Convergent highly stereoselective preparation of the C12-C24 fragment of macrolactin A

Article abstract of DOI:10.1021/jo049556l

The convergent synthesis of the C12-C24 fragment (lower part) of macrolactin A is described. The adapted strategy allowed building up the lower moiety by the assembly of three key intermediates via organometallic addition. One hydroxylic stereogenic cente

Full text of DOI:10.1021/jo049556l

Con ver gen t High ly Ster eoselective P r ep a r a tion of th e C12-C24
F r a gm en t of Ma cr ola ctin A
Carlo Bonini,*,† Lucia Chiummiento,† Maddalena Pullez,† Guy Solladie´,*,‡ and
Franc¸oise Colobert*,‡
Dipartimento di Chimica, Universita` degli Studi della Basilicata, via N. Sauro 85, 85100 Potenza, Italy,
and Laboratoire de Ste´re´ochimie associe´ au CNRS, Universite´ Louis Pasteur, ECPM, 25 rue Becquerel,
67087 Strasbourg Cedex 2, France
bonini@unibas.it
Received March 18, 2004
The convergent synthesis of the C12-C24 fragment (lower part) of macrolactin A is described. The
adapted strategy allowed building up the lower moiety by the assembly of three key intermediates
via organometallic addition. One hydroxylic stereogenic center was introduced by the application
of chiral sulfoxides methodology on fragment C19-C24. The preparation of the versatile 1,3-anti
diol synthon C12-C16 was achieved via opening of chiral epoxide and subsequent oxidation to a
hydroxy ketone. Finally, reductive elimination of the appropriate allylic dibenzoate with Na/Hg
introduced directly the C16-C19 (E,E)-diene unit, in a highly efficient stereoselective fashion.
SCHEME 1
In tr od u ction
Macrolactin A (1), a 24-membered polyene macrolide,
was isolated in 1989 by Fenical and co-workers from a
deep-sea bacterium of unclassified taxonomy along the
coast of California1 and belongs to the class of macrolac-
tins whose other members were recently isolated.2
Macrolactin A displays strong cytotoxic activity in vitro
on B16-F10 murine melanoma cell (IC50 ) 3.5 µg/mL),
as well as powerful antiviral activity against Herpes
simplex types I and II and human HIV-1 virus replica-
tion.1 The synthetically challenging structure combined
with the unique biological activity attracted the attention
of synthetic organic chemists. In 1992 Rychnovsky3
established the relative and absolute stereochemistry of
macrolactin A, and in 1996 Smith4 published the first
total synthesis. After 1998 two total syntheses appeared5
with different partial syntheses and approaches.6
We report herein a highly stereoselective synthesis of
the C12-C24 fragment of macrolactin A, using different
original approaches for the introduction of the (E,E)-diene
stereochemistry and of the stereogenic centers.
Resu lts a n d Discu ssion
In many of the synthetic approaches the step-by-step
addition of the synthons was applied to build up the
stereogenic centers and the diene units (mainly by Stille-
type coupling).4-6 In our retrosynthetic analysis (Scheme
1), we proposed the disconnections at the lactone linkage
* To whom correspondence should be addressed. For C.B.: tel +39
0971 202254, fax + 39 0971 202223.
(6) For partial syntheses, see: (a) Benvegnu, T.; Schio, L.; Le Floc′h,
Y.; Gre`e, R. Synlett 1994, 505. (b) Donaldson, W. A.; Bell, P. T.; Wang,
Z.; Bennett, D. W. Tetrahedron Lett. 1994, 35, 5829. (c) Boyce, R. J .;
Pattenden, G. Tetrahedron Lett. 1996, 37, 3501. (d) Benvegnu, T.;
Toupet, L.; Gree`, R. Tetrahedron 1996, 52, 11811. (e) Benvegnu, T.;
Gree`, R. Tetrahedron 1996, 52, 11821. (f) Prahlad, V.; Donaldson, W.
A. Tetrahedron Lett. 1996, 37, 9169. (g) Gonza`lez, A.; Aiguade`, J .; Urp,
F.; Villarasa, J . Tetrahedron Lett. 1996, 37, 8949. (h) Tanimori, S.;
Morita, Y.; Tsubota, M.; Nakayama, M. Synth. Commun. 1996, 26, 559.
(i) Donaldason, W. A.; Barmann, H.; Prahlad, V.; Tao, C.; Yun, Y., K.;
Wang, Z. Tetrahedron 2000, 56, 2283. (j) Li, S.; Xu, R.; Bai, D.
Tetrahedron Lett. 2000, 41, 3463. (k) Hoffmann, H. M. R.; Vakalopou-
los, A. Org. Lett. 2001, 3, 177. (l) Shukun, L.; Donaldson, W. A.
Synthesis 2003, 13, 2064. (m) Fukuda, A.; Kobayashi, Y.; Kimachi, T.;
Takemoto, Y. Tetrahedron 2003, 59, 9305. For a total synthesis of an
analogue of macrolactin A, see: (n) Kobayashi, Y.; Fukuda, A.;
Kimachi, T.; J u-ichi, M.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 677.
† Universita` degli Studi della Basilicata.
‡ Universite´ Louis Pasteur.
(1) Gustafson, K.; Roman, M.; Fenical, W. J . Am. Chem. Soc. 1989,
111, 7519.
(2) (a) Kim, H.-H.; Kim, W.-G.; Ryoo, I.-J .; Kim, C.-J .; Suk, J .-E.;
Han, K.-H.; Hwang, S.-Y.; Yoo, I.-D. J . Microbiol. Biotechnol. 1997, 7,
429. (b) J aruchoktaweechai, C.; Suwanborirus, K.; Tanasupawatt, S.;
Kittakoop, P.; Menasveta, P. J . Nat. Prod. 2000, 63, 984. (c) Nagao,
T.; Adachi, K.; Sakai, M.; Nishijima, M.; Sano, H. J . Antibiot. 2001,
54, 333.
(3) Rychnovsky, D. S.; Skalitzky, J . D.; Pathirana, C.; J ensen, R.
P.; Fenical, W. J . Am. Chem. Soc. 1992, 114, 671.
(4) Smith, A. B., III; Ott, G. R. J . Am. Chem. Soc. 1996, 118, 13095.
(5) (a) Kim, Y.; Singer, R. A.; Carreira, E. M. Angew. Chem., Int.
Ed. 1998, 37, 1261. (b) Marino, J . P.; McClure, M. S.; Holub, D. P.;
Comasseto, J . V.; Tucci, F. C. J . Am. Chem. Soc. 2001, 124, 1664.
10.1021/jo049556l CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/25/2004
J . Org. Chem. 2004, 69, 5015-5022
5015

Bonini et al.
SCHEME 2
SCHEME 3a
a
Reagents and conditions: (a) (+)-Ipc2BOMe, allylMgBr, Et2O,
-78 °C to rt, 12 h; (b) Ac2O, Pyr, DMAP, CH2Cl2, rt, 24 h.
cessfully utilized for the desymmetrization and resolution
of highly functionalized polyols.12 Both hydrolysis and
transesterification were successful in preparing highly
enantiomerically enriched compounds. In particular the
target alcohol (R)-6 was obtained by hydrolysis of the
acetate (rac)-9 with 94% ee evaluated by HPLC. However,
the low conversion (38%) for the hydrolysis prompted us
to search for another approach.
