Highly efficient stereocontrolled synthesis of danishefsky's taxol CD ring key intermediate

Article abstract of DOI:10.1021/jo800913x

(Chemical Equation Presented) Danishefsky's taxol CD ring key intermediate is synthesized in 15 steps and 11.4% overall yield from a readily available starting material. Absolute stereochemistry of the starting material and stereocontrolled steps determine the absolute configuration of the five requisite contiguous stereocenters.

Full text of DOI:10.1021/jo800913x

Highly Efficient Stereocontrolled Synthesis of
Danishefsky’s Taxol CD Ring Key Intermediate
Paul Brémond, Ge´rard Audran,* and Honore´ Monti
UniVersite´ Paul Ce´zanne, Institut des Sciences Mole´culaires
de Marseille (ISM2), UMR-CNRS-6263, Equipe STe´Re´O
Campus Scientifique de Saint-Je´roˆme, Case 541
13397 Marseille Cedex 20, France
FIGURE 1. Structures of baccatin III, taxol, and taxotere.
framework of taxol have attracted the attention of biologists,
medicinal chemists, and synthetic chemists.
g.audran@uniV-cezanne.fr
ReceiVed April 28, 2008
The synthesis of taxol has presented one of the more difficult
challenges to synthetic chemists, both because of its complex
ring structure and because of its numerous chiral centers. As a
consequence, tremendous efforts toward its synthesis have been
made, which have so far resulted in six successful total syntheses
of this molecule.8–14 Among them, the elegant Danishefsky
group synthesis9 is the only one to start with a preformed CD
ring system (+)-1 (Scheme 1). This pivotal intermediate was
coupled with an A ring synthon to afford the A-CD unit, and
cyclization to the ABCD system was achieved by the Heck
reaction. Subsequent appropriate oxidative chemistry and func-
tional group manipulations led to baccatin III and taxol. The
key to the success of this strategy was the discerning choice of
protecting groups able to resist further chemical steps on the
CD ring unit. Particularly, the protection of the C4 tertiary
hydroxyl center as a benzyl ether rather than as an acetate, thus
avoiding complications from neighboring group participation
by this group later, was crucial (Scheme 2).
Danishefsky’s taxol CD ring key intermediate is synthesized
in 15 steps and 11.4% overall yield from a readily available
starting material. Absolute stereochemistry of the starting
material and stereocontrolled steps determine the absolute
configuration of the five requisite contiguous stereocenters.
(5) Rowinsky, E. K.; Cazenave, L. A.; Donehower, R. C. Nat. Cancer Inst.
1990, 82, 1247–1259.
The tetracyclic diterpenoid paclitaxel (Taxol, Figure 1),1
originally isolated from the Pacific yew tree Taxus breVifolia,2
is a powerful therapeutic drug for cancer chemotherapy.3
Particularly, this molecule and its synthetic analogue docetaxel
(Taxotere, Figure 1)4 exhibit strong antitumor activity against
ovarian and breast cancers,5,6 and additional exciting clinical
uses are anticipated.3c,7 Over the past two decades, important
biological activity, limited supplies, and unique structural
(6) McGuire, W. P.; Rowinsky, E. K.; Rosenhein, N. B.; Grumbine, F. C.;
Ettinger, D. S.; Armstrong, D. K.; Donehower, R. C. Ann. Intern. Med. 1989,
111, 273–279.
(7) (a) Rowinsky, E. K.; Donehower, R. C. Engl. J. Med. 1995, 332, 1004–
1014. (b) Ojima, I.; Bounaud, P.; Ahern, D. G. Bioorg. Med. Chem. Lett. 1999,
9, 1189–1194. (c) Fang, W. S.; Liang, X. T. Mini-ReV. Med. Chem. 2005, 5,
1–12. (d) Galletti, E.; Magnani, M.; Renzulli, M. L.; Botta, M. ChemMedChem
2007, 2, 920–942. (e) Kingston, D. G. I. Phytochemistry 2007, 68, 1844–1854.
(8) (a) Nicolaou, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.;
Guy, R. K.; Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulvannan, K.;
Sorensen, E. J. Nature 1994, 367, 630–634. (b) Nicolaou, K. C.; Ueno, H.; Liu,
J.-J.; Nantermet, P. G.; Yang, Z.; Renaud, J.; Paulvannan, K.; Chadha, R. J. Am.
