Allylation of Erythromycin Derivatives: Introduction of Allyl Substituents into Highly Hindered Alcohols

Article abstract of DOI:10.1021/jo034883z

Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using substituted allyl tert-butyl carbonates under palladium(0) catalysis. This allylation works well where traditional ether-forming protocols function poorly. Allyl

Full text of DOI:10.1021/jo034883z

Allyla tion of Er yth r om ycin Der iva tives: In tr od u ction of Allyl
Su bstitu en ts in to High ly Hin d er ed Alcoh ols
Eric J . Stoner,* Matthew J . Peterson,1 Michael S. Allen, J ohn A. DeMattei,2
Anthony R. Haight, M. Robert Leanna, Subhash R. Patel, Daniel J . Plata,
Ramiya H. Premchandran,3 and Michael Rasmussen
Global Pharmaceutical Research and Development, Abbott Laboratories,
1401 Sheridan Road, North Chicago, Illinois 60064-6290
eric.stoner@abbott.com
Received J une 23, 2003
Functionalized erythromycin 9-oxime derivatives are 6-O-allylated under mild conditions using
substituted allyl tert-butyl carbonates under palladium(0) catalysis. This allylation works well where
traditional ether-forming protocols function poorly. Allyl tert-butyl carbonates provide higher yields
in this reaction than lesser substituted carbonates such as ethyl or isopropyl. Aryl-substituted allyl
carbonates or carbamates may be employed as well and, when used, produce trans-olefinic products.
In tr od u ction
Nearly 50 years after its discovery, erythromycin A (1,
Figure 1) remains one of the most widely used antibiotics
in the world.4 Additionally, antibiotics based on this
macrolide skeleton continue to be powerful treatments
against a wide variety of infections. Erythromycin A,
however, has a poor pharmacokinetic profile with limita-
tions that include instability in gastric acid, short elimi-
nation half-life, gastrointestinal irritation, and a limited
spectrum of activity.5 Moreover, the developing global
resistance of bacteria to erythromycin A and other
antibiotics is a pivotal factor in the continuing search for
more effective medicines.6
One key feature of new macrolide antibiotics is modi-
fication of the macrolide ring to reduce degradation in
gastric acid. The acid-induced formation of the 6,9-
hemiketal initiates a cascade of reactions that results in
compounds that lack the desired antibiotic properties, but
which often possess undesirable motilin activity.7 One
solution to this problem is to “block” the 6-hydroxyl
position with an alkyl substituent, thereby preventing
formation of the 6,9-hemiketal and its degradative path-
way.8 In clarithromycin 2 (Biaxin), for example, the
F IGURE 1. Macrolide antibiotics.
introduction of the 6-O-methyl substituent has been
demonstrated to ameliorate gastrointestinal irritation
and provide enhanced overall activity relative to eryth-
romycin.5
A third-generation macrolide structure, the ketolides,
characterized by the removal of the cladinose sugar and
subsequent oxidation to the 3-ketone, has recently emerged
from our laboratories.9 Abbott’s ketolide clinical candi-
date, ABT-773 (3), is additionally 6-O-substituted with
a trans-2-propenyl-3-(3-quinoline) (PQ) linkage.10
* To whom correspondence should be directed.
(1) Current address: Theravance, Inc. 901 Gateway Blvd, S. San
Francisco, CA 94080.
(2) Array BioPharma, 3200 Walnut St., Boulder, CO 80301.
(3) Current address: MediChem, 12305 S. New Avenue, Lemont,
IL 60439.
(4) Flynn, E. H.; Sigal, M. V., J r.; Wiley, P. F.; Gerzon, K. J . Am.
Chem. Soc. 1954, 76, 3121.
Resu lts a n d Discu ssion
O-Alkylation at the 6-position in functionality-rich
macrolides via Williamson ether formation protocols is
(5) (a) Charles, L.; Segretti, J . Drugs 1997, 53 (3), 349. (b) Clark, R.
F.; Ma, Z.; Wang, S.; Griesgraber, G.; Tufano, M.; Yong, H.; Li, L.;
Zhang, X.; Nilius, A. M.; Chu, D. T. W.; Or, Y. S. Biorg. Med. Chem.
