Macrocycle formation by ring-closing metathesis. Application to the syntheses of novel macrocyclic taxoids

Article abstract of DOI:10.1021/ja000293w

A series of novel macrocyclic taxoids 6 and 6′ bearing 16-, 17-, and 18-membered rings connecting the substituants at the C-2 and C-3′ positions were designed and synthesized. The syntheses of these macrocycles 6 and 6′ were accomplished using the highly

Full text of DOI:10.1021/ja000293w

J. Am. Chem. Soc. 2000, 122, 5343-5353
5343
Macrocycle Formation by Ring-Closing Metathesis. Application to the
Syntheses of Novel Macrocyclic Taxoids
Iwao Ojima,* Songnian Lin, Tadashi Inoue, Michael L. Miller, Christopher P. Borella,
Xudong Geng, and John J. Walsh
Contribution from the Department of Chemistry, State UniVersity of New York at Stony Brook,
Stony Brook, New York 11794-3400
ReceiVed January 26, 2000
Abstract: A series of novel macrocyclic taxoids 6 and 6′ bearing 16-, 17-, and 18-membered rings connecting
the substituents at the C-2 and C-3′ positions were designed and synthesized. The syntheses of these macrocycles
6 and 6′ were accomplished using the highly efficient ruthenium-catalyzed ring-closing metathesis (RCM) of
taxoid-ω,ω′-dienes 7 in the key step. Taxoid-ω,ω′-dienes 7 were obtained through the ring-opening coupling
of 4-alkenyl-â-lactams 9 with 2-alkenoylbaccatins 8 in good to high yields. Although various novel pentacyclic
macrocycles 6 and 6′ were successfully synthesized, there were cases in which the desired RCM did not
proceed. The scope and limitation of RCM in its application to highly functionalized complex substrates are
discussed. All macrocyclic taxoids 6 and 6′ were found to be cytotoxic, with some of them exhibiting
submicromolar IC50 values against a human breast cancer cell line.
Although there are many methods for cyclization and
macrocyclization in organic synthesis, ring-closing metathesis
(RCM) has recently emerged as a powerful tool for the
formation of a variety of ring systems.1-3 While macrocycle
formation by RCM has proven to be effective in the synthesis
of various natural products4-17 and macrocyclic amino acids
or peptides,18-24 it is obvious that the complexity and functional
group tolerance of substrates in this process need to be further
investigated to expand its applicability in organic syntheses.
In the course of our study on the bioactive conformation of
paclitaxel (1) and its congeners,25-27 we have proposed28
a
plausible common pharmacophore for paclitaxel (1),29 epo-
thilones (3 and 4)30 (Figure 1), eleutherobin,31 and discoder-
molide,32 which share the same mechansim of action, i.e.,
inhibition of the cell division cycle by stabilizing microtubules.
On the basis of this common pharmacophore model, we
recognized that macrocyclic taxoids 6 (unsaturated) and 6′
(saturated) which connected the C2 and C3′ positions of taxoids
such as docetaxel (2)33 and nonataxel (5)34 (Figure 1) would
provide hybrid constructs of taxoids and epothilone.28 Accord-
ingly, a series of macrocyclic taxoids 6 and 6′ were designed.
(1) Schuster, M.; Siegfried, B. Angew. Chem., Int. Ed. Engl. 1997, 36,
2036-2056.
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Lett. 1994, 35, 3191.
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2134.
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J.-P. J. Am. Chem. Soc. 1997, 119, 5519-5527.
(26) Ojima, I.; Kuduk, S. D.; Chakravarty, S. In AdVances in Medicinal
Chemistry; Maryanoff, B. E., Reitz, A. B., Eds.; JAI Press: Greenwich,
CT, 1998; Vol. 4, pp 69-124.
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B.; Kuduk, S. D.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 1999,
96, 4256-4261.
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10.1021/ja000293w CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/20/2000

5344 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Ojima et al.
Scheme 1
Scheme 2a
a Key: (a) TES-Cl, imidazole, DMF, room temperature (rt), 96%;
(b) Red-Al (2 equiv), THF, -10 °C, 20 min, quantitative; (c) DCC or
DIC, DMAP, rt to 50 °C, 67-95%; (d) HF/Pyr, rt; (e) TES-Cl (3
equiv), imidazole (4 equiv), 0 °C to rt; (f) LiHMDS (1.1 equiv), AcCl
(1.2 equiv), THF, -40 °C; 50-84% (three steps).
Figure 1.
To synthesize these macrocyclic taxoids, we chose to use the
Ru-catalyzed RCM in the key step. Since the designed RCM
precursor taxoids bearing two olefinic tethers involve many
functional groups and possess highly complex structures, such
a study would provide valuable information about the scope
and limitation of the RCM methodology.
We describe here our successful syntheses of a series of novel
macrocyclic taxoids 6 and 6′ using RCM in the key step and
discuss the scope and limitation of this method observed. All
these novel macrocyclic taxoids were found to be cytotoxic,
which provides supporting evidence for the proposed common
pharmacophore.28
ring 10-deacetylbaccatin III (DAB), while enantiopure â-lactam
9 should be obtained through the highly efficient chiral enolate-
imine cyclocondensation established in these laboratories.35,38-40
The synthesis of macrocyclic taxoids 6 started from the
preparation of a series of C-2-modified baccatins. Reaction of
DAB with TES-Cl and imidazole followed by the removal of
the C-2 benzoyl group with Red-Al gave 7,10,13-triTES-2-
debenzoylbaccatin (10) in 96% yield for two steps (Scheme 2).
Esterification of 10 was carried out using unsaturated carboxylic
acids 11a-g in the presence of DCC/DMAP or DIC/DMAP as
the coupling agents, which gave the desired C-2-modified
baccatins 12a-g in 67-95% yields. The silyl protecting groups
at C-7, C-10, and C-13 were then removed using HF/pyridine.
Selective reprotection of the C-7 hydroxyl group with TES-
Cl and imidazole, followed by acetylation of the C-10 hydroxyl
group using acetyl chloride and LiHMDS gave the desired
baccatins 8a-g in high yields (Scheme 2).
Results and Discussion
The retrosynthetic analysis of the target macrocyclic taxoid
6 bearing 16-, 17-, 18-membered rings is shown in Scheme 1.
As Scheme 1 illustrates, novel taxoid 6 should be obtained
through a Ru-catalyzed RCM of the open-chain precursor,
taxoid-ω,ω′-diene 7, which can be synthesized from C-2-
alkenoylbaccatin 8 and enantiopure 4-alkenyl-â-lactam 9 using
the “Ojima-Holton” ring-opening coupling protocol.26,35-39 The
C-2-modified baccatin 8 can be obtained from naturally occur-
While the coupling method using DCC or DIC/DMAP
worked well with less bulky alkenoic acids, the reactions of
(37) Georg, G. I.; Boge, T. C.; Cheruvallath, Z. S.; Clowers, J. S.;
Harriman, G. C. B.; Hepperle, M.; Park, H. In Taxol®: Science and
Applications; Suffness, M., Ed.; CRC Press: New York, 1995; pp 317-
375.
(35) Ojima, I.; Habus, I.; Zhao, M.; Zucco, M.; Park, Y. H.; Sun, C.-
M.; Brigaud, T. Tetrahedron 1992, 48, 6985-7012.
(36) Holton, R. A.; Biediger, R. J.; Boatman, P. D. In Taxol®: Science
and Applications; Suffness, M., Ed.; CRC Press: New York, 1995; pp 97-
121.
(38) Ojima, I.; Lin, S.; Chakravarty, S.; Fenoglio, I.; Park, Y. H.; Sun,
C.; Appendino, G.; Pera, P.; Veith, J. M.; Bernacki, R. J. J. Org. Chem.
1998, 63, 1637-1645.
(39) Ojima, I.; Lin, S.; Wang, T. Curr. Med. Chem. 1999, 6, 927-954.
(40) Ojima, I.; Lin, S. J. Org. Chem. 1998, 63, 224-225.

Macrocycle Formation by RCM
J. Am. Chem. Soc., Vol. 122, No. 22, 2000 5345
Scheme 3a
Scheme 4a
a Key: (a) acid 11l-o, DCC or DIC, DMAP, rt to 50 °C, 67-85%;
(b) NaBH4, 0 °C to rt; 84-90%.
Scheme 5a
a Key: (a) DCC or DIC, DMAP, rt to 50 °C; (b) triphosgene/Pyr, 0
°C to rt, 97%; (c) RMgBr, THF, -78 °C, 79-96%; (d) HF/Py, rt; (e)
TES-Cl (3 equiv), imidazole (4 equiv), 0 °C to rt; (f) LiHMDS (1.1
equiv), AcCl (1.2 equiv), THF, -40 °C; 55-76% (three steps).
a Key: (i) O3/Me2S, -78 °C to rt, 3 h, quantitative; (ii) Ph3Pd
CHCH2CHdCH2, -78 °C to rt, 2 h, 93%; (iii) CAN, -10 °C, 2 h,
83%; (t-Boc)2O, Et3N, DMAP, rt, 9 h, 96% (Z, E separable); (iv) HF/
Py, rt, 17-24 h; TES-Cl, Et3N/DMAP, rt, 1 h; Z, 88%; E, 77% (two
steps).
bulky ortho- or meta-substituted benzoic acids 11h-k with 10
were very sluggish, forming predominantly the D-ring-opened
products iso-12.41 To circumvent this problem, we employed
the regioselective ring-opening coupling of baccatin-1,2-carbon-
ate 13 with ortho- or meta-substituted phenylmagnesium
bromides.28,41 Baccatin-1,2-carbonate 13 was prepared in 97%
yield from 10 by treatment with triphosgene in the presence of
pyridine at 0 °C.42 Treatment of 13 with the ortho- or meta-
substituted phenylmagnesium bromides afforded baccatins
12h-k in good to high yields (Scheme 3).28,41 Baccatins 12h-k
thus obtained were converted to 8h-k in high yields following
the same three-step procedure as that described above for the
syntheses of 8a-g.
