Practical Syntheses of 13-O-[(2-Methoxyethoxy)methyl]-22,23-dihydroavermectin B1 Aglycon [Dimedectin Isopropanol, MK-324] and 13-epi-O-(Methoxymethyl)-22,23-dihydroavermectin B1 Aglycon [L-694,554], Flea Active Ivermectin Analogues

Article abstract of DOI:10.1021/jo970187l

Practical high yielding syntheses of 13-O-[(2-methoxyethoxy)methyl]-22,23-dihydroavermectin B₁ aglycon (dimedectin 2-propanol, MK-324, 1) and 13-epi-O-(methoxymethyl)-22,23-dihydroavermectin B₁ aglycon (L-694,554, 2), both potent flea insecticides, from ivermectin are presented. The successful selective manipulation of silyl protecting groups on ivermectin aglycon led to the facile preparation of 5,7-O-bis-silyl-22,23-dihydroavermectin B₁ aglycon 7 as the key intermediate for the large scale syntheses of these compounds. Development of a dual pyridine/tertiary amine system for mesylation of the C-13α hydroxyl group of 7 and subsequent displacement with cesium propionate-propionic acid led to the successful inversion of the 13-hydroxy group.

Full text of DOI:10.1021/jo970187l

J . Org. Chem. 1997, 62, 3989-3993
3989
P r a ctica l Syn th eses of
1
3-O-[(2-Meth oxyeth oxy)m eth yl]-22,23-d ih yd r oa ver m ectin B
Aglycon [Dim ed ectin Isop r op a n ol, MK-324] a n d
1
1
3-epi-O-(Meth oxym eth yl)-22,23-d ih yd r oa ver m ectin B
1
Aglycon
[
L-694,554], F lea Active Iver m ectin An a logu es
†
Raymond J . Cvetovich,* Chris H. Senanayake, J oseph S. Amato, Lisa M. DiMichele,
Timothy J . Bill, Robert D. Larsen, R. F. Shuman, Thomas R. Verhoeven, and
Edward J . J . Grabowski
Department of Process Research, Merck Research Laboratories, Division of Merck & Co., Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
Received February 3, 1997X
Practical high yielding syntheses of 13-O-[(2-methoxyethoxy)methyl]-22,23-dihydroavermectin B
aglycon (dimedectin 2-propanol, MK-324, 1) and 13-epi-O-(methoxymethyl)-22,23-dihydroavermectin
aglycon (L-694,554, 2), both potent flea insecticides, from ivermectin are presented. The
successful selective manipulation of silyl protecting groups on ivermectin aglycon led to the facile
preparation of 5,7-O-bis-silyl-22,23-dihydroavermectin B aglycon 7 as the key intermediate for
1
B
1
1
the large scale syntheses of these compounds. Development of a dual pyridine/tertiary amine system
for mesylation of the C-13R hydroxyl group of 7 and subsequent displacement with cesium
propionate-propionic acid led to the successful inversion of the 13-hydroxy group.
The avermectins1a and the related milbemycins,1b 16-
membered macrolides produced by Streptomyces aver-
mitilis or Streptomyces hygroscopicus, respectively, are
potent anthelmintic and insecticidal compounds used in
agriculture, animals, and man. Some of the commercial-
ized successes of this class of compounds are: Agrimec,
Ivomec, Doramectin, Interceptor, Cydectin, and Milbe-
knock. Among the many efforts to improve the biological
profile and reduce toxicity in animals and humans of
avermectins, analogues modified at the C-13 position
were prepared.2 In addition, C-13 epi-avermectin ana-
logues were investigated in the search for improved
safety margins.3 Among the structural variations exam-
ined, those exhibiting interesting insecticidal activity are
1
3-O-[(2-methoxyethoxy)methyl]-22,23-dihydroavermec-
aglycon (MK-324, 1)2 and 13-epi-O-(methoxy-
F igu r e 1. MK-324, 1, and L-694,554, 2.
tin B
methyl)-22,23-dihydroavermectin B aglycon (L-694,554,
, Figure 1) which are active agents for the control of
flea infestations in dogs.
1
1
hydrolyze bis- and tris-MEM substituted intermediates
but failed to produce significant yields of mono-MEM 1.
A selective silylation and desilylation of ivermectin
aglycon was developed to prepare a 5,7-O-bis-protected
aglycon intermediate, which allowed the preparation of
large quantities of MK-324 and L-694,554.