Lett. 2000, 10 (8), 815.
(6) (a) Ball, P.; Baquero, F.; Cars, O.; File, T.; Garau, J .; Klugman,
K.; Low, D. E.; Rubinstein, E.; Wise, R. J . Antimicrobial Chem. 2002,
49 (1), 31. (b) Blondeau, J . M.; DeCarolis, E.; Metzler, K. L.; Hansen,
G. T. Expert Opin. Investig. Drugs 2002, 11 (2), 189.
(7) (a) Klein, L. L.; Freiberg, L. A.; Kurath, P.; Henry, R. F. J . Org.
Chem. 1993, 58 (11), 3209. (b) Burnelle-Curty, C.; Faghih, R.; Pagano,
T.; Henry, R. F.; Lartey, P. A. J . Org. Chem. 1996, 61 (15), 5153.
(8) Another solution is the conversion of the ring to an azalactone
via Beckmann rearrangement as in azithromycin: Yang, B. V.;
Goldsmith, M.; Rizzi, J . P. Tetrahedron Lett. 1994, 35 (19), 3025.
(9) For an excellent review of ketolide chemistry and activity see:
Ma, Z.; Nemoto, P. A. Curr. Med. Chem.sAnti-Infective Agents 2002,
1 (1), 15.
(10) (a) Or, Y. S.; Clark, R. F.; Wang, S.; Chu, D. T. W.; Nilius, A.
M.; Flamm, R. K.; Mitten, M.; Ewing, P.; Alder, J .; Ma, Z. J . Med.
Chem. 2000, 43 (6), 1045. (b) Or, Y. S.; Ma, Z.; Clark, R. F.; Chu, D.
T.; Plattner, J . J .; Griesgraber, G. U.S. Patent 5,866,549, 1999.
10.1021/jo034883z CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/16/2003
J . Org. Chem. 2003, 68, 8847-8852
8847

Stoner et al.
not a trivial matter and involves the careful balancing
of many factors: base, alkylating agent, protecting
groups, rate, and order of addition of reagents and
temperature. Even after extensive optimization, forma-
tion of the desired 6-O-methyl isomer in 2 is accompanied
by undesired overalkylated species.11 Unfortunately, at-
tempts to introduce groups larger than methyl at the
6-position via the same protocols have generally resulted
in poor conversions and product purity.11c To develop an
efficient synthesis of 3 requires the development of
alternative methodologies.
In an early synthesis of 3, the 6-O-PQ moiety was
introduced in two steps: allylation under conditions
similar to those employed for the methylation in 2,
followed by Heck coupling with bromoquinoline.12,13 The
initial allylation protocol required slow addition (3-5 h)
of a DMSO/THF solution of KOC(CH3)3 to a dilute
solution of protected erythromycin A oxime 4 and allyl
bromide affording, under the best circumstances, only a
60-75% conversion to 5 with substantial production of
overallylated species (eq 1, condition A).
The transition-metal-catalyzed allylation of nucleo-
philes has proven to be a versatile methodology in organic
synthesis. A variety of nucleophiles have been shown to
efficiently couple with palladium π-allyl complexes, and
with advances in the regioselective and enantioselective
reactions, the utility of the chemistry continues to be
expanded.14 The palladium-catalyzed allylation of alco-
hols, however, has been utilized to a much lesser extent,
owing to the generally poor nucleophilicity of alcohols.
Most examples of oxygen nucleophiles have been limited
to phenols,15 intramolecular allylations, and other sub-
strate specific systems.16
While Sinou’s group has reported moderate to excellent
yields in the allylation of carbohydrate substrates using
allyl ethyl carbonate, an excess (2-6 equiv) of the
allylating agent was required.17 It seemed likely that the
spectator alkoxy group liberated from the carbonate
competes with the desired nucleophile for the π-allyl
palladium reagent. We reasoned that the increased steric
requirements of the spectator tert-butoxy group could be
utilized to competitively favor allylation of the desired
alcohol.18,19 Thus, exposure of 4 to 1.45 equiv of allyl tert-
butyl carbonate 6 in the presence of Pd(OAc)2/Ph3P in
refluxing THF afforded the desired 6-O-allyl derivative
5 in 77% isolated yield (eq 1, condition B).