Scheme 6a
a Key: (i) LDA, -84 °C; RsCHdNsPMP, -84 °C to rt, overnight;
a, 63%; b, 56%; (ii) CAN, -10 °C, 3 h; (t-Boc)2O, Et3N/DMAP, rt,
15 h; a, 88%; b, 72% (two steps); (iii) HF/Py, rt, 20 h; TES-Cl, Et3N/
DMAP, rt, 1 h; a, 88%; b, 90% (two steps).
For the coupling of bulky alkenoic acids 11l-o bearing a
gem-dimethyl group â to the carboxyl group, less bulky
2-debenzoyl-7-TES-13-oxobaccatin (14)34 was employed. Thus,
the reaction of 13-oxobaccatin 14 with alkenoic acids 11l-o in
the presence of DCC/DMAP or DIC/DMAP gave baccatins
14l-o in 67-85% yields (Scheme 4). Finally, the reduction of
the 13-keto moiety of 14l-o with NaBH4 gave the desired
baccatins 8l-o in 84-90% yields.
The syntheses of â-lactams 9 began with the preparation of
(3R,4S)-1-PMP-3-TIPSO-4-(2-methylprop-1-enyl)azetidin-2-
one (15) (PMP ) p-methoxyphenyl, TIPSO ) triisopropylsi-
loxy) with high enantiopurity (>96% ee) in excellent yield using
a highly efficient chiral enolate-imine cyclocondensation
reaction.35,38-40,43,44 Ozonolysis of the 4-alkenyl moiety of 15
gave 4-formyl-â-lactam 16 in quantitative yield. Reaction of
aldehyde 16 with a Wittig reagent generated in situ from (but-
3-enyl)triphenylphosphonium bromide and n-BuLi afforded
4-(penta-1,4-dienyl)-â-lactams 17a (E/Z ) 1/7) in 93% yield.
The PMP group was removed by treatment with ceric am-
monium nitrate (CAN), followed by protection of the resulting
NH group with (t-Boc)2O, affording â-lactams 18a in excellent
yield. The Z- and E-isomers of 18a were separated by column
chromatography on silica gel. The TIPS group was then removed
by HF/pyridine, followed by reprotection with a smaller TES
group to afford â-lactams 9a-Z and 9a-E in 88% and 77%
yields, respectively (Scheme 5). 4-[(E)-2-Methylhexa-1,5-di-
enyl)]-â-lactam 9b and 4-(but-3-enyl)-â-lactam 9c were syn-
thesized in good overall yields through cyclocondensation of
chiral TIPS-ester 19 with N-PMP-(E)-3-methylhept-2,6-di-
enaldimine and N-PMP-pent-4-enaldimine, giving 17b (97% ee)
and 17c (97% ee), followed by functional group manipulation
analogous to that for 9a (Scheme 6).
(41) Nicolaou, K. C.; Renaud, J.; Nantermet, P. G.; Couladouros, E. A.;
Guy, R. K.; Wrasidlo, W. J. Am. Chem. Soc. 1995, 117, 2409-2420.
(42) Holton, R. A.; Kim, S. U.S. Patent 5,399,726, March 21, 1995.
(43) Ojima, I.; Duclos, O.; Kuduk, S. D.; Sun, C.-M.; Slater, J. C.;
Lavelle, F.; Veith, J. M.; Bernacki, R. J. Bioorg. Med. Chem. Lett. 1994, 4,
2631-2634.
(44) Ojima, I.; Slater, J. S.; Kuduk, S. D.; Takeuchi, C. S.; Gimi, R. H.;
Sun, C.-M.; Park, Y. H.; Pera, P.; Veith, J. M.; Bernacki, R. J. J. Med.
Chem. 1997, 40, 267-278.
4-(Prop-2-enyl)-, 4-vinyl-, 4-(1-hydroxylprop-2-enyl)-, and
4-(3-vinylphenyl)-â-lactams (9d-g) were synthesized according
to the synthetic routes illustrated in Schemes 7 and 8. Thus,
the reaction of 4-formyl-â-lactam 16 with vinylmagnesium
bromide followed by in situ protection of the resulting alcohol
with acetic anhydride gave â-lactam 20a in 98% yield. â-Lactam
20a was subjected to Pd2(dba)3-catalyzed hydrogenolysis using

5346 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Ojima et al.
Scheme 7a
Scheme 9
a Key: (i) CH2dCHMgBr (1.1 equiv), THF, -78 °C; then Ac2O,
-78 °C to rt: 98 % (two steps, R/S ) 11/1); (ii) Pd2(dba)3CHCI3 (0.1
equiv), HCO2NH4 (3 equiv), PBu3 (0.2 equiv), dioxane, reflux, 65%;
(iii) CAN, -10 °C; (t-Boc)2O, Et3N/DMAP, rt; 82-96% (two steps);
(iv) Ph3Pd (1.5 equiv), -78 to 0 °C, 90%; (v) CH2dCHMgBr, THF,
-78 °C; then TBSCl (9 equiv), Et3N (excess), reflux, 2 d; 82% (two
steps); (vi) HF/Py, rt; TES-Cl, Et3N/DMAP, rt, 90% (two steps).
The RCM of taxoid-ω,ω′-diene 7a, bearing a (Z)-penta-1,4-
dienyl group at C-3′ and a pent-4-enoyl group at C-2, catalyzed
by RuCl2(dCHPh)(PCy3)2 (I) (“Grubb’s catalyst”,47 20 mol %)
in CH2Cl2 (1.3 mM) at room temperature for 14 h proceeded
smoothly to afford the desired 17-membered macrocycle 21a
in 92% yield (Z/E ) 9/1) (Scheme 9). The stereochemical
assignment of the newly formed carbon-carbon double bond
was unambiguously determined on the basis of J coupling
constants (major (Z), J ) 9.5 Hz; minor (E), J ) 15.5 Hz).
Encouraged by this exciting result, we carried out the RCM of
taxoid-ω,ω′-dienes 7b-t. Results are summarized in Table 2.
Scheme 8a
As Table 2 shows, the RCM of taxoid-ω,ω′-dienes 7 gives
the desired macrocyclic taxoids 21 in moderate to high yields
for 15 out of the 20 cases studied (entries 1-15). It was
previously reported that the RCM of ω,ω′-diene substrates
bearing a γ,δ- or â,γ-unsaturated carbonyl moiety did not
proceed at all. These negative results were ascribed to the
formation of a very stable and thus inactive five- or six-
membered Ru-chelate complex (e.g., structures A and B, Figure
2) that blocks the catalytic cycle, which was presented as a
general rule characterizing the scope and limitation of RCM.2,48
However, we have found that this general rule proposed on the
basis of the studies for simpler systems is not applicable to the
RCM of highly functionalized taxoids 7a-d, 7j, and 7o wherein
each substrate possesses a γ,δ- or â,γ-unsaturated carbonyl
moiety in the molecule. Thus, these RCM reactions catalyzed
by the Ru-carbene complex I gave the desired 16- and 17-
membered macrocyclic taxoids 21a-d, 21j, and 21o in 67-
92% yields (entries 1-4, 10, and 15). It is noteworthy that the
Ru-catalyzed RCM is found to be applicable to the macrocy-
clization of highly complex and multifunctionalized systems,
further expanding the scope of this synthetic method.
a Key: (i) LDA, -84 °C; m-I-PhsCHdNsPMP, -84 °C to rt,
overnight, 79%; (ii) Pd2(dba)3, vinyl tributyltin, PPh3, dioxane, 80 °C,
overnight, 87%; (iii) CAN, -10 °C, 1.5 h; (t-Boc)2O, Et3N/DAMP, rt;
70% (two steps).
HCO2NH4 as the hydride source45 to give 4-allyl-â-lactam 17d
in 65% yield. Reaction of 16 with the same Grignard reagent,
followed by protection of the resulting alcohol as the TBS ether,
afforded â-lactam 17f in 82% yield. Reaction of 4-formyl-â-
lactam 16 with methylenetriphenylphosphorane gave 4-vinyl-
â-lactam 17e in 90% yield. Removal of the PMP group of
â-lactams 17d-f with CAN followed by protection of the
resulting free NH with (t-Boc)2O afforded â-lactams 9d, 9e,
and 18f in high yields. To reduce the steric bulk of 18f for
efficient ring-opening coupling with C-2-modified baccatin 8,
both the TIPS and TBS groups were replaced with TES to give
â-lactam 9f in 90% overall yield (Scheme 7). 4-(3-Iodophenyl)-
â-lactam 20b was synthesized using cyclocondensation of TIPS
ester 19 with the PMP-aldimine of m-iodobenzaldehyde in 70%
yield (Scheme 8). Stille coupling of â-lactam 20b with vinyl-
tributyltin catalyzed by Pd2(dba)3 afforded 4-(3-vinylphenyl)-
â-lactam 17g in 78% yield, which was then converted to 1-t-
Boc-4-(3-vinylphenyl)-â-lactam 9g in 70% yield for two steps
in the same manner as mentioned above.