In a third attempt we started with the commercially
available11 benzylglycidyl ether (S)-8, already bearing the
stereogenic center at C13. Our first attempts at the
regioselective opening of the epoxide ring with an ap-
propriate vinyl organometallic reagent, following known
procedures,13 were found to be difficult to reproduce in
large scale and highly dependent on different OH pro-
tecting groups. The oxirane ring opening with vinylmag-
nesium halide afforded generally a large amount of the
corresponding halohydrin.
and the C11-C12 bond to generate the upper (C1-C11)
and the lower (C12-C24, 2) moieties. For the lower part
2 of the macrolide further disconnections would expect
an organometallic convergent coupling between the two
optically active aldehydes 3 and 5 and the Grignard
reagent 4. Key elements of the synthesis were (i) the use
of a fully functionalized aldehyde 3, containing a pro-
tected 1,3-anti diol and a primary protected hydroxyl
group; (ii) the application of chiral sulfoxide chemistry
for the synthesis of compound 5; (iii) the coupling of
advanced intermediates 3 and 5 by organometallic ad-
ditions; and (iv) the stereocontrolled introduction of the
(C16-C19) (E,E)-diene by a novel application of sodium
amalgam reductive elimination of allylic dibenzoate.
Syn th esis of (C12-C16) F r a gm en t 3. The aldehyde
3 has been already prepared by different approaches7
requiring, however, long reaction sequences and overall
fair yields. Our shorter synthetic strategy required as key
intermediate the chiral homoallylic alcohol 6. Different
synthetic routes could be followed to this goal, as il-
lustrated in the retrosynthetic Scheme 2: (i) the asym-
metric allylboration of aldehyde 7; (ii) the enzymatic
resolution of rac-6; and (iii) the opening of the appropriate
chiral glycidol 8.
Therefore we undertook a systematic study14 on a
series of different glycidyl ethers, and good reproducible
results have been achieved using various OH protecting
groups. In particular, interesting results never before
reported have been obtained in the opening of tert-
butyldimethylsilyloxy derivatives to the corresponding
silyl protected homoallylic alcohol.
By applying the developed protocol to our synthetic
purpose, the regioselective opening of the oxirane ring
on chiral compound 8 with vinylmagnesium bromide in
THF at -20 °C in the presence of CuI (Scheme 5) afforded
the alcohol 6 in 91% yield.15
Our initial strategy for the direct introduction of the
two hydroxy groups at C15 and C16 was based on the
application of the Sharpless AD16 on the homoallylic
alcohol 6 with the use of the appropriate AD mix-â
reagent. However the reaction (Scheme 5) was not
stereoselective (syn/ anti 42:58 evaluated by 1H NMR and
13C NMR spectra of the corresponding acetonides).17 The
presence of a highly functionalized olefin such as 6, with
The Brown enantioselective allylboration reaction8
performed in classical conditions on the commercially
available benzyloxyacetaldehyde 7 with B-allyldiisopino-
campheylborane was repeated several times (Scheme 3).
Unfortunately, although (R)-6 was obtained in good
chemical yield, the HPLC analysis revealed only 71% ee,
evaluated on the corresponding acetylated compound (R)-
9.9,10
In the second approach (Scheme 4), (rac)-6, easily
prepared by allylation of the benzyloxyacetaldehyde 7,
was subjected to biocatalytic resolution by transesteri-
fication in organic media or by hydrolysis of the corre-
sponding acetate (rac)-9.
(12) (a) Bonini, C.; Chiummiento, L.; Funicello, M.; Marcone, M.;
Righi, G. Tetrahedron: Asymmetry 1998, 9, 2559. (b) Bonini, C.;
Chiummiento, L.; Funicello, M. Tetrahedron: Asymmetry 2001, 12,
2755.
(13) (a) Hashimura, K.; Tomita, S.; Hiroya, K.; Ogasawara, K. J .
Chem. Soc., Chem. Commun. 1995, 2291. (b) Rutjes, F. P. J . T.; Koistra,
T. M.; Hiemstra, H.; Schoemaker, H. E. Synlett 1997, 192. (c)
Crimmins, M. T.; King, B. W. J . Am. Chem. Soc. 1998, 120, 9084. (d)
Gravestock, M. B.; Knight, D. W.; Lovell, J . S.; Thornton S. R. J . Chem.
Soc.; Perkin Trans. 1 1999, 3143. (e) Huang, H.; Mao, C.; J au, S.-T.;
Uckun, F. M. Tetrahedron Lett. 2000, 41, 1699. (f) Uckun, F. M.; Mao,
C.; Vassilev, A. O.; Huang, H.; J an, S.-T. Bioorg. Med. Chem. Lett. 2000,
10, 541. (g) Cossy, J .; Pradaux, F.; BouzBouz, S. Org. Lett. 2001, 3,
2233.
The enzymatic resolutions were performed, after initial
screening, with Pseudomonas sp. lipase,11 already suc-
(7) (a) Solladie´, G.; Hutt, J . Tetrahedron Lett. 1987, 28, 797. For
the synthesis of the precursor alcohol, see: (b) Bru¨ckner, R.; Weigand,
W. Synlett 1996, 225. (c) Solladie´, G.; Colobert, F.; Denni, D. Tetra-
hedron: Asymmetry 1998, 9, 3081.
(8) Brown, H. C.; J adhav, P. K. J . Am. Chem. Soc. 1995, 105, 2092.
(9) Chiralcel column OJ .; eluent hexane/i-PrOH 99.5:0.5; flow rate
0.5 mL/min; tR ) 21.86; tR ) 28.49.
(10) After our use of (+)-Ipc2BOMe we were recently aware that the
use of DIP-Cl gives higher ee as reported in: Reddy, M. V. R.; Brown,
H. C.; Ramachandran, P. V. J . Organomet. Chem. 2001, 624, 239.
(11) Purchased from Aldrich.
(14) Bonini, C.; Chiummiento, L.; Lopardo, M. T.; Pullez, M.;
Colobert, F.; Solladie´, G. Tetrahedron Lett. 2003, 44, 2695.
(15) Traces of the corresponding bromohydrin can be easily sepa-
rated by column chromatography on the protected alcohol 6 as silyl
ether (Scheme 6).
(16) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483.
5016 J . Org. Chem., Vol. 69, No. 15, 2004

Preparation of C12-C24 Fragment of Macrolactin A
SCHEME 4a
a
Reagents and conditions: (a) allylMgBr, THF, 0 °C, 45 min; (b) Ac2O, Et3N, DMAP, CH2Cl2, rt, 24 h; (c) PSL, vinyl acetate, Et2O, rt,
21 h; (d) PSL, phosphate buffer 0.5 M, rt, 6 h.
SCHEME 5a
SCHEME 6a
a
Reagents and conditions: (a) vinylMgBr, CuI, THF, -20 °C,
1 h; (b) AD mix-â, t-BuOH/H2O, 0 °C to rt, 10 h.
a
Reagents and conditions: (a) TBDMSCl, imid., DMF, rt, 3 h;
two proximate hydroxyl groups, could be responsible for
the low chiral recognition of the asymmetric catalyst.
Failure of the Sharpless reaction led us to attempt the
direct conversion of the alkene 6 into the R-hydroxyke-
tone 12 (Scheme 6) via careful chemoselective oxidation,
after previous protection of the secondary hydroxyl group
as silyl ether 11. We found the potassium permanganate
oxidation in acidic medium18 of 11 smoothly afforded the
R-hydroxyketone 12 in 80% yield in only 2 h. This
reaction is indeed a known19 further example of oxidation
of terminal alkene to an R-hydroxyketone in one step and
represents, to our knowledge, a unique pattern of such
reaction on an homoallylic alcohol.
