppm for the C8-C13 portion) can
be explained by the structural differences between our model
and the natural compound. On this basis, the relative con-
figuration of the natural compound A is assigned as isomer
1a (see Table 1 for full NMR comparison between A and 1a
and Supporting Information for full NMR comparison
between A and 1b-f).26
(26) Analysis of the coupling constants also displays a good correlation
between 1a and A.
7040 J. Org. Chem. Vol. 74, No. 18, 2009

Fleury et al.
JOCArticle
Conclusion
-40 °C was slowly added n-BuLi (1.6 M solution in hexanes,
33.1 mL, 31.7 mmol, 2.0 equiv). The mixture was stirred for
15 min at -40 °C before being added via cannula to a suspension
of CuCN (2.4 g, 26.5 mmol, 1.0 equiv) in Et2O (40 mL). The
yellow solution was stirred for 1 h between -30 °C and -20 °C.
In parallel, to a solution of commercial 2,3-dihydrofuran 7
(2.0 mL, 26.5 mmol, 1.0 equiv) in THF (18 mL) at -60 °C was
added tert-BuLi (1.5 M solution in pentane, 21.2 mL,
31.7 mmol, 1.2 equiv). The yellow solution was stirred for
10 min at -60 °C then for 50 min at 0 °C. The solution of
lithio-dihydrofuran, prepared above, was then added via can-
nula to the cyanocuprate and the reaction mixture was stirred at
-5 °C for 90 min. At -30 °C was added freshly distilled MeI
(11.5 mL, 185.0 mmol, 7.0 equiv). The reaction mixture was
allowed to warm to room temperature and stirred for 5 h.
Finally the reaction mixture was poured into a mixture of a
saturated aqueous NH4Cl solution and concentrated ammonia
(4:1) at 0 °C and stirring was maintained for 1 h at 20 °C before
extraction with diethyl ether. The organic layer was washed with
water, brine, dried over MgSO4 and the solvent was removed
under reduced pressure. The crude residue was purified by
chromatography on basic silica gel (cyclohexane/EtOAc
100:0-70:30) to give 9.13 g (92% yield) of the title compound
In summary, the relative stereochemistry of the six con-
tiguous stereogenic centers of the C8-C13 segment of a
recently isolated natural compound was convincingly deter-
mined. A relevant initial NMR analysis allowed us to
decrease the number of putative relative isomers from 32 to
6. The next step consisted in designing a synthetic model of
the C1-C19 part of A, whose isomers were prepared through
a highly convergent strategy. With a high predictability, a
final thorough comparison of the 13C and 1H NMR data of
the natural compound with those of the model isomers
enabled the full relative structural assignment of this large
part of the natural compound.
Experimental Section
(2E,4E)-2-(Trimethylsilyl)ethyl Hexa-2,4-dienoate 6. To a
cooled (0 °C) solution of sorbic acid 5 (1.0 g, 8.9 mmol, 1.0
equiv) in THF (60 mL) were added successively trimethylsilyl-
ethanol (1.7 mL, 11.6 mmol, 1.3 equiv), triphenylphosphine
(4.7 g, 17.8 mmol, 2.0 equiv), and DIAD (3.5 mL, 17.8 mmol, 2
equiv). The mixture was stirred at this temperature for 3 h. The
solvent was then removed in vacuo, and the residue was purified
by chromatography on silica gel (cyclohexane/EtOAc 100:0 to
85:15) to yield ester 6 (1.6 g, 83% yield). 1H NMR (300 MHz,
CDCl3) δ 0.04 (s, 9H), 1.01 (m, 2H), 1.84 (d, J=5.5 Hz, 3H), 4.22
(m, 2H), 5.75 (d, J=15.9 Hz, 1H), 6.05-6.25 (m, 2H), 7.23 (dd,
J = 15.9, 9.9 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ -1.4
(3CH3), 17.3 (CH2), 18.6 (CH3), 62.3 (CH2), 119.2 (CH), 129.8
(CH), 139.1 (CH), 144.7 (CH), 167.4 (C). IR (Film) ν 2981, 1721,
1
8. H NMR (400 MHz, CDCl3) δ 0.80-1.01 (m, 15H), 1.20-
1.40 (m, 6H), 1.42-1.57 (m, 6H), 1.87 (d, J=1.8 Hz, 3H), 2.42
(q, J=6.4 Hz, 2H), 3.66 (t, J=5.9 Hz, 2H), 5.51 (qd, J=7.3, 1.8
Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 9.1 (3CH2), 13.7
(3CH3), 19.3 (CH3), 27.4 (3CH2), 29.2 (3CH2), 31.7 (CH2),
62.3 (CH2), 135.7 (CH), 142.5 (C). HRMS (EIþ) m/z Calcd
for C17H36OSn (Mþ): 376.1788. Found: 376.1776. IR (Film) ν
3340, 2958, 2925, 2871, 2853, 1463, 1046 cm-1
.
(E)-(4-Bromopent-3-enyloxy)(tert-butyl)diphenylsilane 3a. Al-
cohol 8 (3.0 g, 8.0 mmol, 1.0 equiv) was dissolved in dry DMF
(10 mL) at room temperature. To this solution were successively
added imidazole (1.7 g, 24.8 mmol, 3.1 equiv) and TBDPSCl
(3.3 g, 12.0 mmol, 1.5 equiv). After stirring for 1.5 h, the mixture
was quenched with saturated aqueous solution of NH4Cl and
extracted with Et2O. The organic layer was dried over MgSO4
and the solvent was removed under reduced pressure. The
residue was purified by chromatography on basic silica gel
(cyclohexane/Et2O 100:0-90:10) to give 4.9 g (100% yield) of
1644, 1245, 1192, 1147, 1111 cm-1
.
(2E,4E)-2-(Trimethylsilyl)ethyl 6-(Diethoxyphosphoryl)hexa-
2,4-dienoate 2. Ester 6 (1.6 g, 7.4 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (70 mL). The solution was flushed with argon for
10 min. Allylbromide (3.2 mL, 36.9 mmol, 5.0 equiv) and
Grubbs-Hoveyda catalyst second generation (0.1 g, 0.2 mmol,
3 mol %) were then added successively. The mixture was stirred
at room temperature for 2 days. The solvent was then removed
under reduced pressure and the residue was purified by chro-
matography on silica gel (cyclohexane/Et2O 97.5:2.5-80:20) to
afford the expected bromide (1.3 g, 62% yield) as a yellow liquid.
1H NMR (300 MHz, CDCl3) δ 0.05 (s, 9H), 1.02 (m, 2H), 4.03
(d, J=7.2 Hz, 2H), 4.25 (m, 2H), 5.92 (d, J=15.3 Hz, 1H), 6.23
(dt, J=15.6, 7.2 Hz, 1H), 6.38 (dd, J=15.6, 10.8 Hz, 1H), 7.24
(dd, J=15.3, 10.8 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ -1.5
(3CH3), 17.3 (CH2), 31.3(CH2), 62.8 (CH2), 123.5 (CH), 131.9
(CH), 136.4 (CH), 142.3 (CH), 166.6 (C). IR (Film) ν 2985, 1712,
1
the silyl ether. H NMR (300 MHz, CDCl3) δ 0.83-0.94 (m,
15H), 1.06 (s, 9H), 1.26-1.37 (m, 6H), 1.45-1.55 (m, 6H), 1.82
(s, 3H), 2.42 (q, J=6.7 Hz, 2H), 3.69 (t, J=6.7 Hz, 2H), 5.61 (t,
J =6.7 Hz, 1H), 7.35-7.45 (m, 6H), 7.66-7.73 (m, 4H). 13C
NMR (75 MHz, CDCl3) δ 9.0 (3CH2), 13.7 (3CH3), 19.2
(CþCH3), 26.8 (3CH3), 27.4 (3CH2), 29.2 (3CH2), 31.6 (CH2),
63.5 (CH2), 127.6 (4CH), 129.5 (2CH), 134.1 (2C), 135.6 (4CH),
136.8 (CH), 140.0 (C). HRMS (EIþ) m/z Calcd for C33H54OS-
iSn (Mþ): 614.2966. Found: 614.3002. IR (film) ν 2956, 2927,
1642, 1330, 1252, 1191, 1147, 832 cm-1
.