Another unique feature observed in these RCM reactions is
the stereoselective double bond formation. As Table 2 shows,
the stereochemistry of the double bond in 21 formed by the
RCM of taxoids 7 is predominantly or exclusively E in all cases
examined except for the case of 21a in which the Z-isomer is
the predominant product (Z/E ) 9/1). These results make sharp
contrast to the very low or no stereoselectivity previously
reported for the formation of the olefin moiety, which is a
characteristic feature and weakness of the RCM method,2,17 as
The ring-opening coupling of 4-alkenyl-â-lactams 9a-g with
C-2-alkenoylbaccatins 8a-o was carried out under the standard
conditions,26,36-40,44,46 which gave the corresponding taxoid-
ω,ω′-dienes 7a-t bearing two olefinic tethers at the C-2 and
C-3′ positions (Scheme 9). Results are summarized in Table 1.
With taxoid-ω,ω′-dienes 7a-t in hand, the stage is set for
macrocyclization by means of RCM.
(45) Minami, I.; Nisar, M.; Yuhara, M.; Shimizu, I.; Tsuji, J. Synthesis
1987, 992-998.
(46) Ojima, I. Acc. Chem. Res. 1995, 28, 383-389 and references therein.
(47) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041.
(48) Fu¨rstner, A.; Langemann, K. Synthesis 1997, 792-803.

Macrocycle Formation by RCM
J. Am. Chem. Soc., Vol. 122, No. 22, 2000 5347
Table 1. Synthesis of Dienyl Taxoid 7a
a The reaction was carried out with 1.0 equiv of baccatin 8 and 1.5 equiv of â-lactam 9 with 1.5 equiv of LiHMDS in THF at -40 °C for 30
min (see Scheme 9).
exemplified by the formation of E/Z mixtures of 16-membered
rings in the total synthesis of epothilones.8-10,12,49
expected, the tetrasubstituted olefin moiety at the C11-C12
position of the baccatin skeleton is also completely intact in all
cases.
It is also worthy of note that the Ru-catalyzed RCM takes
place exclusively at the terminal olefin moieties of a taxoid-
ω,ω′-diene 7 bearing an additional inner olefin moiety (entries
1-3). Thus, the inner olefin moieties of 7a, 7b, and 7c are not
involved in these RCM reactions, giving the desired RCM
products 21a, 21b, and 21c, respectively, in high yields. As
Table 2 also indicates that the RCM reaction is very sensitive
to the substitution pattern in the proximity of the terminal double
bonds. When the ω-alkenyl moiety at the C-3′ position is a
3-butenyl group (entries 4-7), the RCM reaction proceeds very
smoothly. However, the reaction becomes sluggish, and a higher
catalyst loading (40-60 mol %) and higher temperatures (60-
70 °C) are required to complete the reaction when the ω-alkenyl
(49) It should be noted that stereoselective RCM reactions have recently
been reported; see refs 11, 13, 16, 17, and 19.

5348 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Ojima et al.
Table 2. Macrocyclic Taxoid Formation by Ru-Catalyzed Ring-Closing Metathesisa

Macrocycle Formation by RCM
J. Am. Chem. Soc., Vol. 122, No. 22, 2000 5349
Table 2. (Continued)
a The reactions were carried out using RuCl2(dCHPh)(PCy3)2 (I) as the catalyst (see Scheme 9). b Macrocyclic taxoids 21a-o give 6a-o after
deprotection. c The number in parentheses is the expected ring size if RCM is successful. d Determined by NMR. e The number in parentheses
indicates the percentage of conversion. f Supported by mass spectrometry (MH+ peak observed).
WT.51 All of these novel macrocyclic taxoids are found to be
cytotoxic, and three of them, 6f, 6g, and 6h, exhibit strong
activity with submicromolar level IC50 values, i.e., IC50 ) 0.48,
0.39, and 0.50 µM, respectively.52 Macrocyclic taxoids, 6c, 6e,
6k, 6l, 6m, 6′d, 6′e, 6′f, 6′g, 6′l, and 6′m, also show substantial
activity, i.e., IC50 ) 1.40-4.10 µM. However, macrocyclic
taxoids, 6a, 6b, 6d, 6i, 6j, 6o, 6′a, and 6′o, possess a
Figure 2.
moiety is an allyl group (entries 11-15). The RCM reactions
substantially lower level of activities (IC50 g 10 µM). Several
of taxoid-ω,ω′-dienes 7r-t bearing a vinyl group or 1-TESO-
taxoids were also assayed for their tubulin-polymerization
prop-2-enyl group at the C-3′ position do not take place (entries
activity,51 and it has been found that 6e, 6g, and 6′l show relative
18-20). However, substrates with a vinyl group attached to a
activities of 19%, 36%, and 21%, respectively, as compared to
phenyl moiety (7h and 7j) retain good reactivity (entries 8 and
10). The results clearly indicate that the substitution at the allylic
that of paclitaxel in the same assay. Although the biological
activity profiles of these macrocyclic taxoids have not exceeded
position of the terminal olefin moiety imposes serious limitations
that of paclitaxel (0.0031 µM) yet, it certainly provides
for the scope of RCM with the exception of the vinylphenyl
group. Similar substituent effects are observed for the ω-alkenyl
moiety at the C-2 position.
supporting evidence for the validity of the common pharma-
cophore proposed by these laboratories,28 which serves as the
basis for the design and development of paclitaxel-epothilone
In the cases in which RCM-macrocyclization does not occur
hybrids and de novo anticaner agents. Further studies on the
(entries 16-20), it appears that a dimerization process prevails
structure-activity relationships of macrocyclic taxoids are
at the less sterically hindered ω-olefin moieties. It has been
actively underway and will be reported in due course.
shown that (2,6-iPr2C6H4Nd)Mo(dCHCMe2Ph)[OMe(CF3)2]2
(“Schrock’s catalyst”)50 possesses a significantly higher activity
Conclusion
than that of Ru catalyst in the RCM of sterically demanding
dienes.3 Accordingly, we examined the activity of the Mo
catalyst in the RCM of taxoid-ω,ω-diene 7s. Unfortunately, the
attempted RCM reaction resulted in the ring-opening of the
oxetane ring, leading to the formation of a complex mixture of
products.
A series of novel macrocyclic taxoids bearing various tethers
between the C-2 and C-3′ positions has been designed and
synthesized. The syntheses of these macrocycles were ac-
complished using Ru-complex-catalyzed RCM as the key
reaction. Successful construction of the 16-, 17-, and 18-
membered macrocycles using RCM of the highly functionalized,
complex tetracyclic terpenoid substrates is particularly note-
worthy. These results have clearly expanded the scope of the
RCM methodology. Observation of substantial biological activ-
ity of these highly constrained macrocyclic taxoids provides
RCM-macrocyclization products 21a-o were treated with
HF/pyridine to remove the silyl protecting groups at the C-7
and C-2′ positions to afford the desired macrocyclic taxoids 6a-
o, possessing different substitution and double bond distribution
patterns in the C2-C3′ tether. Hydrogenation of 6a, 6d, 6e-g,
6l, 6m, and 6o on palladium-carbon provided the corresponding
macrocyclic taxoids bearing saturated C2-C3′ tethers, 6′a, 6′d,
6′e-g, 6′l, 6′m, and 6′o, in excellent to quantitative yields
(Scheme 9).
(51) The cytotoxicity assay was performed by Dr. Ralph J. Bernacki
and Ms. Paula Pera, Roswell Park Cancer Institute, and the tubulin-
polymerization activity assay was performed by Dr. Susan B. Horwitz and
Mr. Lifeng He, Albert Einstein College of Medicine. The detailed results
will be reported elsewhere.
(52) Recently, a couple of C2-C3′ connected paclitaxel analogues were
reported, but these compounds did not show any cytotoxicity. See: Boge,
T. C.; Wu, Z.-J.; Himes, R. H.; Vander, D. G.; Georg, G. I. Bioorg. Med.
Chem. Lett. 1999, 9, 3047-3052.
(53) Marder-Karsenti, R.; Dubois, J.; Bricard, L.; Gue´nard, D.; Gue´ritte-
Voegelein, F. J. Org. Chem. 1997, 62, 6631-6637.
These macrocyclic taxoids were evaluated for their cytotox-
icities against a human breast cancer cell line, MDA-435/LCC6-
(50) Bazan, G. C.; Oskam, J. H.; Cho, H.-N.; Park, L. Y.; Schrock, R.
R. J. Am. Chem. Soc. 1991, 113, 6899-6907.

5350 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Ojima et al.
7-triethylsilyl-2-debenzoyl-2-(pent-4-enoyl)baccatin III (8b). To a solu-
tion of baccatin 12b (111 mg, 0.235 mmol) in pyridine-acetonitrile
(1/1, 4 mL) was added dropwise HF/pyridine (70/30, 1.2 mL) at 0 °C,
and the mixture was stirred for 23 h at room temperature. The reaction
was quenched with saturated aqueous sodium carbonate (10 mL). The
reaction mixture was then diluted with ethyl acetate (60 mL), washed
with saturated aqueous copper sulfate (10 mL × 3) and water (10 mL),
dried over anhydrous magnesium sulfate, and concentrated in vacuo
to afford 2-debenzoyl-2-(pent-4-enoyl)-10-deacetylbaccatin III as a
strong supporting evidence for the existence of the proposed
common pharmacophore for microtubule-stabilizing agents.
