Chemoenzymatic taxanes approach using both enantiomers of the same building block. 2. Taxol CD ring unit

Article abstract of DOI:10.1021/jo050039s

(Chemical Equation Presented) The enantioselective synthesis of the Taxol CD ring unit has been achieved starting from an enantiopure building block, the enantiomer of those previously utilized in the synthesis of the A ring unit. The key features of the

Full text of DOI:10.1021/jo050039s

Chemoenzymatic Taxanes Approach Using Both Enantiomers of
the Same Building Block. 2. Taxol CD Ring Unit
Jean-Pierre Uttaro, Ge´rard Audran, and Honore´ Monti*
Laboratoire de Re´activite´ Organique Se´lective, U.M.R. 6180 “Chirotechnologies: catalyse et biocatalyse”,
Universite´ Paul Ce´zanne, Aix-Marseille III, 13397 Marseille Cedex 20, France
honore.monti@univ.u-3mrs.fr
Received January 7, 2005
The enantioselective synthesis of the Taxol CD ring unit has been achieved starting from an
enantiopure building block, the enantiomer of those previously utilized in the synthesis of the A
ring unit. The key features of the present synthesis are astute use of both enantiomers of the same
building block and complete control in the construction of five consecutive chiral centers.
Paclitaxel (Taxol, Figure 1),1 a tetracyclic diterpenoid
originally isolated2 from the bark of the Pacific yew tree
Taxus brevifolia, and its synthetic analogue docetaxel
(Taxotere, Figure 1),3 have attracted considerable interest
owing to their remarkable chemotherapeutic activities.
The low natural availability of Taxol has stimulated
intense attention from synthetic chemists, and to date,
six total syntheses have been accomplished.4 Works
focused on the structure-activity relationships (SAR)1,5
(1) Taxol is the registered trademark of Bristol-Myers Squibb
Company for paclitaxel. General reviews on taxoid chemistry: (a)
Gue´nard, D.; Gueritte-Voegelein, F.; Lavelle, F. Curr. Pharm. Design
1995, 1, 95. (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., Vyas,
D. M., Eds.; ACS Symposium Series 583; American Chemical Society:
Washington DC, 1995; p 31. (c) Arbuck, S. G.; Blaylock, B. A. In
Taxol: Science and Applications; Suffness, M., Ed.; CRC Press: Boca
Raton, 1995; p 379. (d) Rowinsky, E. K.; Donehower, R. C. Engl. J.
Med. 1995, 332, 1004. (e) The Chemistry and Pharmacology of Taxol
and its Derivatives; Farina, V., Ed.; Elsevier: Amsterdam, 1995. (f)
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., Tamm, Ch., Eds.; Spriger-Verlag: Vienna
and New York, 2002; Vol. 84.
FIGURE 1. Structures of paclitaxel (Taxol) and docetaxel
(Taxotere).
have revealed that the C-4 acetoxy group with the oxe-
tane,6 the C-2 benzoyloxy group,7 and the C-2′, C-3′
substituents at the C-13 side chain8 are essential for the
antitumor activity. In this context, convenient access to
the fully functionalized A ring and CD ring unit for the
construction of the sterically congested eight-membered
B ring of Taxol, or analogues with a comparable biological
profile, remain necessary.
Driven by the increased demand of chiral drugs in
enantiomerically pure form, the synthesis of enantiopure
compounds has emerged into one of the most important
fields of organic synthesis. In this context, catalytic
asymmetric synthesis, including both metal- or enzyme-
catalyzed reactions, has been a highly active area of
research. Today, kinetic resolution of racemates mediated
by enzymes has become an efficient process and is a
(2) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J. Am. Chem. Soc. 1971, 93, 2325.
(3) Taxotere is the registered trademark of Rhoˆne-Poulenc Rorer
Co. for docetaxel. (a) Mangatal, L.; Adeline, M. T.; Gue´nard, D.;
Gueritte-Voegelein, F.; Potier, P. Tetrahedron 1989, 45, 4177. (b)
Gueritte-Voegelein, F.; Gue´nard, D.; Mangatal, L.; Potier, P.; Guilhem,
J.; Cesario, M.; Pascard, C. Acta Crystallogr. 1990, C46, 781. Review:
(c) Gue´nard, D.; Gueritte-Voegelein, F.; Potier, P. Acc. Chem. Res. 1993,
26, 160.
10.1021/jo050039s CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/24/2005
3484
J. Org. Chem. 2005, 70, 3484-3489

Chemoenzymatic Taxanes
valuable tool.9 Despite its widespread use, one obvious
limitation with this type of enzymatic resolution is that
the maximum theorical yield of each enantiomer is
limited to 50%, and in the majority of processes, only one
stereomer is desired and there is little or no use for the
other.10
SCHEME 1. Retrosynthetic Analysis of Taxol A
Ring and CD Ring Unit
Examining the absolute configuration of Taxol, and as
part of an A + C connection to form the central B ring4a,b
(Figure 1), we observed that we could turn into an
advantage this limitation using both enantiomers of the
same building block to develop concise and efficient
routes to enantiomerically pure targets (Scheme 1, taxoid
numbering). Following this methodology, we previously
(4) (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. Nicolaou, K.