Chem. Soc. 1995, 117, 653–659.
(1) Taxol is the registered trademark of Bristol-Myers Squibb Company for
paclitaxel.
(2) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggnon, P.; McPhail, A. T.
J. Am. Chem. Soc. 1971, 93, 2325–2327.
(9) (a) Masters, J. J.; Link, J. T.; Snyder, L. B.; Young, W. B.; Danishefsky,
S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1723–1726. (b) Danishefsky, S. J.;
Masters, J. J.; Young, W. B.; Link, J. T.; Snyder, L. B.; Magee, T. V.; Jung,
D. K.; Isaacs, R. C. A.; Bornmann, W. G.; Alaimo, C. A.; Coburn, C. A.; Di
Grandi, M. J. J. Am. Chem. Soc. 1996, 118, 2843–2859.
(3) General reviews on taxoid chemistry: (a) Gue´nard, D.; Gueritte-Voegelein,
F.; Lavelle, F. Curr. Pharm. Des. 1995, 1, 95–112. (b) Holmes, F. A.; Kudelka,
A. P.; Kavanagh, J. J.; Huber, M. H.; Ajani, J. A.; Valero, V. In Taxane
Anticancer Agents: Basic Science and Current Status; Georg, G. I., ; Chen, T. T.,
; Osima, I., ; VyasD. M., Eds.; ACS Symposium Series 583; American Chemical
Society: Washington, DC, 1995; p 31. (c) Arbuck, S. G.; BlaylockB. A. In Taxol:
Science and Applications; SuffnessM., Ed.; CRC Press: Boca Raton, FL, 1995;
p 379. (d) The Chemistry and Pharmacology of Taxol and its DeriVatiVes; Farina,
V., Ed.; Elsevier: Amsterdam, 1995. (e) Kingston, D. G. I.; Yuan, H.; Jagtap,
P. J.; Samala, I. In Progress in the Chemistry of Organic Natural Products;
Herz, W., ; Kirby, G. W., ; Moore, R. E., ; Steglich, W., Eds.; Springer-Verlag:
Vienna and New York, 2002; Vol. 84. (f) Taxus: The Genus Taxus; Itokawa,
H., ; LeeK.-H., Eds.; Taylor & Francis: London and New York, 2003.
(4) Taxotere is the registered trademark of Sanofi Aventis (Rhoˆne-Poulenc
Rorer Company) for docetaxel. (a) Mangatal, L.; Adeline, M. T.; Gue´nard, D.;
Gueritte-Voegelein, F.; Potier, P. Tetrahedron 1989, 45, 4177–4190. (b) Gueritte-
Voegelein, F.; Gue´nard, D.; Mangatal, L.; Potier, P.; Guilhem, J.; Cesario, M.;
Pascard, C. Acta Crystallogr. 1990, C46, 781–784. Review: (c) Gue´nard, D.;
Gueritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993, 26, 160–167.
(10) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger, R. J.;
Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, S.; Nadizadeh, H.; Suzuki, Y.;
Tao, C.; Vu, P.; Tang, S.; Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H.
J. Am. Chem. Soc. 1994, 116, 1597-1598; 1599-1600.
(11) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P. E.; Glass,
T. E.; Houze, J. B.; Crauss, N. E.; Lee, D.; Marquess, D. G.; McGrane, P. L.;
Meng, W.; Natchus, M. G.; Shuker, A. J.; Sutton, J. C.; Taylor, R. E. J. Am.
Chem. Soc. 1997, 119, 2757–2758.
(12) Mukaiyama, T.; Chiina, I.; Iwadare, H.; Saitoh, M.; Nishimura, T.;
Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.-I.; Hasegawa, M.; Yamada,
K.; Saitoh, K. Chem.—Eur. J. 1999, 5, 121–161.
(13) (a) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.;
Kusama, H.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980–12981. (b)
Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.; Kashima, H.; Nakamura,
N.; Morihira, K.; Kuwajima, I. J. Am. Chem. Soc. 2000, 122, 3811–3820.
(14) Formal racemic synthesis of taxol: (a) Doi, T.; Fuse, S.; Miyamoto, S.;
Nakai, K.; Sasuga, D.; Takahashi, T. Chem. Asian J. 2006, 1, 370–383.