Further studies along this line should reveal the way that
paclitaxel binds to microtubules, i.e., the biologically active
conformation of paclitaxel, and provide a solid basis for the
design and synthesis of the next generation antitumor agents
targeting tubulin/microtubules.
Experimental Section
white solid (118 mg, 96% yield): mp 75-77 °C; [R]20 -27.3° (c
D
0.33, CHCl3); 1H NMR (250 MHz, CDCl3/D4-MeOH) δ 0.75 (s, 3 H),
0.80 (s, 3 H), 1.39 (s, 3 H), 1.58 (m, 1 H), 1.74 (s, 3 H), 1.85 (s, 1 H),
1.89 (s, 1 H), 1.92 (s, 3 H), 2.13 (m, 4 H), 2.24 (m, 1 H), 3.57 (d, J )
6.8 Hz, 1 H), 3.94 (d, J ) 7.6 Hz, 1 H), 3.95 (m, 1 H), 4.19 (d, J )
7.8 Hz, 1 H), 4.50 (t, J ) 7.8 Hz, 1 H), 4.73 (m, 1 H), 4.75 (d, J )
10.3 Hz, 1 H), 4.81 (d, J ) 16.1 Hz, 1 H), 4.98 (s, 1 H), 5.11 (d, J )
6.8 Hz, 1 H), 5.58 (m, 1 H); 13C NMR (62.9 MHz, CDCl3/[D4]MeOH)
δ 9.0, 14.0, 19.2, 21.6, 24.1, 25.9, 28.0, 33.6, 35.8, 38.5, 42.1, 46.5,
57.2, 66.4, 74.4, 74.7, 76.3, 77.7, 80.0, 84.4, 115.0, 133.5, 136.3, 143.3,
170.5, 173.4, 210.8; HRMS (FAB, MeOH/NBA/PPG) m/z calcd for
C27H38O10‚Na+ 545.2363, found 545.2341 (∆ ) 4.0 ppm).
To a solution of 2-debenzoyl-2-(pent-4-enoyl)-10-deacetylbaccatin
III thus obtained (118 mg, 0.226 mmol) and imidazole (52.1 mg, 0.765
mmol) in dry DMF (3 mL) was added chlorotriethylsilane (96.3 µL,
0.574 mmol) dropwise via syringe at 0 °C. The reaction mixture was
stirred for 1.5 h at 0 °C and diluted with ethyl acetate (60 mL). The
mixture was then washed with water (15 mL × 3) and brine (10 mL),
dried over anhydrous magnesium sulfate, and concentrated in vacuo.
The crude product was purified on a silica gel column using hexane/
ethyl acetate (4/1 followed by 1/1) as the eluant to give 7-triethylsilyl-
For general methods, materials, and the synthesis of 10 see the
Supporting Information.
General Procedure for the Syntheses of 7,10,13-Tris(triethylsilyl)-
2-debenzoyl-2-alkenoyl-10-deacetylbaccatin III (12a-k). Method A
(for the Syntheses of 12a-g). A typical procedure is described for
the synthesis of 7,10,13-tris(triethylsilyl)-2-debenzoyl-2-(pent-4-enoyl)-
10-deacetylbaccatin III (12b). To a solution of 10 (207 mg, 0.255
mmol), pent-4-enoic acid (130 µL, 1.275 mmol), and 4-(dimethylami-
no)pyridine (DMAP; 31 mg, 0.255 mmol) in dichloromethane (3 mL)
was added 1,3-dicyclohexylcarbodiimide (DCC; 526 mg, 2.55 mmol),
and the reaction mixture was stirred for 16 h at room temperature. The
precipitate was filtered off and washed with ethyl acetate (30 mL).
The filtrate was diluted with ethyl acetate (30 mL), washed with
saturated aqueous sodium bicarbonate (15 mL × 2), dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The residue
was purified on a silica gel column using hexane/ethyl acetate (8/1
followed by 4/1) as the eluant to give 12b as a white solid (204 mg,
89% yield): mp 110-112 °C; [R]20D -28.6° (c 0.35, CHCl3); 1H NMR
(250 MHz, CDCl3) δ 0.63 (m, 18 H), 0.97 (m, 27 H), 1.06 (s, 3 H),
1.10 (s, 3 H), 1.49 (bs, 1 H), 1.58 (s, 3 H), 1.86 (m, 1 H), 1.93 (s, 3
H), 2.00 (s, 1 H), 2.04 (s, 1 H), 2.16 (s, 3 H), 2.39 (m, 4 H), 2.46 (m,
1 H), 3.71 (d, J ) 7.0 Hz, 1 H), 4.14 (d, J ) 7.9 Hz, 1 H), 4.36 (dd,
J ) 10.4, 6.6 Hz, 1 H), 4.42 (d, J ) 7.9 Hz, 1 H), 4.88 (t, J ) 8.5 Hz,
1 H), 4.93 (d, J ) 8.2 Hz, 1 H), 5.02 (d, J ) 9.7 Hz, 1 H), 5.07 (d, J
) 16.0 Hz, 1 H), 5.14 (s, 1 H), 5.37 (d, J ) 7.0 Hz, 1 H), 5.81 (m, 1
H); 13C NMR (62.9 MHz, CDCl3) δ 4.8, 5.2, 5.9, 6.85, 6.91, 10.3,
14.5, 20.5, 22.3, 24.7, 26.4, 28.5, 34.1, 37.2, 39.6, 43.0, 46.8, 58.2,
68.3, 72.5, 75.0, 75.7, 76.7, 79.3, 80.5, 84.1, 115.7, 135.7, 136.6, 139.4,
170.0, 174.0, 205.6; HRMS (FAB, MeOH/NBA/PPG) m/z calcd for
C45H80O10Si3‚H+ 865.5138, found 865.5174 (∆ ) -4.2 ppm).
Method B (for the Syntheses of 12h-k). A typical procedure is
described for the synthesis of 7,10,13-tris(triethylsilyl)-2-debenzoyl-
2-(2-allyloxybenzoyl)-10-deacetylbaccatin III (12i). To a solution of
2-allyloxyphenylmagnesium bromide (0.36 M solution in THF, 4 mL,
1.44 mmol, prepared from allyl 2-bromophenyl ether and magnesium)
was added a solution of 7-TES-2-debenzoylbaccatin-1,2-carbonate (13)42
(293 mg, 0.361 mmol) in THF (2 mL) at -78 °C, and the reaction
mixture was stirred for 2 h at the same temperature. The reaction was
quenched with saturated aqueous ammonium chloride (10 mL) and
extracted with ethyl acetate (20 mL × 3). The combined extracts were
dried over anhydrous magnesium sulfate and concentrated in vacuo.
The crude product was purified on a silica gel column using hexane/
ethyl acetate (10/1 followed by 5/1) as the eluant to afford 12i as a
2-debenzoyl-2-(pent-4-enoyl)-10-deacetylbaccatin III as a white solid
1
(132 mg, 92%): mp 90-92 °C; [R]20 -47.8° (c 0.23, CHCl3); H
D
NMR (250 MHz, CDCl3) δ 0.53 (m, 6 H), 0.91 (m, 9 H), 1.00 (s, 3
H), 1.05 (s, 3 H), 1.51 (br s, 1 H), 1.66 (s, 3 H), 1.89 (m, 1 H), 2.03
(s, 3 H), 2.10 (m, 2 H), 2.16 (s, 3 H), 2.41 (m, 5 H), 3.80 (d, J ) 7.0
Hz, 1 H), 4.15 (d, J ) 7.9 Hz, 1 H), 4.22 (s, 1 H), 4.34 (dd, J ) 10.5,
6.6 Hz, 1 H), 4.45 (d, J ) 7.9 Hz, 1 H), 4.81 (t, J ) 7.8 Hz, 1 H), 4.94
(d, J ) 8.2 Hz, 1 H), 5.02 (d, J ) 9.1 Hz, 1 H), 5.07 (d, J ) 15.8 Hz,
1 H), 5.11 (s, 1 H), 5.33 (d, J ) 7.0 Hz, 1 H), 5.85 (m, 1 H); 13C NMR
(62.9 MHz, CDCl3) δ 5.1, 6.7, 9.8, 15.1, 19.3, 22.5, 26.9, 28.5, 34.1,
37.2, 38.4, 42.6, 46.8, 57.9, 67.8, 72.8, 74.8, 74.6, 75.5, 78.5, 80.4,
84.4, 115.8, 135.0, 136.6, 141.9, 170.8, 173.9, 210.3; HRMS (FAB,
MeOH/NBA/PPG) m/z calcd for C33H52O10Si‚Na+ 659.3227, found
659.3216 (∆ ) 1.7 ppm).