2856, 1463, 1428, 1111, 701 cm-1
.
The previous bromide (1.2 g, 4.3 mmol, 1.0 equiv) was
dissolved in triethylphosphite (5.0 mL, 29.9 mmol, 7.0 equiv)
and the mixture was heated at 120 °C for 1 h. The solution was
then cooled down to 70 °C and the excess triethylphosphite was
removed under reduced pressure (∼1 mmHg). The crude pro-
NBS (2.8 g, 16.0 mmol, 2.0 equiv) was added to a solution of
the silyl ether (4.9 g, 8.0 mmol, 1.0 equiv) in CH2Cl2 (60 mL) at
0 °C. After 1 h at 0 °C, the mixture was concentrated in vacuo.
The residue was purified by chromatography on silica gel
(cyclohexane/Et2O 100:0-70:30) to afford vinyl bromide 3a
(3.2 g, 100% yield). 1H NMR (300 MHz, CDCl3) δ 1.06 (s,
9H), 2.18 (s, 3H), 2.24 (q, J=6.7 Hz, 2H), 3.66 (t, J=6.7 Hz, 2H),
5.86 (t, J=6.7 Hz, 1H), 7.35-7.45 (m, 6H), 7.65-7.75 (m, 4H).
13C NMR (75 MHz, CDCl3) δ 19.1 (C), 23.3 (CH3), 26.8 (3CH3),
32.9 (CH2), 62.6 (CH2), 121.0 (C), 127.7 (4CH), 128.8 (CH),
129.7 (2CH), 133.7 (2C), 135.6 (4CH). IR (film) ν 3070, 2956,
1
duct 2 (1.5 g, 100% yield) was used without purification. H
NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 0.97-1.05 (m, 2H),
1.27-1.36 (m, 6H), 2.71 (dd, J=24.0, 7.7 Hz, 2H), 4.05-4.15 (m,
4H), 4.19-4.26 (m, 2H), 5.83 (d, J=15.5 Hz, 1H), 6.05 (dq, J=
15.9, 7.7 Hz, 1H), 6.30 (ddd, J=15.9, 11.0, 4.9 Hz, 1H), 7.23 (dd,
J = 15.5, 11.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ -1.5
(3CH3), 16.4 (d, 2CH3, 3JC/P=5.9 Hz), 17.3 (CH2), 31.3 (d, CH2,
1JC/P=139.5 Hz), 62.2 (d, 2CH2, JC/P=6.8 Hz), 62.6 (CH2),
121.5 (d, CH, JC/P=4.1 Hz), 131.3 (d, CH, JC/P=12.6 Hz),
132.9 (d, CH, 2JC/P=14.5 Hz), 167.1 (C), 143.3 (d, CH, 4JC/P
4.7 Hz). IR (Film) ν 2954, 1720, 1251, 1168, 1027, 977, 838 cm-1
(E)-4-(Tributylstannyl)pent-3-en-1-ol 8. To a solution of
(Bu3Sn)2 (19.7 mL, 50.3 mmol, 1.9 equiv) in THF (20 mL) at
2
2930, 2857, 1427, 1111, 701 cm-1
.
5
3
(2S,4R,5R,6S)-7-(tert-Butyldimethylsilyloxy)-5-hydroxy-4,6-
dimethyl-3-oxoheptan-2-yl Benzoate 15a. To a cooled solution of
ClB(Cy)2 (5 mL, 22.8 mmol, 1.5 equiv) in anhydrous Et2O (40
mL) at -78 °C were added dropwise freshly distilled Me2NEt
(3.0 mL, 27.4 mmol, 1.8 equiv) followed by ketone 12 (3.1 g,
=
.
J. Org. Chem. Vol. 74, No. 18, 2009 7041

Fleury et al.
JOCArticle
15.2 mmol, 1.0 equiv) in anhydrous Et2O (15 mL). The resulting
milky mixture was stirred at 0 °C for 2 h. The solution was then
cooled to -78 °C before dropwise addition of aldehyde (S)-104c
(4.6 g, 22.8 mmol, 1.5 equiv). The solution was stirred for 2 h at
-78 °C. The mixture was then maintained overnight at -25 °C
without stirring. After one night, the mixture was stirred for
30 min at 0 °C. The reaction was then quenched by addition of
MeOH (50 mL), pH 7 phosphate buffer (50 mL), and H2O2
(35%, 50 mL). The mixture was stirred for 1 h at room
temperature, before being partitioned between water and
CH2Cl2. The aqueous layer was extracted with CH2Cl2 (2ꢀ).
The combined organic extracts were dried (MgSO4) and con-
centrated in vacuo. The residue was purified by column chro-
matography (cyclohexane/Et2O 90:10-80:20) to afford aldol
15a (6.1 g, 98% yield) as colorless oil. RN: 261968-17-6. 1H
NMR (400 MHz, CDCl3) δ 0.04 (s, 6H), 0.87 (s, 9H), 0.93 (d, J=
7.3 Hz, 3H), 1.09 (d, J=6.9 Hz, 3H), 1.57 (d, J=6.9 Hz, 3H),
1.63-1.83 (m, 1H), 2.99 (dq, J=9.6, 6.9 Hz, 1H), 3.06 (d, J=
2.3 Hz, 1H), 3.68 (dd, J=9.6, 4.6 Hz, 1H), 3.79 (dd, J=9.6,
3.7 Hz, 1H), 4.11 (dt, J=9.6, 2.3 Hz, 1H), 5.43 (q, J=6.9 Hz,
1H), 7.44 (t, J=7.3 Hz, 2H), 7.57 (tt, J=7.3, 1.4 Hz, 1H), 8.07
(m, 2H). 13C NMR (100 MHz, CDCl3) δ -5.7 (CH3), -5.6
(CH3), 8.9 (CH3), 13.7 (CH3), 15.4 (CH3), 18.2 (C), 25.8 (3CH3),
35.3 (CH), 45.8 (CH), 68.5 (CH2), 75.3 (CH), 75.6 (CH), 128.4
(2CH), 129.7 (C), 129.8 (2CH), 133.1 (CH), 165.9 (C), 211.0 (C).
HRMS (EIþ) m/z Calcd for C22H36O5Si (Mþ): 408.2332.
Found: 408.2293. [R]D = þ5.0 (c = 0.8, CHCl3). IR (film) ν
residue was directly used in the next step without further
purification.