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Paulvannan, K.; Chadha, R. J. Am. Chem. Soc. 1995, 117, 653 and
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W. B.; Danishefsky, S. J. Angew. Chem., Int. Ed. Engl. 1995, 34, 1723;
Danishefsky, S. J.; Masters, J. J.; Young, W. B.; Link, J. T.; Snyders,
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. (c) Holton, R. A.; Somoza, C.; Kim, H.-B.; Liang, F.; Biediger,
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gawa, M.; Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121. (f)
Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.; Nakamura, N.;
Kusama, H.; Kuwajima, I. J. Am. Chem. Soc. 1998, 120, 12980.
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122, 3811.
(5) Reviews: (a) Kingston, D. G. I. J. Nat. Prod. 2000, 63, 726. (b)
Kingston, D. G. I. Chem. Commun. 2001, 867.
reported an entry to the fully functionalized A ring unit11
(Scheme 1, path a). We present herein a synthesis of the
Taxol CD ring unit12 that demonstrates the validity of
our thinking (Scheme 1, path b).
Recently, we developed a stereocontrolled approach
toward highly oxygenated taxane C and CD ring unit
precursors.13 Following the published achiral five-step
procedure, the enantioselective synthesis of (+)-6 is
described in Scheme 2. Our starting material was (S)-
(-)-2 whose absolute stereochemistry14 correlates cor-
rectly with the C-7-hydroxylated center of taxoids. This
(6) (a) Gunatilaka, L. A. A.; Ramdayal, F. D.; Sarragiotto, M. H.;
Kingston, D. G. I. J. Org. Chem. 1999, 64, 2694. (b) Merckle, L.; Dubois,
J.; Place, E.; Thoret, S.; Gueritte, F.; Gue´nard, D.; Poupat, C.; Ahond,
A.; Potier, P. J. Org. Chem. 2001, 66, 5058 and references therein.
(7) (a) Vander Velde, D. G.; Georg, G. I.; Grunewald, G. L.; Gunn,
C. W.; Mitscher, L. A. J. Am. Chem. Soc. 1993, 115, 11650. (b) Williams,
H. J.; Scott, A. I.; Dieden, R. A.; Swindell, C. S.; Chirlian, L. E.; Francl,
M. M.; Heerding, J. M.; Krauss, N. E. Tetrahedron 1993, 49, 6545. (c)
Mastropaolo, D.; Cmeran, A.; Luo, Y.; Brayer, G. D.; Cameran, N. Proc.
Natl. Acad. Sci. U.S.A. 1995, 92, 6920. (d) Dubois, J.; Gue´nard, D.;
Gueritte-Voegelein, F.; Guedira, N.; Potier, P.; Gillet, B.; Beloeil, J.-
C. Tetrahedron 1993, 49, 6533. (e) Snyder, J. P.; Nevins, N.; Cicero,
D. O.; Jansen, J. J. Am. Chem. Soc. 2000, 122, 724. (f) Snyder, J. P.;
Nettles, J. H.; Cornett, B.; Downing, K. H.; Nogales, E. Proc. Natl.
Acad. Sci. U.S.A. 2001, 98, 5312.
(8) (a) Kant, J.; Huang, S.; Wong, H.; Fairchild, C.; Vyas, D.; Farina,
V. Bioorg. Med. Chem. Lett. 1993, 3, 2471. (b) Loz´yn´ski, M.; Rusin´ska-
Roszak, D. Tetrahedron Lett. 1995, 36, 8849. (c) Moyna, G.; Williams,
H. J.; Scott, A. I. Synth. Commun. 1997, 27, 1561. (d) Jime´nez-Barbero,
J. A.; Souto, A. A.; Abal, M.; Barasoain, I.; Evangelio, J. A.; Acun´a, A.
U.; Andreu, J. M.; Amat-Guerri, F. Bioorg. Med. Chem. 1998, 6, 1857.
(e) Baloglu, E.; Hoch, J. M.; Chatterjee, S. K.; Ravindra, R.; Bane, S.;
Kingston, D. G. I. Bioorg. Med. Chem. 2003, 11, 1557.
(9) Recent books: (a) Enzymatic Reaction in Organic Media; Ko-
skinen, A. M. P., Klibanov, A. M., Eds.; Blackie Academic and
Professional: Glasgow, 1996. (b) Faber, K. Biotransformations in
Organic Chemistry, 3rd ed.; Springer-Verlag: Berlin, 1997. (c) Born-
scheuer, U. T.; Kazlauskas, R. J. Hydrolases in Organic Synthesis;
Wiley-VCH: Weinheim, 1999. (d) Stereoselective Biocatalysis; Patel,
R. N., Ed.; Marcel Dekker, Inc.: New York, 2000.
(10) Reviews for biocatalytic strategies which lead to the formation
of a single enantiomer in 100% theorical yield from a racemate: (a)
Noyori, R.; Tokunaga, M.; Kitamura, M. Bull. Chem. Soc. Jpn. 1995,
68, 36. (b) Stecher, H.; Faber, K. Synthesis 1997, 1. (c) Stu¨rmer, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1173. (d) Persson, B. A.;
Larsson, A. L. E.; Le Ray, M.; Ba¨ckvall, J.-E. J. Am. Chem. Soc. 1999,
121, 1645. (e) El Gihani, M. T.; Williams, J. M. J. Biocatal. Biotrans-
form. 1999, 3, 11. (f) Strauss, U. T.; Felfer, U.; Faber, K. Tetrahedron:
Asymmetry 1999, 10, 107.