10.1021/jo800913x CCC: $40.75
Published on Web 06/18/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6033–6036 6033

SCHEME 1. Danishefsky’s Convergent Synthesis of
Baccatin III and Taxol
SCHEME 3. Retrosynthetic Analysis (Taxane Numbering)
SCHEME 2. Danishefsky’s Synthesis of CD Ring Key
Intermediate (+)-1
SCHEME 4. Synthesis of Fully Protected Allylic Alcohol
(+)-10
Although numerous approaches have been reported for the
synthesis of the fully functionalized CD ring unit,15 none of
them presented functionalities suitable for elaboration into taxol
following the Danishefsky strategy or have been used so far as
part of a novel total synthesis of taxol.
Herein we describe an efficient and stereocontrolled16 syn-
thesis of the Danishefsky CD ring unit (+)-1 based on the
retrosynthetic analysis outlined in Scheme 3. The synthesis of
(+)-3, readily available in multigram quantities, has been
published first from enantiopure (-)-2 obtained by kinetic
enzymatic resolution.15i Subsequent to our initial success, we
recently described a convenient chemoenzymatic enantiocon-
vergent strategy which led to the formation of enantiopure (-)-2
with 100% theoretical yield from the racemate,17 thus improving
presently the former synthesis of (+)-3. Our plan was to first
install the C9-C10 gem-dimethoxyethyl group to obtain (+)-6
regioselectively. If successful, it was envisaged that this group
would survive further reactions avoiding acidic conditions.
For this purpose, our synthetic efforts commenced with the
attempts to hydroborate selectively the monosubstituted vinylic
double bond in (+)-3 in order to obtain (+)-6 after oxidation
of the primary alcohol and protection of the aldehyde. Unfor-
tunately, no reaction occurred using substituted boranes such
as 9-BBN or disiamylborane, and reaction with borane itself
was almost completely nonselective, leading to a complex
mixture. Due to the problems encoutered, we redesigned our
strategy, and Scheme 4 outlines the chemistry involved. Thus,
chemoselective oxidative cleavage of the vinyl double bond in
(+)-3 using OsO4 (cat.) and NaIO4 in THF/water (3:1) gave
aldehyde (+)-4 in 85% yield. Exposure of (+)-4 to the
(15) Syntheses of the fully functionalized taxol CD ring unit: (a) Magee,
T. V.; Bornmann, W. G.; Isaacs, R. C. A.; Danishefsky, S. J. J. Org. Chem.
1992, 57, 3274–3276. (b) Nicolaou, K. C.; Liu, J. J.; Hwang, C.-K.; Dai, W.-
M.; Guy, R. K. J. Chem. Soc., Chem. Commun. 1992, 1118–1120. (c) Isaacs,
R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org. Chem. 1993, 58, 3938–
3941. (d) Takahashi, T.; Hirose, Y.; Iwamoto, H.; Doi, T. J. Org. Chem. 1998,
63, 5742–5743. (e) Momose, T.; Setoguchi, M.; Fujita, T.; Tamura, H.; Chida,
N. Chem. Commun. 2000, 2237–2238. (f) Nakai, K.; Miyamoto, S.; Sasuga, D.;
Doi, T.; Takahashi, T. Tetrahedron Lett. 2001, 42, 7859–7862. (g) Yoshimitsu,
T.; Nakajima, H.; Nagaoka, H. Tetrahedron Lett. 2002, 43, 8587–8590. (h) Shing,
T. K. M.; Lee, C. M.; Lo, H. Y. Tetrahedron 2004, 60, 9179–9197. (i) Uttaro,
J.-P.; Audran, G.; Monti, H. J. Org. Chem. 2005, 70, 3484–3489. Construction
of the oxetane D ring in semisyntheses of taxanes: (j) Original Potier’s procedure
applied in numerous diversified methodologies: Ettouati, L.; Ahond, A.; Poupat,
C.; Potier, P. Tetrahedron 1991, 47, 9823–9838. (k) Zeng, Q.; Paquette, L. A.
Synlett 1999, 1547–1550. (l) Paquette, L. A.; Lo, H. Y. J. Org. Chem. 2003, 68,
2282–2289. (m) Brennan, N. K.; Guo, X.; Paquette, L. A. J. Org. Chem. 2005,
70, 732–734.
(16) The Danishefsky strategy faced two unfortunate steps: (i) a surprising
non-stereoselective osmylation leading to approximatively 15% of a wrong
stereoisomer occurred, and (ii) a by-product arising from a pinacol-like
rearrangement was formed in approximatively 14% yield during the cyclization
of the desired oxetane.