2
Resu lts a n d Discu ssion
Published procedures on the preparation of MK-3242
relied on (2-methoxyethoxy)methyl (MEM) derivatization
of the monoprotected 5-O-tert-butyldimethylsilyl(TBDMS)-
The aglycon of 22,23-dihydroavermectin B
1
(3), (see
Figure 2, only B1a isomer shown) was prepared by acid-
catalyzed solvolysis of ivermectin.4 This hydrolysis was
complicated by the susceptibility of the aglycon toward
acid catalyzed Grob-like fragmentation to produce ring-
opened aldehydes.5 Hydrolysis was best accomplished
2
1
2,23-dihydroavermectin B aglycon 4. This approach
gave rise to the formation of significant amounts of bis-
MEM derivative 5, requiring conventional preparative
silica gel column chromatography to remove this undesir-
able byproduct. Attempts were made to selectively
in 5% H
producing aglycon 3 in 93% yield. Silylation of aglycon
with excess TBDMSCl/imidazole in THF at 55 °C
2 4
SO in methanol at temperatures below 30 °C,
3
†
Current address: Sepracor Inc., Department of Pharmaceuticals,
produced monoprotected aglycon 4, exclusively. The
addition of excess TMSCl/imidazole to monoprotected 4
trimethylsilylated the remaining C-7 and C-13 hydroxy
groups to produce tris-protected aglycon 6 in >95%
1
11 Locke Dr., Marlborough, MA 01752.
X
Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) (a) Albers-Sch o¨ nberg, G.; Arison, B. H.; Chabala, J . C.; Douglas,
A. W.; Eskola, P.; Fisher, M. H.; Mrozik, H.; Smith, J . L.; Tolman, R.
L. J . Am. Chem. Soc. 1981, 103, 4216. (b) Takiguchi, J .; Mihima, H.;
Okuda, M.; Terao, M.; Aoki, A.; Fukuda, R. J . Antibiot. 1980, 33, 1120.
(
2) Mrozik, H.; Linn, B. O.; Eskola, P.; Lusi, A.; Matzuk, A.; Preiser,
F. A.; Ostlind, D. A.; Schaeffer, J . M.; Fisher, M. H. J . Med. Chem.
989, 32, 375.
3) Blizzard, T. A.; Margiatto, G. M.; Mrozik, H.; Shoop, W. L.;
Frankshun, R. A.; Fisher, M. H. J . Med. Chem. 1992, 35, 3873.
(4) Chabala, J . C.; Mrozik, H.; Tolman, R. L.; Eskola, P.; Lusi, A.;
Peterson, L. H.; Woods, M. F.; Fisher, M. H. J . Med. Chem. 1980, 23,
1134.
(5) Blizzard, T. A.; Margiatto, G. M.; Mrozik, H.; Fisher, M. H. J .
Org. Chem. 1993, 58, 3201.
1
(
S0022-3263(97)00187-4 CCC: $14.00 © 1997 American Chemical Society

3
990 J . Org. Chem., Vol. 62, No. 12, 1997
Cvetovich et al.
selenium dioxide allylic oxidation,9 and inversion-
displacement of a tosylate with tetrabutylammonium
nitrate.10
While the preparation of the C-13R O-tosyl of ivermec-
tin B aglycon with p-toluenesulfonic anhydride, dis-
1
placement with nitrate, and reductive removal of the
nitrate ester with Zn/HOAc (50% yield overall) repre-
sented a significant accomplishment in the preparation
of C-13â O-derivatives, problems remained that were
essential to overcome in order to develop an attractive
process for the preparation of L-694,554, 2. Alternate
chemistry11 was explored toward the accomplishment of
the transformation.
When bis-silyl-protected ivermectin aglycon 7 was
treated with methanesulfonyl chloride/triethylamine, a
complex mixture of products was produced with a low
yield of mesylate 9. The use of diisopropylethylamine
as base resulted in an increase in the yield of mesylate 9
to 65%, while the use of bases with the pK in the range
of 5.5-7, such as pyridine, lutidine, (dimethylamino)py-
ridine, or collidine, afforded low yields. However, the
coaddition of a pyridine base ((dimethylamino)pyridine,
collidine, or 2,6-lutidine) with a tertiary alkylamine base
resulted in significant enhancement of the mesylate
formation. A highly effective procedure for the mesyla-
tion of alcohol 7 was developed using methanesulfonyl
chloride (2 equiv) in the presence of diisopropylethy-
lamine (3 equiv) and (dimethylamino)pyridine (2 equiv)
in dichloromethane at -10 °C, which resulted in the
formation of mesylate 9 (Figure 2) in >95% isolated yield.