(11) Audran, G.; Uttaro, J.-P.; Monti, H. Synlett 2002, 1261 and
references therein.
(12) 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. (b) Nicolaou, K. C.; Liu, J. J.; Hwang, C.-
K.; Dai, W.-M.; Guy, R. K. J. Chem. Soc., Chem. Commun. 1992, 1118.
(c) Isaacs, R. C. A.; Di Grandi, M. J.; Danishefsky, S. J. J. Org. Chem.
1993, 58, 3938. (d) Takahashi, T.; Hirose, Y.; Iwamoto, H.; Doi, T. J.
Org. Chem. 1998, 63, 5742. (e) Nakada, M.; Kojima, E.-I.; Iwata, Y.
Tetrahedron Lett. 1998, 39, 313. (f) Momose, T., Setoguchi, M.; Fujita,
T.; Tamura, H.; Chida, N. Chem. Commun. 2000, 2237. (g) Nakai, K.;
Miyamoto, S.; Sasuga, D.; Doi, T.; Takahashi, T. Tetrahedron Lett.
2001, 42, 7859. (h) Yoshimitsu, T.; Nakajima, H.; Nagaoka, H.
Tetrahedron Lett. 2002, 43, 8587. (i) Shing, T. K. M.; Lee, C. M.; Lo,
H. Y. Tetrahedron 2004, 60, 9179. Construction of the oxetane D ring
in semisyntheses of taxanes which lacked functionality at C-7. (j)
Potier’s original procedure applied in numerous diversified methodolo-
gies: Ettovani, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991,
47, 9823. (k) Zeng, Q.; Paquette, L. A. Synlett 1999, 1547. (l) Paquette,
L. A.; Lo, H. Y. J. Org. Chem. 2003, 68, 2282.
(13) Uttaro, J.-P.; Audran, G.; Galano, J.-M.; Monti, H. Tetrahedron
Lett. 2002, 43, 2757 and references therein.
(14) Galano, J.-M.; Audran, G.; Monti, H. Tetrahedron 2000, 56,
7477.
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Uttaro et al.
SCHEME 2a
SCHEME 3a
a Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt,
(96%); (b) CH2dCHMgBr, CuBr.SMe2, THF, -78 °C then HMPA
and NCCO2Me, -78 °C to rt (81%); (c) 1.2 equiv. p-TsOH‚H2O,
toluene, reflux (92%); (d) 2.5 equiv of Ph3P+MeI-, t-BuOK, toluene,
reflux (83%); (e) cat. SeO2, cat. salicylic acid, t-BuOOH 70% in
water, CH2Cl2, reflux (85%).
a Reagents and conditions: (a) TBDMSCl, imidazole, DMF, rt
(80%); (b) cat. OsO4, NaIO4, THF/H2O (3/1), rt (80%); (c) NaBH4,
MeOH, -78 °C (90%); (d) BnBr, NaH, NBu4I, THF, rt (89%); (e)
m-CPBA, CH2Cl2, 37 °C, 5 days (75%); (f) BnBr, NaH, NBu4I, THF,
rt (88%).
stereocenter will control the relative (and consequently
the absolute) configuration of the remaining centers. The
TBDMS (tert-butyldimethylsilane)15-protected ketol (-)-3
was converted to (+)-4 by the copper catalyzed 1,4-
addition of vinylmagnesium bromide followed by quench-
ing with methylcyanoformate16 and treatment of the
crude product by p-TsOH‚H2O. Wittig olefination of (+)-4
and stereoselective hydroxylation of (+)-5 using catalytic
selenium dioxide and t-BuOOH afforded (+)-6 as a single
stereomer. The target cornerstone (+)-6 presents the
correct C-3, C-5, C-7, and C-8 absolute configurations of
taxoids.
SCHEME 4a
With (+)-6 in hand, Schemes 3 and 4 outline the
methodology developed within our group to construct the
CD ring unit in a stereocontrolled manner and with the
functionalities suitable for elaboration into the Taxol
framework. Protection of the secondary alcohol as a
TBDS ether gave (+)-7. Chemoselective oxidative cleav-
age of the vinyl double bond using cat. OsO4 and NaIO4
in THF/water formed aldehyde (+)-8 and reduction with
NaBH4 in methanol furnished alcohol (+)-9. At this stage,
our attention was directed toward the direct bromohy-
dration of the exocyclic double bond using NBS and
water. Our motive for forming the bromohydrin was to
introduce directly the requisite leaving group on C-20.