The effects of the spectator group are quite pronounced
(see Table 1). In attempts to convert protected oxime 4
to its 6-O-allyl derivative 5, allyl methyl20 and allyl ethyl
carbonate proved equally inefficient and unselective,
despite the use of large excesses of reagent. Allyl isopro-
(13) (a) Stoner, E. J .; Peterson, M. J .; Ku, Y.-Y.; Cink, R. D.; Cooper,
A. J .; Deshpande, M. N.; Grieme, T.; Haight, A. R.; Hill, D. R.; Hsu,
M. C.-P.; King, S. A.; Leanna, M. R.; Lee, E. C.; McLaughlin, M. A.;
Morton, H. E.; Napier, J . J .; Plata, D. J .; Raje, P. R.; Rasmussen, M.;
Riley, D.; Tien, J . J .-H. J .; Wittenberger, S. J . U.S. Patent 6,437,106,
2002. (b) Allen, M. S.; Premchandran, R. H.; Chang, S.-J .; Condon, S.;
DeMattei, J . A.; King, S. A.; Kolackowski, L.; Manna, S.; Nichols, P.
J .; Patel, H. H.; Patel, S. R.; Plata, D. J .; Stoner, E. J .; Tien, J . J .-H.
J .; Wittenberger, S. J . U.S. Patent 6,579,986, 2002.
(14) (a) Comprehensive Asymmetric Catalysis; J acobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol 2. (b) Trost,
B. M.; Van Vranken, D. L. Chem Rev. 1996, 96 (1), 395. (c) Shibasaki,
M. In Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.;
J AI Press: Greenwich, 1996; Vol. 5. (d) Tsuji, J . Palladium Reagents
and Catalysts: Innovations in Organic Synthesis; J ohn Wiley and
Sons: New York, 1995. (e) Harrington, P. J . In Comprehensive
Organometallic Chemistry II; Abel, E. W. Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon Press: Oxford, 1995; Vol. 12, pp 798-903
(15) (a) Larock, R. C.; Lee, N. H. Tetrahedron Lett. 1991, 32 (44),
6315. (b) Muzart, J .; Genet, J .-P.; Denis, A. J . Organomet. Chem. 1987,
326 (1), C23.
(16) (a) Burke, S. D.; J iang, L. Org. Lett. 2001, 3, 1953. (b) Vares,
L.; Rein, T. Org. Lett. 2000, 2 (17), 2611. (c) Labrosse, J .-R.; Poncet,
C.; Lhoste, P.; Sinou, D. Tetrahedron Asym. 1999, 10, 1069. (d)
Fournier-Nguefack, C.; Lhoste, P.; Sinou, D. J . Chem. Res. (S) 1998,
105. (e) Thorey, C.; Wilken, J .; Henin, F.; Martens, J .; Mehler, T.;
Muzart, J . Tetrahedron Lett. 1995, 36, 5527. (f) Massacret, M.; Goux,
C.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1994, 35, 6093. (g) Trost,
B. M.; McEachern, E. J .; Toste, F. D. J . Am. Chem. Soc. 1998, 120,
12702. (h) Cuiper, A. D.; Kellogg, R. M. Chem. Commun. 1998, 655
(17) (a) Lakhmiri, R.; Lhoste, P.; Sinou, D. Tetrahedron Lett. 1989,
30 (35), 4669. (b) Lakhmiri, R.; Lhoste, P.; Sinou, D. Synth. Commun.
1990, 20 (10), 1551. (c) Kumar, V.; Gopalakrishnan, V.; Ganesh, K. N.
Bull. Chem. Soc. J pn. 1992, 65 (6), 1665. (d) Lakhmiri, R.; Lhoste, P.;
Kryczka, B.; Sinou, D. J . Carbohydr. Chem. 1993, 12 (2), 223. (e)
Lakhmiri, R.; Lhoste, P.; Boullanger, P.; Sinou, D. J . Chem. Res. (S)
1990, 342.