The mesylation is believed to proceed through the
intermediacy of pyridinium sulfonyl ions and to not
involve formation of sulfenes as the mesylating reagent,
with the more basic tertiary amines serving to deproto-
nate and activate the alcohol (based on NMR studies).
The isolation of mesylate 9 required the avoidance of an
acidic workup due to the presence of the acid-labile
silyloxy protecting groups, and this was accomplished by
precipitation of the trialkylammonium and pyridinium
salts with hexanes, followed by an aqueous bicarbonate
wash.
F igu r e 2. Ivermectin aglycon intermediates.
yield. The combination of these silylation steps was
easily bundled into a one-pot procedure to provide tris-
silyl-protected 6 in 95% overall yield.
The more difficult task of selective removal of either
the C-7 or C-13 TMS group was then tackled. A variety
of acid, solvent, nucleophile, and temperature parameters
were investigated, most of which failed to selectively
remove the less sterically hindered C-13 O-TMS group.
A selective mono-deprotection of the C-13 hydroxyl group
was effected using dichloroacetic acid in 13% aqueous
THF at 20 °C, which left the C-7 O-TMS and C-5
O-TBDMS groups intact affording 5-O-TBDMS-7-O-TMS-
2
2,23-dihydroavermectin B
Alkylation of 7 with MEM-Cl and diisopropylethylamine
DIPEA) was achieved in acetonitrile from which the
1
aglycon, 7, in 93% yield.
(
resulting MEM-ether 8 was directly crystallized in 86%
yield. The rate of alkylation was found to be highly
sensitive to the amount of DIPEA used in the reaction.
An excess of base slowed the alkylation rate. It was also
found that samples of MEM-Cl that contained HCl due
to decomposition led to slower rates of alkylation. In fact,
the addition of excess DIPEA‚HCl to reactions induced
slower rates of alkylation.
The inversion/displacement of mesylate 9 was explored,
utilizing an array of reagents. Tetrabutylammonium
nitrate or Amberlyst A-26 nitrate (prepared from am-
berlyst A-26 chloride) requires long reaction times at 40-
50 °C in toluene to produce 50-58% yields of nitrate ester
10 (see Figure 3, only B1a isomer shown). Potassium
nitrate in DMSO produced mixtures of nitrate ester 10
and nitro derivative 11. Potassium formate, tetrabutyl-
ammonium formate, and potassium superoxide/18-crown-6
displacements led to complex mixtures of byproducts,
some involving epimerization at C-2, migration of the
C-3,4 double bond, and subsequent aromatization due to
the base sensitivity of the avermectins.12 Cesium acetate/
18-crown-6 produced a 50% yield of acetate 12, along with
A mild removal of the TMS and TBDMS protecting
groups in the presence of the MEM group of derivative 8
was accomplished with HCl in methanol at 50 °C.
Following the deprotection, MK-324 (1) was crystallized
from ethanol/water, producing an ethanol solvate which
proved to be unstable to long term storage. Among the
multiple degradates isolated were the 22,23-dihydroaver-
mectin B
1
aglycon, 3, and a ring-opened aldehyde.4
Single crystal X-ray analysis of the ethanolate revealed
that the position of the ethanol in the crystal adjacent
to the MEM group predisposed this group to solvolysis
within the crystal structure. MK-324 (1) was crystallized
from 2-propanol/water to produce a 2-propanol solvate.
Single crystal X-ray analysis of this solvate indicated it
shared the same positioning within the crystal packing
as the ethanolate, but this solvate has proved to be stable
to ambient storage.
(
6) Saito, A.; Naito, M.; Kobayashi, M. Tsuchiya, M.; Toyama, T.;
Kaneko, S.; Nanba, T.; Morisawa, Y. J . Antibiot. 1992, 46, 1252.
7) Frei, B.; Huxley, P.; Maienfisch, P.; Mereyala, H. B.; Rist, G.;
O’Sullivan, A. C. Helv. Chim. Acta 1990, 73, 1905.
8) Nakagawa, K.; Sato, K.; Tsukamoto, Y.; Okazaki, T.; Torikata,
A. J . Antibiot. 1994, 47, 502.
9) Tsukamota, Y.; Sato, K.; Kinoto, T.; Yanai, T. Bull. Chem. Soc.
(
(
(
Procedures for the preparation of inverted 13â-aver-
mectin and 13â-O-milbemycin analogues have been
published, including (1) solvolysis of C-13â iodo inter-
J pn. 1992, 65, 3300.
