Chemical modification of a highly functionalized taxane. The consequences of an absent bridgehead double bond on oxetane D-ring construction

Article abstract of DOI:10.1021/jo0206566

An oxetane D-ring has been fused to the framework of the highly functionalized taxane 2. The synthetic route is based on a trimethylsilyl triflate-promoted epoxide-opening step, followed by stereocontrolled, regioreversed oxirane formation and reductive t

Full text of DOI:10.1021/jo0206566

Ch em ica l Mod ifica tion of a High ly F u n ction a lized Ta xa n e. Th e
Con sequ en ces of a n Absen t Br id geh ea d Dou ble Bon d on Oxeta n e
D-Rin g Con str u ction
Leo A. Paquette* and Ho Yin Lo
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
paquette.1@osu.edu
Received October 17, 2002
An oxetane D-ring has been fused to the framework of the highly functionalized taxane 2. The
synthetic route is based on a trimethylsilyl triflate-promoted epoxide-opening step, followed by
stereocontrolled, regioreversed oxirane formation and reductive transposition of this intermediate
with bis(cyclopentadienyl)titanium(III) chloride. This last key step provides for the convenient
implementation of additional hydroxyl groups ultimately conducive to intramolecular SN2 reaction.
Tangential features of the route outlined herein include specific rearrangement reactions and a
retro-aldol cleavage of ring A.
In our synthetic effort directed toward Taxol, we
targeted a short route that was also sufficiently flexible
to permit practical access to analogues. The combined
application of anionic oxy-Cope1 and R-ketol rearrange-
ments2 has been shown to fulfill our early expectations
in that a convergent route from enantiomerically pure 1
to tricyclic diketone 2 has been realized in only 15 steps
and 5.7% overall yield.3,4 This notably efficient pathway
also allows for incorporation of the absolute configuration
of (+)-camphor into the target compounds. In light of the
high level of substitution in 2 and the essentially
complete overlay of its stereocenters with those resident
in Taxol (5),5 the former was considered to be a good
candidate for forward progress.
heterocyclic ring late in the overall scheme after the
bridgehead (C11-C12) double bond has been installed.
The alternative ploy utilized by Danishefsky comprised
(6) (a) 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. (b) Holton, R. A.;
Kim, H.-B.; Somoza, C.; 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, 1599.
(7) (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. (b) Nicolaou,
K. C.; Nantermet, P. G.; Ueno, H.; Guy, R. K.; Couladouros, E. A.;
Sorensen, E. J . J . Am. Chem. Soc. 1995, 117, 524. (c) Nicolaou, K. C.;
Liu, J .-J .; Yang, Z.; Ueno, H.; Sorensen, E. J .; Claiborne, C. F.; Guy,
R. K.; Hwang, C.-K.; Nakada, M.; Nantermet, P. G. J . Am. Chem. Soc.
1995, 117, 634. (d) Nicolaou, K. C.; Yang, Z.; Liu, J .-J .; Nantermet, P.
G.; Claiborne, C. F.; Renaud, J .; Guy, R. K.; Shibayama, K. J . Am.
Chem. Soc. 1995, 117, 645. (e) 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.
(8) (a) Masters, J . J .; Link, J . T.; Snyder, L. B.; Young, W. B.;
Danishefsky, S. J . Angew. Chem., Int. Ed. Engl. 1995, 34, 1723. (b)
Danishefsky, S. J .; Masters, J . J .; Young, W. B.; Link, J . T.; Snyder,
L. B.; Magee, T. V.; J ung, 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.
(9) (a) Wender, P. A.; Badham, N. F.; Conway, S. P.; Floreancig, P.
E.; Glass, T. E.; Gra¨nicher, C.; Houze, J . B.; J a¨nichen, J .; Lee, D.;
Marquess, D. G.; McGrane, P. L.; Meng, W.; Mucciaro, T. P.; Mu¨hle-
bach, M.; Natchus, M. G.; Paulsen, H.; Rawlins, D. B.; Satkofsky, J .;
Shuker, A. J .; Sutton, J . C.; Taylor, R. E.; Tomooka, K. J . Am. Chem.
Soc. 1997, 119, 2755. (b) Wender, P. A.; Badham, N. F.; Conway, S.
P.; Floreancig, P. E.; Glass, T. E.; Houze, J . B.; Krauss, 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.
(10) (a) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Sakoh, H.; Tani,
Y.; Hasegawa, M.; Saitoh, K.;Proc. J apan Acad. 1997, 73, Ser. B, 95.
(b) Mukaiyama, T.; Shiina, 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.
(11) (a) Morihira, K.; Hara, R.; Kawahara, S.; Nishimori, T.;
Nakamura, N.; Kusama, H.; Kuwajima, I. J . Am. Chem. Soc. 1998,
120, 12980. (b) Kusama, H.; Hara, R.; Kawahara, S.; Nishimori, T.;
Kashima, H.; Nakamura, N.; Morihira, K.; Kuwajima, I. J . Am. Chem.
Soc. 2000, 122, 3811.
Consideration of the chemical complexities to be dealt
with does not make apparent which of two possible
directions to advance on first. Completion of the western
sector translates into immediate investigation of A-ring
chemistry. The second option involves the eastern sector
of 2 and gives priority to proper introduction of the
oxetane ring. Of the six prior successful de novo syntheses
of taxol,6-11 all but one entails construction of the strained
(1) (a) Paquette, L. A. Tetrahedron 1997, 53, 13971. (b) Paquette,
L. A. Angew. Chem., Int. Ed. Engl. 1990, 29, 609.
(2) Paquette, L. A.; Hofferberth, J . E. Org. React., in press.
(3) Paquette, L. A.; Hofferberth, J . E. J . Org. Chem. 2003, 68, 2266.
(4) Paquette, L. A.; Lo, H. Y.; Hofferberth, J . E.; Gallucci, J . C. J .
Org. Chem. 2003, 68, 2276.
(5) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A.
T. J . Am. Chem. Soc. 1971, 93, 2325.
10.1021/jo0206566 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003
2282
J . Org. Chem. 2003, 68, 2282-2289

Chemical Modification of a Highly Functionalized Taxane
SCHEME 1 a
early introduction of the oxetane D-ring with the
Wieland-Miescher ketone serving as the matrix.8 Since
no attention had yet been paid to 11,12-dihydro systems,
we decided to proceed from 2 in the general direction of
4. A comparative analysis would thereby be enabled. The
presence of bridgehead unsaturation in 5 and its im-
mediate congeners flattens the A-ring sector and thereby
releases nonbonded steric compression throughout the
core structure to an appreciable level. On the other hand,
2, 4, and relatives thereof are not subject to comparable
diminution of steric strain and have a very crowded
hemispherical topology. The challenges associated with
this plan of action form the subject of this paper.
Resu lts a n d Discu ssion
The first attempts made to carry 2 forward involved
the isomerization of its epoxide to the ring-cleaved allylic
alcohol. In view of precedent,8 aluminum isopropoxide
was initially resorted to. However, only wholesale de-
a
Key: (a) TMSOTf, 2,6-lutidine, TfOH, -78 to 0 °C (55%); (b)
CSA, CH2Cl2, rt (55%); (a, b) as above, no intermediate workup
(75% for two steps); (c) TMSOTf, 2,6-lutidine, DBU, 0 °C (91%);
(d) TESOTf, DBU, 0 °C (68%); (e) Ac2O, Et3N, DMAP, CH2Cl2
(100%).
conditions, particularly the addition of triflic acid as a
co-catalyst, proved successful. The reactivity of the ep-
oxide is significantly enhanced by protonolysis and
conversion to 6 proceeds effectively as long as conditions
remain acidic even after the addition of DBU. Product 6
was expectedly sensitive to chromatographic conditions.
Practical considerations led us to hydrolyze 6 directly to
allylic alcohol 7, this two-step conversion proceeding in
an acceptable 75% overall yield.
All attempts to bring about the dihydroxylation of 7
with osmium tetraoxide were to no avail, undoubtedly a
direct consequence of the considerable steric hindrance
in the vicinity of the endocyclic double bond. In the
case of ruthenium tetraoxide, which has a smaller size,
uncontrolled oxidation was noted and considerable C-ring
cleavage ensued. An unexpected observation was the
formation of R,â-unsaturated aldehyde 11 when 7 was
exposed to OsO4 in the presence of DABCO as an
accelerating ligand (Scheme 2).
composition was seen in refluxing benzene or toluene.