Crude diols were diluted in MeOH (40 mL) and water (20 mL)
at room temperature. NaIO4 (11.2 g, 52.5 mmol, 6.0 equiv) was
added and the mixture was stirred for 25 min. The resulting
milky solution was quenched by addition of water (80 mL) and
extracted with Et2O. The combined organic layers were dried
over MgSO4 and concentrated in vacuo. The crude residue was
purified by column chromatography (cyclohexane/Et2O 95:5-
85:15) to afford aldehyde 9a (2.0 g, 84% yield over two steps) as
a colorless oil. 1H NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.88
(d, J=6.9 Hz, 3H), 0.89 (s, 9H), 1.02 (d, J=7.3 Hz, 3H), 1.72-
1.90 (m, 1H), 2.65 (qd, J=7.3, 2.3 Hz, 1H), 3.41 (s, 3H), 3.42-
3.62 (m, 2H), 3.56 (dd, J=7.8, 3.7 Hz, 1H), 9.80 (d, J=2.3 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ -5.5 (CH3), -5.4 (CH3),
10.7 (CH3), 11.1 (CH3), 18.2 (C), 25.9 (3CH3), 38.2 (CH), 49.2
(CH), 60.5 (CH3), 64.8 (CH2), 82.1 (CH), 204.9 (C). HRMS
(EIþ) m/z Calcd for C14H30O3Si (Mþ): 274.1964. Found:
274.1972. [R]D = -15.1 (c = 0.7, CHCl3). IR (Film) ν 2955,
2930, 2895, 2857, 1725, 1461, 1091, 836, 775 cm-1
.
(S)-4-Benzyl-3-((2S,3R,4S,5R,6S)-7-(tert-butyldimethylsilyl-
oxy)-3-hydroxy-5-methoxy-2,4,6-trimethylheptanoyl)oxazoli-
din-2-one 18a. (S)-4-Benzyl-3-propionyl-2-oxazolidinone (S)-17
(595 mg, 2.6 mmol, 1.4 equiv) was dissolved in CH2Cl2 (4 mL)
and cooled to 0 °C. n-Bu2BOTf (1.0 M solution in CH2Cl2,
2.8 mL, 2.8 mmol, 1.55 equiv) was added over 5 min, followed by
freshly distilled Et3N (585 μL, 4.2 mmol, 2.3 equiv). After
30 min, the solution was cooled to -78 °C and aldehyde 9a
(500 mg, 1.8 mmol, 1.0 equiv) in CH2Cl2 (2.5 mL) was added via
cannula. The mixture was stirred at -78 °C for 90 min then at
0 °C for 1 h. The reaction was quenched at 0 °C by addition of
pH 7 phosphate buffer (3 mL), MeOH (7 mL), and MeOH/35%
H2O2 (4 mL, 2:1). The mixture was stirred for 1 h before being
partitioned between Et2O and saturated aqueous NaCl. The
combined organic layers were dried over MgSO4 and solvents
were removed in vacuo. The crude residue was purified by
column chromatography (cyclohexane/Et2O 80:20-50:50) to
3505, 2932, 2855, 1720 cm-1
.
(2R,3R,4S)-5-(tert-Butyldimethylsilyloxy)-3-methoxy-2,4-di-
methylpentanal 9a. Aldol 15a (4.2 g, 10.1 mmol, 1.0 equiv) was
dissolved in anhydrous CH2Cl2 (120 mL) at room temperature.
To this solution was added 2,6-di-tert-butyl-4-methylpyridine
(25.0 g, 121.9 mmol, 12.0 equiv) followed by methyl trifluor-
omethanesulfonate (6.9 mL, 61.0 mmol, 6.0 equiv). The solution
was heated to reflux of CH2Cl2 for 8 h, and then 6.0 equiv of
methyl trifluoromethanesulfonate were further added. The solu-
tion was refluxed overnight. The mixture was then cooled to
0 °C and a 7 M aqueous solution of NH4OH (17.0 mL,
120 mmol, 12.0 equiv) diluted in water (120 mL) was added
dropwise very carefully. Finally, the mixture was extracted with
Et2O, dried over MgSO4, and solvents were removed in vacuo.
The residue was purified by column chromatography
(cyclohexane/Et2O 100:0-90:10) to afford the methylated aldol
product 16a (3.3 g, 76% yield) as pale yellow oil. 1H NMR (400
MHz, CDCl3) δ 0.04 (s, 3H), 0.05 (s, 3H), 0.79 (d, J=6.9 Hz,
3H), 0.89 (s, 9H), 1.07 (d, J=6.9 Hz, 3H), 1.56 (d, J=7.3 Hz,
3H), 1.70-1.90 (m, 1H), 3.05 (dq, J=10.1, 6.9 Hz, 1H), 3.27 (s,
3H), 3.41-3.61 (m, 2H), 3.75 (dd, J=10.1, 1.8 Hz, 1H), 5.41 (q,
J=7.3 Hz, 1H), 7.44 (m, 2H), 7.57 (tt, J=7.3, 0.9 Hz, 1H), 8.09
(m, 2H). 13C NMR (100 MHz, CDCl3) δ -5.4 (CH3), -5.3
(CH3), 9.2 (CH3), 14.2 (CH3), 14.9 (CH3), 18.2 (C), 25.9 (3CH3),
37.4 (CH), 45.1 (CH), 60.8 (CH3), 65.2 (CH2), 75.2 (CH), 81.6
(CH), 128.4 (2CH), 129.7 (C), 129.8 (2CH), 133.1 (CH), 165.8
(C), 210.2 (C). HRMS (EIþ) m/z Calcd for C23H38O5Si (Mþ):
422.2489. Found: 422.2508. [R]D=þ22.1 (c=1.7, CHCl3). IR
(film) ν 2958, 2935, 2898, 2858, 1664, 1462, 1385, 1251, 1130,
1
afford imide 18a (2.4 g, 91% yield) as a slightly yellow oil. H
NMR (400 MHz, CDCl3) δ 0.05 (s, 6H), 0.84 (d, J=6.9 Hz, 3H),
0.88 (d, J=6.4 Hz, 3H), 0.89 (s, 9H), 1.24 (d, J=6.9 Hz, 3H),
1.78-1.82 (m, 1H), 1.90 (sext d, J=6.9, 2.3 Hz, 1H), 2.76 (dd, J=
13.3, 9.6 Hz, 1H), 3.37 (dd, J=13.3, 2.7 Hz, 1H), 3.44 (dd, J=
5.9, 2.3 Hz, 1H), 3.45 (s, 3H), 3.50 (d, J=6.9 Hz, 2H), 4.02-3.92
(m, 2H), 4.17 (dd, J=9.2, 2.7 Hz, 1H), 4.21 (dd, J=9.2, 6.9 Hz,
1H), 4.36 (s, 1H), 4.70 (ddt, J=9.6, 6.9, 2.7 Hz, 1H), 7.19-7.24
(m, 2H), 7.26-7.37 (m, 3H). 13C NMR (100 MHz, CDCl3) δ -
5.4 (CH3), -5.3 (CH3), 8.7 (CH3), 10.5 (CH3), 13.6 (CH3), 18.3
(C), 26.0 (3CH3), 37.8 (CH2), 38.4 (CH), 38.7 (CH), 41.0 (CH),
56.0 (CH), 60.7 (CH3), 66.0 (CH2), 66.2 (CH2), 74.3 (CH), 86.0
(CH), 127.4 (2CH), 129.0 (CH), 129.6 (2CH), 135.6 (C), 153.4
(C), 175.7 (C). HRMS (EIþ) m/z Calcd for C27H45NO6Si (Mþ):
507.3016. Found: 507.3024. [R]D=þ39.2 (c=2.0, CHCl3). IR
(Film) ν 2955, 2929, 2857, 1782, 1702, 1455, 1387, 1210, 1093,
837, 776 cm-1
.