(17) Palombo, E.; Audran, G.; Monti, H. Synlett 2006, 3, 403–406.
6034 J. Org. Chem. Vol. 73, No. 15, 2008

SCHEME 5. Synthesis of CD Ring Key Intermediate (+)-1
oxetane (-)-15 in four steps and 65% overall yield without
isolation of intermediates as follows: temporary protection of
the C20 hydroxy group as an acetate 12 (Ac2O, cat. DMAP,
Pyr.), formation of secondary C5R mesylate 13 (MsCl), hy-
drolysis of the temporary acetyl protecting group to give 14
(K2CO3, MeOH), and cyclization (DBU, refluxing toluene).
With oxetane (-)-15 in hand, we had to install the C4
protecting group as the tertiary benzyl ether of the Danishefsky’s
taxol CD ring intermediate. For this purpose, (-)-15 was treated
with BnBr, NaH, and TBAI (cat.) to give (+)-16 in 87% yield.
At this junction, and to our delight, selective removal of the
PMB group could be accomplished as wished with perfect
chemoselective control and without any deprotection of the frail
dimethyl acetal group. Thus, exposure of (+)-16 to DDQ in
CH2Cl2/water (9:1) afforded the corresponding primary alcohol
(+)-17 in 95% yield. Derivative (+)-17 was finally converted
into the requisite target molecule (+)-1 in 78% yield and without
any epimerization by treatment with TPAP (cat.) and NMO in
CH2Cl2 at 0 °C.20 Spectroscopic data and optical rotation of
(+)-1 perfectly matched those reported by Danishefsky and co-
workers.
In conclusion, we have achieved a novel, highly efficient and
fully stereocontrolled strategy to the Danishefsky taxol CD ring
key intermediate in 15 steps and 11.4% overall yield from easily
available (+)-3.21 This approach further improves and shortens
the original strategy of Danishefsky, thus highlighting his elegant
and convergent total synthesis of taxol.
R-methoxy-substituted ylid, obtained by reacting methoxy-
methyltriphenylphosphonium chloride18 with KOtBu in THF
afforded 5 as a mixture of stereomers in 90% yield, then
refluxing the enol ethers with anhydrous methanol containing
CSA produced the dimethyl acetal (+)-6 in 93% yield. Reduc-
tion of the lactone functionality of (+)-6 with LiAlH4 in ether
at 0 °C provided diol (-)-7 in 95% yield.
Experimental Section
(1S,3R,4S,5S)-5-(tert-Butyldimethylsilyloxy)-4-(2,2-dimethoxy-
ethyl)-3-((4-methoxybenzyloxy)methyl)-4-methyl-2-methylenecy-
clohexanol (+)-10. To an ice-cold stirred solution of (+)-9 (500
mg, 1.04 mmol) in dry CH2Cl2 (20 mL) was added tert-butylhy-
droperoxide (434 µL, 3.13 mmol, 3.0 equiv, 70% in water) followed
by a catalytic amount of selenium dioxide and salicylic acid under
argon atmosphere. The mixture was stirred at rt for 4 h, then poured
into an aqueous Na2SO3 solution. After extraction with ether, the
organic layer was washed with water and brine, dried with MgSO4,
and concentrated under reduced pressure. Purification of the residue
by column chromatography gave (+)-10 (336 mg, 65%) as a clear
oil: [R]25D +8.6 (c 1.0, CHCl3); IR (film) ν 3408, 3013, 1147, 1043
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.22 (br d, J ) 8.7 Hz, 2H),
6.85 (br d, J ) 8.7 Hz, 2H), 5.14 (br s, 1H), 4.90 (br s, 1H), 4.48
and 4.36 (AB, J ) 11.8 Hz, 2H), 4.46 (dd, J ) 10.3, 4.3 Hz, 1H,
partially overlapped), 4.42-4.35 (m, 1H), 3.79 (s, 3H), 3.73-3.64
(m, 3H), 3.28 (s, 3H), 3.27 (s, 3H), 2.60 (dd, J ) 8.5, 4.9 Hz, 1H),
1.85-1.71 (m, 3H), 1.52 (dd, J ) 14.6, 6.0 Hz, 1H), 0.88 (s, 3H),
0.85 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 158.9, 148.8, 130.6, 129.0 (2C), 113.5 (2C), 109.6, 102.4, 73.4,
72.3, 68.5, 67.5, 55.0, 52.7, 52.1, 49.6, 40.6, 40.0, 39.1, 25.7 (3C),
18.4, 17.8, 4.4, 5.2. Anal. Calcd for C27H46O6Si: C, 65.55; H, 9.37.