For this purpose, (+)-9 was protected as the benzyl ether
(+)-10, and the bromohydrin formation protocols17 cur-
rently used were tried in different aqueous organic
solvents (acetone, THF, toluene, dichloromethane). Un-
fortunately, they led to the formation of complex mixtures
and the outcome of the reaction could not be clearly
established. To solve this problem, we then turned our
attention toward the possibility of forming the epoxide
of (+)-9 and to regioselectively cleave it to halohydrin.
With a hydroxyl group present, the metal-catalyzed
epoxidation of a remote double bond can occur if the
intermediate, in which the hydroxyl group is coordinated
a Reagents and conditions: (a) (i) DIBAL, toluene, -78 °C, (ii)
Tebbe reagent, toluene/THF/Pyr, -78 °C to rt (76%); (b) BzCl,
DMAP, Pyr, rt (86%); (c) Et2AlCl, CH2Cl2, -78 °C (78%); (d)
MOMCl, (iPr)2NEt, CH2Cl2, rt (91%); (e) TBAF, THF, rt (98%), (f)
NaH, THF, 40 °C, then TBDMSCl, imidazole, 40 °C (71%); (g) cat.
OsO4, NaIO4, THF/H2O, rt (82%).
(15) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94,
6190.
(16) Mander, L. N.; Sethi, P. Tetrahedron Lett. 1983, 24, 5425.
(17) Larock, R. C. Comprehensive Organic Transformations; Wiley-
VCH: New York 1999; p 640.
to the metal, can adopt a conformation which minimizes
steric interactions when it delivers an oxygen atom to
3486 J. Org. Chem., Vol. 70, No. 9, 2005

Chemoenzymatic Taxanes
the double bond.18 In this respect, a path using vanadium-
catalyzed epoxidation of alcohol (+)-9 according to the
Sharpless procedure19 was pursued but neither experi-
ment proved fruitful, probably as a direct consequence
of the size of the oxidant and the steric hindrance in the
vicinity of the exocyclic double bond. So, with some
reluctance due to the expected steric hindrance, we
focused our attention on m-CPBA epoxidation. To our
surprise and delight, R-epoxidation to give (-)-11 could
be accomplished efficiently and with perfect stereochem-
ical control. The stereochemistry of (-)-11 was not proven
at this stage but unequivocally established through X-ray
crystallography analysis carried out on the crystaline
benzyl ether (-)-12. Under no conditions was any sign
of the â-epoxide found. Concurrent studies of the m-
CPBA epoxidation of (+)-10 having the primary alcohol
function protected as the benzyl ether showed a complete
lack of reactivity and simple intermolecular epoxidation
does not proceed. It was made clear that precoordination
of the peracid to the remote trishomoallylic hydroxyl in
(+)-9, which is a likely prerequisite to oxirane formation,
is allowed in this case.
FIGURE 2. Selected NOESY interactions for (-)-18.
tertiary alcohol as a methoxymethyl(MOM) ether24 led
to (+)-16 (91% yield) and subsequent removal of the silyl
group from compound (+)-16 by exposure to TBAF15
produced derivative (+)-17 in 98% yield. Compound (+)-
17 was treated with NaH in DMF at 40 °C and the
reaction was monitored by TLC. 1H NMR analysis of
aliquots showed that the fastest reaction was the removal
of the benzoate ester.21 After complete cyclization, excess
TBDMSCl/imidazole were added to give (-)-18 in 71%
overall yield. The structural and stereochemical assign-
ment of (-)-18 were achieved through the unambiguous
At this junction, we were mindful that the congested
environment in the vicinity of the oxirane ring might
again restrict the scope of feasible operations. So, the
stereochemistry at C-4 being secured, it was decided that
the lactone moiety would be opened at this stage. This
was accomplished by a two-step procedure as follows
(Scheme 4). Lactone (-)-12 was reduced with DIBAL in
toluene, and the resultant crude mixture of lactols (15%
1
rationalization of H- and 13C NMR resonances using a
combinaison of HMBC, HMQC, DEPT, and NOESY
techniques. In particular, a NOESY correlation between
the 8â-Me (δH ) 1.02 ppm) and the 6â-H (δH ) 1.93 ppm)
and one proton 20-H of the oxetane cycle (δH ) 4.66 ppm)
established the cis spatial orientation of these two
protons and the methyl group (Figure 2). Furthermore,
strong NOESY correlations between 3R-H (δH ) 2.85
1
ratio of the opened aldehyde form, based on H NMR
analysis) underwent Tebbe olefination20 to produce univo-
cally (-)-13 in 76% yield for two steps. In the target
molecule, we needed to have the C-7 remaining hydroxyl
group of (-)-13 protected as a TBDMS blocking group in
order to differentiate this site from the other two alcohol
centers at C-4 and C-9. However, the presence of the C-5
TBDMS blocking group, susceptible to removal at a late
stage, rendered this path incompatible at the present
time. On the basis of these considerations, we decided to
install a benzoate protecting group on the secondary
alcohol because we were full of hope that this functional-
ity could be removed and replaced during the oxetane
ring formation conditions (NaH, THF) like precedence.21
Fortunately, this will be so (vide infra). This transforma-
tion was accomplished in high yield on derivative (-)-13
giving rise to benzoate ester (+)-14. The regioselective
ring-opening of epoxides to vicinal halohydrins is a
reaction of continued interest and a large variety of
reagents are known.22 Among them, diethylaluminum
chloride is extremely useful for the ease of the procedure
and the regio- and chemoselectivity observed.23 The
submission of (+)-14 to this reagent afforded the desired
chlorohydrin (+)-15 in 78% yield. Next, protection of the
ppm) and 7R-H (δH ) 3.94 ppm), 7R-H and 6R-H (δH
)
2.29 ppm), and in addition, 6R-H and 5R-H (δH ) 4.91
ppm) established the cis spatial orientation of these
protons on the opposite side. Finally, oxidative cleavage
of (-)-18 using cat. OsO4 and NaIO4 gave the target
molecule (-)-1 in 82% yield.