Subsequently, various alternative methods were probed
including MICA,12 diethylaluminum tetramethylpiperi-
dide,13 lithium amide bases,14 and boron trifluoride
etherate with and without added DBU. All of these
reagents except for the Lewis acid combination led again
to decomposition. These observations prompted our con-
sideration of the trimethylsilyl triflate-DBU tandem15,16
to realize our goal. When these conditions were applied
in the predescribed manner, only silyl enol ether 9 was
isolated (91%, Scheme 1). An increase in the amount of
the silyl triflate resulted only in bis-silylation as exempli-
fied by 10. However, more careful control of reaction
Foreshadowed by the above experiments was the need
to effect translocation of the double bond to the somewhat
less crowded external position. Initially, a path adapted
from Mukaiyama et al.10 was pursued. Exposure of 7 to
the action of triphenylphosphine and carbon tetrabromide
did indeed furnish primary bromide 12. However, 12
totally resisted CuBr-promoted allylic rearrangement to
13 when heated in acetonitrile for extensive periods of
time. The thermodynamic bias in favor of 12 can also be
reasoned in terms of the heightened crowding in 13.
Concurrent studies of the epoxidation of 7 with m-
CPBA revealed that R-epoxidation to give 14 could be
accomplished efficiently. The stereochemistry of 14 was
(12) Swindell, C. S.; Britcher, S. F. J . Org. Chem. 1986, 51, 793.
(13) Paquette, L. A.; Ross, R. J .; Shi, Y. J . Org. Chem. 1990, 55,
1589.
1
1
unequivocally established by H-1H COSY and H-1H
NOESY experiments (see A). Beyond this objective,
attempts were made to epoxidize acetate 8 with m-CPBA,
dimethyl dioxirane, and via the halohydrin. In light of
the singular lack of reactivity of this substrate and of
bromide 12, it was made clear that precoordination of
the peracid to the allylic hydroxyl in 7 is a likely
(14) (a) LDA, KO-t-Bu: Mordini, A.; Ben Rayana, E.; Margot, C.;
Schlosser, M. Tetrahedron 1990, 46, 2401. (b) LiN(C2H5)2: Sheng, M.
N. Synthesis 1972, 194. (c) LiNHCH2CH2NH2: Giguere, R. J .; Hoff-
mann, H. M. R. Tetrahedron Lett. 1981, 22, 5039.
(15) Wovkulich, P. M.; Tang, P. C.; Chadha, N. K.; Batcho. A. D.;
Barrish, J . C.; Uskokovic, M. R. J . Am. Chem. Soc. 1989, 111, 2596.
(16) Murata, S.; Suzuki, M.; Noyori, R. J . Am. Chem. Soc. 1979,
101, 2738.
J . Org. Chem, Vol. 68, No. 6, 2003 2283

Paquette and Lo
SCHEME 2 a
TABLE 1. Con d ition s Exa m in ed for th e Red u ctive
Deoxygen a tion of 14
product ratio
run
a
conditions
T, °C yield, %
16/17
1.2 equiv of Cp2TiCl2,
5 equiv of activated Zn,
1.2 equiv of ZnCl2, THF
25
25
82
72
1:1.2
1:0
b
c
10 equiv of Cp2TiCl2,
20 equiv of activated Zn,
10 equiv of ZnCl2, THF
1.2 equiv of Cp2TiCl2,
5 equiv of activated Zn,
1.2 equiv of ZnCl2, THF
0
NRa
NRa
d
5 equiv of Cp2TiCl2, THF
25
a
NR signifies that no observable reaction was seen.
reagents (run b) proved particularly efficacious in deliv-
ering 16 (72% yield) without contamination by diol 17.
The insufficiency of titanocene reagent apparent in runs
a and c conforms to the proposed mechanistic analysis
of this process,17,18 where the involvement of at least two
equiv of the titanium complex is believed to be involved.
Also relevant to these studies is the observation that
epoxy acetate 15 was unaffected by this reagent combi-
nation, in conformity with the proposition that the OH
functionality is the initial site of reaction.
When an opportunity presented itself to bring about
the mesylation of 16 under conventional conditions,
quantitative conversion to 18 was noted. The ready
isomerization observed with sulfonate ester formation
was not matched by acetylation.19 This dichotomy sug-
gests that mesylation also occurs with derivatization of
the secondary alcohol. However, ionization to the allylic
cation is now energetically feasible, with covalent capture
subsequently materializing at the less crowded primary
site.
The time had now arrived to examine the dihydroxy-
lation of 16. This chemistry was initially pursued by
exposure of the allylic alcohol to osmium tetraoxide in a
THF/pyridine solvent system. The presence of pyridine
was essential to the reaction, which however resulted in
formation of osmate ester 19 (Scheme 3). Rather unex-
pectedly, this substance was highly resistant to controlled
hydrolysis. Conditions were not found to bring about its
conversion to the triol, cyclic carbonate, or TMS-protected
tetrol. When aqueous acetone served as the reaction
medium, conversion to 21 was seen. The formation of this
ring-cleaved product is presumably the result of over-
oxidation of the dihydroxy aldehyde level followed by
retro-aldol cleavage and intramolecular transesterifica-
tion. This unwanted side reaction was curtailed to some
degree (20/21 ) 1:1.1) through use of ruthenium trichlo-
ride-sodium periodate.20 To our delight, substitution of
DABCO for pyridine as the accelerating ligand for OsO4
gave rise to 20 as the sole observable product in 75% yield
after chromatography.
a
Key: (a) OsO4, DABCO, THF, rt; Na2S2O4 (90%); (b) PPh3,
CBr4, CH2Cl2, rt (96%); (c) CuBr, CH3CN, 50 °C to reflux; (d)
m-CPBA, NaHCO3, CH2Cl2 (90%); (e) Ac2O, DMAP, Et3N (100%);
(f) Cp2TiCl2, Zn, ZnCl2, THF (82%; 16/17 ) 1:1.2); (g) MsCl, Et3N,
DMAP, CH2Cl2 (100%).
prerequisite to oxirane formation. Under no conditions
was any sign of the â-epoxide found.
When arrival at the halo epoxide could be realized
neither by the epoxidation of 12 nor by reaction of 14
with triphenylphosphine and iodine, the role of 14 as a
key intermediate was pursued. Bis(cyclopentadienyl)-
titanium(III) chloride has been shown to react cleanly
with epoxy alcohols to deliver allylic alcohols in which
the original OH group is transposed.17 Of the various
conditions explored by us for the formation of 16 (Table
1), the use of a substantial excess of all three necessary
This tetraol was integrated into the main synthetic
pathway by quantitative monosilylation of the primary
(18) Yadav, J . S.; Shekharam, T.; Gadgil, V. R. J . Chem. Soc., Chem.
Commun. 1990, 843.
(19) Lo, H. Y. Unpublished results.
(20) Shing, T. K. M.; Tai, V. W.-F.; Tam, E. K. W. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 2312.
(17) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1994, 116,
986.
2284 J . Org. Chem., Vol. 68, No. 6, 2003

Chemical Modification of a Highly Functionalized Taxane
SCHEME 3 a
temperature. Quite unexpectedly, these conditions proved
conducive to loss of the trimethylsilyl substituent and its
transformation into a mesylate. This undesired reaction
was skirted by performing the activation step in CH2Cl2
solution with DMAP as the activator. The regioselectivity
associated with the formation of 24 has its origins in
steric accessibility as usual. Deprotection of the primary
alcohol to deliver 25 proceeded without incident.
The final stage of the pursuit of 28 was to involve
intramolecular SN2 displacement with configurational
inversion at C-5. This goal proved more elusive than
projected. Recourse to tetra-n-butylammonium acetate in
butanone at 25 °C in an adaptation of Nicolaou’s best
conditions for construction of the Taxol D-ring7 caused
rapid decomposition. In an interesting development, a
change in solvent to CH2Cl2 exhibited a profound effect
on the reaction pathway. Under these circumstances,
benzoyl migration occurred to generate 26, thereby
making possible retro-aldol fragmentation of the A-ring
with conversion to 27 (70%).19 The same transformation
accompanied the use of DMAP in THF at room temper-
ature (82% yield). At this point, the timely observation
was made that the exposure of 25 to aluminum tert-
butoxide in benzene promoted the desired ring closure
and furnished 4a . Accordingly, the feasibility of laterally
fusing an oxetane ring onto 2 has been demonstrated.
The assembly process required eight laboratory opera-
tions and proceeded in 18% overall yield. The effective-
ness of the titanium(III)-mediated reductive deoxygen-
ation of 14 to give 16 was demonstrated in a highly
functionalized structural setting, and augurs well for its
exploitation in other complex settings. The successful
route reflects a number of deterrents brought on by sub-
stantive steric congestion. The adaptations made neces-
sary by these factors resulted in modest prolongation of
the synthetic pathway. We anticipate more favorable
consequences once the A-ring is suitably modified6-11 and
hope to be in a position to report on this matter soon.
a
Key: (a) OsO4, THF/py, rt; Na2S2O4 (75% at 65% conversion);
(b) OsO4, DABCO, THF, rt (75%); (c) RuCl3, NaIO4, CH3CN, H2O,
EtOAc (85%; 20/21 ) 1:1.1); (d) OsO4, H2O, acetone; Na2S2O4
(71%).