(2S,3R,4R,5R,6S)-7-(tert-Butyldimethylsilyloxy)-N-5-dimet-
hoxy-N-2,4,6-tetramethyl-3-(trimethylsilyloxy)heptanamide 4a.
N,O-Dimethylhydroxylamine hydrochloride (0.56 g, 5.8 mmol,
2.5 equiv) was suspended in CH2Cl2 (20 mL) and cooled to 0 °C.
AlMe3 (2 M solution in heptane, 2.9 mL, 5.8 mmol, 2.5 equiv)
was added dropwise over 5 min and the resulting clear solution
was stirred at room temperature for 1 h. Imide 18a (1.17 g,
2.3 mmol, 1.0 equiv) in CH2Cl2 (10 mL) was added dropwise at
-20 °C over 5 min. The reaction mixture was allowed to stir at
room temperature overnight and was then transferred via
cannula onto a vigorously stirred aqueous tartaric acid 1 M
solution (60 mL) at 0 °C. The mixture was stirred for 5 h until
two layers appeared. The aqueous layer was extracted with
CH2Cl2 and the combined organic layers were washed with
1075, 1056, 997, 890, 838, 775 cm-1
.
The methylated aldol compound 16a (3.7 g, 8.7 mmol,
1.0 equiv) was dissolved in THF (40 mL) at -78 °C before
addition of LiBH4 (2.0 M solution in THF, 87.0 mL,
174.0 mmol, 20.0 equiv). The solution was allowed to warm to
room temperature and stirred overnight. At 0 °C, water
(100 mL) was added slowly followed by a saturated aqueous
solution of Rochelle salt (100 mL). The mixture was stirred for
1 h at room temperature before being partitioned between
CH2Cl2 and saturated aqueous NH4Cl. The aqueous layer was
extracted with CH2Cl2 (2ꢀ). The combined organic layers were
dried over MgSO4 and solvents were removed in vacuo. The
7042 J. Org. Chem. Vol. 74, No. 18, 2009

Fleury et al.
JOCArticle
brine and dried over MgSO4. After removal of the solvent, the
residue was purified by column chromatography (cyclohexane/
EtOAc 90:10-70:30) to afford the corresponding Weinreb
amide (676 mg, 75% yield) as a colorless oil. 1H NMR
(400 MHz, CDCl3) δ 0.04 (s, 6H), 0.85 (d, J = 6.9 Hz, 3H),
0.87 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 1.17 (d, J=6.9 Hz, 3H),
1.88-1.94 (m, 1H), 1.94-2.02 (m, 1H), 2.95-3.10 (m, 1H), 3.19
(s, 3H), 3.41 (s, 3H), 3.45-3.65 (m, 3H), 3.71 (s, 3H), 3.80-3.86
(m, 1H), 4.08 (d, J=1.8 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ
-5.4 (2CH3), 10.3 (CH3), 11.6 (CH3), 12.7 (CH3), 18.3 (C), 25.9
(3CH3), 32.2 (CH3), 37.0 (CH), 37.6 (CH), 38.2 (CH), 59.5
(CH3), 61.3 (CH3), 66.6 (CH2), 73.3 (CH), 83.1 (CH), 177.9
(C). HRMS (EIþ) m/z Calcd for C19H41NO5Si (Mþ): 391.2754.
Found: 391.2746. [R]D=þ5.1 (c=2.5, CHCl3). IR (Film) ν 3454,
6.3 Hz, 2H), 3.37-3.40 (m, 1H), 3.40 (s, 3H), 3.45 (dd, J=6.3,
2.7 Hz, 1H), 3.46 (dd, J=9.9, 6.2 Hz, 1H), 3.51 (dd, J=9.9,
7.5 Hz, 1H), 3.79 (t, J=6.3 Hz, 2H), 3.83-3.90 (m, 1H), 3.94 (d,
J=2.1 Hz, 1H), 6.71 (t, J=7.3 Hz, 1H), 7.35-7.47 (m, 6H),
7.63-7.68 (m, 4H). 13C NMR (75 MHz, CDCl3) δ -5.4 (2CH3),
11.2 (CH3), 11.3 (CH3), 11.9 (CH3), 13.4 (CH3), 18.3 (C), 19.2
(C), 25.9 (3CH3), 26.8 (3CH3), 32.5 (CH2), 37.9 (CH), 38.7 (CH),
41.4 (CH), 59.8 (CH3), 62.4 (CH2), 66.4 (CH2), 74.0 (CH), 83.9
(CH), 127.7 (4CH), 129.8 (2CH), 133.5 (2C), 135.5 (4CH), 137.5
(C), 138.6 (CH), 205.9 (C). HRMS (TOF MS ESþ) m/z Calcd for
C38H62O5Si2 (M þ Naþ): 677.4034. Found: 677.4048. [R]D
=
þ2.0 (c=2.4, CHCl3). IR (Film) ν 2955, 2929, 2857, 2359, 2341,
1651, 1471, 1428, 1091, 701 cm-1
.
To a cooled (-78 °C) solution of this β-keto alcohol (715 mg,
1.10 mmol, 1.0 equiv.) in CH2Cl2 (20 mL) was added dropwise
Zn(BH4)2 (0.15 M solution in Et2O, 36.0 mL, 5.50 mmol,
5.0 equiv.). The mixture was stirred at -60 °C for 1 h, then
the temperature was allowed to warm to -40 °C. After 4 h at
-40 °C, the reaction was quenched by addition of MeOH (5 mL)
at this temperature. The mixture was extracted with CH2Cl2
(3ꢀ) and the combined organic layers were washed with a
saturated aqueous solution of NH4Cl, dried over MgSO4, and
concentrated in vacuo. The residue was purified by chromato-
graphy on silica gel (cyclohexane/Et2O 90:10-50:50) to afford
2957, 2932, 2858, 1641, 1462, 1399, 1255, 1090, 837, 775 cm-1
.
This Weinreb amide (1.3 g, 3.3 mmol, 1.0 equiv) was dissolved
in CH2Cl2 (35 mL) and the reaction mixture was cooled to
-30 °C. 2,6-Lutidine (1.6 mL, 13.3 mmol, 4.0 equiv) was added,
followed by TMSOTf (1.2 mL, 6.6 mmol, 2.0 equiv). After
stirring for 1 h at -30 °C, the reaction mixture was quenched by
addition of saturated aqueous NH4Cl at -30 °C and the mixture
was allowed to warm to room temperature. The mixture was
extracted with CH2Cl2 and the combined organic layers were
dried over MgSO4 and the solvent was removed in vacuo. The
crude residue was purified by column chromatography
(cyclohexane/EtOAc 90:10-75:25) to afford title compound
1
diol 19a (655 mg, 91% yield). H NMR (300 MHz, CDCl3) δ
0.06 (s, 6H), 0.75 (d, J=6.8 Hz, 3H), 0.80 (d, J=7.0 Hz, 3H), 0.83
(d, J=6.9 Hz, 3H), 0.90 (s, 9H), 1.04 (s, 9H), 1.52 (s, 3H), 1.72-
1.78 (m, 1H), 1.80-1.92 (m, 2H), 2.34 (q, J=7.0 Hz, 1H), 2.37
(q, J=7.0 Hz, 1H), 3.38-3.52 (m, 3H), 3.48 (s, 3H), 3.68 (t, J=
7.0 Hz, 2H), 3.77 (br d, J=10.0 Hz, 1H), 4.16 (br s, 1H), 4.20 (br
s, 1H), 4.74 (br s, 1H), 5.52 (t, J=7.0 Hz, 1H), 7.31-7.42 (m,
6H), 7.62-7.71 (m, 4H). 13C NMR (75 MHz, CDCl3) δ -5.5
(CH3), -5.4 (CH3), 4.2 (CH3), 10.4 (CH3), 13.6 (2CH3), 18.3 (C),
19.2 (C), 25.9 (3CH3), 26.9 (3CH3), 31.4 (CH2), 36.2 (CH), 38.3
(CH), 38.6 (CH), 60.8 (CH3), 63.7 (CH2), 65.9 (CH2), 79.8 (CH),
80.4 (CH), 86.2 (CH), 120.3 (CH), 127.6 (4CH), 129.5 (2CH),
134.1 (2C), 135.6 (4CH), 136.6 (C). HRMS (TOF MS ESþ) m/z
Calcd for C38H64O5Si2 (M þ Naþ): 679.4190. Found: 679.4173.