After this crucial step, the subsequent protection of the
primary hydroxyl group as acetate ester (94%) was
followed by desilylation under acidic conditions (THF/
AcOH/H2O) to the â-hydroxyketone 14 in 82% yield.20
With 14 in hand, we prepared the 1,3-anti-diol by
diastereoselective reduction with Me4NBH(OAc)3,21 ob-
taining the diol 15 with excellent yield (95%).
(b) KMnO4, AcOH, acetone, H2O, rt, 2 h; (c) Ac2O, Pyr, CH2Cl2,
rt, 24 h; (d) THF/AcOH/H2O, rt to 50 °C, 48 h; (e) Me4NBH(OAc)3,
AcOH, CH3CN, -20 °C, 15 h; (f) Me2C(OMe)2, CSA, rt, 24 h; (g)
NaOMe/MeOH, rt, 18 h; (h) Dess-Martin periodinane, CH2Cl2,
rt, 3 h.
Protection of the diol 15 as acetonide 16 under usual
conditions also made it possible to determine the relative
stereochemistry and the diastereomeric ratio of the
1
reduction via 13C and H NMR (de > 98%).17a,b The final
steps for the synthesis of the C12-C16 fragment required
the transformation of 16 to the aldehyde 3. This was
achieved by hydrolysis of the acetate ester 16 to give the
alcohol 17 in 90% yield and subsequent oxidation to
aldehyde 3 using the Dess-Martin periodinane proce-
dure22 (95% yield). The aldehyde 3 can be conveniently
used in the further synthetic steps (see below) without
purification in order to avoid any epimerization process.
In summary, the key fragment 3 was obtained in nine
steps starting from benzylglycidyl ether 8 with an overall
yield of 46%, which greatly improves its preparation (in
number of steps and overall yield) in comparison to the
known early syntheses.7
(17) The relative stereochemistry of 10 was assigned by 13C NMR
chemical shift analysis of the derived acetonide. The 13C NMR signals
at δ ) 24.6 and 24.7 ppm and at δ ) 100.7 ppm are consistent with
the presence of an anti-1,3-diol. The values at δ ) 19.9 and 30.8 ppm
and at δ ) 99.2 ppm confirmed the presence of the syn-1,3-diol. The
diastereomeric ratio was determined by 1H NMR chemical shift
analysis. The methyl groups of anti-acetonide have 1H NMR chemical
shifts of 1.29 ppm, and the methyl groups of syn-acetonide have 1H
NMR chemical shifts of 1.32 and 1.39 ppm. See: (a) Rychnovsky, S.
D.; Skalitzky, D. J . Tetrahedron Lett. 1990, 31, 945. (b) Rychnovsky,
S. D.; Rogers, B.; Yang, G. J . Org. Chem. 1993, 58, 3511.
(18) (a) Srinivasan, N. S.; Lee, D. G. Synthesis 1979, 520. (b)
Sundarababu, B.; J agattaran, D.; Srinivasan, C. J . Org. Chem. 1989,
54, 5182.
Syn th esis of (C19-C24) F r a gm en t 5. The synthesis
of fragment 523 was performed using the well-known
(20) Desilylation under usual conditions (using TBAF) was unsuc-
cessful because of the strong basic conditions that affect the highly
sensitive â-ketol system in 13: Corey, E. J .; Venkateswarlu, A. J . Am.
Chem. Soc. 1972, 94, 6190.
(21) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
(22) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277.
(23) For different approaches to the synthesis of 5, see: Shiinan, I.;
Fujisawa, H.; Ishii, T.; Fukuda, Y. Heterocycles 2000, 52, 1105 and
references therein.
(19) Bonini, C.; Chiummiento, L.; Evidente, A.; Funicello, M.
Tetrahedron Lett. 1995, 36, 7285.
J . Org. Chem, Vol. 69, No. 15, 2004 5017

Bonini et al.
SCHEME 7a
SCHEME 8
SCHEME 9a
a
Reagents and conditions: (a) TBDMSCl, imid., DMF, rt,
33 h; (b) Raney Ni, MeOH, rt, 16 h; (c) DIBAL, toluene, 0 °C, 2 h;
(d) Dess-Martin periodinane, CH2Cl2, rt, 3 h.
diastereoselective reduction of â-ketosulfoxides.24 A par-
tial achievement of this synthesis was already reported
in late 2000.25 The known â-ketosulfoxide 18 (prepared
in one step from glutaric anhydride and (+)-(R)-methyl
p-tolylsulfoxide)26 was the starting chiral product (Scheme
7) for the introduction of the chiral hydroxyl group at
C23. Reduction of â-ketosulfoxide 18 with DIBAL27
afforded the â-hydroxysulfoxide [S,(S)R]-19 (70%) with
an excellent diastereoselectivity (de > 98%). The (S)
absolute configuration of the hydroxylic carbon of 19 was
assigned on the basis of the already published mecha-
nism24 and from the 1H NMR spectra of the crude
reduction mixture. Protection of the hydroxyl group with
TBDMSCl and desulfurization with Raney nickel af-
forded the hydroxy ester 21.27 Reduction of the ester
group with DIBAL (3 equiv) in toluene at 0 °C afforded
the alcohol (R)-22 in 98% yield,28 with a sequence of five
steps and 50% overall yield, which competes well with
the reported synthesis of (R)-22 by Marino,5b requiring
seven steps from a commercially available product.
Alcohol (R)-22 was finally oxidized to the resulting
aldehyde 5 in 95% yield using Dess-Martin periodinane
protocol in CH2Cl2 at room temperature. In summary,
aldehyde 5 was prepared in six steps from glutaric
anhydride in 48% overall yield.
a
Reagents and conditions: (a) 4, THF, 0 °C, 4 h; (b) n-BuLi,
isobutyraldehyde, THF; -78 °C to rt, 16 h; (c) H2, Pd/BaSO4, Pyr/
MeOH, rt, 2 h; (d) BzCl, Pyr/THF, rt, 6 h; (e) Na/Hg 6%, Na2HPO4,
THF/MeOH, -20 °C, 4 h.
reagent 4 (Scheme 1) in order to introduce the (E,E)-diene
moiety (C16-C19) of the lower part of macrolactin A.
This kind of coupling could allow the synthesis of an
alkyne diol of type A (Scheme 8), necessary to perform
the stereocontrolled reductive elimination by Na/Hg of
the corresponding alkene dibenzoate B, according to the
well-known methodology to generate an all-trans diene
as C.29
The crucial step of the reductive elimination was
checked with a model compound bearing a similar
sensitive R-hydroxyl group and protected as an acetonide.
Therefore, as outlined in Scheme 9, the chosen model
compound 25 was prepared starting from commercially
available (R)-glyceraldehyde 23. (R)-23 was smoothly
condensed with ethylnylmagnesium bromide 4 to give the
propargylic alcohol 24 and then with isobutyraldehyde
to obtain a mixture of diols 25. Subsequent partial
reduction to compound 26 and benzoylation afforded the
key olefin 27.
F in a l Cou p lin g Assem bly. We next turned out our
attention to the critical, convergent coupling step of the
two chiral aldehydes 3 and 5 with the acetylenic Grignard
(24) (a) Carren˜o, M. C.; Garcia Ruano, J . L.; Martin, A.; Pedregal,
C.; Rodriguez, J . H.; Rubio, A.; Sanchez, J .; Solladie´, G. J . Org. Chem.
