Synthesis of the chiral CD rings of paclitaxel from 2-deoxy-D-ribose: Novel 1,2-addition of a dienolate to a chiral ketone

Full text of DOI:10.1021/jo9810563

5742
J . Org. Chem. 1998, 63, 5742-5743
Sch em e 1
Syn th esis of th e Ch ir a l CD Rin gs of
P a clita xel fr om 2-Deoxy-D-r ibose: Novel
1,2-Ad d ition of a Dien ola te to a Ch ir a l Keton e
Takashi Takahashi,* Yoichiro Hirose,
Hajime Iwamoto, and Takayuki Doi
Tokyo Institute of Technology, Department of Chemical
Engineering, 2-12-1 Ookayama, Meguro,
Tokyo 152-8552, J apan
Sch em e 2
Received J une 3, 1998
Paclitaxel (1, Scheme 2) is an antitumor agent that has a
6-8-6-4 ring system containing a fully functionalized
carbon skeleton.1 There have been numerous reports on
approaches to the synthesis of paclitaxel, and we previously
reported an efficient method for constructing the B ring of
taxoids (AC f ABC) by way of an intramolecular alkylation
of the protected cyanohydrin ether (Scheme 1).2 Although
many approaches have been reported for the synthesis of
CD rings, only two approaches have accomplished complete
formation of the CD rings.3 We have previously disclosed a
novel approach to the C-ring formation using a (3 + 2)
cycloaddition of a nitrile oxide, thereby constructing the
(3,8)-trans configuration on the C ring.4 We now report the
synthesis of the fully functionalized taxane CD ring system.
The synthetic plan is shown in Scheme 2. Our target CD
ring is 2, which possesses not only a fully functionalized CD
ring but also an aldehyde at the C-2 position and an alkoxy
group at the C-9 position corresponding to paclitaxel. The
former can be used for the coupling reaction with an A-ring
moiety, and the latter can be converted to a leaving group
for the intramolecular alkylation of A in the formation of
the B ring. The diol at the C-7 and C-9 positions in 2 can
be prepared from 3 by reductive cleavage of an isoxazoline
ring followed by the stereoselective reduction of the resulting
ketone at the C-7 position. The isoxazoline 3 can be
constructed from the nitrile oxide 4 via (3 + 2) cycloaddi-
tion,4,5 which creates a six-membered ring C and a stereo-
genic center at the C-8 position. MM2 transition-structure
model calculations6,7 suggested that protective groups on the
tetraol of 4 should control the stereochemistry at the C-8
position. Interestingly, 4b with an acetonide protective
group for the diol at the C-2 and C-4 positions (R3, R4 ) Me)
will give rise to a â-methyl group at the C-8 position with
complete stereoselection.8 On the other hand, acyclic pro-
tected compounds, such as 4a (R1, R2, R3, R4 ) Me), are
predicted to give an R-methyl group at the C-8 position with
67% stereoselectivity.8 All carbon units and the stereogenic
centers at C3, C4, and C5 in 4 can be prepared by the 1,2-
addition of ester 5 to chiral ketone 6. However, few
examples of the aldol reaction of dienolates and ketones have
Sch em e 3
been reported. To achieve success in this strategy, we must
consider the following points: (i) the addition occurs at the
R-position of the dienolate of 5 rather than the γ-position,9
(ii) the 1,2-addition should be faster than the enolization of
the ketone (proton transfer), (iii) stereocontrol occurs from
the ketone 6 to the newly formed stereogenic centers at the
C-3 and C-4 positions in 4.10,11
The ketone 6 was prepared from 2-deoxy-D-ribose (7)12 as
shown in Scheme 3. Acetal formation of 7 (0.05% HCl in
MeOH) followed by protection of the resulting diol as the
corresponding benzyl ether (BnBr/NaH) gave 8 in 92% yield.
Oxidation of acetal 8 (BF3‚Et2O/m-CPBA)13,14 to the lactone
was followed by reduction (LiAlH4), affording diol 9 in 83%
(1) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J .
Am. Chem. Soc. 1971, 93, 2325-2327.
(2) Takahashi, T.; Iwamoto, H.; Nagashima. K.; Okabe, T.; Doi, T. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1319 and references therein.