[R]D=þ1.4 (c=0.2, CHCl3). IR (Film) ν 3445, 2928, 2857, 1471,
1
4a (1.4 mg, 93% yield) as a colorless oil. H NMR (400 MHz,
CDCl3) δ 0.03 (s, 6H), 0.15 (s, 9H), 0.68 (d, J=6.9 Hz, 3H), 0.88
(d, J=6.9 Hz, 3H), 0.90 (s, 9H), 1.08 (d, J=6.9 Hz, 3H), 1.63-
1.72 (m, 2H), 3.16 (s, 3H), 3.39 (s, 3H), 3.49-3.41 (m, 4H), 3.72
(s, 3H), 3.92-3.95 (m, 1H). 13C NMR (100 MHz, CDCl3) δ -5.4
(CH3), -5.3 (CH3), 0.9 (3CH3), 9.5 (CH3), 16.1 (CH3), 17.4
(CH3), 18.2 (C), 25.9 (3CH3), 32.0 (CH3), 38.1 (CH), 38.9 (CH),
40.8 (CH), 59.3 (CH3), 61.3 (CH3), 65.5 (CH2), 77.3 (CH), 80.3
(CH), 177.7 (C). HRMS (EIþ) m/z Calcd for C22H49NO5Si2
(Mþ): 463.3149. Found: 463.3161. [R]D=þ22.1 (c=1.7, CHCl3).
IR (Film) ν 2958, 2935, 2898, 2858, 1664, 1462, 1385, 1251, 1130,
1075, 1056, 97, 890, 838, 775 cm-1
.
(9R,10S,11S,12S,13R,14S,E)-13-Methoxy-2,2,8,10,12,14,-
17,17,18,18-decamethyl-3,3-diphenyl-4,16-dioxa-3,17-disilano-
nadec-7-ene-9,11-diol 19a. Vinyl bromide 3a (1.60 g, 3.98 mmol,
3.0 equiv) was diluted in Et2O (20 mL). To remove dissolved O2,
the mixture was frozen at -196 °C under argon and then allowed
to melt in vacuo. This procedure was repeated three times. At
-78 °C, under argon, t-BuLi (1.7 M solution in pentane, 4.70 mL,
7.96 mmol, 6.0 equiv) was added dropwise. The mixture was
stirred at this temperature for 10 min, then amide 4a (615 mg,
1.33 mmol, 1.0 equiv) was quickly added, and the mixture was
stirred at -50 °C for 1 h. After this time, the reaction mixture
was quenched by addition of 4 mL of MeOH at -50 °C. The
mixture was then extracted with Et2O (2ꢀ), and the combined
organic layers were washed with a saturated aqueous solution of
NH4Cl, dried over MgSO4, and the solvent was removed under
reduced pressure. The residue was purified by chromatography
on silica gel (cyclohexane/Et2O 100:0-70:30) to afford the
expected enone which could not be separated from the excess
of reduced vinyl compound.
This enone was dissolved in MeOH (15 mL) at room tem-
perature and 50 beads of Amberlyst-15 were added. The reac-
tion was monitored by thin layer chromatography and the
mixture was filtered as soon as the starting material was totally
consumed. The solvent was removed under reduced pressure
and the residue was purified by chromatography on silica gel
(cyclohexane/EtOAc 100:0-80:20) to give 735 mg (85% yield
over two steps) of the desired β-keto alcohol. 1H NMR
(300 MHz, CDCl3) δ 0.03 (s, 6H), 0.81 (d, J = 7.0 Hz, 3H),
0.84 (d, J=6.9 Hz, 3H), 0.89 (s, 9H), 1.05 (s, 9H), 1.13 (d, J=
7.0 Hz, 3H), 1.76 (s, 3H), 1.80-1.95 (m, 2H), 2.50 (dt, J=7.3,
1427, 1255, 1111, 1089, 701 cm-1
.
(2R,3S,4R,5R,6S,7R,E)-11-(tert-Butyldiphenylsilyloxy)-3-
methoxy-2,4,6,8-tetramethyl-5,7-bis(triethylsilyloxy)undec-8-
enal 20a. Diol 19a (550 mg, 0.84 mmol, 1.0 equiv) was dissolved
in THF (20 mL) at room temperature. Water (10 mL) followed
by acetic acid (30 mL) were then added. The mixture was stirred
at room temperature for 18 h. The solution was diluted in Et2O
and carefully washed with saturated aqueous solution of NaH-
CO3 (2ꢀ). The organic layer was dried over MgSO4 and the
solvent was removed under reduced pressure. The residue was
purified by chromatography on silica gel (cyclohexane/EtOAc
1
80:20-40:60) to give the wanted triol (400 mg, 88% yield). H
NMR (300 MHz, CDCl3) δ 0.79 (d, J=6.9 Hz, 3H), 0.80 (d, J=
7.0 Hz, 3H), 0.91 (d, J=7.0 Hz, 3H), 1.04 (s, 9H), 1.52 (s, 3H),
1.71-1.81 (m, 1H), 1.87-1.99 (m, 2H), 2.29-2.40 (m, 2H), 3.40
(dd, J=6.9, 3.0 Hz, 1H), 3.47 (s, 3H), 3.53 (dd, J=10.5, 8.1 Hz,
1H), 3.62 (dd, J=10.5, 5.1 Hz, 1H), 3.68 (t, J=6.8 Hz, 2H), 3.77
(dd, J=9.5, 1.7 Hz, 1H), 4.19 (br s, 1H), 5.50 (t, J=7.3 Hz, 1H),
7.33-7.45 (m, 6H), 7.64-7.71 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ 4.3 (CH3), 11.4 (CH3), 13.6 (CH3), 14.0 (CH3), 19.1 (C),
26.8 (3CH3), 31.3 (CH2), 36.1 (CH), 37.8 (CH), 38.2 (CH),
60.4 (CH3), 63.6 (CH2), 66.2 (CH2), 79.2 (CH), 80.6 (CH),
86.5 (CH), 120.6 (CH), 127.6 (4CH), 129.5 (2CH), 134.0 (2C),
135.6 (4CH), 136.7 (C). HRMS (TOF MS ESþ) m/z Calcd for
C32H50O5Si (M þ Naþ): 565.3325. Found: 565.3334. [R]D
=
þ2.3 (c=0.5, CHCl3). IR (Film) ν 3418, 2932, 1462, 1427, 1111,
702 cm-1
.