(10) J ones, T. K.; Mrozik, H.; Fisher, M. H. J . Org. Chem. 1992, 57,
3
248.
11) Senanayake, C. H.; Singh, S. B.; Bill, T. J .; DiMichele, L. M.;
(
3
,6
mediates, (2) epoxidation, ring opening, and rearrange-
Liu, J .; Larsen, R. D.; Verhoeven, T. R. Tetrahedron Lett. 1993, 34,
2425.
ment of milbemycin,7 microbiological hydroxylation,8

Syntheses of 22,23-Dihydroavermectin B
1
Aglycons
J . Org. Chem., Vol. 62, No. 12, 1997 3991
propionate/propionic acid to produce propionate 13, which
was hydrolyzed via Ti(O-i-Pr)
4
-catalyzed transesterifica-
tion. Preparation of the O-MOM derivative and selective
desilylation successfully yielded L-694,554. Both agents
have exhibited antiflea activity on dogs and are being
evaluated for their commercial opportunities.
Exp er im en ta l Section
Gen er a l. HPLC analyses were performed using a Spectra-
Physics SP8700 ternary solvent delivery system, a Vydac C18
protein/peptide column (250 × 4.6 mm, 5 µm) reverse phase
column, solvent system A:B, acetonitrile:water (with 0.1 v %
3 4
H PO ), at 25 °C, 3.0 mL/min, with UV detection at 245 nm.
Samples of each product for characterization and use as HLPC
standards were isolated and purified by column chromatog-
raphy (E. Merck Silica Gel 60, 230-400 mesh ASTM) using
ethyl acetate:hexanes mixtures. All reactions were carried out
2
under an atmosphere of N , and solvents and reagents were
dried only where needed over 3 Å or 4 Å molecular sieves prior
to use. Karl Fisher water analyses of reaction mixtures and
solvents were carried out on a Metrohm 684 KF coulometer
and were generally in the 50-100 µg/mL range. High resolu-
tion mass spectroscopy studies were performed in the FAB
F igu r e 3. Inverted C-13 intermediates.
base-derived decomposition (∼25%). Capitalizing on the
positive effect of cesium13 and attempting to buffer the
basicity of the reagent, we treated cesium acetate with
an equimolar amount of acetic acid, which resulted in
control of the base-catalyzed decomposition (<5%). Due
to the hygroscopicity of cesium acetate, cesium propi-
onate/propionic acid was utilized for further development.
Hydrolytic workup resulted in a 10-20% loss of the C-7
O-TMS group to give C-7 alcohol 14. Consequently, crude
product was treated with TMS-Cl/imidazole to give
propionate 13 in a 68% yield from mesylate 9. The
sensitivity of the C-7 O-TMS group required that mild
propionate hydrolysis conditions be developed. Smooth
mode. Proton and carbon-13 spectra were recorded in CDCl
3
on a Bruker AM-400 at a frequency of 400.13 and 100.16 MHz,
respectively.
22,23-Dih yd r o-5-O-TBDMS-7,13-O-b is-TMS-a ver m ec-
tin B
1
Aglycon (6). A solution of 22,23-dihydroavermectin
4
B
1
aglycon 3 (55.6 g, 0.095 mol) in THF (600 mL) was treated
with imidazole (27.7 g, 0.39 mol) and tert-butyldimethylsilyl
chloride (26.3 g, 0.175 mol). The mixture was heated to 55 °C
and stirred for 4 h. The reaction mixture was cooled to 10 °C,
and additional imidazole (43.6 g, 0.64 mol) and trimethylsilyl
chloride (41.4 mL, 0.325 mol) were added. The mixture was
stirred for 15 h at 20-25 °C, cooled to 5 °C, and then diluted
with hexanes (750 mL). The mixture was washed with cold
3 4 3
5% aqueous H PO , saturated aqueous NaHCO , and then
water. The organic phase was concentrated in vacuo and
dissolved with THF to give 77.6 g (95.5% yield) of 6 by HPLC
analysis. 1H NMR: δ 5.79-5.61 (om, 3H), 5.47 (br s, 1H), 5.35
transesterification conditions using titanium tetraiso-
propoxide14 in 2-propanol were found, and, with the
3 4
workup modified using 2% aqueous H PO , inverted
(
)
1
m, 1H), 4.80 (m, 1H), 4.66 (dd, J ) 14.1, 2.0, 1H), 4.55 (dd, J
alcohol 15 was isolated in 90% yield as a crystalline solid.
This route afforded inverted alcohol 15 in 60% yield from
alcohol 7.