(3) Magee, T. V.; Bornmann, W. G.; Isaacs, R. C. A.; Danishefsky, S. J .
J . Org. Chem. 1992, 57, 3274. Nicolaou, K. C.; Hwang, C.-K.; Sorensen, E.
J .; Clairborne, C. F. J . Chem. Soc., Chem. Commun. 1992, 1117.
(4) Takahashi, T.; Iwamoto, H. Tetrahedron Lett. 1997, 38, 2483.
(5) For a review, see: Kanemasa, S.; Tsuge, O. Heterocycles 1990, 30,
719.
(9) The R-preference regioselectivity observed in the aldol reaction of the
dienolate of 3-methylcrotonate with a steroidal aldehyde has been reported.
Kajikawa, A.; Morisaki, M.; Ikekawa, N. Tetrahedron Lett. 1975, 47, 4135.
(10) Preliminary stereochemical studies on the reactions of the dienolate
of 3-methylcrotonate with aldehydes have been reported. Dugger, R. W.;
Heathcock, C. H. J . Org. Chem. 1980, 45, 1181. Majewski, M.; Mpango, G.
B.; Thomas, M. T.; Snieckus, V. J . Org. Chem. 1981, 46, 2029.
(11) For recent examples of stereocontrolled aldol reactions of a dienolate
bearing a chiral auxiliary to aldehydes, see: Black, W. C.; Giroux, A.;
Greidanus, G. Tetrahedron Lett. 1996, 37, 4471. Tomooka, K.; Nagasawa,
A.; Wei, S.-Y.; Nakai, T. Tetrahedron Lett. 1996, 37, 8899.
(12) 2-Deoxy-D-ribose was a gift from Kobayashi Koryo Kagaku.
(13) Grieco, P. A.; Oguri, T.; Yokoyama, Y. Tetrahedron Lett. 1978, 419.
(14) Acid hydrolysis, followed by reduction, gave the desired diol 9 in
rather low yield because of â-elimination of the lactol.
(15) Mancuso, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978, 43,
2480.
(6) Brown F. K.; Raimondi, L.; Wu, Y.-D.; Houk, K. N. Tetrahedron Lett.
1992, 33, 4405. Takahashi, T.; Nakazawa, M.; Sakamoto, Y.; Houk, K. N.
Tetrahedron Lett. 1993, 34, 4075.
(7) All calculations were performed on MacroModel/BATCHMIN (ver 4.5).
Initial coordinations generated by 1000 Monte Carlo steps were energy
minimized by MM2 and Transition State Model. We are grateful to Professor
W. C. Still for providing a copy of this program. Mohamadi, F.; Richards,
N. G. J .; Guida, W. C.; Liskamp, T.; Lipton, M.; Caufield, C.; Chang, G.;
Hendrickson, T.; Still, W. C. J . Comput. Chem. 1990, 11, 440.
(8) Details of the calculations and those of other candidates are presented
in the Supporting Information.
S0022-3263(98)01056-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/05/1998

Communications
J . Org. Chem., Vol. 63, No. 17, 1998 5743
Sch em e 4
Sch em e 5
F igu r e 1. MM2 transition-state models.
Sch em e 6
yield. Selective protection of the primary alcohol of 9
(TBSCl, imidazole) and subsequent Swern oxidation15 of the
secondary alcohol provided ketone 6 in 89% overall yield.
The 1,2-addition of 5 to 6 was carried out as follows
(Scheme 4): A THF solution of ketone 6 was added to 3 equiv
of the lithium dienolate of ester 5 prepared with LDA at -78
°C. The reaction was complete within 10 min, providing only
the R-adducts in 70% yield. HPLC analysis of the adducts
showed four diastereomers in a ratio of 76:9:8:7. None of
the γ-adduct was observed. The stereochemistry of the
major diastereomer 10 was determined at a later stage in
the synthesis. As the lithium enolate of ester 5 is known to
be prepared as a 1:1 mixture of (E)- and (Z)-isomers,16 it is
conceivable that the (E)-enolate selectively reacted with
ketone 6 via transition state B where the primary benzyloxy
group of 6 could coordinate to a lithium cation through a
chairlike six-membered transition state. It is noteworthy
that the kinetic resolution of the (E)- and (Z)-enolates was
observed in the 1,2-addition to the chiral ketone, producing
two new stereogenic centers with high stereocontrol.17
DIBAL reduction of ester 10 followed by protection of the
resulting diol (isopropenyl methyl ether, CSA) gave the
acetonide whose TBS group was deprotected (TBAF, THF),
leading to alcohol 11 in 83% overall yield (Scheme 5).