SCHEME 4 a
Exp er im en ta l Section
Ep oxid e Rin g Op en in g in 2. To a solution of 2 (10.7 mg,
0.15 µmol) in dry toluene (5 mL) were added 2,6-lutidine (1.6
µL, 0.015 mmol) and TMSOTf (5.4 µL, 0.03 mmol) at -78 °C
under N2. Trific acid (0.13 µL, 0.15 µmol) was added, and the
solution was stirred at -78 °C for 3 h. DBU (2 µL, 0.015 mmol)
was introduced, the reaction flask was immediately transferred
from the dry ice-acetone bath to an ice water bath, stirring
at this temperature was maintained for 5 h, and saturated
NaHCO3 solution (10 mL) was added. After 10 min, the
resulting mixture was extracted with EtOAc (2 × 20 mL), the
combined organic extracts were dried and filtered, and the
residue was subjected to flash chromatography on silica gel
(elution with 8:1 hexane/EtOAc) to afford 6 (6.4 mg, 55%) as
a colorless oil: IR (neat, cm-1) 3491, 1729, 1701, 1513; 1H NMR
(500 MHz, C6D6) δ 8.18-8.16 (m, 2 H), 7.46 (d, J ) 8.6 Hz, 2
H), 7.05-7.02 (m, 3 H), 6.84 (d, J ) 8.6 Hz, 2 H), 6.27 (d, J )
4.3 Hz, 1 H), 5.67 (br s, 1 H), 4.65 (d, J ) 10.2 Hz, 1 H), 4.49
(d, J ) 3.8 Hz, 1 H), 4.30 (d, J ) 12.1 Hz, 1 H), 4.22 (s, 1 H),
4.19 (br s, 1 H), 4.14 (d, J ) 12.1 Hz, 1 H), 3.95 (t, J ) 7.7 Hz,
1 H), 3.88 (d, J ) 10.3 Hz, 1 H), 3.26 (s, 3 H), 3.26-3.24 (m,
1 H), 2.64-2.59 (dd, J ) 6.8, 18.3 Hz, 1 H), 2.29 (br s, 1 H),
2.09-2.05 (m, 3 H), 1.79-1.77 (m, 1 H), 1.77 (s, 3 H), 1.34 (s,
3 H), 0.93 (s, 9 H), 0.76 (s, 3 H), 0.19 (s, 9 H), 0.00 (s, 3 H),
0.11 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 212.1, 209.2, 164.5,
159.6, 153.1, 135.9, 132.8, 130.5, 129.8, 129.5, 128.5, 126.9,
113.8, 84.7, 83.5, 73.6, 72.0, 71.5, 66.2, 57.7, 54.4, 51.9, 43.0,
a
Key: (a) TMSCl, 2,6-lutidine, CH2Cl2, -78 °C (100%); (b) MsCl,
py, rt (85%); (c) MsCl, DMAP, CH2Cl2, (90%); (d) CSA, CH2Cl2, rt
(95-100%); (e) (n-Bu)4NOAc, CH2Cl2, rt (70%) or DMAP, THF, rt
(82%); (f) Al(O-t-Bu)3, C6H6, rt (54%).
hydroxyl group as in 22 (Scheme 4). For the purpose of
transforming the OH at C-5 into a leaving group, 22 was
exposed to methanesulfonyl chloride in pyridine at room
J . Org. Chem, Vol. 68, No. 6, 2003 2285

Paquette and Lo
40.4, 38.4, 30.9, 30.7, 27.9, 25.9, 22.5, 18.3, 12.0, -0.1, -2.1,
-4.1; ES HRMS m/z (M - Me3Si + Na + H) calcd 739.3429,
EI HRMS (M + 1)+ calcd 779.4005, obsd 779.3986; [R]20 +23
D
(c 0.24, CHCl3).
obsd 729.3439; [R]20 +19 (c 0.22, CHCl3).
D
Bis-silyla tion of 2. To a solution of 2 (3.1 mg, 0.004 mmol)
in dry toluene (2 mL) were added DBU (2.8 µL, 0.02 mmol)
and TESOTf (2 µL, 0.009 mmol) at -78 °C under N2. The
solution was slowly warmed to 0 °C during 2 h prior to
quenching with saturated NaHCO3 solution (10 mL). After 10
min, the mixture was extracted with EtOAc (2 × 20 mL), and
the combined organic phases were dried and filtered. Concen-
tration of the filtrate followed by flash chromatography on
silica gel (elution with 20:1 hexane/EtOAC) afforded 10 (2.5
mg, 68%) as a colorless oil: 1H NMR (500 MHz, C6D6) δ 8.40-
8.38 (m, 2 H), 7.46 (d, J ) 8.5 Hz, 2 H), 7.29-7.17 (m, 3 H),
6.83 (d, J ) 8.5 Hz, 2 H), 5.93 (d, J ) 4.0 Hz, 1 H), 4.96 (d, J
) 3 Hz, 1 H), 4.77 (d, J ) 10.4 Hz, 1 H), 4.59 (d, J ) 4.8 Hz,
1 H), 4.39-3.38 (m, 1 H), 4.18 (d, J ) 10.4 Hz, 1 H), 3.40 (d,
J ) 4.0 Hz, 1 H), 3.27 (s, 3 H), 3.05 (br s, 1 H), 2.59 (dd, J )
4.0, 15.8 Hz, 1 H), 2.31-2.29 (m, 1 H), 2.12 (dd, J ) 5.3, 18
Hz, 1 H), 2.04 (d, J ) 4.1 Hz, 1 H), 1.88-1.85 (m, 1 H), 1.62
(s, 3 H), 1.55-1.51 (m, 1 H), 1.39 (s, 3 H), 1.28 (m, 2 H), 1.14
(t, J ) 7.4 Hz, 9 H), 1.13-1.08 (m, 9 H), 0.94 (s, 9 H), 0.81 (t,
J ) 7.9 Hz, 9 H), 0.77-0.64 (m, 3 H), 0.59-0.51 (m, 3 H), 0.00
(s, 3 H), -0.03 (s, 3 H).
Hyd r olysis of 6 to 7. A 10 mg (0.013 mmol) sample of 6 in
5 mL of CH2Cl2 was treated with 15 mg (0.642 µmol) of CSA.
The reaction mixture was stirred for 30 min at rt, quenched
with a saturated solution of aqueous NaHCO3, transferred to
a separatory funnel, and extracted with EtOAc. The combined
organic extracts were dried, filtered, and concentrated under
reduced pressure to give a residue that was purified by column
chromatography on silica gel (elution with 5:1 hexane/EtOAc)
to give 5.0 mg (55%) of 7 as a colorless oil: IR (neat, cm-1
)
3488, 1725, 1514; 1H NMR (500 MHz, C6D6) δ 8.11 (d, J ) 7.9
Hz, 2 H), 7.47 (d, J ) 8.4 Hz, 2 H), 7.08-6.98 (m, 3 H), 6.84
(d, J ) 8.4 Hz, 2 H), 6.25 (d, J ) 4.3 Hz, 1 H), 5.36 (br s, 1 H),
4.67 (d, J ) 10.2 Hz, 1 H), 4.48 (d, J ) 4.1 Hz, 1 H), 4.23 (d,
J ) 12 Hz, 1 H), 4.20 (s, 1 H), 4.14 (br s, 1 H), 3.97-3.94 (m,
2 H), 3.84 (d, J ) 12 Hz, 1 H), 3.34-3.27 (m, 1 H), 3.27 (s, 3
H), 2.59 (dd, J ) 6.6, 18.3 Hz, 1 H), 2.35-2.28 (m, 1 H), 2.08-
1.99 (m, 3 H), 1.86-1.76 (m, 1 H), 1.72 (s, 3 H), 1.33 (s, 3 H),
0.94 (s, 9 H), 0.91-0.89 (m, 1 H), 0.77 (s, 3 H), 0.02 (s, 3 H),
-0.05 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 213.8, 210.6, 165.0,
159.3, 136.5, 133.2, 129.7, 129.6, 129.5, 128.6, 126.8, 113.8,
84.3, 83.4, 73.2, 71.9, 71.6, 66.6, 57.5, 55.2, 52.1, 43.1, 39.3,
38.2, 30.9, 30.8, 27.6, 25.9, 22.6, 18.3, 14.1, 11.9, -1.9, -3.9;
Acetyla tion of 7. A solution of 7 (5 mg, 0.007 mmol) in
CH2Cl2 (3 mL) was treated sequentially with Et3N (3 µL, 0.021
mmol), acetic anhydride (0.8 µL, 0.008 mmol), and DMAP (0.1
mg, 0.8 µmol), stirred at rt for 1 h, and quenched with
saturated NaHCO3 solutions (10 mL). After 3 min of stirring,
the mixture was extracted with EtOAc (2 × 20 mL), the
combined organic phases were dried and filtered, and the
residue was subjected to flash chromatography on silica gel
(elution with 10:1 hexane/EtOAc) to afford 8 (5.3 mg, 100%)
ES HRMS m/z (M + Na)+ calcd 729.3429, obsd 729.3411; [R]20
D
-2.3 (c 0.64, CHCl3).