14.1, 2.0, 1H), 4.39 (m, 1H), 3.94 (br s, 1H), 3.80 (d, J ) 5.2,
H), 3.67 (m, 1H), 3.22 (m, 2H), 2.51 (m, 1H), 2.36 (dd, J )
10.7, 3.4, 1H), 2.32-2.22 (om, 2H), 1.82 (m, 1H), 1.78 (s, 3H),
1.65-1.32 (om, 9H), 1.50 (s, 3H), 1.16 (t, J ) 11.4, 1H), 1.08
(
Preparation of the MOM-derivative of alcohol 15
1
3
d, J ) 6.9, 3H), 0.97-0.77 (om, 18H), 0.13 (s, 24H).
C
utilized MOM-Cl prepared via the procedure of Amato
et al.15 This alkylation gave MOM-intermediate 16 in
NMR: δ 170.7, 139.7, 138.1, 137.3, 134.2, 124.4, 121.1, 120.5,
1
4
2
18.4, 97.5, 83.5, 80.7, 78.6, 76.6, 69.5, 69.1, 67.5
1.9, 40.3, 36.4, 35.7, 35.6, 34.2, 31.3, 28.2, 27.2, 25.9 (3C),
0.0, 19.9, 18.4, 17.5, 14.6, 12.4, 12.0, 2.4 (3C), 0.12 (3C), -4.4
4.6
5-O-TBDMS-7-O-TMS-22,23-Dih yd r oa ver m ectin B Ag-
0 4
, 67.4 , 47.3,
9
8% yield. Use of commercially available MOM-Cl led
to formation of minor amounts of chloro-analogues (due
to the presence of bis-(chloromethoxymethyl) ether) which
were difficult to remove from the product without exten-
sive chromatography. Removal of the silyl-based protect-
ing groups in the presence of the MOM-group, as in the
case of selective deprotection of MEM-intermediate 8,
was achieved using 1% HCl in methanol at 25 °C with
stirring for 2.5 h. This mild deprotection produced
L-694,554, 2, in 98% yield.
6
,
-
6
.
1
lycon (7). A solution of 5-O-TBDMS-7,13-O-bis-TMS-22,23-
dihydroavermectin B aglycon (6, 77.6 g, 0.0918 mol) in THF
700 mL) was treated with water (104 mL) and dichloroacetic
acid (4.5 mL, 0.055 mol) and stirred at 20-25 °C for 48 h. The
reaction was poured into saturated aqueous NaHCO (650 mL)
and extracted with MTBE (650 mL). The organic phase was
washed with saturated aqueous NaHCO (650 mL) and with
1
(
3
3
The selective manipulation of protecting groups on
ivermectin aglycon produced intermediate bis-silyl iver-
mectin aglycon 7, which was derivatized and converted
to MK-324. In addition, bis-silyl ivermectin aglycon 7
was successfully inverted via its mesylate, using cesium
saturated aqueous NaCl (250 mL). The organic phase was
azeotropically dried, concentrated, and then diluted with
acetonitrile to give 66.0 g (92.6% yield) of 7 by HPLC analysis.
1
H NMR: δ 5.81 (m, 1H), 5.46 (m, 2H), 5.48-5.40 (om, 2H),
4
2
3
2
1
.81 (m, 1H), 4.67 (dd, J ) 14.2, 2.1, 1H), 4.55 (dd, J ) 14.2,
.1, 1H), 4.39 (br s, 1H), 3.80 (d, J ) 5.2, 1H), 3.70 (m, 1H),
.22 (br s, 1H), 3.18 (br d, J ) 7.5, 1H), 2.58 (m, 1H), 2.40-
.23 (om, 3H), 1.83 (m, 1H), 1.78 (s, 2H), 1.70 (d, J ) 3.3, 1H),
.65-1.58 (om, 2H), 1.55 (s, 3H), 1.55-1.44 (om, 5H), 1.38 (m,
(12) (a) Fraser-Reid, B.; Wolleb, H.; Faghih, R.; Barchi, J . J . Am.
Chem. Soc. 1987, 109, 933. (b) Hanessian, S.; Dube, D.; Hodges, P. J .
J . Am. Chem. Soc. 1987, 109, 7063. (c) Blizzard, T. A.; Mrozik, H.;
Fisher, M. H. Tetrahedron Lett. 1988, 29, 3163.