Oxidation of 11 (TPAP, NMO, 77%)18 followed by treatment
of the resulting aldehyde 12 with hydroxylamine furnished
oxime 13 as a mixture of (E)- and (Z)-isomers in 73% yield.
The key (3 + 2) cycloaddition of 4c was carried out as
follows: Treatment of 13 with an excess of aqueous NaOCl
solution at 0 °C for 15 min produced 4c, which underwent
cycloaddition upon addition of triethylamine at room tem-
perature for 3 h.19 As the MM2 transition-structure model
calculations had suggested, the reaction proceeded stereo-
selectively via transition state 4cq (Figure 1) giving 3c in
56% yield.20 The structure of 3c was determined by NOE
measurement as shown in the Supporting Information.
Reductive cleavage of the isoxazoline 3c (Raney-Ni, H2;
B(OH)3, MeOH, H2O)21 followed by stereoselective reduction
(NaBH4) of the resulting ketone at the C-7 position afforded
the diol, which was protected as its diTBS ether 14 (TBSCl,
imidazole, three steps, 41% yield, Scheme 6). Removal of
the dibenzyl ether of 14 under Birch reduction conditions
gave the diol. Subsequent acetylation of the primary alcohol
followed by mesylation led to 15 in 48% overall yield.
Deacetylation of 15 (K2CO3, MeOH) followed by treatment
with DBU provided oxetane 16 in 40% overall yield.22,23
Deprotection of the acetonide of 16 (PPTS, MeOH, 0 °C, 59%)
followed by TPAP oxidation of the resulting diol 17 furnished
the desired aldehyde 2 in 50% yield.
We have demonstrated that the novel stereocontrolled 1,2-
addition of ester 5 to chiral ketone 6, easily prepared from
2-deoxy-D-ribose (7), generated all of the carbon units
required for the synthesis of paclitaxel’s CD rings, and the
(3 + 2) cycloaddition of the nitrile oxide proceeds stereose-
lectively to provide the 8â-methyl group during C-ring
formation. Five consecutive chiral centers on the fully
functionalized taxane CD ring system were successfully
generated from only the one chiral center of ketone 6 in this
synthesis.
Ack n ow led gm en t. We thank the Ministry of Educa-
tion, Science, Sports, and Culture, J apan for supports of
this work (Grant-in-aid No. 08245103). We also thank
Professors Takeshi Nakai and Katsuhiko Tomooka (Tokyo
Institute of Technology) for helpful discussions about aldol
reactions of the dienolate.
(16) Casey, C. P.; J ones, C. R.; Tukada, H. J . Org. Chem. 1981, 46, 2089.
(17) Addition of 1 equiv of the ester enolate of 5 gave a low yield (30%).
This also suggests that the (E)-enolate is less reactive in the 1,2-addition.
(18) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13.
(19) Lee, G. A. Synthesis 1982, 508.
Su p p or tin g In for m a tion Ava ila ble: Synthetic procedures,
spectral data, and MM2 transition-structure model calculations
(41 pages).
(20) Compound
i was also formed in 33% yield, probably from the
regioisomeric product in the (3 + 2) cycloaddition. This regioselectivity has
previously observed in the intramolecular (3 + 2) cycloaddition of N-
substituted nitrones. Majumdar, S.; Bhattacharjya, A.; Patra, A. Tetrahe-
dron Lett. 1997, 38, 8581.
J O9810563
(21) Kozikowski, A. P.; Stein, P. D. J . Am. Chem. Soc. 1982, 104, 4023.
Curran, D. P. J . Am. Chem. Soc. 1982, 104, 4024.
(22) Ettouati, L.; Ahond, A.; Poupat, C.; Potier, P. Tetrahedron 1991, 47,
9823.
(23) 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.