In summary, five consecutive chiral centers on the fully
functionalized Taxol CD ring unit have been successfully
generated from only the one chiral center of the keto
alcohol (-)-2 obtained by enzymatic resolution and which
correlates correctly with the C-7 hydroxylated center of
taxoids. This approach is complementary with our early
synthesis of Taxol A ring unit starting from (+)-2 and
discloses the possibility to access to these two substruc-
tures using both enantiomers of the same building block.
Experimental Section
(1R,3R,5S,8S)-3-(tert-Butyldimethylsilyloxy)-8-methyl-
2-methylene-7-oxo-6-oxabicyclo[3.2.1]octane-8-carbalde-
hyde (+)-8. To a stirred solution of (+)-7 (1.55 g, 5.02 mmol)
in 60 mL of a THF/water (3/1) mixture was added a catalytic
amount of OsO4 (4.0 wt. % in water). The solution turned black,
sodium metaperiodate (3.20 g, 15.0 mmol) was added, and the
(18) (a) Kobayashi, M.; Kurozumi, S.; Toru, T.; Ishimoto, S. Chem.
Lett. 1976, 1341. (b) Breslow, R.; Maresca, L. M. Tetrahedron Lett.
1977, 623.
(22) Methods for the preparation of 1,2-halohydrins from epoxides:
(a) Fieser and Fieser’s Reagents for Organic Synthesis; Smith, J. G.,
Fieser, M., Eds.; Collect. Index for Vols. 1-12; John Wiley: New York,
1990. (b) Larock, R. C. Comprehensive Organic Transformations; Wiley-
VCH: New York, 1999; pp 1027-1030. Reviews: (c) Hanson, R. M.
Chem. Rev. 1991, 91, 437. (d) Bonini, C.; Righi, G. Synthesis 1994,
225.
(23) (a) Gao, L.; Saitoh, H.; Feng, F.; Murai, A. Chem. Lett. 1991,
1787. (b) Gao, L.; Murai, A. Tetrahedron Lett. 1992, 33, 4349.
(24) Stork, G.; Takahashi, T. J. Am. Chem. Soc. 1977, 99, 1275.
(19) (a) Sharpless, K. B.; Michaelson, R. C. J. Org. Chem. 1973, 38,
6136. (b) Sharpless, K. B.; Teranichi, A. Y.; Backva¨ll, J.-E. J. Am.
Chem. Soc. 1977, 99, 3120.
(20) Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J. Am. Chem. Soc.
1978, 100, 3611.
(21) Boesen, T.; Feeder, N.; Eastgate, M. D.; Fox, D. J.; Medlock, J.
A.; Tyzack, C. R.; Warren, S. J. Chem. Soc., Perkin Trans. 1 2001,
118.
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Uttaro et al.
reaction mixture was stirred for 6 h at rt under an argon
atmosphere. After dilution with water and extraction with
CH2Cl2, the combined extracts were dried with MgSO4 and
concentrated in vacuo to afford crude aldehyde. After purifica-
tion by column chromatography and crystallization from
Et2O-hexane, 1.25 g (80%) of pure aldehyde (+)-8 was
obtained as white crystals. Mp ) 75 °C. [R]25D ) +80.2 (c 1.0,
CHCl3). IR (KBr): ν 3078, 2723, 1773, 1649, 891 cm-1. 1H NMR
(300 MHz, CDCl3): δ 9.50 (s, 1H), 5.10 (s, 1H), 5.07 (s, 1H),
4.63 (br-d, J ) 3.5 Hz, 1H), 4.31 (d, J ) 5.2 Hz, 1H), 3.20 (s,
1H), 2.32 (ddd, J ) 15.4, 5.2, 1.5 Hz, 1H), 2.16 (dd, J ) 15.4,
3.5 Hz, 1H), 1.32 (s, 3H), 0.84 (s, 9H), 0.04 (s, 3H), 0.00 (s,
3H). 13C NMR (75 MHz, CDCl3): δ 199.3 (CH), 173.2 (C), 142.6
(C), 116.1 (CH2), 81.2 (CH), 69.0 (CH), 57.1 (C), 53.2 (CH), 34.3
(CH2), 25.4 (CH3), 18.6 (CH3), 17.8 (C), -4.8 (CH3), -5.1 (CH3).