2H), 1.27 (m, 1H), 1.20 (d, J ) 7.0, 3H), 1.16 (t, J ) 11.5, 1H),
(
13) (a) Huffman, J . W.; Desai, R. C. Synth. Commun. 1983, 13, 553.
b) Dijkstra, G.; Kruizinga, W. H.; Kellog, R. M. J . Org. Chem. 1987,
2, 4230.
14) Seebach, D.; Hungerbuher, E.; Naef, R.; Schnurrenberger, P.;
Weidmann, B.; Zuger, M. Synthesis 1982, 138.
15) Amato, J . S.; Karady, S.; Sletzinger, M.; Weinstock, L. M.
Synthesis 1979, 970.
1.03-0.83 (om, 16H), 0.79 (d, J ) 5.4, 3H), 0.13, (s, 6H), 0.11
(
13
(s, 9H). C NMR: δ 170.6, 140.1, 138.7, 136.0, 134.2, 124.9,
5
1
6
2
21.1, 120.3, 117.6, 97.5, 83.4, 80.8, 77.6, 77.3, 68.5, 69.0, 67.4
7.3
5.9 (3C), 20.0, 19.3, 18.4, 17.5, 14.6, 12.5, 11.6, 2.3 (3C), -4.4
0
,
(
4
, 47.4, 41.9, 39.6, 36.4, 35.7, 35.6, 34.3, 31.3, 28.1, 27.5,
6
,
(
6
-4.6 .

3
992 J . Org. Chem., Vol. 62, No. 12, 1997
Cvetovich et al.
1
3-O-ME M-5-O-TBDMS-7-O-TMS-22,23-Dih yd r oa ver -
m ectin B Aglycon (8). To a solution of 5-O-TBDMS-7-O-
TMS-22,23-dihydroavermectin B aglycon (7, 66.0 g, 0.085
mol) in acetonitrile (400 mL) were added DIPEA (82.3 mL,
.472 mol) and MEM chloride (51.2 mL, 0.44 mol). The
by HPLC). HPLC: gradient elution, A:B, 90:10 to 100:0 in
1
30 min, t
R
(min) 13R-alcohol 7, B1b, B1a 5.75, 6.43 min; 13R-
1
1
mesylate 9, B1b, B1a 4.50, 5.16 min. H NMR: δ 5.85 (dd, J )
15.0, 11.3, 1H), 5.70 (dt, J ) 11.3, 2.2, 1H), 5.59 (dd, J ) 15.0,
9.7, 1H), 5.51-5.47 (om, 2H), 4.95 (br s, 1H), 4.84 (m, 1H),
4.68 (dd, J ) 14.3, 2.3, 1H), 4.56 (dd, J ) 14.3, 2.1, 1H), 4.40
(m, 1H), 3.81 (d, J ) 5.2, 1H), 3.71 (m, 1H), 3.23 (q, J ) 2.3,
1H), 3.17 (m, 1H), 3.03 (s, 3H), 2.74 (m, 1H), 2.36-2.25 (om,
3H), 1.79 (s, 3H), 1.77 (om, 1H), 1.63-1.37 (om, 6H), 1.62 (s,
3H), 1.41 (m, 2H), 1.24 (d, J ) 7.0, 3H), 1.16 (t, J ) 11.5, 1H),
0.98-0.83 (om, 4H), 0.94 (s, 9H), 0.87 (d, J ) 6.7, 3H), 0.79
0
solution was warmed to 55-60 °C and aged for 4 h. The
mixture was cooled to 5 °C, and water (20 mL) was added
dropwise over 10 min. The solution was seeded and aged for
0 h at 0 °C. The crystals were filtered, washed with cold
acetonitrile, and dried with a stream of nitrogen to give 63 g
2
1
of 8 as a white solid, mp 152-155 °C. H NMR: δ 5.78 (dd, J
1
3
)
(
1
4
3
2
14.9, 11.0, 1H), 5.71-5.61 (om, 2H), 5.46 (br s, 1H), 5.28
(m, 3H), 0.15 (s, 3H), 0.14 (s, 12H). C NMR: δ 170.5, 141.6,
134.3, 134.2, 133.3, 126.0, 120.7, 120.5, 120.3, 95.6, 87.8, 83.4,
80.7, 77.5, 69.4, 68.7, 67.3, 67.0, 47.3, 41.8, 39.4, 38.9, 36.5,
35.7, 35.6, 34.4, 31.2, 28.1, 27.5, 25.9 (3C), 20.0, 19.4, 18.4,
m, 1H), 4.81 (m, 1H), 4.77 (d, J ) 7.0, 1H), 4.70 (d, J ) 7.0,
H), 4.67 (dd, J ) 14.3, 2.0, 1H), 4.54 (dd, J ) 14.3, 2.0, 1H),
.39 (br s, 1H), 4.00 (br s, 1H), 3.65 (dt, J ) 11.2, 4.5, 2H),
.79 (d, J ) 5.2, 1H), 3.73-3.62 (om, 2H), 3.56 (t, J ) 4.7,
H), 3.39 (s, 3H), 3.21 (m, 1H), 3.17 (br d, J ) 7.6, 1H), 2.61
+
17.5, 14.7, 12.5, 11.6, 2.4 (3C), -4.5, -4.7. HRMS: [M + H]
) 851.3054 (calculated ) 851.4619).