To a solution of 7-triethylsilyl-2-debenzoyl-2-(pent-4-enoyl)-10-
deacetylbaccatin III (130 mg, 0.204 mmol) thus obtained in dry THF
(13 mL) was added 1.0 M LiHMDS in THF (0.225 mL, 0.225 mmol)
dropwise via syringe at -40 °C. The mixture was stirred at -40 °C
for 5 min, and freshly distilled acetyl chloride (17.4 µL, 0.245 mmol)
was added dropwise. After 20 min, the reaction was quenched with
saturated aqueous ammonium chloride (10 mL) and extracted with
dichloromethane (20 mL × 3). The combined extracts were dried over
anhydrous magnesium sulfate and concentrated in vacuo. The crude
product was purified on a silica gel column using hexane/ethyl acetate
(2/1 followed by 1/1) as the eluant to afford 8b as a white solid (131
mg, 95% yield): mp 186-187 °C; [R]20D -46.7° (c 0.30, CHCl3); 1H
NMR (250 MHz, CDCl3) δ 0.57 (m, 6 H), 0.90 (m, 9 H), 1.00 (s, 3
H), 1.11 (s, 3 H), 1.55 (br s, 1 H), 1.66 (s, 3 H), 1.86 (m, 1 H), 2.10
(m, 2 H), 2.15 (m, 9 H), 2.39 (m, 4 H), 2.51 (m, 1 H), 3.73 (d, J ) 7.1
Hz, 1 H), 4.15 (d, J ) 8.0 Hz, 1 H), 4.43 (m, 1 H), 4.45 (d, J ) 8.0
Hz, 1 H), 4.79 (t, J ) 7.8 Hz, 1 H), 4.94 (d, J ) 8.6 Hz, 1 H), 5.03 (d,
J ) 9.3 Hz, 1 H), 5.08 (d, J ) 15.9 Hz, 1 H), 5.37 (d, J ) 7.1 Hz, 1
H), 5.83 (m, 1 H), 6.40 (s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 5.2,
6.7, 9.9, 14.9, 19.9, 20.9, 22.6, 26.8, 28.5, 30.1, 37.2, 38.1, 42.7, 47.1,
58.6, 67.8, 72.2, 74.3, 75.7, 76.6, 78.5, 80.5, 84.4, 115.8, 132.5, 136.5,
144.0, 169.3, 170.8, 173.9, 202.2; HRMS (FAB, MeOH/NBA/PPG)
m/z calcd for C35H54O11Si‚Na+ 701.3333, found 701.3345 (∆ ) -1.7
ppm).
1
white solid (267 mg, 79% yield): mp 182 °C; H NMR (250 MHz,
CDCl3) δ 0.47-0.67 (m, 18 H), 0.87-0.99 (m, 27 H), 1.11 (s, 3 H),
1.14 (s, 3 H), 1.63 (s, 3 H), 1.83 (m, 1 H), 1.92 (s, 3 H), 1.95 (m, 1 H),
2.09 (s, 3 H), 2.44 (m, 2 H), 3.73 (d, J ) 6.5 Hz, 1 H), 4.18 (d, J )
8.3 Hz, 1 H), 4.26 (d, J ) 8.3 Hz, 1 H), 4.34 (dd, J ) 10.3, 6.5 Hz, 1
H), 4.64 (d, J ) 4.2 Hz, 2 H), 4.84 (d, J ) 8.9 Hz, 1 H), 4.91 (m, 1
H), 5.13 (s, 1 H), 5.23 (d, J ) 10.6 Hz, 1 H), 5.37 (d, J ) 17.4 Hz, 1
H), 5.58 (d J ) 6.5 Hz, 1H) 5.81 (m, 1 H), 6.91 (m, 2 H), 7.37 (t, J )
7.9 Hz, 1 H), 7.74 (d, J ) 7.6 Hz, 1 H); 13C NMR (62.9 MHz, CDCl3)
δ 4.9, 5.2, 5.9, 6.8, 6.9, 10.4, 14.6, 20.7, 22.3, 26.4, 37.4, 40.8, 42.8,
46.8, 58.4, 68.4, 69.1, 72.6, 75.9, 78.5, 80.7, 84.0, 113.4, 117.9, 120.2,
120.5, 131.7, 132.3, 133.6, 136.0, 139.2, 157.7, 166.9, 205.8; HRMS
(FAB, MeOH/NBA/PPG) m/z calcd for C50H82O11Si3‚Na+ 965.5063,
found 965.5065 (∆ ) -0.2 ppm).
For other baccatins 12, see the Supporting Information.
General Procedure for the Syntheses of 7-Triethylsilyl-2-deben-
zoyl-2-alkenoylbaccatin III (8a-o). Method A (for the Syntheses
of 8a-k). A typical procedure is described for the synthesis of
Method B (for the Syntheses of 8l-o). A typical procedure is
described for the synthesis of 7-triethylsilyl-2-debenzoyl-2-(3,3-di-
methylhept-6-enoyl)baccatin III (8l). To a solution of 7-TES-13-

Macrocycle Formation by RCM
J. Am. Chem. Soc., Vol. 122, No. 22, 2000 5351
oxobaccatin 1434 (143 mg, 0.24 mmol), DMAP (29 mg, 0.24 mmol),
and 3,3-dimethylhept-6-enoic acid 11l (187 mg, 1.20 mmol) in
dichloromethane (3 mL) was added N,N′-diisopropylcarbodiimide (DIC;
0.23 mL, 1.44 mmol), and the mixture was allowed to stir overnight.
The precipitate was filtered off and washed with ethyl acetate (30 mL).
The filtrate was diluted with ethyl acetate (30 mL), washed with a
saturated aqueous sodium bicarbonate (15 mL × 2), dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The residue
was purified on a silica gel column using hexane/ethyl acetate (8/1
followed by 4/1) as the eluant to give 7-TES-2-debenzoyl-2-(3,3-
dimethylhept-6-enoyl)-13-oxo-baccatin III as a white solid (153 mg,
85% yield): mp 190 °C; [R]20D -9.1° (c 0.22, CHCl3); 1H NMR (300
MHz, CDCl3) δ 0.57 (t, J ) 7.5 Hz, 6 H), 0.89 (t, J ) 8.1 Hz, 9 H),
1.02 (s, 3 H), 1.04 (s, 1.04), 1.14 (s, 3 H), 1.19 (s, 3 H), 1.43 (m, 2 H),
1.58 (s, 3 H), 1.68 (m, 1 H), 1.84 (m, 1 H), 2.03 (m, 1 H), 2.04 (s, 3
H), 2.12 (s, 3 H), 2.19 (s, 3 H), 2.20 (s, 2 H), 2.51 (m, 1 H), 2.58 (d,
J ) 20.1 Hz, 1 H), 2.74 (d, J ) 20.1 Hz, 1 H), 3.79 (d, J ) 6.6 Hz,
1 H), 4.14 (d, J ) 8.0 Hz, 1 H), 4.42 (dd, J ) 10.5, 6.6 Hz, 1 H), 4.51
(d, J ) 8.0 Hz, 1 H), 4.90 (d, J ) 9.6 Hz, 1 H), 4.94 (d, J ) 11.7 Hz,
1 H), 5.01 (dd, J ) 17.1, 1.5 Hz, 1 H), 5.38 (d, J ) 6.6 Hz, 1 H), 5.80
(m, 1 H), 6.54 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 5.2, 6.7, 9.5,
13.5, 18.0, 20.8, 21.6, 24.9, 25.6, 27.2, 27.3, 28.5, 33.1, 33.6, 33.9,
37.1, 40.9, 42.2, 43.5, 46.2, 46.5, 49.1, 59.4, 72.2, 76.0, 76.4, 78.4,
80.2, 84.0, 114.4, 138.8, 140.2, 152.8, 168.8, 170.2, 173.3, 198.4, 200.3;
HRMS (FAB) m/z calcd for C39H60O11Si‚H+ 733.3983, found
733.3985 (∆ ) -0.2 ppm).
(3R,4S)-1-(4-Methoxyphenyl)-3-triisopropylsiloxy-4-(penta-1,4-
dienyl)azetidin-2-one (17a-E,Z). To a suspension of (3-butenyl)-
triphenylphosphonium bromide (147.3 mg, 0.371 mmol) in anhydrous
THF (3 mL) at -78 °C was added n-BuLi (0.195 mL, 2.5 M in hexane,
0.371 mmol) under nitrogen. The solution was allowed to warm to
room temperature and stirred for 20 min. The solution was cooled to
-78 °C, and a solution of 4-formyl-â-lactam 16 (70 mg, 0.185 mmol)
in THF (2 mL) was added dropwise at that temperature. The reaction
mixture was allowed to warm to room temperature over a period of 2
h with stirring. The reaction was then quenched with water (10 mL),
extracted with dichloromethane (15 mL × 3), dried over anhydrous
magnesium sulfate, and concentrated in vacuo. The crude product was
purified on a silica gel column using hexane/ethyl acetate (10/1) as
the eluant to afford 17a as a colorless oil (72 mg, 93% yield; Z/E >
1
9/1 based on H NMR).
Z-isomer (17a-Z): 1H NMR (250 MHz, CDCl3) δ 1.11 (m, 21 H),
3.04 (m, 2 H), 3.76 (s, 3 H), 4.88 (dd, J ) 10.0, 4.9 Hz, 1 H), 5.09 (d,
J ) 4.9 Hz, 1 H), 5.12 (dd, J ) 9.5, 1.4 Hz, 1 H), 5.15 (dd, J ) 15.3,
1.4 Hz, 1 H), 5.63 (dd, J ) 10.9, 10.1 Hz, 1 H), 5.86 (m, 2 H), 6.82
(d, J ) 9.0 Hz, 2 H), 7.33 (d, J ) 9.0 Hz, 2 H); 13C NMR (62.9 MHz,
CDCl3) δ 11.9, 17.6, 17.7, 31.9, 55.3, 56.1, 77.5, 114.2, 115.8, 118.3,
125.8, 128.6, 133.8, 135.5, 156.1, 165.3.