Anal. Calcd for C16H26O4Si: C, 61.90; H, 8.44. Found: C, 62.19;
H 8.39.
(CH3), -5.0 (CH3), -5.2 (CH3). Anal. Calcd for C24H38O4Si: C,
68.86; H, 9.15. Found: C, 68.49; H 9.12.
(1S,2R,3S,4R,5R)-2-Benzyloxymethyl-5-(tert-butyldi-
methylsilyloxy)-4-chloromethyl-4-hydroxy-2-methyl-3-
vinylcyclohexyl benzoate (+)-15. Et2AlCl (5.50 mL of 1 M
in hexane, 5.50 mmol) was added dropwise to a solution of
(+)-14 (520 mg, 0.99 mmol) in CH2Cl2 (50 mL) at -78 °C, and
the reaction mixture was allowed reach rt overnight. The
mixture was quenched with 5% HCl, and the organic layer
was washed with 10% Na2CO3 and brine and dried. Solvent
evaporation afforded a residue which was purified by column
chromatography to afford 432 mg (78%) of chlorohydrin (+)-
15. [R]25D ) +32.6 (c 1.0, CHCl3). IR (film): ν 3409, 3098, 1251,
1
1053, 721 cm-1. H NMR (300 MHz, CDCl3): δ 7.99 (d, J )
7.3 Hz, 2H), 7.56 (br-t, J ) 7.3 Hz, 1H), 7.42 (t, J ) 7.3 Hz,
2H), 7.26-7.18 (m, 5H), 6.23 (ddd, J ) 16.5, 10.7, 10.7 Hz,
1H), 5.35 (dd, J ) 8.8, 4.4 Hz, 1H), 5.21 (dd, J ) 10.7, 2.1 Hz,
1H), 5.19 (dd, J ) 16.5, 2.1 Hz, 1H), 4.45 and 4.39 (AB, J )
12.1 Hz, 2H), 3.97 and 3.84 (AB, J ) 11.5 Hz, 2H), 3.83 (dd, J
) 8.8, 4.4 Hz, 1H), 3.27 and 3.21 (AB, J ) 9.0 Hz, 2H), 2.96
(s, OH), 2.60 (d, J ) 10.7 Hz, 1H), 2.27 (ddd, J ) 14.2, 4.4, 4.4
Hz, 1H), 1.87 (ddd, J ) 14.2, 8.8, 8.8 Hz, 1H), 1.05 (s, 3H),
0.80 (s, 9H), 0.08 (s, 3H), 0.00 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ ) 165.7 (C), 138.1 (C), 134.3 (CH), 132.9 (CH), 130.5
(C), 129.6 (2 CH), 128.3 (2 CH), 128.2 (2 CH), 127.6 (2 CH),
127.5 (CH), 119.4 (CH2), 74.0 (CH2), 73.8 (C), 73.6 (CH), 73.1
(CH2), 71.6 (CH), 52.8 (CH), 50.3 (CH2), 41.4 (C), 32.5 (CH2),
25.7 (3 CH3), 17.9 (C), 16.4 (CH3), -4.4 (CH3), -5.1 (CH3). Anal.
Calcd for C31H43ClO5Si: C, 66.58; H, 7.75. Found: C, 66.81;
H 7.79.
(3S,4S,5R,6S,8R)-8-(tert-Butyldimethylsilyloxy)-5-hy-
droxymethyl-5-methyl-1-oxaspiro[2.5]octane-4,6-carbo-
lactone (-)-11. To a stirred solution of (+)-9 (1.00 g, 3.20
mmol) in CH2Cl2 (60 mL) was added m-CPBA (1.58 g, 6.40
mmol, 70 wt % in water) at rt. The solution was stirred at 37
°C for 5 days. The mixture was poured into a solution of Na2-
SO3 (3.23 g, 25.6 mmol) and extracted with CH2Cl2. The
organic layer were combined, washed with a saturated solution
of NaHCO3, dried, filtered, and concentrated to afford after
purification by column chromatography 788 mg (75%) of (-)-
11. Mp ) 110 °C. [R]25 ) -8.0 (c 1.0, CHCl3). IR (KBr): ν
D
1
3431, 1763, 1259, 1053 cm-1; H NMR (300 MHz, CDCl3): δ
4.48 (br-d, J ) 4.0 Hz, 1H), 3.90 and 3.63 (ABX, J ) 11.6, 7.9,
4.1 Hz, 2H), 3.55 (d, J ) 5.5 Hz, 1H), 2.90 and 2.73 (AB, J )
4.2 Hz, 2H), 2.24 (ddd, J ) 15.6, 5.5, 1.5 Hz, 1H), 2.09 (dd, J
) 15.6, 4.0 Hz, 1H), 1.92 (br-s, 1H), 1.29 (s, 3H), 0.86 (s, 9H),
0.04 (s, 3H), -0.02 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 173.5
(C), 82.2 (CH), 70.6 (CH), 64.6 (CH2), 60.0 (C), 51.9 (CH), 51.6
(CH2), 48.0 (C), 32.9 (CH2), 25.3 (3 CH3), 21.0 (CH3), 17.6 (C),
-4.7 (CH3), -4.9 (CH3). Anal. Calcd for C16H28O5Si: C, 58.50;
H, 8.59. Found: C, 58.89; H 8.64.