1990, 55, 2120. For an overview of the work on sulfoxides, see: (b)
Carren˜o, M. C. Chem. Rev. 1995, 95, 1717. (c) Solladie´, G.; Carren˜o,
M. C. In Organosulfur Chemistry: Synthetic Aspects; Academic
Press: New York, 1995; pp 1-47. (d) Solladie´, G. Heteroat. Chem. 2002,
13, 443. (e) Hanquet, G.; Colobert, F.; Lanners, S.; Solladie´, G. Arkivoc
2003.
(25) Bonini C.; Chiummiento L.; Funicello, M.; Pullez, M.; Solladie´,
G.; Colobert, F. V Convegno Nazionale-Giornate di Chimica delle
Sostanze Organiche Naturali, Napoli, 21-23 giugno 2000; Abstract
number P54.
(26) (a) Solladie´, G.; Hutt, J .; Girardin, A. Synthesis 1987, 173. (b)
Colobert, F.; Des Mazery, R.; Solladie´, G.; Carren˜o, M. C. Org. Lett.
2002, 4, 1723. (c) Carren˜o, M. C.; Des Mazery, R.; Urbano, A.;
Colobert,.F.; Solladie´, G. J . Org. Chem. 2003, 68, 7779.
(27) (a) Solladie´, G.; Maestro, M. C.; Rubio, A.; Pedregal, C.; Carren˜o,
M. C.; Garc´ıa-Ruano, J . L. J . Org. Chem. 1991, 56, 2317. (b) Solladie´,
G.; Huser, N.; Garc´ıa-Ruano, J . L.; Adrio, J .; Carren˜o, M. C.; Tito, A.
Tetrahedron Lett. 1994, 35, 5297.
The reductive elimination was then achieved with the
established procedure (Na/Hg 6%, Na2HPO4, THF/MeOH,
(29) (a) Solladie´, G.; Stone, G. B.; Andre´s, J .-M.; Urbano, A.
Tetrahedron Lett. 1993, 34, 2835. For an overview of application of
reductive elimination with Na/Hg to the synthesis of natural products,
see: (b) Solladie´, G.; Urbano, A.; Stone, G. B. Tetrahedron Lett. 1993,
34, 6489. (c) Solladie´, G.; Urbano, A.; Stone, G. B. Synlett 1993, 548.
(d) Solladie´, G.; Adamy, M.; Colobert, F. J . Org. Chem. 1996, 61, 4369.
(e) Solladie´, G.; Somny, F.; Colobert, F. Tetrahedron: Asymmetry 1997,
8, 801.
(28) S)-22 was prepared for the synthesis of (+)-brefeldin A, using
LiAlH4 as reducing reagent, as reported: Solladie´, G.; Lohse, O. J .
Org. Chem. 1993, 58, 4555.
5018 J . Org. Chem., Vol. 69, No. 15, 2004

Preparation of C12-C24 Fragment of Macrolactin A
SCHEME 10a
a
Reagents and conditions: (a) 4, THF, 0 °C, 4 h; (b) n-BuLi, 5, -78 °C, THF, rt, 16 h. (c) H2, Pd/BaSO4, Pyr/MeOH, rt, 2 h; (d) BzCl,
Pyr/THF, rt, 19 h; (e) Na/Hg (6%), Na2HPO4, THF/MeOH, -20 °C, 5 h.
5.0 mmol). The resultant reaction mixture was stirred for 15
min at -78 °C and warmed to room temperature (1 h). The
allylborane was cooled to -78 °C, and aldehyde 7 (0.5 g, 3.3
mmol) in Et2O (1.5 mL) was added via cannula with stirring.
The reaction mixture was stirred for 1 h at -78 °C and then
allowed to warm to 25 °C. After 18 h the reaction mixture was
quenced with 3 N NaOH (5.6 mL) and 30% H2O2 (2.3 mL),
and the contents were refluxed for 1 h. The aqueous layer was
extracted with Et2O, and the combined organic layers were
dried over Na2SO4, filtered, and concentrated. Two purifica-
tions on silica gel (Et2O/pentane 1:9 followed by CHCl3/MeOH
99:1) provided the compound 6 as a colorless oil (0.6 g, 95%).
Compound 6 shows the same spectroscopic data as reported
in the literature.13d
(+)-(2R)-1-Ben zyloxy-p en t-4-en -2-ol (6) (via En zym a tic
Hyd r olysis). To a solution of allylmagnesium bromide (1 M
in Et2O, 5.0 mL, 5.0 mmol) in THF (5 mL) at 0 °C was quickly
added a solution of aldehyde 7 (0.5 g, 3.3 mmol) in THF
(2 mL). After 45 min at 0 °C a saturated aqueous solution of
NH4Cl was added (20 mL). The mixture was diluted with Et2O
(30 mL), and the aqueous phase was extracted with Et2O. The
combined organic phases were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude residue was
purified on silica gel (petroleum ether/EtOAc 85:15) to afford
(rac)-6 (0.59 g, 93%) as a colorless oil.
-20 °C), affording in an excellent 90% yield, after
chromatography purification, the unique (E,E)-diene 28
without traces of other isomers.
In light of this successful result, we next turned out
our attention to the final coupling of compounds 3 and 5
(Scheme 10). Aldehyde 3 was allowed to react with an
excess of ethynylmagnesium bromide (4) in THF at 0 °C
to give propargylic alcohol 29, as an inseparable mixture
1
of diastereomers (24/76 ratio determined by H NMR).
Acetylenic alcohol 29 was then treated with 2.2 equiv
of n-BuLi in THF at -78 °C to afford the corresponding
lithium acetylide. Aldehyde 5 was added at -78 °C to
give the diol 30, as a mixture of diastereomers. Because
of the moderate overall yield of this last reaction, we tried
to improve it without remarkable results.30
Adduct 30 was therefore converted to (Z)-alkene 31 by
partial stereoselective reduction with Pd/BaSO4 in Pyr/
MeOH under H2 atmosphere. Activation of the free
hydroxylic groups as dibenzoate esters with benzoyl
chloride in Pyr/THF at room temperature afforded allylic
dibenzoate (Z)-32.
Finally, the reductive elimination protocol on the
dibenzoate 32 gave the diene 2 in 60% yield and >98%
isomeric purity after column chromatography (no traces
of other possible double bond isomers were observed). The
(E) geometry for the C16-C17 (J ) 15.2 Hz) and C18-
To a solution of alcohol (rac)-6 (0.4 mg, 2.1 mmol) in CH2-
Cl2 (3 mL) were added triethylamine (0.2 mL, 2.5 mmol) and
acetic anhydride (0.68 mL, 3.1 mmol) followed by a catalytic
amount of DMAP. After 24 h at room temperature, the reaction
mixture was treated with a saturated solution of NH4Cl (10
mL). The aqueous layer was extracted with CH2Cl2. The
organic layer was washed with brine before drying over Na2-
SO4. After concentration in vacuo pure compound (rac)-9 was
obtained as a colorless oil (0.49 g, 100%): Rf ) 0.6 (petroleum
1
C19 (J ) 15.1 Hz) double bonds was established by H
NMR, showing it to be a single pure (E,E)-diene.
After this successful preparation of the lower part of
macrolactin A, we are currently working on the prepara-
tion of the upper C1-C11 fragment and on their final
couplings to complete macrolactin’s skeleton. The results
will be reported in due course.