E-isomer (17a-E): 1H NMR (250 MHz, CDCl3) δ 1.11 (m, 21 H),
2.87 (m, 2 H), 3.76 (s, 3 H), 4.55 (dd, J ) 8.6, 5.0 Hz, 1 H), 5.03 (d,
J ) 10.5 Hz, 1 H), 5.11 (m, 2 H), 5.64 (m, 1 H), 5.86 (m, 2 H), 6.83
(d, J ) 9.0 Hz, 2 H), 7.34 (d, J ) 9.0 Hz, 2 H); HRMS (DCI/NH3/
PPG) m/z calcd for C24H37O3SiN‚H+ 416.2621, found 416.2633 (∆ )
-2.9 ppm).
7-TES-2-debenzoyl-2-(3,3-dimethylhept-6-enoyl)-13-oxo-baccatin III
thus obtained (80 mg, 0.11 mmol) was dissolved in 4 mL of MeOH
and 1 mL of THF, and NaBH4 (100 mg, 2.0 mmol) was added in small
portions at 0 °C. The reaction mixture was stirred at 0 °C for 30 min
and quenched by saturated aqueous ammonium chloride (5 mL). The
aqueous layer was extracted with ethyl acetate (20 mL × 3). The
combined extracts were dried over anhydrous magnesium sulfate and
concentrated in vacuo. The crude product was purified on a silica gel
column using hexane/ethyl acetate (4/1 followed by 2/1) as the eluant
to afford 40 mg (50% recovery yield) of 7-TES-2-debenzoyl-2-(3,3-
dimethylhepta-6-enoyl)-13-oxo-baccatin III and 34 mg of 8l (85% yield
(3R,4S)-1-(tert-Butoxycarbonyl)-3-triisopropylsiloxy-4-(penta-1,4-
dienyl)azetidin-2-one (18a-E,Z). To a solution of N-PMP-â-lactam
17a (154 mg, 0.371 mmol) in acetonitrile (17 mL) and water (3.5 mL)
was added dropwise a solution of CAN (673 mg, 1.227 mmol) in water
(13.5 mL) at -10 °C. The reaction mixture was stirred at -10 °C for
2 h. The reaction was then quenched with saturated aqueous sodium
sulfite (15 mL). The aqueous layer was extracted with ethyl acetate
(40 mL × 3), and the combined organic layers were washed with
aqueous sodium sulfite and brine, dried over anhydrous magnesium
sulfate, and concentrated in vacuo. The crude product was purified on
a silica gel column using hexane/ethyl acetate (4/1 followed by 2/1) as
the eluant to afford (3R,4S)-3-triisopropylsiloxy-4-(penta-1,4-dienyl)-
azetidin-2-ones as a colorless oil (95 mg, 83% yield; Z/E ) 7/1 based
based on 50% conversion) as a colorless film: mp 73-74 °C; [R]20
-72.2° (c 0.18, CHCl3); H NMR (250 MHz, CDCl3) δ 0.58 (t, J )
D
1
7.7 Hz, 6 H), 0.91 (t, J ) 7.9 Hz, 9 H), 1.02 (s, 3 H), 1.04 (s, 3 H),
1.06 (s, 3 H), 1.13 (s, 3 H), 1.42 (m, 2 H), 1.60 (s, 3 H), 1.88 (m, 1 H),
2.01-2.25 (m, 6 H), 2.16 (s, 9, H), 2.50 (m, 2 H), 3.75 (d, J ) 6.0 Hz,
1 H), 4.13 (d, J ) 7.9 Hz, 1 H), 4.44 (dd, J ) 10.5, 6.4 Hz, 1 H), 4.50
(d, J ) 7.9 Hz, 1 H), 4.79 (m, 1 H), 4.96 (m, 3 H), 5.34 (d, J ) 6.9
Hz, 1 H), 5.82 (m, 1 H), 6.41 (s, 1 H); 13C NMR (63 MHz, CDCl3)
δ5.3, 6.7, 9.9, 14.9, 19.9, 20.9, 22.6, 26.9, 27.3, 28.6, 29.7, 33.6, 37.2,
38.0, 41.0, 42.9, 46.7, 47.4, 58.6, 68.0, 72.3, 74.0, 75.7, 76.5, 78.6,
80.6, 84.4, 101.9, 114.2, 132.6, 139.1, 143.9, 169.3, 170.6, 170.9, 173.6,
202.3; HRMS (FAB) m/z calcd for C39H62O11Si‚H+ 735.4140, found
735.4137 (∆ ) 0.4 ppm).
1
on H NMR).
Z-isomer: 1H NMR (250 MHz, CDCl3) δ 1.07 (m, 21 H), 2.84 (m,
2 H), 4.50 (dd, J ) 8.9, 4.7 Hz, 1H), 4.96-5.07 (m, 3 H), 5.73 (m, 3
H), 6.36 (br s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 11.8, 17.6, 31.7,
52.1, 79.3, 115.4, 126.9, 132.4, 135.8, 169.9.
E-isomer: 1H NMR (250 MHz, CDCl3) δ 1.08 (m, 21 H), 2.88 (m,
2 H), 4.16 (dd, J ) 7.8, 4.7 Hz, 1H), 4.94-5.07 (m, 3 H), 5.70 (m, 3
H), 6.45 (br s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 12.3, 17.6, 36.5,
58.0, 79.3, 116.0, 127.7, 133.5, 135.7, 169.9.
To a solution of the NH-â-lactams thus obtained (92 mg, 0.307
mmol), di-tert-butyl dicarbonate (80.4 mg, 0.368 mmol), and DMAP
(9.4 mg, 0.077 mmol) in dichloromethane (5 mL) was added dropwise
triethylamine (0.128 mL, 0.921 mmol) at room temperature. The
mixture was stirred for 9 h at room temperature, and the reaction was
quenched with saturated aqueous ammonium chloride (15 mL). The
reaction mixture was then extracted with ethyl acetate (30 mL × 3).
The combined extracts were dried over anhydrous magnesium sulfate
and concentrated in vacuo. The crude product was purified on a silica
gel column using hexane/ethyl acetate (20/1 followed by 10/1) as the
eluant to afford 18a-Z (102.5 mg) and 18a-E (14.5 mg) as colorless
For other baccatins 8, see the Supporting Information.
(3R,4S)-1-(4-Methoxyphenyl)-3-triisopropylsiloxy-4-formylazeti-
din-2-one (16). Nitrogen gas was bubbled into a solution of 4-(2-
methylprop-2-enyl)-â-lactam 15 (500 mg, 1.239 mmol) in MeOH/
CH2Cl2 (1/2, 27 mL) at -78 °C for 3 min. Then, ozone gas was bubbled
into the solution until the color of the solution turned blue (2 min),
and nitrogen gas was bubbled into the solution for another 3 min.
Dimethyl sulfide (0.458 mL, 6.194 mmol) was added to the solution,
and the reaction mixture was allowed to warm to room temperature.
The reaction mixture was stirred for 3 h at room temperature. The
solvents were removed in vacuo, and the residue was purified on a
neutral alumina column using hexane/ethyl acetate (4/1 followed by
2/1) as the eluant to afford 16 as a white solid (467.5 mg, 100%): mp
oils (total 117 mg, 96% yield).
1
Z-isomer (18a-Z): [R]20 +20.0° (c 0.15, CHCl3); H NMR (250
D
MHz, CDCl3) δ 1.05 (m, 21 H), 1.48 (s, 9 H), 2.97 (m, 2 H), 4.82 (dd,
J ) 9.7, 5.7 Hz, 1H), 5.04 (m, 3 H), 5.57 (dd, J ) 10.9, 9.9 Hz, 1 H),
5.81 (m, 2 H); 13C NMR (62.9 MHz, CDCl3) δ 11.8, 17.60, 17.65,
31.9, 55.3, 77.3, 83.2, 115.6, 123.9, 134.2, 135.9, 165.1; HRMS (FAB)
m/z calcd for C22H39O4SiN‚H+ 410.2727, found 410.2734 (∆ ) -1.8
ppm).
78-80 °C; [R]20 +158.0° (c 0.50, CHCl3); 1H NMR (250 MHz,
D
CDCl3) δ 1.06 (m, 21 H), 3.74 (s, 3 H), 4.43 (dd, J ) 5.2, 3.8 Hz, 1
H), 5.25 (d, J ) 5.2 Hz, 1 H), 6.81 (d, J ) 8.8 Hz, 1 H), 7.22 (d, J )
8.8 Hz, 1 H), 9.72 (d, J ) 3.8 Hz, 1 H); 13C NMR (62.9 MHz, CDCl3)
δ 11.6, 17.4, 55.3, 64.2, 78.6, 114.4, 117.8, 130.7, 156.7, 164.2, 199.6.
Anal. Calcd for C20H31NO4Si: C, 63.63; H, 8.28; N, 3.71. Found: C,
63.80; H, 8.05; N, 3.72.