(1S,2S,3R,4S,6R)-3-Benzyloxymethyl-1-methoxy-
methoxy-3-methyl-2-vinyl-7-oxabicyclo[4.2.0]oct-4-yl-
oxy-tert-butyldimethylsilane (-)-18. To a suspension of
NaH (50% dispersion, 46 mg, 0.94 mmol) in DMF (4 mL) was
added dropwise at rt a DMF solution (3 mL) of alcohol (+)-17
(230 mg, 0.47 mmol), and the mixture was stirred at 40 °C.
After 2 h, the reaction was complete (aliquots). Imidazole (800
mg, 11.8 mmol) and TBDMSCl (1.42 g, 9.42 mmol) were then
added, and the solution was stirred again at 40 °C for 12 h.
The reaction mixture was poured into water, and the resulting
aqueous layer was extracted with CH2Cl2. The combined
extracts were washed with H2O and brine, dried (MgSO4),
concentrated, and purified by column chromatography to afford
(3S,4S,5R,6S,8R)-5-Benzyloxymethyl-8-(tert-butyldi-
methylsilyloxy)-5-methyl-4-vinyl-1-oxaspiro[2.5]octan-
6-ol (-)-13. A 780 mg portion (1.86 mmol) of (-)-12 was
dissolved in 30 mL of anhydrous toluene, and a 1 M toluene
solution of diisobutylaluminum hydride (4.60 mL, 4.60 mmol)
was added dropwise at -80 °C under an argon atmosphere.
The reaction mixture was stirred for 20 min at this temper-
ature, quenched with Na2SO4‚10H2O (4.7 g) and Celite (4.7
g), and allowed to rise to rt. Filtration through a pad of MgSO4
and concentration gave 767 mg of a mixture of lactols and
aldehyde as a clear oil. This mixture was used for the next
reaction without further purification. To a stirred solution of
above mixture of lactols and aldehyde (767 mg) in benzene
(10 mL) were added tetrahydrofuran (2.5 mL) and pyridine
(100 µL). The resulting mixture was cooled to -78 °C, Tebbe
reagent (4.46 mL of 0.5 M in benzene, 2.23 mmol) was added,
and the solution was allowed to rise to rt overnight. The
reaction mixture was quenched with 15% sodium hydroxide
solution (2.5 mL) and diluted with ether. The organic phase
was dried, filtered through a Celite pad, and evaporated.
Purification by column chromatography gave 592 mg of alcohol
155 mg of oxetane (-)-18 (71%). [R]25 ) -6.1 (c 1.0, CHCl3).
D
IR (film): ν 3049, 3053, 1252, 1078 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.40-7.24 (m, 5H), 5.69 (ddd, J ) 16.9, 10.2, 9.3
Hz, 1H), 5.14 (dd, J ) 10.2, 2.1 Hz, 1H), 5.06 (dd, J ) 16.9,
2.1 Hz, 1H), 4.91 (br-dd, J ) 9.2, 3.8 Hz, 1H), 4.90 and 4.76
(AB, J ) 7.3 Hz, 2H), 4.66 and 4.55 (ABX, J ) 7.7, 1.2, 0.8
Hz, 2H), 4.46 and 4.28 (AB, J ) 11.6 Hz, 2H), 3.94 (dd, J )
11.2, 6.4 Hz, 1H), 3.39 and 3.05 (AB, J ) 8.6 Hz, 2H), 3.39 (s,
3H), 2.85 (d, J ) 9.3 Hz, 1H), 2.29 (ddd, J ) 15.0, 9.2, 6.4 Hz,
1H), 1.93 (ddd, J ) 15.0, 11.2, 3.8 Hz, 1H), 1.02 (s, 3H), 0.88
(s, 9H), 0.03 (s, 3H), 0.02 (s, 3H). 13C NMR (125 MHz, CDCl3):
δ ) 138.6 (C), 132.7 (CH), 128.1 (2 CH), 127.5 (2 CH), 127.3
(CH), 120.1 (CH2), 91.9 (CH2), 84.3, (CH), 80.0 (C), 75.9 (CH2),
72.7 (CH2), 72.3 (CH2), 68.1 (CH), 55.6 (CH3), 47.4 (CH), 42.1
(C), 37.0 (CH2), 25.8 (3 CH3), 18.0 (C), 10.8 (CH3), -4.1 (CH3),
-5.1 (CH3). Anal. Calcd for C26H42O5Si: C, 67.49; H, 9.15.
Found: C, 67.87; H 9.12.