Dir ect Con ver sion of 2 to 7. To a solution of 2 (10 mg,
0.014 mmol) in dry toluene (5 mL) were added 2,6-lutidine (1.6
µL, 0.014 mmol) and TMSOTf (5.4 µL, 0.028 mmol) at -78 °C
under N2. Triflic acid (0.13 µL, 0.15 µmol) was added, and the
solution was stirred at -78 °C for 3 h. DBU (2 µL, 0.015 mmol)
was introduced, the reaction flask was immediately transferred
from the dry ice-acetone bath to an ice-water bath, stirring
at this temperature was maintained for 5 h, and saturated
NaHCO3 solution (10 mL) was added. After 10 min, the
resulting mixture was extracted with EtOAc (2 × 20 mL), and
the combined organic extracts were dried and filtered. CSA
(16 mg, 0.07 mmol) was added, and the solution was stirred
at rt for 1 h prior to quenching with saturated NaHCO3
solution (20 mL). After 10 min, the resulting mixture was
extracted with EtOAc (2 × 20 mL), the combined organic
phases were dried and filtered, and the concentrate was
subjected to flash chromatography on silica gel (elution with
2:1 hexane/EtOAc) to give 7 (7.5 mg, 75%) as a colorless oil
identical to the material isolated above.
1
as a colorless oil: IR (neat, cm-1) 3482, 1733, 1252; H NMR
(400 MHz, C6D6) δ 8.30 (d, J ) 8.2 Hz, 2 H), 7.57 (d, J ) 8.6
Hz, 2 H), 7.19-7.11 (m, 3 H), 6.97 (d, J ) 8.6 Hz, 2 H), 6.40
(d, J ) 5.1 Hz, 1 H), 5.61 (br s, 1 H), 4.87 (d, J ) 4.3 Hz, 1 H),
4.82 (d, J ) 10.2 Hz, 1 H), 4.77 (d, J ) 13.5 Hz, 1 H), 4.63 (br
s, 1 H), 4.57 (d, J ) 13.5 Hz, 1 H), 4.37 (s, 1 H), 4.20 (t, J )
7.6 Hz, 1 H), 4.13 (d, J ) 10.2 Hz, 1 H), 3.96-3.86 (m, 1 H),
3.40 (s, 3 H), 2.83 (dd, J ) 6.4, 18.4 Hz, 1 H), 2.43 (br s, 1 H),
2.23-2.14 (m, 3 H), 2.02-1.97 (m, 1 H), 1.90 (s, 3 H), 1.76 (s,
3 H),1.46 (s, 3 H), 1.06 (s, 9 H), 0.91 (s, 3 H), 0.12 (s, 3 H),
0.00 (s, 3 H); 13C NMR (125 MHz, C6D6) δ 213.3, 209.5, 170.6,
164.8, 159.9, 134.4, 133.3, 130.7, 130.4, 130.2, 130.0, 129.0,
124.9, 114.1, 84.4, 84.1, 74.0, 71.99, 71.94, 67.5, 57.9, 54.7, 52.1,
43.1, 42.3, 38.5, 31.2, 31.1, 28.1, 26.2, 23.1, 23.1, 20.7, 18.6,
12.4, -1.8, -3.8; ES HRMS m/z (M + Na)+ calcd 771.3534,
obsd 771.3562; [R]20 +3.2 (c 0.47, CHCl3).
Silyl En ol Eth er 9. To a solution of 2 (10 mg, 0.014 mmol)
in dry toluene (5 mL) were added 2,6-lutidine (1.6 µL, 0.014
mmol) and TMSOTf (5.4 µL, 0.028 mmol) at -78 °C under N2.
The solution was stirred at -78 °C for 3 h, DBU (9.6 µL, 0.07
mmol) was added, and the reaction flask was immediately
transferred from the dry ice-acetone bath to an ice-water
bath. After 5 h of stirring at this temperature, saturated
NaHCO3 solution (10 mL) was added, and the mixture was
stirred for 10 min, extracted with EtOAc (2 × 20 mL), dried,
and filtered. Concentration of the filtrate followed by flash
chromatography on silica gel (elution with 12:1 hexane/EtOAc)
D
Un sa tu r a ted Ald eh yd e 11. A solution of 7 (2.8 mg, 0.004
mmol) in THF (2 mL) containing DABCO (0.9 mg, 0.008 mmol)
was treated with OsO4 (1 mg, 0.004 mmol) at rt. After 6 h,
Na2S2O4 (3.5 mg, 0.02 mmol) dissolved in water (2 mL) was
introduced, and stirring was maintained for 3 h. The resulting
mixture was extracted with EtOAc (2 × 10 mL), the combined
organic phases were dried and filtered, and the residue was
purified by flash chromatography on silica gel (elution with
6:1 hexane/EtOAc) to give 11 (2.5 mg, 90%) as a colorless oil:
IR (neat, cm-1) 3459, 1724, 1514; 1H NMR (400 MHz, C6D6) δ
9.26 (s, 1 H), 7.84 (d, J ) 8.6 Hz, 2 H), 7.54-7.50 (m, 1 H),
7.38 (t, J ) 7.8 Hz, 2 H), 7.27-7.25 (m, 2 H), 6.85 (d, J )
8.6 Hz, 2 H), 6.49 (br s, 1 H), 5.78 (d, J ) 5.5 Hz, 1 H), 4.59-
4.54 (m, 2 H), 4.44 (br s, 1 H), 4.22 (s, 1 H), 4.01-3.97 (m, 2
H), 3.79 (s, 3 H), 3.37 (m, 1 H), 2.92 (dd, J ) 6.0, 17 Hz, 1 H),
2.50 (d, J ) 5.2 Hz, 1 H), 2.45-2.38 (m, 2 H), 2.25 (br s, 1 H),
1.87 (dd, J ) 7.6, 13.8 Hz, 1 H), 1.57 (s, 3 H), 1.23 (s, 3 H),
1.00 (s, 3 H), 0.92 (s, 9 H), 0.12 (s, 3 H), 0.00 (s, 3 H); 13C
NMR (75 MHz, C6D6) δ 209.9, 209.5, 192.3, 164.9, 159.4, 141.7,
140.8, 133.3, 130.0, 129.5, 129.2, 128.5, 113.9, 83.9, 83.8,
71.7, 71.6, 71.5, 55.6, 55.2, 52.1, 43.5, 38.3, 37.4, 31.3, 30.6,
29.6, 27.9, 25.8, 23.2, 18.3, 12.4, -1.9, -4.0; ES HRMS m/z
furnished 9 (9.9 mg, 91%) as a colorless oil: IR (neat, cm-1
)
1
1724, 1513; H NMR (500 MHz, C6D6) δ 8.27-8.25 (m, 2 H),
7.44 (d, J ) 8.6 Hz, 2 H), 7.14-7.11 (m, 3 H), 6.83 (d, J ) 8.6
Hz, 2 H), 5.93 (br s, 1 H), 4.926-4.921 (m, 1 H), 4.77 (d, J )
10.6 Hz, 1 H), 4.60 (d, J ) 4.6 Hz, 1 H), 4.43 (br s, 1 H), 4.20
(d, J ) 10.6 Hz, 1 H), 3.44 (br s, 1 H), 3.30 (s, 3 H), 3.09 (d, J
) 4.3 Hz, 1 H), 2.94 (s, 1 H), 2.55 (dd, J ) 3.8, 15.2 Hz, 1 H),
2.28-2.26 (m, 1 H), 2.17-2.11 (m, 2 H), 1.92-1.89 (m, 1 H),
1.71 (s, 3 H), 1.55-1.51 (m, 1 H), 1.38 (s, 3 H), 1.33-1.25 (m,
2 H), 1.15 (s, 3 H), 0.94 (s, 9 H), 0.24 (s, 9 H), 0.03 (s, 3 H),
0.00 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 209.4, 164.9, 159.5,
149.8, 132.9, 130.9, 130.4, 130.0, 129.4, 128.4, 128.3, 113.7,
103.1, 77.7, 74.0, 72.5, 71.1, 57.8, 54.4, 51.7, 50.6, 40.3, 30.7,
30.2, 30.1, 29.9, 29.8, 25.9, 22.4, 18.2, 11.8, -0.1, -2.2, -4.2;
(M + Na)+ calcd 727.3272, obsd 727.3286; [R]20 +36 (c 0.46,
D
CHCl3).