1
ether/EtOAc 9:1); H NMR (300 MHz, CDCl3) δ 2.08 (s, 3H),
2.39 (m, 2H), 3.54 (m, 2H), 4.51 and 4.57 (AB system, J ) 12
Hz, 2H), 5.10 (m, 2H), 5.78 (m, 2H), 7.32 (m, 5H)); 13C NMR
(75 MHz, CDCl3) δ 19.9, 34.9, 70.5, 72.9, 73.5, 116.1, 127.5,
128.4, 135.0, 138.1, 169.3. EI-MS m/z: M+, 234, (100), 91. Anal.
Calcd for C14H18O3: C, 71.77; H, 7.74. Found: C, 71.80; H,
7.77. Analysis via HPLC using the following experimental
conditions: Chiralcel OJ ; eluent hexane/i-PrOH 99.5:0.5; flow
rate 0.5 mL/min gave tR ) 21.86 and tR ) 28.49.
Exp er im en ta l Section
(+)-(2R)-1-Ben zyloxy-p en t-4-en -2-ol (6) (via Allylbor a -
tion ).8a To a solution of (+)-B-methoxydiisopinocampheyl-
borane (1.57 g, 5.0 mL) in Et2O at -78 °C was added dropwise
over 20 min allylmagnesium bromide (1 M in Et2O, 5.0 mL,
A 0.1 M solution of (rac)-9 (2 g, 8.5 mmol) in 0.5 M
phosphate buffer (pH ) 7) was stirred vigorously at room
temperature. Pseudomonas sp. lipase (PSL, 30 U/mg, 0.28 g)
was added, and the reaction was monitored by TLC. After
about 6 h the enzyme was filtered, and the filtrate was washed
with EtOAc. After the separation of the phases the organic
solvent was evaporated under reduced pressure. The crude
(30) Because of low conversion of compound 29, it could be recovered
unreacted. We tried to add first the aldehyde 5 to the ethynylmagne-
siumbromide followed by the addition of either 2.2 equiv of n-Buli or
EtMgBr and the aldehyde 3, but it did not improve the yield of the
resulting propargylic diol.
J . Org. Chem, Vol. 69, No. 15, 2004 5019

Bonini et al.
product was purified on a silica gel column (petroleum ether/
EtOAc 9:1) to provide pure (+)-(6) (0.5 g, 31%), with the same
spectroscopic data as reported in the previous preparation of
6. The ee of 94% was determined via HPLC on the acetylated
product using the following experimental conditions: Chiralcel
OJ ; eluent hexane/i-PrOH 99.5:0.5; flow rate 0.5 mL/min;
tR ) 28.49.
(+)-(2R)-1-Ben zyloxy-p en t -4-en -2-ol (6) (via Oxir a n e
Op en in g).13 To a 0.15 M solution in THF of 8 (3.8 g, 23.2
mmol) and CuI (4.4 g, 23.2 mmol) at -20 °C was quickly added
a solution 1 M in THF of vinylmagnesium bromide (92.8 mL,
92.8 mmol). After 20 min a saturated aqueous solution of NH4-
Cl was added to the dark mixture reaction. The mixture was
diluted with EtOAc and stirred until complete separation of
the layers. The aqueous layer was extracted several times with
EtOAc, and then the combined organic layers were washed
with brine, dried over Na2SO4 and concentrated to afford 6 as
a pure colorless oil without purification (4.1 g, 91%), with the
same spectroscopical data as previously reported.
(-)-(2R)-1-Ben zyloxy-2-(ter t-b u t yld im et h ylsilyloxy)-
p en t-4-en (11). To a cooled (0 °C) solution of the alcohol 6
(4.1 g, 21.1 mmol) in DMF (50 mL) were added imidazole (4.3
g, 63.4 mmol) and TBDMSCl (47.7 g, 31.7 mmol). The mixture
was stirred at room temperature for 3 h, hydrolyzed with H 2O
(100 mL), and diluted with Et2O (150 mL). The aqueous layer
was extracted with Et2O. The combined organic layers were
washed with a saturated aqueous solution of NH4Cl and with
brine and dried over Na2SO4. The concentrate was purified
by column chromatography (hexane/Et2O 99:1) on silica gel
to provide 11 (6.46 g, 100%) as a yellow oil. Compound 11
shows the same spectroscopic data reported in the literature.13e,f
13C NMR (75 MHz, CDCl3) δ -4.6, 18.0, 20.5, 25.8, 44.2, 68.0,
69.0, 73.3, 73.8, 127.7, 128.4, 138.0, 170.1, 202.1. EI-MS m/z:
M+ - 15, 368, (100), 91. Anal. Calcd for C20H32O5Si: C, 63.12;
H, 8.48. Found: C, 63.18; H, 8.52.
(+)-(4R)-1-Acetyloxy-5-ben zyloxy-4-h yd r oxy-p en ta n -2-
on e (14). In a solution (343.8 mL) of acetic acid, THF, and
water (ratio 3/1/1, respectively) was dissolved the ketone 13
(4.3 g, 11.2 mmol), and the mixtures was stirred at room
temperature for 18 h. The acetic acid was removed under
reduced pressure (40 mmHg), and the resulting mixture was
diluted with EtOAc, washed with a saturated aqueous solution
of NaHCO3 and then with brine, and dried over Na2SO4. The
solvent was removed in vacuo, and the mixture was purified
on silica gel (hexane/EtOAc 6:4) to provide 14 as a yellow oil
(2.4 g, 82%): Rf ) 0.48 (hexane/EtOAc 6:4); [R]25 +22.2 (c 1,
D
1
acetone); H NMR (300 MHz, CDCl3) δ 2.17 (s, 3H), 2.61 and
2.69 (AB part of an ABX system, J AB ) 18 Hz, J AX ) 9 Hz,
J BX ) 4.5 Hz, 2H), 2.79 (bs, 1H), 3.46 and 3.54 (AB part of an
ABX system, J AB ) 9.4 Hz, J AX ) 6 Hz, J BX ) 4.3 Hz, 2H),
4.29 (m, X part of two ABX systems, 1H), 4.56 (s, 2H), 4.69
(s, 2H), 7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 20.4, 42.4,
60.7, 68.5, 73.1, 73.4, 127.7, 127.9, 128.4, 137.7, 170.2, 203.3.
EI-MS m/z: M+ - 59, 207; (100), 91. Anal. Calcd for C14H18
O5: C, 63.15; H, 6.81. Found: C, 63.10; H, 6.84.
-
(+)-(2R,4R)-5-Acet yloxy-1-b en zyloxy-2,4-p en t a n -d iol
(15). A solution of (Me)4NHB(OAc)3 (15.4 g, 58.6 mmol) in CH3-
CN (40 mL) and acetic acid (20 mL) was stirred at room
temperature for 30 min and after was cooled to -20 °C. A
solution of 14 (1.9 g, 7.3 mmol) in CH3CN (16 mL) was
cannulated therein and stirred at this temperature for 15 h.