The isolated yields from this process were generally
40-50%, and all attempts to further improve this pro-
cedure have thus far failed.
(11) (a) Watanabe, Y.; Morimoto, S.; Adachi, T.; Kashimura, M.;
Asaka, T. J . Antibiotics 1993, 46 (4), 647. (b) Morimoto, S.; Adachi, T.;
Matsunaga, T.; Kashimura, M.; Asaka, T.; Watanabe, Y.; Sota, K.;
Sekiuchi, K. U.S. Patent 4,990,602, 1991. (c) Morimoto, S.; Misawa,
Y.; Adachi, T.; Nagate, T.; Watanabe, Y.; Omura, S. J . Antibiotics 1990,
43 (5), 286.
(18) An alternative approach is incorporation of the desired alcohol
in the allyl carbonate: Oltvoort, J . J .; Kloosterman, M.; VanBoom, J .
H. Recl. Trav. Chim. Pays-Bas 1983, 102, 501.
(12) For an improved synthesis of ABT-773 incorporating this
chemistry, see: Plata, D. J .; Leanna, M. R.; Rasmussen, M.; McLaugh-
lin, M. A.; Condon, S. L.; Kerdesky, F. A. J .; King, S. A.; Peterson, M.
A.; Stoner, E. J .; Wittenberger, S. J ., submitted.
(19) Reviews of π-allyl palladium chemistry (a) Trost, B. M. Acc.
Chem. Res. 1980, 13 (11), 386. (b) Tsuji, J . Tetrahedron 1986, 42 (16),
4361.
(20) Commercially available.
8848 J . Org. Chem., Vol. 68, No. 23, 2003

Allylation of Erythromycin Derivatives
TABLE 1. Effects of Ca r bon a te/Ca r ba m a te Su bstitu tion
on Allyla tion
of the E-configuration shown (the thermodynamically
preferred isomer).25 The procedure used for the isolation
of the parent erythromycin 9-oxime, the starting material
for all of our substrates, incorporates a crystallization
protocol that virtually eliminates the other geometrical
isomer, which is typically present in from 5 to 7%.11
We have observed this allylation strategy to be useful
for erythromycin derivatives with a wide variety of
protecting groups (see Tables 2 and 3). Labile trimeth-
ylsilyl ethers (as in 4 and 13) remain intact during
allylation, whereas other alkylation protocols resulted in
their cleavage, contributing to significant purification
difficulties. A variety of protecting groups may also be
successfully employed on the 9-oxime as well. Both acyl
moieties (as represented by benzoate 8) and ketals (4)
may be used with success. When the free oxime (13) is
present, initial allylation with 6 occurs at the more
nucleophilic oxime-hydroxyl, yielding 9-O-allyl derivative
14 (see Table 3, entry 10). Subsequent allylation of 14
with 6 occurs, as expected, at the 6-hydroxyl, affording
6,9-bis-O-allyl adduct 15 (see Table 3, entry 11).
A principle advantage of this methodology is the ability
to use substituted allyl carbonates as well. For example,
carbonate 9a couples cleanly with 8, affording the cor-
responding 6-O-PQ derivative 10.
% yielda
XR
OCH3
OC2H5
O-i-C3H7
N(i-C3H7)2
equiv
5
4
7
7.0
7.0
1.8
1.8
2.9
1.5
4.0
67
69
80
41
71
96
0
28
19
13
59
29
0
5
11
7
0
0
4
O-t-C4H9 (6)
0
100
a
Ratios obtained from HPLC (205 nm) and are uncorrected for
response factors.
pyl carbonate,21 which liberates more hindered isopro-
poxide as the spectator, produces higher conversions.
Allyl N,N-diisopropyl carbamate22 may be employed as
well; however, high overall conversions do not seem
attainable without the use of a considerable excess of
reagent. Of the carbonates and carbamate examined, only
allyl tert-butyl carbonate 6 produced a high degree of
selective monoallylation. The use of a larger excess of 6
(4.0 equiv) affords exclusively 6,12-bis-O-allylated com-
pound 7.