E-isomer (18a-E): 1H NMR (250 MHz, CDCl3) δ 1.05 (m, 21 H),
1.48 (s, 9 H), 2.85 (m, 2 H), 4.49 (dd, J ) 8.4, 5.8 Hz, 1H), 5.04 (m,

5352 J. Am. Chem. Soc., Vol. 122, No. 22, 2000
Ojima et al.
3 H), 5.57 (dd, J ) 15.4, 8.5 Hz, 1 H), 5.83 (m, 2 H); 13C NMR (62.9
MHz, CDCl3) δ 11.8, 17.6, 36.5, 61.0, 77.4, 83.2, 115.9, 124.6, 135.4,
135.6, 166.1; HRMS (FAB) m/z calcd for C22H39O4SiN‚H+ 410.2727,
found 410.2734 (∆ ) -1.8 ppm).
154.9, 169.1, 169.9, 171.6, 173.7, 201.8; HRMS (FAB, CHCl3/NBA/
NaCl) m/z calcd for C54H87NO15Si2‚Na+ 1068.5512, found 1068.5546
(∆ ) -3.2 ppm).
In the same manner, 7b-t were synthesized. See the Supporting
Information.
(3R,4S)-1-(tert-Butoxycarbonyl)-3-triethylsiloxy-4-[(Z)-pent-1,4-
dienyl]azetidin-2-one (9a-Z). To a solution of 18a-Z (70 mg, 0.171
mmol) in pyridine-acetonitrile (1/1, 2 mL) was added dropwise HF/
pyridine (70/30, 0.3 mL) at 0 °C, and the mixture was allowed to warm
to room temperature. The mixture was stirred for 17 h at room
temperature. The reaction was quenched with saturated aqueous sodium
carbonate (10 mL), and the reaction mixture was diluted with ethyl
acetate (60 mL), washed with saturated aqueous copper sulfate (15 mL
× 3), water, and brine, dried over anhydrous magnesiun sulfate, and
concentrated in vacuo to afford (3R,4S)-1-(tert-butoxycarbonyl)-3-
hydroxy-4-[(Z)-pent-1,4-dienyl]azetidin-2-one as a colorless oil (40 mg).
To a solution of the 3-OH-â-lactam thus obtained (40 mg, 0.158
mmol) and DMAP (4.8 mg, 0.039 mmol) in dichloromethane (2 mL)
were added dropwise chlorotriethylsilane (32 µL, 0.190 mmol) and
triethylamine (66 µL, 0.474 mmol) at room temperature, and the mixture
was stirred for 1 h at the same temperature. The reaction was quenched
with saturated aqueous ammonium chloride (5 mL), and the reaction
mixture was extracted with dichloromethane (15 mL × 3). The
combined extracts were dried over anhydrous magnesium sulfate and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using hexane/ethyl acetate (10/1) as the
eluant, affording 9a-Z as a colorless oil (55.5 mg, 88% yield for two
steps): [R]20D +36.4° (c 0.22, CHCl3); 1H NMR (250 MHz, CDCl3) δ
0.63 (m, 6 H), 0.93 (m, 9 H), 1.47 (s, 9 H), 2.94 (m, 2 H), 4.77 (dd,
J ) 9.2, 5.6 Hz, 1H), 4.87 (d, J ) 5.6 Hz, 1 H), 5.01 (dd, J ) 10.0,
1.4 Hz, 1 H), 5.06 (dd, J ) 16.7, 1.4 Hz, 1 H), 5.52 (dd, J ) 10.9, 9.5
Hz, 1 H), 5.83 (m, 2 H); 13C NMR (62.9 MHz, CDCl3) δ 4.7, 6.4,
28.0, 31.8, 55.1, 76.8, 83.1, 11.5, 123.9, 133.8, 135.8, 147.9, 166.0;
HRMS (FAB) m/z calcd for C19H33O4SiN‚H+ 368.2257, found 368.2252
(∆ ) 1.4 ppm).
General Procedure for the Synthesis of Macrocyclic Taxoids 21
by Ring-Closing Metathesis. A typical procedure is described for the
synthesis of 7-triethylsilyl-2-debenzoyl-2,13-[(10R,9S,7Z)-9-tert-bu-
toxycarbonylamino-10-triethylsiloxy-1,11-diketoundeca-4,7-dienylene]-
baccatin III (21a). To a solution of taxoid 7a (63 mg, 0.060 mmol) in
dry dichloromethane (30 mL) was added dropwise a solution of bis-
(tricyclohexylphosphine)benzylideneruthenium(IV) dichloride (catalyst
I; 7.4 mg, 0.009 mmol) in dry dichloromethane (15 mL) via cannula
over a period of 2 h at room temperature, and the solution was stirred
for 14 h. The solvents were removed in vacuo to afford a deep brown
residue. The residue was purified on a silica gel column using hexane/
ethyl acetate (3/1) as the eluant to afford macrocyclic taxoid 21a as a
white solid (56.5 mg, 92% yield; Z/E ) 9/1 as indicated by 1H NMR):
1H NMR (500 MHz, CDCl3) δ 0.56 (m, 6 H), 0.64 (m, 6 H), 0.92 (m,
9 H), 0.97 (m, 9 H), [1.09 (major), 1.13 (minor)] (s, 3 H), [1.11 (major),
1.15 (minor)] (s, 3 H), [1.38 (major), 1.40 (minor)] (s, 9 H), 1.64 (s, 3
H), 1.88 (m, 1 H), [1.99 (major), 2.02 (minor)] (s, 3 H), 2.14 (s, 3 H),
2.34-2.57 (m, 4 H), 2.62 (m, 2 H), 2.73 (m, 1 H), 3.11 (m, 2 H),
[3.78 (minor), 3.80 (major)] (d, J ) 8.0 Hz, 1 H), [4.12 (minor), 4.15
(major)] (s, 1 H), 4.24 (d, J ) 8.0 Hz, 1 H), [4.42 (major), 4.43 (minor)]
(d, J ) 8.0 Hz, 1 H), 4.49 (dd, J ) 11.0, 6.5 Hz, 1 H), 4.88 (br t, 1 H),
4.90 (d, J ) 8.5 Hz, 1 H), [5.03 (minor), 5.05 (major)] (d, J ) 9.5 Hz,
1 H), 5.30 (d, J ) 8.0 Hz, 1 H), [5.42 (d, J ) 15.5 Hz) (minor), 5.47
(d, J ) 9.5 Hz) (major)] (1 H), [5.44 (d, J ) 15.5 Hz) (minor), 5.47
(d, J ) 9.5 Hz) (major)] (1 H), 5.48 (d, J ) 9.5 Hz, 1 H), 5.52 (dd, J
) 10.5, 9.5 Hz, 1 H), 5.67 (dt, J ) 10.5, 7.0 Hz, 1 H), 5.80 (t, J ) 8.5
Hz, 1 H), [6.39 (major), 6.41 (minor)] (s, 1 H); 13C NMR (62.9 MHz,
CDCl3) δ 4.6, 5.2, 6.6, 6.7, 10.4, 14.2, 20.8, 21.0, 21.3, 22.6, 23.4,
25.8, 26.8, 28.2, 35.5, 36.5, 36.8, 42.9, 47.0, 50.6, 57.9, 60.3, 71.7,
73.9, 74.7, 75.6, 76.1, 79.6, 80.1, 80.7, 84.4, 127.2, 128.0, 128.8, 130.9,
133.5, 140.4, 155.1, 169.1, 169.6, 172.3, 172.5, 201.2; HRMS (FAB,
CHCl3/NBA/NaCl/PPG) m/z calcd for C52H83NO15Si2‚Na+ 1040.5199,
found 1040.5170 (∆ ) 2.8 ppm).
In the same manner, 9a-E was synthesized.
(3R,4S)-1-(tert-Butoxycarbonyl)-3-triethylsiloxy-4-[(E)-pent-1,4-
dienyl]azetidin-2-one (9a-E): 77% yield from 18a-E (two steps);
1
colorless oil; H NMR (250 MHz, CDCl3) δ 0.64 (m, 6 H), 0.95 (m,
9 H), 1.48 (s, 9 H), 2.85 (m, 2 H), 4.46 (dd, J ) 8.4, 5.8 Hz, 1H), 4.87
(d, J ) 5.6 Hz, 1 H), 5.06 (m, 2 H), 5.54 (dd, J ) 15.5, 8.5 Hz, 1 H),
5.82 (m, 2 H); 13C NMR (62.9 MHz, CDCl3) δ 4.6, 6.5, 28.0, 36.5,
64.7, 76.9, 83.1, 115.8, 124.5, 136.4, 136.7, 147.7, 166.0; HRMS (FAB)
m/z calcd for C19H33O4SiN‚H+ 368.2257, found 368.2252 (∆ ) 1.4
ppm).
In a similar manner, macrocyclic taxoids 21b-o were synthesized
from 7b-o. Toluene was used as the solvent instead of dichloromethane
wherever a higher reaction temperature (>40 °C) was necessary.
Catalyst loading ranges from 20 to 60 mol %. See the Supporting
Information.
General Procedure for the Synthesis of Macrocyclic Taxoids 6.