A saturated solution of Rochelle salts was added (100 mL),
and the mixture was diluted with CH2Cl2 (150 mL). The
organic layer was washed with a saturated aqueous solution
of NaHCO3 and with brine and then dried over Na2SO4. The
filtrate was concentrated under reduced pressure and purified
by column chromatography of silica gel (petroleum ether/
EtOAc 1:1) to afford the pure 15 as a yellow oil (1.9 g, 95%):
Rf ) 0.19 (petroleum ether/EtOAc 1:1); [R]25D +11 (c 1 acetone);
1H NMR (300 MHz, CDCl3) δ 1.59-1.65 (m, 2H), 2.10 (s, 3H),
2.65 (bs, 1H), 2.78 (bs, 1H), 3.42 and 2.54 (AB part of an ABX
system, J AB ) 9.2 Hz, J AX ) 7.6 Hz, J BX ) 2 Hz, 2H), 3.99-
4.19 (m, 4H), 4.57 (s, 2H), 7.32 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ 21.2, 35.9, 67.2, 67.7, 68.8, 73.6, 74.5, 128.0, 128.2,
128.8, 138.0, 171.5. EI-MS m/z: M+, 268; (100), 91. Anal. Calcd
for C14H20O5: C, 62.67; H, 7.51. Found: C, 62.64; H, 7.49.
(+)-Acetic Acid [(4R,6R)]-6-Ben zyloxym eth yl-2,2-d i-
m eth yl-[1,3]d ioxa n -4-yl Meth yl Ester (16). To the diol 15
(0.50 g, 1.9 mmol) were added 2,2-dimethoxypropane (20 mL)
and a catalytic amount of camphorsulfonic acid (0.04 g, 0.19
mmol) at room temperature. After 24 h the solvent was
removed in vacuo, and the crude was diluted with Et2O. A
saturated aqueous solution of NaHCO3 was added, and the
organic layer was washed with brine and then dried over Na2-
SO4. The filtrate was concentrated under reduced pressure and
purified by silica gel chromatography (hexane/EtOAc 9:1) to
(+)-(4R)-5-Ben zyloxy-4-(ter t-bu tyld im eth ylsilyloxy)-1-
h yd r oxy-p en ta n -2-on e (12). To a solution of acetone (170
mL), water (38 mL), and acetic acid (8 mL) was added the
alkene 11 (6.5 g, 21.1 mmol). A solution of KMnO4 (5.4 g, 34.3
mmol) in acetone (64 mL) and water (21 mL) was added
dropwise, and the resulting mixture was stirred at room
temperature for 2 h. EtOH was added until effervescence
stopped. The crude was filtered over Celite and washed several
times with hexane. The filtrate was concentrated, diluted with
Et2O, and washed with a saturated aqueous solution of
NaHCO3 until pH ) 8. The organic layer was then washed
with brine and dried over MgSO4. The concentrate was purified
by column chromatography on silica gel (hexane/EtOAc 85:
25) to afford 12 as a colorless oil (5.7 g, 80%): Rf ) 0.23
(hexane/EtOAc 8:2); [R]25 +19.4 (c 2, acetone); 1H NMR (300
D
MHz, CDCl3) δ 0.03 (s, 3H), 0.06 (s, 3H), 0.86 (s, 9H), 2.56-
2.72 (m, 2H), 3.14 (m, 1H), 3.36 and 3.48 (AB part of an ABX
system, J AB ) 9.8 Hz, J AX ) 6.4 Hz, J BX ) 4.5 Hz, 2H), 4.24
(m, 2H), 4.35 (m, X part of an ABX system, 1H), 4.52 (s, 2H),
7.32 (m, 5H); 13C NMR (75 MHz, CDCl3) δ -4.6, 18.0, 25.7,
43.9, 68.3, 69.6, 73.4, 73.9, 127.6, 127.7, 128.4, 137.9, 208.5.
EI-MS m/z: M+, 338, (100), 91. Anal. Calcd for C18H30O4Si:
C, 63.87; H, 8.93. Found: C, 63.92; H, 8.89.
(+)-(4R)-1-Acetyloxy-5-ben zyloxy-4-(ter t-bu tyld im eth -
ylsilyloxy)-p en ta n -2-on e (13). To a solution of 12 (3.9 g, 11.5
mmol) in CH2Cl2 (50 mL) at room temperature were added
pyridine (1.6 mL, 17.3 mmol), acetic anhydride (1.3 mL, 17.3
mmol), and a catalytic amount of DMAP. After 24 h the
mixture was cooled at 0 °C, and a 10% aqueous solution of
HCl was added until pH ) 1. The organic layer was washed
with a saturated aqueous solution of NaHCO3 and then with
brine and dried over Na2SO4. The concentrate was purified
by chromatography on silica gel (petroleum ether/EtOAc 9:1)
to afford 13 as a pale yellow oil (4.1 g, 94%): Rf ) 0.40
afford 16 as a yellow oil (0.57 g, 100%): Rf ) 0.52 (hexane/
1
EtOAc 9:1); [R]25 +15 (c 0.66, acetone); H NMR (300 MHz,
D
CDCl3) δ 1.41 (s, 3H), 1.42 (s, 3H), 1.56-1.69 (m, 2H), 2.10 (s,
3H), 3.47 and 3.55 (AB part of a ABX system, J AB ) 10.3 Hz,
J AX ) 6.2 Hz, J BX ) 4.3 Hz, 2H), 3.99-4.16 (m, 4H), 4.58 and
4.64 (AB system, J ) 12.2 Hz, 2H), 7.32 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 20.9, 24.7, 24.8, 30.6, 65.0, 66.1, 66.3, 72.5,
73.4, 100.7, 127.6, 127.7, 128.4, 138.2, 171.0. EI-MS m/z:
M+ - Me, 293, (100), 91. Anal. Calcd for C17H24O5: C, 66.21;
H, 7.84. Found: C, 66.27; H, 7.89.
(petroleum ether/EtOAc 9:1); [R]25 +13.3 (c 1, acetone); 1H
(+)-[(4R,6R)-6-Ben zyloxym et h yl-2,2-d im et h yl-[1,3]d i-
oxa n -4-yl] Meth a n ol (17). To a solution of the acetonide 16
(0.57 g, 1.9 mmol) in dry methanol (20 mL), at room temper-
ature, was quickly added a catalytic amount of metallic
sodium. The mixture was stirred for 18 h, and then the solvent
was removed under reduced pressure. The crude mixture was
diluted with EtOAc (20 mL) and washed with brine. The
D
NMR (300 MHz, CDCl3) δ -0.14 (s, 3H), -0.12 (s, 3H), 0.94 (s,
9H), 2.24 (s, 3H), 2.68 and 2.76 (AB part of an ABX system,
J AB ) 15.3 Hz, J AX ) 6.5 Hz, J BX ) 5.2 Hz, 2H), 3.45 and 3.55
(AB part of an ABX system, J AB ) 9.8 Hz, J AX ) 7 Hz, J BX
)
6 Hz, 2H), 4.43 (m, X part of two ABX systems, 1H), 4.59 (s,
2H), 4.69 and 4.81 (AB system, J ) 17 Hz, 2H), 7.36 (m, 5H);
5020 J . Org. Chem., Vol. 69, No. 15, 2004

Preparation of C12-C24 Fragment of Macrolactin A
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo. The mixture was purified by chromatography on
silica gel (hexane/EtOAc 6:4) to provide 17 as a colorless oil
(0.45 g, 90%). Compound 17 shows the same spectroscopic data
reported in the literature.7b,c
alkynol 29 (0.20 g, 0.7 mmol) in THF (3 mL) was added
dropwise a solution of n-BuLi (1.6 M in hexane, 0.9 mL, 1.5
mmol). After 45 min, at the same temperature, a solution of
the aldehyde 5 (0.19 g, 0.8 mmol) in THF (4 mL) was slowly
added. The temperature was allowed to warm to room tem-
perature, and the mixture was stirred for 20 h. The reaction
mixture was then diluted with Et2O (20 mL) and washed with
a saturated aqueous solution of NH4Cl (25 mL). The aqueous
layer was extracted with Et2O. The combined organic layers
were dried over MgSO4, filtered, and concentrated under
reduced pressure. The crude mixture was then purified on
silica gel by column chromatography (Et2O/hexane 6:4) to give
the diols 30 (0.14 g, 40%) (a mixture of diastereomers) as a
colorless oil: Rf ) 0.21 (Et2O/hexane 7:3); 1H NMR (300 MHz,
CDCl3) δ 0.053 (s, 6H), 0.89 (s, 9H), 1.12 (d, J ) 6 Hz, 3H),
1.41 (s, 6H), 1.44-2.38 (m, 8H), 2.55 (m, 2H), 3.45 and 3.53
(AB part of an ABX system, J AB ) 10.4 Hz, J AX ) 6.4 Hz,
J BX ) 4.3 Hz, 2H), 3.60-4.50 (m, 5H), 4.56 and 4.62 (AB
system, J ) 12.2 Hz, 2H), 7.34 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ -4.7, -4.4, 18.1, 21.3, 21.4, 23.7, 24.7, 24.8, 25.0,
25.9, 28.5, 30.5, 37.6, 38.8, 39.2, 62.3, 62.4, 64.5, 65.4, 66.3,
66.7, 68.4, 68.9, 70.1, 72.5, 73.3, 81.8, 87.2, 87.3, 100.9, 101.1,
127.6, 127.7, 128.4, 138.2. Anal. Calcd for C29H48O6Si: C, 66.88;
H, 9.29. Found: C, 66.91; H, 9.24.