The regioselectivity of methylation in 2 for the 6-hy-
droxy position has been studied by computational meth-
ods and appears to be derived from altered acidities of
the macrolide hydroxyls.11a,23 As an extension of this
work, we have explored this allylation chemistry with
respect to more accessible aliphatic alcohols24 and have
noted that alcohol acidity plays a significant role in
selectivity. All of the oximes examined in this work are
We have demonstrated that 8 reacts equally well with
cis-primary carbonate 9b or secondary carbonate 9c
(Table 3, entries 3-5). Ketal-protected oxime 4 acts
similarly and is allylated in high yield with carbonates
9a -c, affording 12 (Table 3, entries 7-9). In each case,
the crude yield is nearly quantitative and only the trans-
(24) (a) Haight, A. R.; Stoner, E. J .; Peterson, M. J .; Grover, V. J .
Org. Chem. 2003, 68, 8092-8096. (b) Another application of this
chemistry has been published based on prior verbal communication:
Marmsa¨ter, F. P.; Vanecko, J . A.; West, F. G. Tetrahedron 2002, 58
(10), 2027.
(25) Erythromycin A oxime (E and Z isomers): (a) Egan, R. S.;
Freiberg, L. A.; Washburn, W. H. J . Org. Chem. 1974, 39 (17), 2492,
(b) Massey, E. H.; Kittchell, B.; Marti, L. D.; Gerzon, K.; Murphy, H.
W. Tetrahedron Lett. 1970, 11 (2), 157. (c) Hatton, I. K.; Tyler, J . W.
Tetrahedron Lett. 1989, 30 (5), 605.
(21) Brettle, R.; Khan, M. A. J . Chem. Res. 1989, 1, 240.
(22) Tsuji, J .; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.;
Takahashi, K. J . Org. Chem. 1985, 50, 1523.
(23) Goto, H.; Kawashima, Y.; Kashimura, M.; Morimoto, S.; Osawa,
E. J . Chem. Soc., Perk. Trans 2 1993, 1647. The results obtained by
these computational methods are consistent with observed experimen-
tal data in ref 11.
J . Org. Chem, Vol. 68, No. 23, 2003 8849

Stoner et al.
TABLE 2. Sta r tin g Ma ter ia ls a n d Allyla tion P r od u cts
F IGURE 2. Formation of bis-allyl ethers.
tion protocol represents a significant development in that
two problematic, low yielding steps from the original
synthetic protocol (Williamson ether formation and Heck
coupling) are replaced with a single high-yielding con-
vergent transformation.12
In general, either THF or toluene may be employed as
solvent for these allylations. Since the reaction must be
run under strictly anhydrous conditions (water content
< 2 mol %), toluene offers the advantage of more efficient
removal of water by azeotropic distillation. This is
accomplished by the in vacuo distillation of a portion of
the toluene from the starting materials prior to the
addition of the catalyst. A similar, albeit less efficient,
process may be accomplished with THF.
Water is detrimental to the reaction by competing as
a nucleophile twice, affording dimeric allyl ethers, after
the initial formation of an intermediate allyl alcohol
(Figure 2). While bisallyl ether 6a (from 6) has not been
observed (and is not of concern to us due to its volatile
nature), dimeric ethers arising from 9a -c, such as 9d ,
have been detected and represent a minor purification
issue. Ether 9d is the principle carbonate-related impu-
rity in “wet” allylations and can be independently pre-
pared by the reaction of 9a with water in the presence
of a Pd(0) catalyst. The formation of bis-allyl ethers in
this manner is an interesting testament to the low reac-
tivity of our substrates as even trace amounts of water
are removed by ether formation prior to the initiation of
our desired macrolide allylation. Under strictly anhy-
drous conditions, however, only a slight molar excess of
carbonate (∼1.05 equiv) is required to give complete
consumption of starting material.