Found: C, 65.80; H, 9.41.
(1S,2S,4S,5S,6R)-4-(tert-Butyldimethylsilyloxy)-5-(2,2-dimethoxy-
ethyl)-1-(hydroxymethyl)-6-((4-methoxybenzyloxy)methyl)-5-me-
thylcyclohexane-1,2-diol (-)-11. To an ice-cold solution of (+)-10
(300 mg, 0.61 mmol) in 20 mL of tBuOH/H2O (3/1) was added
N-methylmorpholine N-oxide (142 mg, 1.21 mmol, 2.0 equiv)
followed by a catalytic amount of OsO4 (4% in water) and a
catalytic amount of quinuclidine. The resulting brown mixture was
stirred at rt for 12 h, then poured into aqueous Na2SO3 solution.
After extraction with ethyl acetate, the organic layer was washed
with water and brine, dried with MgSO4, and concentrated under
At this stage, we had to protect the two hydroxy centers of
compound (-)-7. Logically, protection of the secondary alcohol
as a TBS ether present in the target molecule (+)-1 should not
be a problem, but we were mindful that the presence of the
dimethyl acetal group restricted the scope of possible temporary
protecting groups for the primary alcohol. Much would be
expected from this protecting group, not the least demanding
property being its susceptibility to removal at a late step of our
strategy under essentially neutral conditions. On the basis of
these considerations, we decided to install a PMB protecting
group on the primary alcohol because PMB ethers are especially
susceptible to oxidative cleavage under neutral reaction condi-
tions (DDQ, CH2Cl2/water) to give the desired alcohol, whereas
acetals and TBS ethers are generally stable to these conditions,
though exceptions do occur. This installation was accomplished
chemoselectively (PMBCl, NaH, cat. TBAI), giving rise to
monoprotected (-)-8 in 85% yield. The hindered secondary
hydroxy group of the molecule was then protected as the TBS
ether (TBS-OTf, Et3N, 0 °C) to give the fully protected
derivative (+)-9. Stereoselective allylic oxidation19 of (+)-9
from the less hindered R-face (cat. SeO2, tBuOOH) afforded
allylic alcohol (+)-10 as a single isomer in 65% yield. The
ensuing dihydroxylation of the methylene bond within (+)-10
(NMO, cat. OsO4, cat. quinuclidine) proceeded selectively from
the face opposite the axial C8 methyl group, thus furnishing
the expected triol (-)-11 in 80% yield (Scheme 5).15f According
to the reported procedure,14 triol (-)-11 was converted to
(18) Soderquist, J. A.; Ramos-Veguilla, J. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; John Wiley & Sons: Chichester, 1995;
Vol. 5, pp 3363-3365.
(19) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526–
5528.
(20) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666.
J. Org. Chem. Vol. 73, No. 15, 2008 6035

reduced pressure. Purification of the residue by column chroma-
aqueous Na2SO3. After extraction with ether, the organic layer was
washed with water and brine, dried with MgSO4, and concentrated
under reduced pressure. Purification of the residue by column
tography gave (-)-11 (255 mg, 80%) as a clear oil: [R]25 -10.0
D
(c 1.0, CHCl3); IR (film) ν 3380, 1248, 1129, 1037 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.23 (d, J ) 8.6 Hz, 2H), 6.88 (d, J ) 8.6
Hz, 2H), 4.54 (t, J ) 4.9 Hz, 1H), 4.46 and 4.38 (AB, J ) 11.3
Hz, 2H), 3.85-3.25 (m, 4H, partially overlapped), 3.80 (s, 3H),
3.62 (br s, 2H), 3.35 (s, 3H), 3.28 (s, 3H), 2.45-2.16 (m, 2H),
1.98 (ddd, J ) 13.8, 8.0, 3.3 Hz, 1H), 1.73-1.75 (m, 1H), 1.42
(dd, J ) 14.5, 4.5 Hz, 1H), 0.89 (s, 3H), 0.86 (s, 9H), 0.07 (s, 3H),
0.04 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.6, 129.7 (2C),
129.2, 114.0 (2C), 102.5, 76.4, 73.2, 69.2, 67.1, 67.0, 65.7, 55.3
(2C), 53.2, 52.2, 44.2, 41.0, 39.5, 34.0, 25.9 (3C), 21.1, -4.1, -5.1.