2,6-Lutidine (178 μL, 1.53 mmol, 12.0 equiv) and TESOTf
(261 μL, 1.15 mmol, 9.0 equiv) were added to a solution of the
J. Org. Chem. Vol. 74, No. 18, 2009 7043

Fleury et al.
JOCArticle
previous triol (69 mg, 0.13 mmol, 1.0 equiv) in CH2Cl2 (4 mL) at
0 °C. The mixture was stirred at 0 °C for 45 min before being
quenched by addition of a saturated aqueous solution of
NH4Cl. The mixture was then extracted with CH2Cl2 (3ꢀ).
The combined organic layers were dried over MgSO4 and the
solvent was removed in vacuo. The residue was purified by
chromatography on silica gel (cyclohexane/EtOAc 100:0-
80:20) to afford the expected silyl ether (111 mg, 99% yield) as
a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.47-0.65 (m, 18H),
0.79 (d, J=6.8 Hz, 3H), 0.83-1.03 (m, 33H), 1.06 (s, 9H), 1.49 (s,
3H), 1.75-1.85 (m, 1H), 1.86-1.98 (m, 2H), 2.20-2.40 (m, 2H),
3.30 (s, 3H), 3.35 (dd, J=8.9, 1.9 Hz, 1H), 3.46 (dd, J=9.6, 6.7
Hz, 1H), 3.56 (dd, J=9.6, 8.0 Hz, 1H), 3.62-3.66 (m, 1H), 3.66
(t, J=7.5 Hz, 2H), 3.95 (d, J=5.8 Hz, 1H), 5.40 (t, J=6.7 Hz,
1H), 7.34-7.44 (m, 6H), 7.66-7.72 (m, 4H). 13C NMR (75
MHz, CDCl3) δ 4.4 (3CH2), 5.0 (3CH2), 5.7 (3CH2), 6.8 (3CH3),
7.0 (3CH3), 7.2 (3CH3), 10.0 (CH3), 10.9 (CH3), 12.7 (CH3), 15.4
(CH3), 19.1 (C), 26.8 (3CH3), 31.3 (CH2), 38.3 (CH), 39.6 (2CH),
59.4 (CH3), 63.5 (CH2), 65.8 (CH2), 76.4 (CH), 79.3 (CH), 81.0
(CH), 121.9 (CH), 127.6 (4CH), 129.5 (2CH), 134.0 (2C), 135.5
(4CH), 138.7 (C). HRMS (TOF MS ESþ) m/z Calcd for
2H), 1.06 (s, 9H), 1.47 (s, 3H), 1.80-1.95 (m, 2H), 2.20-2.40 (m,
2H), 2.40-2.52 (m, 1H), 3.03 (dd, J=7.0, 3.7 Hz, 1H), 3.25 (s,
3H), 3.62-3.66 (m, 1H), 3.66 (t, J=7.7 Hz, 2H), 3.86 (d, J=
7.5 Hz, 1H), 4.20-4.27 (m, 2H), 5.41 (t, J=6.4 Hz, 1H), 5.82 (d,
J=15.5 Hz, 1H), 5.94 (dd, J=15.1, 7.3 Hz, 1H), 6.10 (dd, J=
15.1, 10.2 Hz, 1H), 6.20 (dd, J=14.5, 11.4 Hz, 1H), 6.50 (dd, J=
14.5, 10.2 Hz, 1H), 7.28 (dd, J=15.5, 11.4 Hz, 1H), 7.33-7.44
(m, 6H), 7.65-7.71 (m, 4H). 13C NMR (75 MHz, CDCl3) δ -1.5
(3CH3), 5.0 (3CH2), 5.8 (3CH2), 6.9 (3CH3), 7.2 (3CH3), 10.9
(CH3), 12.4 (CH3), 14.1 (CH3), 15.2 (CH3), 17.3 (CH2), 19.1 (C),
26.8 (3CH3), 31.3 (CH2), 39.3 (CH), 39.4 (CH), 39.9 (CH), 59.6
(CH3), 62.4 (CH2), 63.4 (CH2), 76.8 (CH), 84.0 (CH), 87.6 (CH),
120.5 (CH), 122.8 (CH), 127.6 (4CH), 127.7 (CH), 128.7 (CH),
129.6 (2CH), 133.9 (2C), 135.5 (4CH), 138.6 (C), 140.9 (CH),
144.3 (CH), 144.4 (CH), 167.3 (C).
To a solution of this ester (75 mg, 0.08 mmol, 1.0 equiv) in dry
DMF at 0 °C (0.7 mL) was added a solution of TAS-F (150 mg,
0.42 mmol, 7.0 equiv) in dry DMF (0.2 mL). The resulting
purple solution was stirred at 0 °C for 15 min then at room
temperature for 9 h. The mixture was then diluted with EtOAc
and washed with an aqueous pH 2-3 HCl solution. The
aqueous layer was extracted with EtOAc (2ꢀ) and the combined
organic layers were washed (4ꢀ) with small quantities of a
saturated aqueous NaCl solution, dried over MgSO4, and
concentrated in vacuo. The residue was purified by chromato-
graphy on silica gel (EtOAc/MeOH 100:0-80:20) to give title
compound 1a (20 mg, 67% yield). 1H NMR (300 MHz, MeOD)
δ 0.87 (d, J=7.1 Hz, 3H), 0.97 (d, J=6.8 Hz, 3H), 1.11 (d, J=6.6
Hz, 3H), 1.54 (s, 3H), 1.73-1.83 (m, 1H), 1.98-2.08 (m, 1H),
2.33 (q, J=6.7 Hz, 2H), 2.48-2.60 (m, 1H), 3.30-3.34 (m, 1H),
3.41 (s, 3H), 3.48 (dd, J=10.1, 1.7 Hz, 1H), 3.66 (t, J=6.7 Hz,
2H), 3.96 (d, J=8.2 Hz, 1H), 5.50 (t, J=6.7 Hz, 1H), 5.90 (d, J=
15.2 Hz, 1H), 5.95 (dd, J=15.3, 9.2 Hz, 1H), 6.23 (dd, J=15.3,
10.7 Hz, 1H), 6.37 (dd, J=14.8, 11.3 Hz, 1H), 6.65 (dd, J=14.8,
10.7 Hz, 1H), 7.36 (dd, J = 15.2, 11.3 Hz, 1H). 13C NMR
(75 MHz, MeOD) δ 7.9 (CH3), 11.9 (CH3), 12.4 (CH3), 18.1
(CH3), 32.4 (CH2), 38.6 (CH), 40.3 (CH), 41.8 (CH), 59.1 (CH3),
62.8 (CH2), 74.5 (CH), 82.2 (CH), 87.3 (CH), 121.7 (CH), 125.6
(CH), 129.7 (CH), 130.7 (CH), 139.0 (C), 142.9 (CH), 144.7
(CH), 146.8 (CH), 170.8 (C). HRMS (TOF MS ESþ) m/z Calcd
for C22H36O6 (M þ Naþ): 419.2404. Found: 419.2418. [R]D=
-2.5 (c=0.3, CHCl3). IR (Film) ν 3370, 2932, 1688, 1612, 1260,
C50H92O5Si4 (M þ Naþ): 907.5920. Found: 907.5883. [R]D
=
-1.1 (c=2.2, CHCl3). IR (Film) ν 2956, 2876, 1459, 1427, 1239,
1094, 1008, 822, 757, 701 cm-1
.