Although a variety of Pd(0) catalysts will work ef-
fectively in this allylation, we prefer to use the Pd(OAc)2/
Ph3P system rather than Pd2(dba)3 or Pd(Ph3P)4 for
economic and stability reasons.27 In general, laboratory-
scale allylations use 0.5-1 mol % palladium, while larger
scale reactions can be accomplished with significantly
less catalyst (0.05% or less). The preferred ligands are
dppb or Ph3P.28 Reactions are typically performed at
reflux temperature and are complete in 1-3 h with 1 mol
% catalyst loading.
TABLE 3. Allyla tion of Er yth r om ycin A Oxim e
Der iva tives
starting
entry
material
carbonate
product
% yielda
1
2
3
4
5
6
7
8
9
4
4
8
8
8
8
4
4
4
6
5
7
77
75
99
89
95
91
92b
94
97
94
82
6 (xs)
9a
9b
9c
6
9a
9b
9c
6
10
10
10
11
12
12
12
14
15
10
11
13
13
6 (xs)
a
b
Isolated yield of material >95% pure. Crude yield.
terminally substituted olefin (10, 12) is detected.26 With
respect to the synthesis of ABT-773 (3), this new allyla-
(26) Reviews of selectivities and basic aspects of π-allyl palladium
chemistry: (a) Tsuji, J . Pure Appl. Chem. 1989, 61 (10), 1673. (b) Trost,
B. M. Angew. Chem., Int. Ed. Eng. 1989, 28, 1173.
(27) In situ formation of Pd(0) from Pd(OAc)2: Amatore, C.; J utand,
A.; M’Barki, M. A. Organometallics 1992, 11 (9), 3009.
8850 J . Org. Chem., Vol. 68, No. 23, 2003

Allylation of Erythromycin Derivatives
TABLE 4. Allyla tion of Oxim e 8 w ith Ca r ba m a tes 16a -e
imidazolide 16e proved to be unproductive in this ally-
lation, affording as the principle product the correspond-
ing allylamines 17d -e. These results further emphasize
the special nature of the tert-butyl carbonate for these
allylations. As demonstrated, reactions of 8 with carbon-
ates 6 or 9a -c are very high yielding using small
excesses of reagent.
The carbamates employed were prepared by reaction
of trans-alcohol 19a with commercially available car-
bamoyl chlorides (affording 16a -d ) or 1,1′-carbonyldi-
imidazole (CDI) (affording 16e).
% yielda
carbamate
equiv
product (10)
amine (17a -e)b
16a
16b
16c
16d
16e
2.6
3.1
2.4
1.6
2.4
36
63
20
0
35
19
0
100
>90
The tert-butyl carbonates (6, 9a -c) used in these
allylations are conveniently obtained by the reaction of
the appropriate alcohols with di-tert-butyl dicarbonate
under phase transfer conditions.29 For example, allyl
alcohol is converted into 6 in 68% yield. Carbonates 9a
or 9b are prepared from alkenols 19a and 19b, which
are derived from propargylquinoline alcohol 1830 via one
of two reductive protocols (eq 4). trans-Alkenol 19a was
<5
a
Relative HPLC ratios unadjusted for response factors. Re-
maining material is predominantly starting material 8. Amines
17a -e were characterized by mass spectroscopy only.
b
Polymer-supported Pd catalysts were not examined
with respect to this chemistry, owing in part to the rapid
development and scale-up of the key allylated intermedi-
ate. Although residual metal contamination can be a
significant issue in pharmaceutical intermediates, the
allylation in ABT-773 occurs early in the synthesis, and
residual palladium is reduced significantly throughout
the remaining synthetic procedures prior to final active
pharmaceutical ingredient (API) isolation.
Although reactions of this type involving more nucleo-
philic partners (malonates, phenols, amines) have been
performed at 25 °C or colder, in our hands allylations of
these highly hindered macrolides have not been observed
below 50 °C. We have demonstrated that the π-allyl
species forms at room temperature by trapping experi-
ments with n-Bu3SnH.