(
m, 1H), 2.38-2.23 (om, 3H), 1.83 (m, 1H), 1.78 (s, 3H), 1.64-
13â-O-P r op ion yl-5-O-TBDMS-7-O-TMS-22,23-d ih yd r o-
a ver m ectin B1 Aglycon (13). A mixture of cesium carbon-
ate (3.53 g, 10.0 mmol), 18-crown-6 (3.8 g, 11.7 mmol), toluene
(240 mL), and propionic acid (3.0 mL, 40.0 mmol) was heated
at 110 °C for 2 h. Mesylate 9 (10 g, 11.7 mmol) in toluene (30
mL) was added, and the reaction mixture was heated at 110
°C for 2.5 h. The mixture was then cooled to 10 °C, hexanes
(500 mL) were added, the mixture was filtered, and the filtrate
was diluted with ethyl acetate (250 mL). The solution was
1
1
.43 (om, 7H), 1.52 (s, 3H), 1.38 (m, 2H), 1.18 (d, J ) 6.9, 3H),
.03-0.76 (om, 18H), 0.13
4
(s, 3H), 0.12 (s, 3H), 0.11 (s, 9H).
9
1
3
C NMR: δ 170.6, 140.2, 136.7, 135.1, 134.1, 124.9, 121.0,
1
6
3
1
6
20.3, 118.6, 97.5, 94.5, 83.4, 82.6, 80.7, 77.3, 71.8, 69.4, 68.9,
7.7, 67.3 (2C), 59.1, 47.3, 41.9, 39.4, 36.5, 35.6
1.2, 28.1, 27.5, 25.9 (3C), 20.0, 19.8, 18.4, 17.4, 14.8, 12.4,
1.5, 2.3 (3C), -4.5, -4.7. Anal. Calcd for C47
5.54 ; H, 9.36. Found: C, 65.14; H, 9.36.
5 9
, 35.5 , 34.3,
80 2
H O10Si : C,
1
3-O-ME M-22,23-Dih yd r oa ver m ect in B
A solution of 13-O-MEM-5-O-TBDMS-7-O-TMS-22,23-dihy-
droavermectin B aglycon (8, 63.0 g, 0.073 mol) in methanol
600 mL) at 50 °C was treated with a solution of HCl in
1
Aglycon (1).
3
washed with 5% aqueous NaHCO (300 mL) and saturated
aqueous NaCl (300 mL) and then dried over magnesium
sulfate (20 g), filtered, and concentrated in vacuo to afford 9.3
g of crude 13â-propionate 13. Due to partial desilylation, the
crude propionate and imidazole (5.69 g, 89 mmol) were
dissolved in THF (140 mL), and the solution was cooled to 0
°C. Chlorotrimethylsilane (5.34 mL, 42 mmol) was added, and
the mixture was stirred at 0 °C for 10 min. The reaction
mixture was then allowed to warm to room temperature and
stirred for 19 h. Hexanes (300 mL) were added, and the
mixture was filtered. The filtrate was washed with 5%
1
(
methanol (1.55 mL of 12 N HCl in 100 mL methanol). After
complete addition, the mixture was cooled to 20 °C and aged
for 14 h. MTBE (80 mL) and 4% aqueous NaHCO (1.6 L)
3
were added and the phases separated. The aqueous phase was
extracted with MTBE (80 mL), and the combined organic
phases were washed with water (100 mL). The solvent was
evaporated, and the residue was dissolved into acetonitrile
(
400 mL) and washed with heptane (5 × 80 mL). The
aqueous NaHCO
3
(300 mL) and saturated aqueous NaCl (300
acetonitrile was evaporated in vacuo, and the residue was
dissolved into i-PrOH (400 mL). The solution was warmed to
mL), dried over sodium sulfate (50 g), filtered, and concen-
trated in vacuo to afford 9.4 g of crude 13â-propionoate 13.