Anal. Calcd for C27H48O8Si: C, 61.33; H, 9.15. Found: C, 61.18;
H, 9.06.
chromatography gave (+)-1 (54 mg, 78%) as a clear oil: [R]25
D
+9.2 (c 1.0, CHCl3); [R]20 lit.9 +9.4 (c 0.5, CHCl3); IR (film) ν
D
2848, 2799, 1712, 1088 cm-1; 1H NMR (500 MHz, CDCl3) δ 9.99
(d, J ) 2.6 Hz, 1H), 7.35-7.28 (m, 5H), 4.94 (br dd, J ) 7.7, 2.5
Hz, 1H), 4.66 and 4.55 (AB, J ) 7.8 Hz, 2H), 4.57 and 4.46 (AB,
J ) 11.4 Hz, 2H), 4.50 (ABX, J ) 6.0, 4.6 Hz, 1H), 3.73 (dd, J )
6.3, 4.9 Hz, 1H), 3.25 (s, 3H), 3.24 (s, 3H), 2.96 (d, J ) 2.6 Hz,
1H), 2.23 (ddd, J ) 15.4, 7.7, 4.9 Hz, 1H), 1.98 (ddd, J ) 15.4,
6.3, 2.5 Hz, 1H), 1.77 and 1.70 (ABX, J ) 14.4, 6.0, 4.6 Hz, 2H),
1.20 (s, 3H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 203.9, 138.0, 128.4 (2C), 127.6, 127.4 (2C), 101.9,
83.1, 77.4, 76.0, 71.7, 65.5, 56.7, 52.8, 52.4, 39.6, 39.4, 34.1, 25.8
(3C), 19.2, 18.1, -4.0, -4.9. Anal. Calcd for C26H42O6Si: C, 65.24;
H, 8.84. Found: C, 64.99; H, 8.81. HRMS (ESI) calcd for
C26H46N1O6Si1: 496.3088 [M + NH4+]; found 496.3090.
(1S,2S,3S,4S,6R)-1-(Benzyloxy)-4-(tert-butyldimethylsilyloxy)-3-
(2,2-dimethoxyethyl)-3-methyl-7-oxabicyclo[4.2.0]octane-2-carbal-
dehyde (+)-1. To an ice-cold stirred solution of (+)-17 (70 mg,
0.15 mmol) in CH2Cl2 (5 mL) were added powdered 4 Å molecular
sieves (1 g) then N-methylmorpholine N-oxide (34 mg, 0.29 mmol,
2.0 equiv) followed by a catalytic amount of TPAP. The deep green
solution was stirred at rt under argon for 1 h and poured into
Acknowledgment.P.B.thankstheMiniste`redel’Enseignement
Supe´rieur et de la Recherche for a Ph.D. grant. The authors are
thankful to Dr. R. Faure for 2D NMR experiments, and to D.
Pujol for technical assistance.
(21) The starting material in Danishefsky’s strategy is the useful synthon
(S)-Wieland-Miescher ketone. (S)-W.-M. ketone is commercially available but
very expensive. The cost exhibits the difficulty of the experimental technique to
obtain enantiopure W.-M. ketone. Indeed, this is not a trivial manipulation to
obtain a large amount of this enantiopure derivative efficiently, and this remains
difficult. The most direct and practical method seems to be the asymmetric
Robinson annulation of a precursor with proline followed by repeated recrys-
tallizations (Buchschacher, P.; Fu¨rst, A.; Gutzwiller, J. Organic Syntheses; Wiley
& Sons: New York, 1990; Collect. Vol. VII, pp 368-372). See also: Kasai, Y.;
Shimanuki, K.; Kuwahara, S.; Watanabe, M.; Harada, N. Chirality 2006, 18,
177–187.
Supporting Information Available: Additional experimental
procedures and spectroscopic data for (+)-4-(+)-9 and 12-(+)-
1
17; copies of H and 13C NMR spectra for all compounds and
NOESY experiments for (+)-1. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO800913X
6036 J. Org. Chem. Vol. 73, No. 15, 2008