2286 J . Org. Chem., Vol. 68, No. 6, 2003

Chemical Modification of a Highly Functionalized Taxane
Allylic Br om id e 12. A solution of 7 (8.5 mg, 0.012 mmol)
in dry CH2Cl2 (6 mL) was treated with PPh3 (6.3 mg, 0.024
mmol) and CBr4 (12 mg, 0.036 mmol) under N2. The solution
was stirred at rt for 20 min, saturated NaHCO3 solution (10
mL) was added, and the reaction mixture was warmed to rt
and extracted with EtOAc (2 × 20 mL). The combined organic
phases were dried and filtered. Flash chromatography of the
residue on silica gel (elution with 12:1 hexane/EtOAc) fur-
nished 12 (8.9 mg, 96%) as a colorless oil: IR (neat, cm-1) 1729,
1699, 1513; 1H NMR (500 MHz, C6D6) δ 8.05 (d, J ) 7.3 Hz, 2
H), 7.44 (d, J ) 8.6 Hz, 2 H), 7.06-7.04 (m, 1 H), 6.97-6.94
(m, 2 H), 6.84 (d, J ) 8.6 Hz, 2 H), 6.23 (d, J ) 4.6 Hz, 1 H),
5.54 (br s, 1 H), 4.67 (d, J ) 10.4 Hz, 1 H), 4.62 (d, J ) 4.3 Hz,
1 H), 4.33 (d, J ) 10.5 Hz, 1 H), 4.27 (br s, 1 H), 4.15 (s, 1 H),
4.01 (t, J ) 7.5 Hz, 1 H), 3.97 (d, J ) 10.5 Hz, 1 H), 3.96 (d, J
) 10.4 Hz, 1 H), 3.59-3.51 (m, 1 H), 3.27 (s, 3 H), 2.69 (dd, J
) 6.7, 18.7 Hz, 1 H), 2.26 (s, 1 H), 2.06-1.98 (m, 1 H), 1.93-
1.92 (m, 2 H), 1.78-1.73 (m, 1 H), 1.69 (s, 3 H), 1.31 (s, 3 H),
0.93 (s, 9 H), 0.76 (s, 3 H), -0.02 (s, 3 H), -0.09 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 213.3, 210.4, 164.7, 159.4 134.8,
133.4, 132.2, 129.9, 129.7, 129.3, 129.2, 128.7, 113.8, 83.4, 83.1,
73.1, 71.6, 71.5, 57.1, 55.3, 51.8, 42.8, 39.2, 38.7, 37.3, 31.3,
31.0, 27.2, 25.8, 22.8, 18.3, 12.6, -1.9, -4.0; ES HRMS m/z
-2.4, -4.1; ES HRMS m/z (M + Na)+ calcd 787.3484, obsd
787.3480; [R]20 +4.4 (c 0.58, CHCl3).
D
Tita n iu m -P r om oted Deoxygen a tion /Red u ction of 14.
Activated zinc powder (2.2 mg, 0.035 mmol), ZnCl2 (1.1 mg,
8.3 µmol), and Cp2TiCl2 (2.1 mg, 8.3 µmol) were transferred
in a flame-dried 10 mL round-bottomed flask equipped with a
stirrer bar from a drybox. Dry THF (2 mL) was introduced,
and the mixture was stirred at rt under N2 for 1 h while the
color changed from red to green. The green solution was
transferred to a solution of 14 (5 mg, 7.0 µmol) in dry THF (1
mL), stirred for another 10 min, and treated with 3% HCl (5
mL). After 10 min, the mixture was extracted with EtOAc (2
× 20 mL); the combined organic extracts were dried, filtered,
and concentrated; and the residue was purified by flash
chromatography on silica gel (elution with 5:1 hexane/EtOAc)
to furnish 16 (1.9 mg, 39%) and 17 (2.1 mg, 43%), both as
colorless oils.
For 16: IR (neat, cm-1) 3470, 1718, 1508; 1H NMR (500
MHz, C6D6) δ 8.09 (m, 2 H), 7.43 (d, J ) 8.4 Hz, 2 H), 7.07-
6.98 (m, 3 H), 6.83 (d, J ) 7.9 Hz, 2 H), 6.03 (d, J ) 7.9 Hz, 1
H), 5.22 (s, 1 H), 4.89 (s, 1 H), 4.77-4.75 (m, 1 H), 4.73 (d, J
) 9.3 Hz, 1 H), 4.62-4.55 (m, 1 H), 4.37 (s, 1 H), 4.28 (d, J )
8.5 Hz, 1 H), 4.10 (d, J ) 10.1 Hz, 1 H), 3.89-3.85 (m, 1 H),
3.26 (s, 3 H), 2.93-2.90 (m, 1 H), 2.57-2.54 (m, 1 H), 2.40-
2.30 (m, 1 H), 2.24 (br s, 1 H), 1.98-1.96 (m, 1 H), 1.84-1.83
(m, 1 H), 1.66-1.63 (m, 2 H), 1.55 (s, 3 H), 1.27 (s, 3 H), 0.94
(s, 9 H), 0.73 (s, 3 H), 0.40 (s, 3 H), 0.00 (s, 3 H); ES HRMS
(M + Na)+ calcd 791.2585, obsd 791.2570; [R]20 +13 (c 0.88,
D
CHCl3).
Ep oxid a tion of 7. To a solution of 7 (4 mg, 5.7 µmol) in
CH2Cl2 (4 mL) at 0 °C were added NaHCO3 (2.4 mg, 0.029
mmol) and m-CPBA (2 mg, 0.011 mmol). The mixture was
stirred vigorously at 0 °C for 48 h, quenched with saturated
NaHCO3 solution (10 mL), and extracted with EtOAc (2 × 20
mL). The combined organic phases were dried, filtered, and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel (elution with 2:1 hexane/EtOAc) to afford
14 (3.6 mg, 90%) as a colorless oil: IR (neat, cm-1) 1731, 1700,
m/z (M + Na)+ calcd 729.3435, obsd 729.3387; [R]20 +16 (c
D
0.63, CHCl3).
1
For 17: IR (neat, cm-1) 3473, 1718, 1702, 1509; H NMR
(500 MHz, C6D6) δ 8.06-9.01 (m, 2 H), 7.41 (d, J ) 8.6 Hz, 2
H), 7.04-7.00 (m, 3 H), 6.81-6.77 (m, 2 H), 5.99 (d, J ) 3.5
Hz, 1 H), 4.81 (d, J ) 3.9 Hz, 1 H), 4.78-4.75 (m, 1 H), 4.71
(d, J ) 10.3 Hz, 1 H), 4.14 (d, J ) 10.3 Hz, 1 H), 3.97 (dd, J )
4.1, 10.6 Hz, 1 H), 3.97 (s, 1 H), 3.84 (s, 1 H), 3.56 (dd, J )
2.2, 10.4 Hz, 1 H), 3.45-3.43 (m, 1 H), 3.42 (dd, J ) 3.4, 11.7
Hz, 1 H), 3.21 (s, 3 H), 3.12-3.08 (m, 1 H), 2.42-2.38 (m, 1
H), 2.25 (s, 1 H), 1.95-1.90 (m, 2 H), 1.69-1.60 (m, 1 H), 1.43
(s, 3 H), 1.39 (s, 3 H), 1.30-1.10 (m, 3 H), 0.92 (s, 9 H), 0.69
(s, 3 H), 0.03 (s, 3 H), 0.00 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 215.8, 211.4, 165.2, 159.3, 133.2, 129.87, 129.83, 129.6, 113.8,
82.7, 82.5, 74.4, 71.2, 71.1, 67.7, 66.1, 60.4, 55.2, 51.7, 42.7,
39.6, 38.3, 36.9, 32.9, 30.7, 29.6, 27.2, 25.9, 22.1, 18.3, 8.9, -2.5,
-4.0; ES HRMS m/z (M + Na)+ calcd 747.3540, obsd 747.3467;
1
1514; H NMR (500 MHz, C6D6) δ 8.12 (d, J ) 7.4 Hz, 2 H),
7.45 (d, J ) 8.6 Hz, 2 H), 7.04-7.01 (m, 1 H), 6.95-6.92 (m, 2
H), 6.82 (d, J ) 8.6 Hz, 2 H), 5.99 (d, J ) 1.8 Hz, 1 H), 4.70 (d,
J ) 10.4 Hz, 1 H), 4.47 (s, 1 H), 4.39-4.36 (dd, J ) 5.4, 10.4
Hz, 1 H), 4.14 (d, J ) 10.4 Hz, 1 H), 4.11 (s, 1 H), 4.00 (d, J )
12.7 Hz, 1 H), 3.97 (br s, 1 H), 3.57 (s, 1 H), 3.28 (s, 3 H),
3.16-3.08 (m, 2 H), 2.57-2.51 (m, 1 H), 2.51 (d, J ) 9 Hz, 1
H), 2.16-2.10 (m, 2 H), 1.76-1.71 (m, 1 H), 1.63 (s, 1 H), 1.47-
1.44 (m, 1 H), 1.41 (s, 3 H), 1.31 (s, 3 H), 0.88 (s, 9 H), 0.69 (s,
3 H), 0.00 (s, 3 H), -0.03 (s, 3 H); 13C NMR (75 MHz, C6D6) δ
212.9, 208.5, 164.4, 159.6, 133.0, 130.5, 129.9, 129.8, 129.3,
128.7, 113.8, 88.0, 81.8, 72.7, 72.1, 70.5, 62.7, 59.7, 57.9, 57.6,
54.4, 52.4, 43.2, 41.4, 36.5, 29.8, 29.5, 27.4, 25.8, 20.8, 18.2,
10.0, -2.3, -4.0; ES HRMS m/z (M + Na)+ calcd 745.3378,
[R]20 +18 (c 0.25, CHCl3).