Our early sucesses with an allyl carbamate (Table 1)
led us to reexamine this functionality with respect to the
PQ side chain. To this end, substituted carbamates
16a -e were prepared and their utility examined in the
allylation of oxime 8 (see eq 3, Table 4). These reactions
suffered from the generation of a competitive nucleophilic
amine once the π-allyl Pd species was formed. Not
surprisingly, the most hindered carbamates (16a -c)
produced the highest conversions of starting material 8
to product 10. Morpholine-derived carbamate 16d and
generated by chemical reduction of the alkyne using Red-
Al. The cis-isomer 19b was prepared by partial hydro-
genation in the presence of a Lindlar-type catalyst (5%
Pd/CaCO3-Pb). A secondary sulfur-based catalyst poison,
3,6-dithia-1,8-octanediol, is employed to slow the hydro-
genation and provide control over alkane formation. This
hydrogenation also generated small amounts of 19a ,
which was effectively removed by crystallization. Second-
ary carbonate 9c was prepared by treatment of com-
mercially available 3-quinolinecarboxaldehyde with vinyl
(29) Houlihan, F.; Bouchard, F.; Fre`chet, J . M. J .; Willson, C. G.
Can. J . Chem. 1985, 63, 153.
(30) (a) Glase, S. A.; Akunne, H. C.; Heffner, T. G.; J aen, J . C.;
MacKenzie, R. G.; Meltzer, L. T.; Pugsley, T. A.; Smith, S. J .; Wise, L.
D. J . Med. Chem. 1996, 39 (16), 3179. (b) Yamanaka, H.; Shiraiwa,
M.; Edo, K.; Sakamoto, T. Chem. Pharm. Bull. 1979, 27 (1), 270.
(28) Less reactive carbonates 9a -c do not react well using Ph3P as
ligand: dppb is preferred.
J . Org. Chem, Vol. 68, No. 23, 2003 8851

Stoner et al.
Grignard, followed by in situ quenching of the resulting
Su m m a r y
alkoxide with di-tert-butyl dicarbonate (eq 5).
We have demonstrated a new and highly effective
method for the Pd-catalyzed O-allylation of the sterically
hindered 6-hydroxyl of erythromycin derivatives with
substituted allyl tert-butyl carbonates. This allylation
protocol allows for the full elaboration of the 6-OH in
ABT-773 in one synthetic step, with high yield and
selectivity. This methodology offers significant advan-
tages over traditional means for the functionalization of
macrolides. Among these benefits are operational sim-
plicity; substantial increases in yield, throughput, and
product purity; milder reaction conditions; and reduction
of hazardous waste. This methodology has been applied
to the synthesis of production-scale batches of erythro-
mycin A intermediates. The method should be applicable
to a wide array of subtrates with inaccessible or hindered
alcohol functionalities.24a,24b
Exp er im en ta l Section
Rep r esen ta tive Allyla tion P r oced u r e. 2′,4′′-O-d iben -
zoyl-6-O-P Q-er yt h r om ycin A 9-O-Ben zoyloxim e (10)
(Ta ble 3, En tr y 3). To a suitable reaction vessel was charged
erythromycin A oxime tribenzoate 8 (41.1 g, 38.6 mmol, 1
equiv) and trans-carbonate 9a (12.6 g, 44.2 mmol, 1.15 equiv)
in 300 mL of toluene. The solvent was removed in vacuo and
300 mL of THF added (K.F. titration 0.01%). The catalyst
Pd2(dba)3 (170 mg, 0.005 equiv) and dppb (160 mg, 0.01 equiv)
were added, and the reaction mixture was degassed by
evacuation and venting to nitrogen three times. The reaction
was heated to reflux for 3 h, cooled to room temperature, and
reduced to dryness in vacuo. The crude residue (49 g, 105%
theory) was dissolved in 100 mL of CH3CN at 60 °C, filtered,
and reduced to dryness, affording 46.8 g of 10 (99%) as a pale
yellow foam (>96% purity by HPLC).
Ack n ow led gm en t. The authors thank Drs. Momir
Cirovic, Steven Hollis, and Ian Malcolm for their
invaluable assistance with NMR interpretation and
compound characterization.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O034883Z
8852 J . Org. Chem., Vol. 68, No. 23, 2003