To a cooled (-78 °C) solution of oxalyl chloride (49 μL, 0.57
mmol, 5.0 equiv) in CH2Cl2 (2 mL) was added dropwise DMSO
(87 μL, 1.13 mmol, 10.0 equiv). After 10 min at -78 °C, a
solution of the TES ether (100 mg, 0.11 mmol, 1.0 equiv) in
CH2Cl2 (1 mL) was slowly added. The mixture was stirred at
-78 °C for 20 min and then at -40 °C for 20 min. At -78 °C,
triethylamine (284 μL, 2.03 mmol, 18.0 equiv) was added
dropwise and the mixture was allowed to warm to room
temperature over 2 h. The resulting white and milky solution
was diluted in Et2O and washed successively with a saturated
aqueous solution of NH4Cl and water. The organic layer was
dried over MgSO4 and the solvent was removed in vacuo. The
crude aldehyde 20a (100 mg) was directly used in the next step
without further purification. 1H NMR (300 MHz, CDCl3)
δ 0.48-0.66 (m, 12H), 0.85-1.00 (m, 24H), 1.05 (s, 9H), 1.09 (d,
J=7.0 Hz, 3H), 1.48 (s, 3H), 1.76-1.86 (m, 1H), 1.89-2.01 (m,
1H), 2.20-2.35 (m, 2H), 3.42-3.54 (m, 1H), 3.07 (s, 3H), 3.65 (t,
J=7.5 Hz, 1H), 3.70-3.80 (m, 3H), 3.89 (d, J=7.2 Hz, 1H), 5.39
(t, J=7.1 Hz, 1H), 7.33-7.44 (m, 6H), 7.63-7.70 (m, 4H), 9.80
(s, 1H). 13C NMR (75 MHz, CDCl3) δ 5.0 (3CH2), 5.7 (3CH2),
6.6 (CH3), 7.1 (3CH3), 7.2 (3CH3), 11.0 (CH3), 12.0 (CH3), 14.2
(CH3), 19.1 (C), 26.8 (3CH3), 31.3 (CH2), 39.1 (CH), 40.4 (CH),
49.0 (CH), 58.0 (CH3), 63.4 (CH2), 74.1 (CH), 80.0 (CH), 80.5
(CH), 122.8 (CH), 127.6 (4CH), 129.5 (2CH), 133.9 (2C), 135.5
(4CH), 138.4 (C), 204.8 (C).
1078, 1007, 702 cm-1
.
(2E,4E,6E,8R,9R,10S,11S,12S,13R,14E)-11,13,17-Trihy-
droxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tet-
1
raenoic Acid 1b. H NMR (300 MHz, MeOD) δ 0.79 (d, J=
7.1 Hz, 3H), 0.96 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.9 Hz, 3H), 1.62
(s, 3H), 1.75-1.87 (m, 1H), 2.04-2.15 (m, 1H), 2.38 (q, J=7.1
Hz, 2H), 2.63-2.72 (m, 1H), 3.39 (dd, J=5.4, 3.2 Hz, 1H), 3.43
(s, 3H), 3.54 (dd, J=10.0, 1.6 Hz, 1H), 3.65 (t, J=7.1 Hz, 2H),
4.02 (d, J=8.1 Hz, 1H), 5.53 (t, J=7.1 Hz, 1H), 5.90 (d, J=
14.9 Hz, 1H), 6.09 (dd, J=15.3, 8.3 Hz, 1H), 6.18 (dd, J=15.3,
9.6 Hz, 1H), 6.34 (dd, J=14.5, 11.1 Hz, 1H), 6.64 (dd, J=14.5,
9.6 Hz, 1H), 7.33 (dd, J = 14.9, 11.1 Hz, 1H). 13C NMR
(75 MHz, MeOD) δ 7.9 (CH3), 12.0 (CH3), 12.8 (CH3), 20.1
(CH3), 32.4 (CH2), 38.5 (CH), 39.2 (CH), 40.8 (CH), 59.3 (CH3),
62.8 (CH2), 75.5 (CH), 81.9 (CH), 88.1 (CH), 121.4 (CH), 125.0
(CH), 129.4 (CH), 130.7 (CH), 139.2 (C), 142.9 (CH), 144.6
(CH), 146.9 (CH), 170.8 (C). HRMS (TOF MS ESþ) m/z Calcd
for C22H36O6 (M þ Naþ): 419.2404. Found: 419.2400. [R]D =
-28.3 (c=0.6, CHCl3). IR (Film) ν 3368, 2932, 1688, 1611, 1260,
(2E,4E,6E,8S,9R,10S,11S,12S,13R,14E)-11,13,17-Trihy-
droxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tet-
raenoic Acid 1a. n-BuLi (1.6 M solution in hexanes, 622 μL,
0.99 mmol, 1.7 equiv) was added to a solution of diisopropyla-
mine (140 μL, 0.99 mmol, 1.7 equiv) in THF (3 mL) at -78 °C.
The resulting pale yellow solution was stirred at -78 °C for
5 min and then at 0 °C for 15 min. A solution of phosphonate 2
(347 mg, 0.99 mmol, 1.7 equiv) in THF (5 mL) was slowly added
at -78 °C. The resulting dark-brown solution was stirred for
15 min at -78 °C before addition of aldehyde 20a (450 mg,
0.58 mmol, 1.0 equiv) in THF (5 mL). The mixture was stirred
for 15 min at -78 °C then 30 min at 0 °C. The mixture was then
extracted with Et2O (2ꢀ) and washed with a saturated aqueous
solution of NH4Cl. The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel (cyclohexane/
Et2O 100:0-90:10) to afford the desired ester (330 mg, 59%
1078, 1007, 702 cm-1
.
(2E,4E,6E,8S,9S,10S,11S,12S,13R,14E)-11,13,17-Trihydr-
oxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tetra-
enoic Acid 1c. 1H NMR (300 MHz, MeOD) δ 0.80 (d, J=7.0 Hz,
3H), 0.94 (d, J=6.8 Hz, 3H), 1.02 (d, J=6.8 Hz, 3H), 1.64 (s,
3H), 1.72-1.82 (m, 1H), 1.80-1.89 (m, 1H), 2.34 (q, J=7.1 Hz,
2H), 2.43-2.59 (m, 1H), 3.41 (s, 3H), 3.46 (dd, J=8.6, 1.7 Hz,
1
yield over two steps). H NMR (300 MHz, CDCl3) δ 0.05 (s,
9H), 0.45-0.65 (m, 12H), 0.85-0.95 (m, 27H), 0.99-1.05 (m,
7044 J. Org. Chem. Vol. 74, No. 18, 2009

Fleury et al.