D
Im p r oved P r ep a r a tion of 16. Activated zinc powder (8
mg, 0.12 mmol), ZnCl2 (8 mg, 0.06 mmol), and Cp2TiCl2 (15
mg, 0.06 mmol) were transferred in a flame-dried 10-mL
round-bottomed flask equipped with a stirrer bar from a
drybox. Dry THF (2 mL) was introduced, and the mixture was
stirred at rt under N2 for 1 h while the color changed from
red to green. The green solution was transferred to neat 14
(4.5 mg, 0.006 mmol), and the solution was stirred for 10 min
prior to treatment with 3% HCl (5 mL). After 10 min, the
resulting mixture was extracted with EtOAc (2 × 20 mL); the
combined organic extracts were dried, filtered, and concen-
trated; and the residue was purified by flash chromatography
on silica gel (elution with 5:1 hexane/EtOAc) to provide 16 (3
mg, 72%) as the only product.
Mesyla tion of 16 w ith Allylic Rea gen t. To a solution of
16 (2.0 mg, 2.8 µmol) in dry CH2Cl2 (3 mL) were added Et3N
(7.8 µL, 0.056 mmol), DMAP (6.8 mg, 0.056 mmol), and
methanesulfonyl chloride (2.2 µL, 0.028 mmol) at rt under N2.
The reaction mixture was stirred for 1 h, diluted with
saturated NaHCO3 solution (10 mL), stirred for 10 min, and
extracted with EtOAc (2 × 10 mL). The combined organic
extracts were dried, filtered, and concentrated. The residue
was purified by flash chromatography on silica gel (elution
with 5:1 hexane/EtOAc) to give 18 (2.1 mg, 100%) as a colorless
oil: IR (neat, cm-1) 3482, 1724, 1699, 1514; 1H NMR (500 MHz,
C6D6) δ 8.11-8.09 (m, 2 H), 7.46 (d, J ) 8.6 Hz, 2 H), 7.08-
7.00 (m, 3 H), 6.85 (d, J ) 8.6 Hz, 2 H), 6.22 (d, J ) 4.7 Hz, 1
obsd 745.3328; [R]20 -12 (c 0.23, CHCl3).
D
Acetyla tion of 14. A solution of 14 (6.7 mg, 0.009 mmol)
in dry CH2Cl2 (5 mL) was treated with Et3N (13 µL, 0.09
mmol), DMAP (0.1 mg, 0.9 µmol), and Ac2O (4.3 µL, 0.045
mmol) at rt under N2, stirred for 1 h, quenched with saturated
NaHCO3 solution (10 mL), and extracted with EtOAc (2 × 20
mL). The combined organic extracts were dried, filtered, and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel (elution with 5:1 hexane/EtOAc) to afford
15 (7 mg, 100%) as a colorless oil: IR (neat, cm-1) 3462, 1734,
1514; 1H NMR (500 MHz, C6D6) δ 8.19-8.17 (m, 2 H), 7.44 (d,
J ) 8.6 Hz, 2 H), 7.08-7.06 (m, 3 H), 6.04 (d, J ) 2.2 Hz, 1
H), 4.72 (d, J ) 12.6 Hz, 1 H), 4.68 (d, J ) 10.5 Hz, 1 H), 4.46
(s, 1 H), 4.35 (dd, J ) 5.3, 10.3 Hz, 1 H), 4.23 (d, J ) 12.6 Hz,
1 H), 4.21 (s, 1 H), 4.14 (d, J ) 10.5 Hz, 1 H), 3.69 (s, 1 H),
3.38-3.29 (m, 1 H), 3.28 (s, 3 H), 2.82 (s, 1 H), 2.61 (dd, J )
8.9, 19 Hz, 1 H), 2.49 (d, J ) 9.2 Hz, 1 H), 2.13-2.10 (m, 2 H),
1.76-1.71 (m, 1 H), 1.69 (s, 3 H), 1.54-1.52 (m, 1 H), 1.42 (s,
3 H), 1.41 (s, 3 H), 0.89 (s, 9 H), 0.68 (s, 3 H), 0.00 (s, 3 H),
-0.02 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 212.3, 208.3, 169.6,
164.5, 159.6, 133.0, 130.5, 130.0, 129.3, 128.7, 116.4, 113.8,
88.1, 81.9, 72.5, 72.0, 70.2, 65.2, 58.1, 57.7, 56.8, 54.4, 52.3,
43.3, 41.6, 36.5, 29.9, 29.6, 27.5, 25.8, 20.8, 19.9, 18.2, 10.3,
J . Org. Chem, Vol. 68, No. 6, 2003 2287

Paquette and Lo
H), 5.66 (d, J ) 6.7 Hz, 1 H), 4.74 (d, J ) 12.1 Hz, 1 H), 4.69-
4.65 (m, 2 H), 4.59 (d, J ) 4.2 Hz, 1 H), 4.20 (s, 1 H), 4.11 (s,
1 H), 4.07 (dd, J ) 5.4, 10.0 Hz, 1 H), 4.01 (d, J ) 10.3 Hz, 1
H), 3.28 (s, 3 H), 3.27 (m, 1 H), 2.62 (dd, J ) 6.6, 18.6 Hz, 1 H)
2.39 (s, 3 H), 2.26-2.25 (m, 1 H), 2.07-1.91 (m, 3 H), 1.80-
1.79 (m, 1 H), 1.66 (s, 3 H), 1.30 (s, 3 H), 0.93 (s, 9 H), 0.75 (s,
3 H), 0.07 (s, 3 H), -1.84 (s, 3 H); 13C NMR (75 MHz, CDCl3)
δ 213.8, 210.2, 164.6, 159.4, 133.5, 131.5, 130.6, 129.8, 129.6,
129.3, 128.8, 113.9, 83.4, 83.2, 73.4, 73.1, 71.7, 71.2, 57.4, 55.2,
51.8, 42.7, 40.4, 38.2, 37.9, 31.4, 30.9, 27.4, 25.8, 22.7, 18.3,
11.8, -1.9, -4.0; ES HRMS m/z (M + Na)+ calcd 807.3210,
3.27 (m, 1 H), 2.44-2.40 (m, 2 H), 2.38-2.29 (m, 2 H), 2.21-
2.05 (m, 1 H), 1.94-1.89 (m, 1 H), 1.81-1.79 (m, 1 H), 1.58 (s,
3 H), 1.51 (s, 3 H), 0.97 (s, 3 H), 0.83 (s, 9 H), -0.04 (s, 3 H),
-0.18 (s, 3 H); ES HRMS m/z (M + Na)+ calcd 761.3333, obsd
761.3340; [R]20 -53 (c 0.16, CHCl3).
D
Rin g Clea va ge of 16 w ith Osm iu m Tetr a oxid e. To a
solution of 16 (2 mg, 2.8 µmol) in acetone (1 mL) and H2O (0.2
mL) was added neat OsO4 (0.8 mg, 3.1 µmol). The solution was
stirred at rt for 5 h, sodium dithionite solution (5 mL) was
introduced, and after 3 h the resulting mixture was extracted
with EtOAc (2 × 10 mL). The combined organic extracts were
dried, filtered, and concentrated. The residue was subjected
to flash chromatography on silica gel (elution with 1:1 hexane/
EtOAc) to furnish 21 (1.5 mg, 71%) as a colorless oil identical
to the material isolated above.
obsd 807.3198; [R]20 +7.3 (c 0.66, CHCl3).
D
Osm a te Ester 19. To a solution of 16 (8.3 mg, 0.012 mmol)
in THF (2 mL) and pyridine (1 mL) was added neat OsO4 (3.3
mg, 0.013 mmol) at 0 °C. The reaction mixture was stirred for
20 min, treated with saturated sodium hydrosulfite solution
(5 mL), and stirred for 3 h. Following extraction with EtOAc
(2 × 10 mL), the combined organic phases were dried, filtered,
and concentrated. Flash chromatography of the residue on
silica gel (elution with EtOAc) afforded 19 (4.7 mg, 83% at
65% conversion) as a pale brown oil along with 2.9 mg (35%)
of recovered 16.