A typical procedure is described for the synthesis of taxoid 2-debenzoyl-
2,13-[(10R,9S,7Z)-9-tert-butoxycarbonylamino-10-hydroxy-1,11-dike-
toundeca-4,7-dienylene]baccatin III (6a). To a solution of 21a (50 mg,
0.049 mmol) in pyridine-acetonitrile (1/1, 5 mL) was added dropwise
HF/pyridine (70/30, 0.4 mL) at 0 °C, and the mixture was stirred at
room temperature for 11 h. The reaction was quenched with saturated
aqueous sodium carbonate solution (5.0 mL). The mixture was then
diluted with ethyl acetate (70 mL), washed with saturated aqueous
copper sulfate (10 mL × 3), water (10 mL), and brine, dried over
anhydrous magnesium sulfate, and concentrated in vacuo. The crude
product was purified on a silica gel column using hexane/ethyl acetate
(1/1 followed by 1/2) as the eluant to afford macrocyclic taxoid 6a as
a white solid (35.0 mg, 90% yield; Z/E ) 9/1 based on 1H NMR): 1H
NMR (250 MHz, CDCl3) δ [1.02 (major), 1.05 (minor)] (s, 3 H), [1.16
(major), 1.20 (minor)] (s, 3 H), 1.37 (s, 9 H), 1.62 (s, 3 H), 1.85 (m,
1 H), 1.89 (s, 3 H), 2.11 (s, 3 H), 2.22 (s, 3 H), 2.52 (m, 6 H), 2.85 (m,
1 H), 3.06 (m, 2 H), 3.77 (d, J ) 8.0 Hz, 1 H), 4.06 (s, 1 H), 4.23 (d,
J ) 8.0 Hz, 1 H), 4.42 (d, J ) 8.0 Hz, 1 H), 4.43 (m, 1 H), 4.79-4.94
(m, 3 H), 5.28 (d, J ) 8.0 Hz, 1 H), [5.40 (minor), 5.46 (major)] (m,
2 H), 5.60 (m, 1 H), 5.70 (m, 1 H), 5.86 (t, J ) 8.2 Hz, 1 H), [6.19
(major), 6.22 (minor)] (s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 9.8,
15.2, 20.8, 22.1, 22.5, 23.2, 26.1, 26.8, 28.2, 35.0, 35.4, 36.8, 42.8,
45.7, 50.6, 58.1, 71.6, 72.0, 72.8, 75.5, 75.7, 76.0, 80.1, 80.5, 80.6,
84.7, 126.4, 127.7, 128.9, 131.9, 132.8, 142.4, 155.0, 169.7, 171.3,
172.3, 174.2, 203.4; HRMS (FAB, CHCl3/NBA/NaCl/PPG) m/z calcd
for C40H55NO15‚Na+ 812.3469, found 812.3459 (∆ ) 1.3 ppm).
For the synthesis and characterization data for other â-lactams 17,
18, 20, and 9, see the Supporting Information.
General Procedure for the Synthesis of taxoids 7. A typical
procedure is described for the synthesis of 2-debenzoyl-2-(pent-4-
enoyl)-7-triethylsilyl-13-[(2R,3S,Z)-3-tert-butoxycarbonylamino-2-tri-
ethylsiloxyocta-4,6-dienoyl]baccatin III (7a). To a solution of 8b (53
mg, 0.078 mmol) and â-lactam 9a-Z (43 mg, 0.117 mmol) in dry THF
(3 mL) was added a solution of 1.0 M LiHMDS in THF (0.12 mL,
0.12 mmol) dropwise at -40 °C, and the solution was stirred at -40
°C for 35 min. The reaction was quenched with saturated aqueous
ammonium chloride (10 mL), and the aqueous layer was extracted with
dichloromethane (25 mL × 3). The combined extracts were dried over
anhydrous magnesium sulfate and concentrated in vacuo. The residue
was purified on a silica gel column using hexane/ethyl acetate (8/1
followed by 4/1) as the eluant to afford the coupling product 7a as a
white solid (77 mg, 94%): mp 82-83 °C; [R]20 -55.0° (c 0.20,
D
1
CHCl3); H NMR (250 MHz, CDCl3) δ 0.59 (m, 12 H), 0.94 (m, 18
H), 1.14 (s, 6 H), 1.38 (s, 9 H), 1.61 (s, 3 H), 1.86 (m, 1 H), 1.94 (s,
3 H), 2.14 (s, 3 H), 2.18 (m, 2 H), 2.21 (s, 3 H), 2.41 (m, 4 H), 2.52
(m, 1 H), 2.90 (m, 2 H), 3.68 (d, J ) 6.8 Hz, 1 H), 4.17 (d, J ) 7.9
Hz, 1 H), 4.24 (d, J ) 2.8 Hz, 1 H), 4.40 (dd, J ) 8.2, 6.6 Hz, 1 H),
4.44 (d, J ) 7.9 Hz, 1 H), 4.76 (br t, 1 H), 4.90 (br d, 2 H), 5.06 (m,
4 H), 5.42 (d, J ) 6.8 Hz, 1 H), 5.60 (m, 2 H), 5.81 (m, 2 H), 6.05 (t,
J ) 8.5 Hz, 1 H), 6.40 (s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 4.6,
5.2, 6.7, 9.9, 14.1, 20.8, 21.1, 22.6, 26.4, 28.2, 28.4, 32.1, 34.0, 35.0,
37.1, 43.2, 46.5, 50.5, 58.3, 71.5, 72.1, 74.1, 74.5, 75.0, 76.6, 78.5,
79.6, 80.7, 84.3, 115.5, 115.9, 126.9, 131.1, 133.3, 135.8, 136.5, 140.7,

Macrocycle Formation by RCM
J. Am. Chem. Soc., Vol. 122, No. 22, 2000 5353
In the same manner, macrocyclic taxoids 6b-o were synthesized.
For the characterization data of 6b-o, see the Supporting Information.
General Procedure for the Synthesis of Macrocyclic Taxoids 6′.
A typical procedure is described for the synthesis of 2-debenzoyl-2,
13-[(2R,3S)-3-tert-butoxycarbonylamino-2-hydroxy-1,11-diketounde-
cylene]baccatin III (6′a). A solution of 6a (15.0 mg, 0.019 mmol) in
ethyl acetate (2 mL) was added to 10% palladium on carbon (10 mg)
under a hydrogen atmosphere, and the reaction mixture was stirred for
18 h at room temperature. The reaction mixture was then filtered
through Celite and concentrated in vacuo. The crude product was
purified on a silica gel column using hexane/ethyl acetate (1/2) as the
HRMS (FAB, CHCl3/NBA/NaCl) m/z calcd for C40H59NO15‚Na+
816.3782, found 816.3822 (∆ ) -4.8 ppm).
In the same manner, macrocyclic taxoids 6′d, 6′e, 6′f, 6′g, 6′l, 6′m,
and 6′o were obtained. For the characterization data, see the Supporting
Information.
Acknowledgment. This research was supported by grants
from the National Institutes of Health (GM417980). Generous
support from Indena, SpA, is also gratefully acknowledged. We
thank Dr. Ralph J. Bernacki and Ms. Paula Pera, Roswell Park
Cancer Institute, for the cytotoxicity assay and Dr. Susan B.
Horwitz and Mr. Lifeng He, Albert Einstein College of
Medicine, for the tubulin binding assay. We thank Dr. Fang
Liu for her helpful advice on NMR techniques. We also
acknowledge the support from the National Science Foundation
(Grant CHE 9413510) for the NMR Facilities at Stony Brook.
eluant to afford macrocyclic taxoid 6′a as a white solid (15.0 mg,
1
100%): mp 156-158 °C; [R]20 -76.2° (c 0.21, CHCl3); H NMR
D
(250 MHz, CDCl3) δ 1.04 (s, 3 H), 1.19 (s, 3 H), 1.38 (s, 9 H), 1.39-
1.44 (m, 8 H), 1.60 (s, 3 H), 1.72 (m, 2 H), 1.86 (m, 1 H), 1.90 (s, 3
H), 2.221 (s, 3 H), 2.224 (s, 3 H), 2.28 (m, 2 H), 2.40 (dd, J ) 6.9, 6.4
Hz, 2 H), 2.53 (m, 2 H), 2.70 (m, 1 H), 3.03 (br s, 1 H), 3.78 (d, J )
7.7 Hz, 1 H), 3.98 (s, 1 H), 4.02 (br s, 1 H), 4.17 (d, J ) 7.8 Hz, 1 H),
4.42 (m, 1 H), 4.46 (d, J ) 7.8 Hz, 1 H), 4.53 (d, J ) 9.7 Hz, 1 H),
4.96 (d, J ) 7.9 Hz, 1 H), 5.33 (d, J ) 7.7 Hz, 1 H), 5.90 (t, J ) 8.1
Hz, 1 H), 6.21 (s, 1 H); 13C NMR (62.9 MHz, CDCl3) δ 9.7, 15.2,
20.8, 21.9, 22.5, 23.6, 24.3, 26.1, 28.2, 28.4, 29.7, 30.6, 35.1, 35.4,
36.4, 43.0, 45.7, 51.2, 58.2, 71.8, 73.4, 75.0, 75.3, 75.6, 76.1, 79.9,
80.8, 84.6, 87.2, 132.5, 142.8, 155.8, 169.5, 171.3, 173.2, 174.8, 203.5;
Supporting Information Available: Characterization data
for new compounds 7-10, 12, 17, 18, 20, and 21 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA000293W