(+)-(4R,6R)-6-Ben zyloxym eth yl-2,2-d im eth yl-[1,3]d iox-
a n e-ca r ba ld eh yd e (3). Into a solution of Dess-Martin pe-
riodinane (0.48 g, 1.13 mmol) in dry CH2Cl2 (3.5 mL), at room
temperature, was cannulated a solution of the alcohol 17 (0.20
g, 0.75 mmol) in dry CH2Cl2 (7 mL). After 3 h the pale pink
mixture was transferred into an Erlenmeyer flask containing
a saturated aqueous solution of NaHCO3 (20 mL) and a small
amount of Na2S2O5. The separated organic layer was washed
with brine, dried over Na2SO4, and filtered, and the solvent
was removed in vacuo. The crude mixture of the aldehyde 3
(0.19 g, 95%), a yellow oil, was utilized in the next step without
previous purification. Compound 3 shows the same spectro-
scopic data reported in the literature.7a
(+)-Meth yl [5S,(S)R]-5-(ter t-Bu tyld im eth ylsilyloxy)-6-
(p-tolylsu lfin yl)h exa n oa te (20). The reaction and the spec-
troscopic data were already reported;27a [R]25 +149 (c 1,
D
CHCl3).
(-)-Meth yl (5S)-5-(ter t-Bu tyld im eth ylsilyloxy)h exa n -
oa te (21). The reaction and the spectroscopic data were
already reported.27
(2Z,4R,6R,8R)-1-(6-Ben zyloxym eth yl-2,2-dim eth yl-[1,3]-
d ioxa n -4-yl)-8-(ter t-b u t yld im et h ylsilyloxy)-n on -2-en e-
1,4-d iol (31). To a solution of alkyndiol 30 (0.06 g, 0.11 mmol)
in Pyr/MeOH 2/1 (2.7 mL) was added Pd/BaSO4 (20 wt %, 0.012
g), and then the mixture was put under a hydrogen atmo-
sphere. After 2 h the mixture was diluted with Et2O and
filtered over Celite, and the solvents were removed in vacuo.
The crude residue was diluted with Et2O and washed with
brine. The organic layer was dried over MgSO4 and filtered.
Concentration under reduced pressure afforded 31 (0.06 g,
100%), a mixture of diastereomers, as a yellow oil that was
used in the next step without further purification: Rf ) 0.21
(-)-(5R)-5-(ter t-Bu tyld im eth ylsilyloxy)-h exa n -1-ol (22).
To a 0 °C cooled solution of the ester 21 (0.50 g, 1.9 mmol) in
dry toluene (10 mL) was added dropwise a solution of DIBAL
(1.5 M in toluene, 3.8 mL, 5.8 mmol). The mixture was stirred
for 2 h. At the same temperature a saturated aqueous solution
of sodium and potassium tartrate (20 mL) was added and left
until complete dissolution. Then EtOAc was added, and the
mixture was stirred until complete separation of the layers.
The organic layer was dried over MgSO4 and filtered, and the
solvent was removed in vacuo. The crude colorless oil 22 (0.44
g, 98%) was not purified. Rf ) 0.38 (hexane/Et2O 1:1); [R]25
D
1
(Et2O/hexane 7:3); H NMR (300 MHz, CDCl3) δ 0.05 (s, 6H),
-10.3 (c 1.6, CHCl3). The spectroscopic data were reported for
(ent)-22.29
0.89 (s, 9H), 1.12 (d, J ) 6.0 Hz, 3H), 1.30-1.49 (m, 10H),
1.59 (m, 2H), 1.68-1.93 (m, 2H), 3.39-3.66 (m, 2H), 3.72-
4.25 (m, 3H), 4.30-4.66 (m, 4H), 5.40-5.72 (m, 2H), 7.30 (m,
5H); 13C NMR (75 MHz, CDCl3) δ-4.6, -4.4, 18.2, 21.7, 23.7,
23.8, 24.7, 24.9, 25.0, 25.9, 28.1, 31.3, 37.0, 38.2, 66.3, 66.5,
67.3, 67.5, 67.8, 68.5, 68.9, 69.1, 69.5, 69.8, 70.4, 72.4, 73.5,
100.7, 100.9, 127.6, 127.7, 128.4, 128.5, 128.8, 130.9, 136.6,
137.5, 137.6, 138.2. Anal. Calcd for C29H50O6Si: C, 66.63; H,
9.64. Found: C, 66.69; H, 9.63.
(-)-(5R)-5-(ter t-Bu tyldim eth ylsilyloxy)-h exan al (5). The
oxidation of the alcohol 22 (0.20 g, 0.86 mmol) was performed
with the Dess-Martin periodinane according to the conditions
followed for the oxidation of the alcohol 17. The crude was
purified by column chromatography on silica gel (hexane/Et2O
1:1) to afford compound 5 (0.19 g, 95%) as a white oil.
Compound 5 shows the same spectroscopic data as reported
in the literature.23
(2Z,4R,6R,8R)-Ben zoic Acid 4-Ben zoyloxy-1-(6-ben zyl-
oxym eth yl-2,2-d im eth yl-[1,3]-d ioxa n -4-yl)-8-(ter t-bu tyld i-
m eth ylsilyloxy)-n on -2-en yl Ester (32). To a solution of the
alkendiol 31 (0.06 g, 0.11 mmol) in pyridine (1.12 mL) at room
temperature was added a solution of benzoyl chloride (0.03
mL, 0.28 mmol) in THF (0.4 mL). After 19 h the mixture was
diluted with Et2O and put into an Erlenmeyer flask, cooled to
0 °C, and washed with a 10% aqueous solution of HCl (5 mL).