Mon osilyla tion of 20. To a solution of 20 (2.0 mg, 2.7 µmol)
in CH2Cl2 (2 mL) were added 2,6-lutidine (9.4 µL, 0.081 mmol)
and TMSCl (3.4 µL, 0.027 mmol) sequentially at -78 °C under
N2. The reaction mixture was stirred at this temperature for
20 min, saturated NaHCO3 solution (5 mL) was introduced,
and stirring was maintained for 10 min prior to extraction with
EtOAc (2 × 10 mL). The combined organic extracts were dried,
filtered, and concentrated. Flash chromatography of the
residue on silica gel (elution with 10:1 hexane/EtOAc) afforded
22 (2.2 mg, 100%) as a colorless oil: IR (neat, cm-1) 3452, 1723,
1252; 1H NMR (400 MHz, C6D6) δ 8.39-8.19 (m, 2 H), 7.45 (d,
J ) 8.6 Hz, 2 H), 6.99-6.96 (m, 3 H), 6.79 (d, J ) 13.7 Hz, 2
H), 6.15-6.13 (m, 1 H), 5.05 (d, J ) 3.9 Hz, 1 H), 4.85 (dd, J
) 5.0, 11.6 Hz, 1 H), 4.70 (d, J ) 10.1 Hz, 1 H), 4.32 (s, 1 H),
4.24 (d, J ) 10.1 Hz, 1 H), 4.11 (d, J ) 5.2 Hz, 1 H), 3.88 (d,
J ) 10.2 Hz, 1 H), 3.72 (s, 1 H), 3.69 (s, 1 H), 3.37 (d, J ) 10.3
Hz, 1 H), 3.26 (s, 3 H), 2.84 (br s, 1 H), 2.56 (dd, J ) 6.8, 19
Hz, 1 H), 2.31 (br s, 1 H), 2.28-2.25 (m, 1 H), 2.16-2.03 (m,
2 H), 1.84-1.78 (m, 2 H), 1.67 (s, 3 H), 1.31 (s, 3 H), 0.92 (s, 9
For 19: IR (neat, cm-1) 3451, 1718, 1512; 1H NMR (400
MHz, CDCl3) δ 8.42-8.40 (m, 2 H), 7.36-7.29 (m, 5 H) 6.86-
6.84 (m, 2 H), 5.73 (d, J ) 2.7 Hz, 1 H), 4.95-4.92 (m, 1 H),
4.92 (s, 1 H), 4.78 (dd, J ) 4.8, 11.8 Hz, 1 H), 4.57 (br s, 1 H),
4.50 (d, J ) 10.7 Hz, 1 H), 4.19 (d, J ) 2.7 Hz, 1 H), 4.10 (d,
J ) 8.4 Hz, 1 H), 4.02 (s, 1 H), 3.98 (d, J ) 7.4 Hz, 1 H), 3.78
(s, 3 H), 3.53-3.48 (m, 1 H), 2.52 (s, 1 H), 2.37-2.30 (m, 5 H),
2.03-1.91 (m, 2 H), 1.34 (s, 3 H), 1.10 (s, 3 H), 0.85 (s, 3 H),
0.82 (s, 9 H), 0.07 (s, 3 H), 0.00 (s, 3 H); [R]20 -89 (c 0.24,
D
CHCl3).
Osm iu m Tetr a oxid e Oxid a tion of 16. To a solution of
16 (2 mg, 2.8 µmol) in THF (2 mL) and DABCO (0.6 mg, 5.6
µmol) was added neat OsO4 (0.7 mg, 2.8 µmol) at rt. As the
reaction mixture turned to bright red, it was stirred for 24 h,
treated with sodium dithionite (4.9 mg, 0.028 mmol) in water
(2 mL), stirred 3 h longer, and extracted with EtOAc (2 × 10
mL). The combined organic extracts were dried, filtered, and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel (elution with 1:1 hexane/EtOAc) to give 20
(1.8 mg, 75%) as a colorless oil: IR (neat, cm-1) 3470, 1719,
1706, 1514; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J ) 7.2 Hz,
2 H), 7.54-7.52 (m, 1 H), 7.44-7.40 (m, 2 H), 7.26 (d, J ) 8.5
Hz, 2 H), 6.81 (d, J ) 8.5 Hz, 2 H), 5.71 (d, J ) 5.8 Hz, 1 H),
4.79 (d, J ) 4.0 Hz, 1 H), 4.55 (dd, J ) 4.3, 11.6 Hz, 1 H), 4.43
(d, J ) 10.5 Hz, 1 H), 4.06 (d, J ) 10.6 Hz, 1 H), 3.99 (s, 1 H),
3.87 (br s, 1 H), 3.82 (d, J ) 5.8 Hz, 1 H), 3.74 (s, 3 H), 3.56 (d,
J ) 10.2 Hz, 1 H), 3.43-3.41 (m, 1 H), 3.36 (s, 1 H), 3.16-
3.06 (m, 1 H), 2.77 (s, 1 H), 2.77-2.72 (m, 1 H), 2.36-2.26 (m,
2 H), 2.18-2.16 (m, 1 H), 1.94-1.93 (m, 1 H), 1.88-1.80 (m, 1
H), 1.80-1.70 (m, 1 H), 1.30 (s, 3 H), 1.03 (s, 3 H), 0.87 (s, 3
H), 0.78 (s, 9 H), 0.01 (s, 3 H), -0.06 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 212.3, 208.9, 165.2, 159.4, 152.8, 133.8, 129.8,
129.5, 128.98, 128.9, 113.8, 84.2, 81.6, 75.2, 74.0, 73.5, 71.5,
67.2, 62.9, 58.7, 55.2, 51.3, 42.1, 38.9, 38.0, 32.9, 31.0, 29.6,
25.7, 22.7, 18.2, 10.0, -2.1, -4.2; ES HRMS m/z (M + Na)+
H), 0.76 (s, 3 H), 0.01 (s, 3 H), 0.00 (s, 3 H), -0.34 (s, 9 H); 13
C
NMR (75 MHz, C6D6) δ 210.8, 208.3, 177.6, 165.5, 159.6, 132.8,
130.2, 130.1, 129.8, 128.4, 113.7, 84.2, 82.9, 74.2, 73.9, 71.1,
67.6, 62.9, 59.0, 54.4, 51.4, 42.3, 38.9, 37.7, 33.2, 30.8, 28.2,
25.7, 22.6, 18.2, 10.1, -1.7, -2.3, -4.6; ES HRMS m/z (M +
Na)+ calcd 835.3885, obsd 835.3837; [R]20D +3.1 (c 0.37, CHCl3).
Desilyla tive Mesyla tion of 22. To a solution of 22 (2 mg,
2.0 µmol) in pyridine (2 mL) was added MsCl (2 µL, 0.02 mmol)
at 0 °C. The solution was warmed to rt, stirred for 24 h, and
quenched with NaHCO3 solution (5 mL). The resulting mixture
was extracted with EtOAc (2 × 10 mL), and the combined
organic extracts were dried, filtered, and concentrated. Flash
chromatography of the residue on silica gel (elution with 1:1
hexane/EtOAc) afforded 23 (2 mg, 100%) as a colorless oil: 1H
NMR (500 MHz, C6D6) δ 8.18 (d, J ) 7.2 Hz, 2 H), 7.42 (d, J
) 8.6 Hz, 2 H), 7.04-6.96 (m, 3 H), 6.82 (d, J ) 8.6 Hz, 2 H),
6.10 (d, J ) 5 Hz, 1 H), 4.64 (d, J ) 10 Hz, 1 H), 4.73 (dd, J )
5.1, 11.5 Hz, 1 H), 4.64 (d, J ) 10 Hz, 1 H), 4.53 (d, J ) 12 Hz,
1 H), 4.29 (d, J ) 12 Hz, 1 H), 4.25 (s, 1 H), 4.18 (d, J ) 10 Hz,
1 H), 4.12 (d, J ) 4.8 Hz, 1 H), 4.09 (br s, 1 H), 3.30 (s, 1 H),
3.26 (s, 3 H), 3.26-3.25 (m, 1 H), 2.55 (dd, J ) 7.1, 18 Hz, 1
H), 2.41 (br s, 2 H), 2.27-2.13 (m, 2 H), 2.12-2.08 (m, 2 H),
1.75 (s, 3 H), 1.74-1.73 (m, 1 H), 1.58 (s, 3 H), 1.27 (s, 3 H),
0.91 (s, 9 H), 0.72 (s, 3 H), -0.037 (s, 3 H), -0.039 (s, 3 H); ES
HRMS m/z (M + Na)+ calcd 841.3265, obsd 841.3295.
Silyl-P r otected Mesyla te 24. To a solution of 22 (2 mg,
0.002 mmol) in CH2Cl2 (20 mL) were added DMAP (48 mg,
0.4 mmol) and methanesulfonyl chloride (2 µL, 0.02 mmol)
sequentially at 0 °C. The reaction mixture was warmed to rt,
stirred for 24 h, and quenched with saturated NaHCO3
solution (5 mL). The product was extracted into EtOAc (2 ×
10 mL), the combined organic extracts were dried, filtered, and
concentrated, and the residue was flash chromatographed
(elution with 5:1 hexane/EtOAc) to afford 24 (1.9 mg, 90%) as
a colorless oil: IR (neat, cm-1) 3461, 1724, 1513; 1H NMR (500
MHz, C6D6) δ 8.11 (d, J ) 7.2 Hz, 2 H), 7.50 (d, J ) 8.6 Hz, 2
H), 7.05-7.02 (m, 1 H), 6.98-6.95 (m, 2 H), 6.90 (d, J ) 8.6
Hz, 2 H), 6.15-6.13 (m, 1 H), 5.11 (d, J ) 3.6 Hz, 1 H), 5.06
calcd 763.3490, obsd 763.3432; [R]20 +5.2 (c 0.56, CHCl3).