JOCArticle
1H), 3.53 (dd, J=11.3, 1.3 Hz, 1H), 3.61 (t, J=7.1 Hz, 2H), 4.04
(d, J=7.7 Hz, 1H), 5.54 (t, J=7.1 Hz, 1H), 5.89 (d, J=15.1 Hz,
1H), 6.08 (dd, J=15.1, 8.2 Hz, 1H), 6.28 (dd, J=15.1, 10.4 Hz,
1H), 6.37 (dd, J=14.8, 11.3 Hz, 1H), 6.69 (dd, J=14.8, 10.4 Hz,
1H), 7.35 (dd, J = 15.1, 11.3 Hz, 1H). 13C NMR (75 MHz,
MeOD) δ 7.4 (CH3), 10.0 (CH3), 12.1 (CH3), 17.6 (CH3), 32.3
(CH2), 38.1 (CH), 39.9 (CH), 42.5 (CH), 61.5 (CH3), 62.8 (CH2),
74.7 (CH), 82.2 (CH), 85.9 (CH), 121.4 (CH), 124.8 (CH), 129.6
(CH), 131.0 (CH), 139.2 (C), 142.8 (CH), 145.1 (CH), 146.9
(CH), 170.8 (C). HRMS (TOF MS ESþ) m/z Calcd for
1H), 6.07 (dd, J=15.2, 7.9 Hz, 1H), 6.29 (dd, J=15.2, 10.4 Hz,
1H), 6.39 (dd, J=14.7, 11.2 Hz, 1H), 6.68 (dd, J=14.7, 10.4 Hz,
1H), 7.34 (dd, J = 15.1, 11.2 Hz, 1H). 13C NMR (75 MHz,
MeOD) δ 9.5 (CH3), 11.7 (CH3), 13.9 (CH3), 14.9 (CH3), 32.3
(CH2), 39.1 (CH), 39.9 (CH), 40.9 (CH), 61.4 (CH3), 62.9 (CH2),
73.9 (CH), 78.0 (CH), 89.3 (CH), 121.7 (CH), 122.2 (CH), 129.9
(CH), 130.7 (CH), 139.4 (C), 142.7 (CH), 144.9 (CH), 146.7
(CH), 170.9 (C). HRMS (TOF MS ESþ) m/z Calcd for
C22H36O6 (M þ Naþ): 419.2404. Found: 419.2420. [R]D
=
þ10.0 (c = 0.6, CHCl3). IR (Film) ν 3391, 2933, 1688, 1614,
C22H36O6 (M þ Naþ): 419.2404. Found: 419.2408. [R]D
=
-13.5 (c = 0.4, CHCl3). IR (Film) ν 3370, 2932, 1688, 1612,
1261, 1078, 1007 cm-1
.
(2E,4E,6E,8R,9R,10S,11R,12R,13S,14E)-11,13,17-Trihydr-
oxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tetra-
enoic Acid 1f. 1H NMR (300 MHz, MeOD) δ 0.93 (d, J=6.8 Hz,
3H), 0.95 (d, J=6.8 Hz, 3H), 1.18 (d, J=6.9 Hz, 3H), 1.62 (s,
3H), 1.70-1.80 (m, 1H), 1.89-1.97 (m, 1H), 2.35 (q, J=7.0 Hz,
2H), 2.52-2.64 (m, 1H), 3.19 (dd, J=7.3, 3.3 Hz, 1H), 3.52 (s,
3H), 3.61 (t, J=7.0 Hz, 2H), 3.82 (dd, J=7.1, 3.2 Hz, 1H), 4.01
(d, J=4.4 Hz, 1H), 5.51 (t, J=7.0 Hz, 1H), 5.88 (d, J=15.4 Hz,
1H), 6.06 (dd, J=15.2, 8.6 Hz, 1H), 6.25 (dd, J=15.2, 10.4 Hz,
1H), 6.35 (dd, J=14.7, 11.3 Hz, 1H), 6.65 (dd, J=14.7, 10.4 Hz,
1H), 7.33 (dd, J = 15.4, 11.3 Hz, 1H). 13C NMR (75 MHz,
MeOD) δ 9.7 (CH3), 10.6 (CH3), 10.9 (CH3), 13.6 (CH3), 32.1
(CH2), 39.2 (CH), 39.8 (CH), 41.2 (CH), 61.3 (CH3), 62.8 (CH2),
73.6 (CH), 77.7 (CH), 89.1 (CH), 122.0 (CH), 122.1 (CH), 129.5
(CH), 131.2 (CH), 139.3 (C), 142.4 (CH), 143.0 (CH), 146.3
(CH), 171.1 (C). HRMS (TOF MS ESþ) m/z Calcd for
1260, 1078, 1007, 702 cm-1
.
(2E,4E,6E,8R,9S,10S,11S,12S,13R,14E)-11,13,17-Trihydr-
oxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tetra-
enoic Acid 1d. 1H NMR (300 MHz, MeOD) δ 0.76 (d, J=6.9 Hz,
3H), 0.88 (d, J=6.8 Hz, 3H), 1.17 (d, J=6.6 Hz, 3H), 1.64 (s,
3H), 1.66-1.76 (m, 1H), 1.76-1.86 (m, 1H), 2.34 (q, J=7.1 Hz,
2H), 2.45-2.61 (m, 1H), 3.47 (dd, J=8.9, 1.9 Hz, 1H), 3.50-3.52
(m, 1H), 3.52 (s, 3H), 3.61 (t, J=7.1 Hz, 2H), 4.03 (d, J=7.7 Hz,
1H), 5.54 (t, J=7.1 Hz, 1H), 5.86 (dd, J=15.2, 9.3 Hz, 1H), 5.89
(d, J=15.0 Hz, 1H), 6.25 (dd, J=15.2, 10.6 Hz, 1H), 6.37 (dd, J=
14.9, 11.2 Hz, 1H), 6.64 (dd, J=14.9, 10.6 Hz, 1H), 7.33 (dd, J=
15.0, 11.2 Hz, 1H). 13C NMR (75 MHz, MeOD) δ 7.4 (CH3), 9.9
(CH3), 12.1 (CH3), 18.7 (CH3), 32.3 (CH2), 38.1 (CH), 40.6
(CH), 42.9 (CH), 61.8 (CH3), 62.8 (CH2), 74.8 (CH), 82.3 (CH),
85.6 (CH), 121.6 (CH), 124.8 (CH), 129.8 (CH), 130.9 (CH),
139.2 (C), 142.6 (CH), 143.7 (CH), 146.8 (CH), 170.8 (C).
HRMS (TOF MS ESþ) m/z Calcd for C22H36O6 (M þ Naþ):
419.2404. Found: 419.2415. [R]D =þ8.4 (c=0.5, CHCl3). IR
C22H36O6 (M þ Naþ): 419.2404. Found: 419.2416. [R]D
=
þ2.1 (c = 0.1, CHCl3). IR (Film) ν 3391, 2933, 1688, 1614,
1261, 1078, 1007 cm-1
.
(Film) ν 3397, 2933, 1689, 1614, 1261, 1078, 1007, 705 cm-1
.
(2E,4E,6E,8S,9R,10S,11R,12R,13S,14E)-11,13,17-Trihydr-
oxy-9-methoxy-8,10,12,14-tetramethylheptadeca-2,4,6,14-tetra-
enoic Acid 1e. 1H NMR (300 MHz, MeOD) δ 0.94 (d, J=6.9 Hz,
3H), 0.99 (d, J=7.1 Hz, 3H), 1.11 (d, J=6.8 Hz, 3H), 1.63 (s,
3H), 1.73-1.84 (m, 1H), 1.95-2.04 (m, 1H), 2.35 (q, J=7.1 Hz,
2H), 2.53-2.66 (m, 1H), 3.20 (dd, J=6.2, 5.1 Hz, 1H), 3.47 (s,
3H), 3.61 (t, J=7.1 Hz, 2H), 3.85 (dd, J=6.7, 3.5 Hz, 1H), 4.02
(d, J=3.6 Hz, 1H), 5.53 (t, J=7.1 Hz, 1H), 5.89 (d, J=15.1 Hz,
Acknowledgment. We thank Pierre Fabre Laboratories
and CNRS for a doctoral fellowship for E.F.
Supporting Information Available: Full data analysis of 13
C
and 1H NMR values for all examples. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 18, 2009 7045