The solution of HCl was added until pH ) 1. The mixture was
then washed with a saturated aqueous solution of NaHCO3
and extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The crude was purified on silica gel by chromatog-
raphy (hexane/Et2O 85:15) to afford 32 (0.06 g, 72%), a mixture
of diastereomers, as a colorless oil: Rf ) 0.16 (hexane/Et2O
85:15); 1H NMR (300 MHz, CDCl3) δ 0.05 (m, 6H), 0.86 (m,
9H), 1.07 (m, 3H), 1.36 (s, 3H), 1.40 (s, 3H), 1.42-1.95 (m, 8H),
3.35-3.55 (m, 2H), 3.73 (m, 1H), 4.01-4.23 (m, 2H), 4.63-
4.75 (m, 2H), 5.60-5.84 (m, 2H), 5.99 (m, 2H), 7.30 (m, 5H),
7.38-7.72 (m, 5H), 8.00-8.19 (m, 5H); 13C NMR (75 MHz,
CDCl3) δ -4.8, -4.4, 18.1, 21.5, 23.7, 23.8, 24.6, 24.7, 24.9, 25.9,
30.1, 30.3, 35.0, 39.5, 65.1, 66.1, 66.2, 67.9, 68.3, 68.4, 71.2,
71.5, 71.8, 72.2, 72.6, 73.3, 73.4, 100.8, 127.6-133.7, 138.2,
165.3, 165.6, 171.2. Anal. Calcd for C43H58O8Si: C, 70.65; H,
8.00. Found: C, 70.67; H, 8.07.
(4R,6R)-1-(6-Ben zyloxym eth yl-2,2-dim eth yl-[1,3]dioxan -
4-yl)-p r op -2-yn e-1-ol (29). To a 0 °C cooled solution of
ethynylmagnesium bromide 4 (0.5 M in THF, 2.3 mL, 1.13
mmol) in dry THF (0.25 mL) was added dropwise by syringe
a solution of the aldehyde 3 (0.20 g, 0.76 mmol) in dry THF
(1.5 mL). The mixture was stirred at this temperature for 4
h, and then a saturated aqueous solution of NH4Cl (10 mL)
was added. The aqueous layer was extracted with EtOAc, and
the combined organic layers were washed with brine and dried
over Na2SO4. The filtrate was then concentrated under reduced
pressure and purified on silica gel by column chromatography
(hexane/EtOAc 7:3) to give the alcohols 29 (0.17 g, 77%), a
mixture 24:76 of diastereomers, as a colorless oil: Rf ) 0.50
(hexane/EtOAc 1:1); 1H NMR (300 MHz, CDCl3) δ 1.42 (s, 6H),
1.64-2.07 (m, 2H), 2.39 (bd, 1H), 2.45 (d, J ) 2.2 Hz, 1H),
2.52 (bd, 1H), 3.44-3.57 (m, 2H), 3.87-4.48 (m, 3H), 4.57 and
4.63 (AB system, J ) 12.2 Hz, 2H), 7.34 (m, 5H); 13C NMR (75
MHz, CDCl3) δ 24.7, 24.8, 24.9, 25.0, 28.6, 30.4, 64.4, 65.3,
66.3, 66.6, 68.8, 70.0, 72.3, 72.4, 73.3, 73.4, 74.1, 74.2, 80.9,
81.0, 100.9, 101.1, 127.6, 127.7, 128.3, 128.4, 130.1, 138.2. EI-
MS m/z: M+ - Me, 275, (100), 91. Anal. Calcd for C17H22O4:
C, 70.32; H, 7.64. Found: C, 70.38; H, 7.59.
(4R,6R,8R)-1-(6-Ben zyloxym eth yl-2,2-d im eth yl-[1,3]-d i-
oxa n -4-yl)-8-(ter t-bu tyld im eth ylsilyloxy)-n on -2-yn e-1,4-
d iol (30). To a stirring and -78 °C cooled solution of the
J . Org. Chem, Vol. 69, No. 15, 2004 5021

Bonini et al.
(+)-[1R,4R,6R,5E,7E]-[8-(6-Ben zyloxym eth yl-2,2-dim eth -
yl-[1,3]-d ioxa n -4-yl)-1-m eth yl-octa -5,7-d ien yloxy]-ter t-bu -
tyld im eth ylsila n e (2). To a solution of 32 (0.04 g, 0.05 mmol)
in THF/MeOH 3/1 (3.5 mL) at room temperature was quickly
added sodium hydrogenphosphate (Na2HPO4, 0.05 g, 0.38
mmol). After 5 min the mixture was cooled at -20 °C, and
Na/Hg 6% (0.21 g, 0.55 mmol) was added and stirred for an
additional 5 h. The mixture was diluted with Et2O and filtered
over silica gel. The residue was dried over MgSO4 and
concentrated under reduced pressure. The crude was then
purified on silica gel by column chromatography (hexane/Et2O
15 Hz, J 6-7 ) 10.5 Hz, 1H), 6.18 (dd, J 7-8 ) 15.2 Hz, J 6-7 )
10.4 Hz, 1H), 7.3 (m, 5H); 13C NMR (100 MHz, CDCl3) δ -4.3,
-4.0; 18.5, 24.3, 25.3, 25.8, 25.9, 26.3, 33.0, 34.6, 39.6, 66.5,
67.8, 68.8, 73.1, 73.7, 100.8, 128.0, 128.1, 128.8, 130.0, 131.0,
131.8, 136.0, 138.7. Anal. Calcd for C29H48O4Si: C, 71.26; H,
9.90. Found: C, 71.30; H, 9.83.
Ack n ow led gm en t. Thanks are due the University
of Basilicata and the MIUR (FIRB-Progettazione,
preparazione e valutazione biologica e farmacologica di
nuove molecole organiche quali potenziali farmaci in-
novativi grant) for financial support.
85:15) to give 2 (0.008 g, 60%) as a colorless oil: Rf ) 0.32
1
(hexane/Et2O 85:15); [R]25 +25 (c 0.3, CHCl3); H NMR (400
D
MHz, CDCl3) δ 0.05 (s, 6H), 0.89 (s, 9H), 1.12 (d, J ) 6.2 Hz,
3H), 1.37-1.51 (m, 4H), 1.42 (s, 6H), 1.75 (t, J ) 8 Hz, 2H),
2.07 (m, 2H), 3.48 and 3.52 (AB part of an ABX system, J AB
Su p p or tin g In for m a tion Ava ila ble: General procedures
for the preparation of compounds 24-28; 1H NMR data for
compounds 24-28 and 13C data for compound 28; copies of
1H, 13C, and COSY NMR spectra for compound 2. This material
is available free of charge via the Internet at http://pubs.acs.org.
)
10.3 Hz, J AX ) 6.2 Hz, J BX ) 4.3 Hz, 2H), 3.78 (qt, J ≈ 6 Hz,
1H), 4.10 (tdd, X part of an ABX system, 1H), 4.40 (tdd,
J 4′-5A′ ≈ J 4′-5B′ ≈ J 4′-8 ≈ 7 Hz, 1H), 4.56 and 4.62 (AB system,
J ) 12.2 Hz, 2H), 5.58 (dd, J 7-8 ) 15.2 Hz, J 4′-8 ) 6.3 Hz,
1H), 5.70 (dt, J 5-6 ) 15 Hz, J 4-5 ) 7 Hz, 1H), 6.01 (dd, J 5-6
)
J O049556L
5022 J . Org. Chem., Vol. 69, No. 15, 2004