(-)-13 (76% yield from compound (-)-12). [R]25 ) -17.7 (c
D
1.0, CHCl3). IR (film): ν 3429, 3061, 1258, 1053 cm-1. 1H NMR
(300 MHz, CDCl3): δ 7.34-7.27 (m, 5H), 5.44 (ddd, J ) 16.6,
10.1, 10.1 Hz, 1H), 5.15 (dd, J ) 10.1, 2.0 Hz, 1H), 5.08 (dd, J
) 16.6, 2.0 Hz, 1H), 4.47 (s, 2H), 3.89 (dd, J ) 12.1, 4.8 Hz,
1H), 3.78 (dd, J ) 12.1, 4.8 Hz, 1H), 3.39 and 3.27 (AB, J )
9.1 Hz, 2H), 2.97 and 2.56 (AB, J ) 5.3 Hz, 2H), 2.33 (d, J )
10.1 Hz, 1H), 2.11 (ddd, J ) 12.1, 4.8, 4.8 Hz, 1H), 1.70 (ddd,
J ) 12.1, 12.1, 12.1 Hz, 1H), 0.97 (s, 3H), 0.85 (s, 9H), 0.04 (s,
3H), 0.03 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 137.7 (C), 130.1
(CH), 128.5 (2 CH), 127.8 (CH), 127.5 (2 CH), 121.2 (CH2), 78.2
(CH), 73.6 (CH2), 72.2 (CH2), 67.8 (CH), 59.9 (C), 47.3 (CH),
44.2 (CH2), 43.0 (C), 38.6 (CH2), 25.7 (3 CH3), 18.1 (C), 10.8
(1S,2S,3R,4S,6R)-3-Benzyloxymethyl-4-(tert-butyldi-
methylsilyloxy)-1-methoxymethoxy-3-methyl-7-oxabi-
cyclo[4.2.0]octane-2-carbaldehyde (-)-1. To a stirred solu-
tion of (-)-18 (100 mg, 0.22 mmol) in 8.0 mL of a THF/water
(3/1) mixture was added OsO4 (0.11 mmol, 4 wt % in water).
The solution turned black, sodium metaperiodate (140 mg, 0.66
mmol) was added, and the reaction mixture was stirred for 4
days at rt under an argon atmosphere. After dilution with
water and extraction with CH2Cl2, the combined extracts were
dried with MgSO4 and concentrated in vacuo to afford crude
aldehyde. After purification by column chromatography and
crystallization from Et2O-hexane, 82 mg (82%) of pure alde-
3488 J. Org. Chem., Vol. 70, No. 9, 2005

Chemoenzymatic Taxanes
hyde (-)-1 was obtained as a clear oil. [R]25 ) -24.7 (c 1.0,
Acknowledgment. We are thankful to Dr. R. Faure
and Dr. M. Giorgi for 2D-NMR and X-ray diffraction
experiments. We thank P. Fournier for the English
language revision of the manuscript.
D
CHCl3). IR (film): ν 2847, 1704, 1391, 1257, 703 cm-1; 1H NMR
(500 MHz, CDCl3): δ 9.68 (d, J ) 1.1 Hz, 1H), 7.35-7.28 (m,
5H), 4.86 and 4.75 (AB, J ) 7.4 Hz, 2H), 4.83 and 4.73 (br-
AB, J ) 8.7 Hz, 2H), 4.82 (partially overlaped br-dd, J ) 9.0,
4.4 Hz, 1H), 4.60 and 4.39 (AB, J ) 11.8 Hz, 2H), 3.89 (dd, J
) 10.7, 5.6 Hz, 1H), 3.52 and 3.35 (AB, J ) 9.3 Hz, 2H), 3.35
(s, 3H), 3.22 (br-s, 1H), 2.25 (ddd, J ) 14.8, 9.0, 5.6 Hz, 1H),
1.97 (ddd, J ) 14.8, 10.7, 4.4 Hz, 1H), 1.11 (s, 3H), 0.88 (s,
9H), 0.05 (s, 3H), 0.04 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
202.0 (C), 138.0 (C), 128.4 (2 CH), 127.8 (CH), 127.7 (2 CH),
92.1 (CH2), 84.4 (CH), 78.0 (C), 77.2 (CH2), 73.1 (CH2), 72.7
(CH2), 68.4 (CH), 55.6 and 55.5 (CH3/CH), 42.7 (C), 36.2 (CH2),
25.8 (3 CH3), 18.0 (C), 12.9 (CH3), -4.1 (CH3), -5.1 (CH3). Anal.
Calcd for C25H40O6Si: C, 64.62; H, 8.68. Found: C, 64.94; H
8.64.
Supporting Information Available: Experimental pro-
cedures as well as complete 1H and 13C NMR spectral data of
compounds (-)-3, (+)-4, (+)-5, (+)-6, (+)-7, (+)-9, (-)-12, (+)-
1
14, (+)-16, and (+)-17. Copies of the high-field H NMR and
13C NMR spectra of all compounds reported herein. NOESY
experiments for compound (-)-18. X-ray crystal structure of
(-)-12 in CIF format and ORTEP view. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO050039S
J. Org. Chem, Vol. 70, No. 9, 2005 3489