D
Ru th en iu m Tetr a oxid e-P r om oted Oxid a tion of 16. A
solution of 16 (5 mg, 7.0 µmol) in 1:1 acetonitrile/EtOAc (2 mL)
cooled to 0 °C was treated via cannula with a solution of
ruthenium trichloride (0.1 m, 0.49 µmol) and sodium periodate
(1.5 mg, 7.0 µmol) in water (0.5 mL). The reaction mixture
was stirred at 0 °C for 2 min, treated with a saturated solution
of sodium dithionite (5 mL), and extracted with EtOAc (2 × 5
mL). The combined organic phases were processed as described
above to give 2.5 mg (40%) of 20 and 2.7 mg (47%) of 21.
1
For 21: colorless oil; IR (neat, cm-1) 3446, 1717, 1515; H
NMR (500 MHz, CDCl3) δ 9.61 (s, 1 H), 8.06-8.04 (m, 2 H),
7.63-7.60 (m, 1 H), 7.52-7.49 (m, 2 H), 7.294-7.290 (m, 2
H), 6.95-6.93 (m, 2 H), 4.82 (d, J ) 10.6 Hz, 1 H), 4.19 (d, J
) 2.5 Hz, 1 H), 4.07 (s, 1 H), 3.86 (s, 3 H), 3.43 (s, 1 H), 3.34-
2288 J . Org. Chem., Vol. 68, No. 6, 2003

Chemical Modification of a Highly Functionalized Taxane
(d, J ) 3.6 Hz, 1 H), 4.89 (dd, J ) 5.1, 11.6 Hz, 1 H), 4.77 (d,
J ) 10.3 Hz, 1 H), 4.40 (d, J ) 10.3 Hz, 1 H), 4.26 (s, 1 H),
4.08 (d, J ) 5 Hz, 1 H), 3.87 (d, J ) 11.1 Hz, 1 H), 3.67 (d, J
) 11.1 Hz, 1 H), 3.51-3.47 (m, 1 H), 3.36 (s, 1 H), 3.29 (s, 3
H), 2.68-2.61 (m, 2 H), 2.53 (s, 3 H), 2.36 (br s, 1 H), 2.12-
2.04 (m, 2 H), 2.02-1.90 (m, 1 H), 1.73 (s, 3 H), 1.30 (s, 3 H),
0.89 (s, 9 H), 0.74 (s, 3 H), 0.08 (s, 3 H), -0.02 (s, 3 H), -0.32
(s, 9 H); 13C NMR (75 MHz, C6D6) δ 211.4, 207.3, 165.0, 159.7,
145.7, 145.2, 133.2, 130.1, 130.0, 128.7, 114.0, 83.9, 83.4, 82.8,
74.7, 73.9, 71.5, 67.5, 64.3, 58.8, 54.4, 51.6, 45.1, 43.2, 37.3,
34.0, 29.8, 29.5, 28.0, 25.6, 22.4, 18.1, 10.6, -1.3, -2.8, -4.8;
ES HRMS m/z (M+Na)+ calcd 841.3265, obsd 841.3238; [R]20
+7 (c 0.25, CHCl3).
D
Oxeta n e 28. To a solution of 25 (2.5 mg, 0.003 mmol) in
dry benzene (5 mL) was added Al(O-t-Bu)3 (3.7 mg, 0.015
mmol) at rt under N2. The reaction mixture was stirred for 10
h, treated with 3% HCl (5 mL), and extracted with EtOAc (2
× 10 mL). The combined organic extracts were dried, filtered,
and evaporated. The residue was purified by flash chroma-
tography on silica gel (elution with 3:1 hexane/EtOAc) to afford
28 (1.2 mg, 54%) as a colorless oil: IR (neat, cm-1) 3464, 1724,
1
1514; H NMR (500 MHz, CDCl3) δ 7.84 (d, J ) 7.4 Hz, 2 H),
ES HRMS m/z (M + Na)+ calcd 913.3660, obsd 913.3643; [R20
7.55-7.44 (m, 1 H), 7.42-7.40 (m, 2 H), 7.37 (d, J ) 8.6 Hz, 2
H), 6.96 (d, J ) 8.6 Hz, 2 H), 5.88-5.81 (m, 1 H), 4.81 (d, J )
6.5 Hz, 1 H), 4.73 (d, J ) 10.9 Hz, 1 H), 4.63 (dd, J ) 4.9, 10.9
Hz, 1 H), 4.32 (s, 1 H), 4.26 (d, J ) 10.9 Hz, 1 H), 4.09-4.06
(m, 1 H), 3.88 (s, 3 H), 3.86-3.83 (m, 1 H), 3.70-3.65 (m, 1
H), 3.50-3.47 (m, 1 H), 2.91-2.90 (m, 1 H), 2.81-2.78 (m, 2
H), 2.38-2.32 (m, 2 H), 2.30-2.27 (m, 1 H), 2.20-2.03 (m, 1
H), 1.90-1.83 (m, 1 H), 1.40 (s, 3 H), 1.11 (s, 3 H), 0.96 (s, 3
H), 0.93 (s, 9 H), 0.15 (s, 3 H), 0.11 (s, 3 H); 13C NMR (150
MHz, C6D6) δ 208.5, 206.6, 159.9, 133.4, 132.5, 131.0, 130.2,
129.9, 129.7, 129.3, 114.0, 79.5, 71.7, 71.0, 60.9, 54.6, 51.0, 42.6,
40.4, 40.0, 37.8, 37.0, 34.1, 29.6, 29.2, 25.8, 22.9, 18.3, 14.1,
10.2, -2.0, -4.2; ES HRMS m/z (M + Na)+ calcd 745.3384,
D
+32 (c 0.33, CHCl3).
Desilyla tion of 24. A solution of 24 (1 mg, 0.001 mmol) in
CH2Cl2 (1 mL) was treated with CSA (0.5 mg, 0.002 mmol) at
rt, stirred for 2 h, and quenched with saturated NaHCO3
solution (3 mL) prior to extraction with EtOAc (2 × 10 mL).
The combined organic extracts were dried, filtered, and
evaporated. The residue was subjected to flash chromatogra-
phy on silica gel (elution with 2:1 hexane/EtOAc) to give 25
(0.9 mg, 95-100%) as a colorless oil: IR (neat, cm-1) 3456,
1706, 1359, 1260; 1H NMR (500 MHz, C6D6) δ 8.14 (d, J ) 7.3
Hz, 2 H), 7.48 (d, J ) 8.6 Hz, 2 H), 7.08-7.05 (m, 1 H), 7.03-
7.00 (m, 2 H), 6.88 (d, J ) 8.6 Hz, 2 H), 6.08 (d, J ) 5.1 Hz, 1
H), 5.05 (d, J ) 3.4 Hz, 1 H), 4.80 (dd, J ) 4.9, 11.5 Hz, 1 H),
4.75-4.73 (m, 2 H), 4.36 (d, J ) 10.2 Hz, 1 H), 4.26 (s, 1 H),
4.20 (s, 1 H), 3.96 (d, J ) 5 Hz, 1 H), 3.48 (d, J ) 11.8 Hz, 1
H), 3.46-3.42 (m, 1 H), 3.29 (s, 3 H), 3.23 (s, 1 H), 3.07 (d, J
) 11.4 Hz, 1 H), 3.07 (d, J ) 11.4 Hz, 1 H), 2.59 (dd, J ) 6.6,
18 Hz, 1 H), 2.51-2.49 (m, 1 H), 2.47 (s, 3 H), 2.33 (br s, 1 H),
2.05-2.00 (m, 1 H), 1.92-1.87 (m, 1 H), 1.76-1.63 (m, 1 H),
1.55 (s, 3 H), 1.27 (s, 3 H), 0.90 (s, 9 H), 0.70 (s, 3 H), 0.06 (s,
3 H), -0.01 (s, 3 H); 13C NMR (75 MHz, C6D6) δ 214.3, 210.2,
167.6, 162.5, 136.0, 132.8, 132.7, 132.5, 131.5, 116.7, 86.5, 86.1,
85.2, 77.5, 76.8, 74.3, 70.3, 66.2, 61.5, 57.2, 54.4, 45.0, 43.0,
40.0, 39.9, 36.6, 33.4, 30.6, 28.4, 25.1, 20.9, 13.3, 0.00, -2.0;
obsd 745.3381; [R]20 +36 (c 0.17, CHCl3).
D
Ack n ow led gm en t. This work was financially sup-
ported by a grant from the National Cancer Institute
(CA-83830).
Su p p or tin g In for m a tion Ava ila ble: Copies of the high
1
field H NMR spectra of all compounds reported herein. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0206566
J . Org. Chem, Vol. 68, No. 6, 2003 2289