The crude product was chromatographed on silica gel (250 g,
hexanes:ethyl acetate, 95:5) to afford 6.67 g of off-white solid
of 13-â-propionate 13 in 68% yield with a purity of >96 area
5
0 °C, water was added (240 mL), and the mixture was seeded.
The crystalline mixture was cooled to 0 °C over 6 h, aged for
8 h, and filtered and washed with 1:1 i-PrOH:water. The
crystalline cake was dried in vacuo at 25 °C to give 44.6 g of
1
% by HPLC. HPLC: gradient elution, A:B, t (min) 13R-
R
1
8
as a crystalline white solid, mp 103.5-105 °C, containing
mesylate, 9 B1b, B1a 4.47, 5.16; 13â-propionate 13 B1b, B1a 9.78,
1
1
.2 wt % i-PrOH (GC assay). H NMR: δ 5.82 (m, 1H), 5.70
10.94; 13â-propionate-7-OH 14 B1b, B1a 4.71, 4.8. H NMR: δ
(om, 2H), 5.41 (br s, 1H), 5.30 (m, 1H), 5.17 (br d, J ) 11.1,
5.87 (dd, J ) 14.8, 11.4, 1H), 5.68 (dt, J ) 11.4, 2.1, 1H), 5.47
(d, J ) 1.6, 1H), 5.45 (om, 1H), 5.35 (dd, J ) 14.8, 10.0, 1H),
5.03 (d, J ) 10.4, 1H), 4.79 (m, 1H), 4.67 (dd, J ) 14.3 2.2,
1H), 4.58 (dd, J ) 14.3, 2.0, 1H), 4.40 (m, 1H), 3.81 (d, J )
5.2, 1H), 3.63 (m, 1H), 3.23 (q, J ) 2.2, 1H), 3.16 (d, J ) 7.4,
1H), 2.59 (m, 1H), 2.42-2.21 (om, 5H), 1.79 (br s, 3H), 1.74
(om, 1H), 1.63-1.35 (om, 8H), 1.57 (s, 3H), 1.19-1.13 (om, 1H),
1.15 (t, J ) 7.6, 3H), 1.04 (d, J ) 6.6, 3H), 1.01-0.83 (om,
1
3
3
3
H), 4.71-4.62 (om, 4H), 4.28 (m, 1H), 4.09 (s, active H), 3.95-
.94 (om, 2H), 3.90 (m, 1H), 3.71-3.62 (om, 2H), 3.55 (m, 2H),
.39 (s, 3H), 3.25 (q, J ) 2.3, 1H), 3.19 (dd, J ) 9.0, 1.4, 1H),
.09 (dd, J ) 9.5, 2.0, 1H, B1b component), 2.53 (m, 1H), 2.39
(
1
1
d, J ) 8.2, active H), 2.28 (om, 2H), 1.97 (ddd, J ) 11.8, 4.8,
.3, 1H), 1.86 (s, 3H), 1.75 (dm, J ) 12.5, 1H), 1.65 (m, 1H),
.58-1.38 (om, 7H), 1.50 (s, 3H), 1.32 (t, J ) 11.8, 1H), 1.14
(
d, J ) 6.9, 3H), 1.05 (d, J ) 6.9, 3H, B1b component), 0.95 (t,
4H), 0.94 (s, 9H), 0.86 (d, J ) 6.8, 3H), 0.80 (m, 3H), 0.14
4
1
3
13
J ) 7.3, 3H), 0.85 (d, J ) 6.8, 3H), 0.85-0.75 (om, 4H).
NMR: δ 173.6, 139.7, 138.0, 137.8, 135.1, 124.7, 120.4, 118.3,
C
0
(s, 3H), 0.14 (s, 3H), 0.13 (s, 9H). C NMR: δ 173.7, 170.6,
141.2, 137.0, 135.7, 134.3, 126.2, 124.5, 120.8, 120.3, 97.5, 83.6,
83.4, 80.8, 77.1, 69.4, 69.1, 67.3, 67.1, 47.3, 41.9, 39.8, 36.4,
35.6 , 35.5 , 34.5, 31.3, 28.1, 27.9, 27.4, 25.9 (3C), 20.0, 19.0,
5 7
9
6
2
7.4, 94.4, 82.6, 80.3, 79.1, 77.3, 71.8, 68.6, 68.5, 67.8, 67.6,
7.3, 59.1, 45.7, 41.3, 39.9, 36.9, 35.8, 35.6, 34.3, 31.3, 28.1,
7.5, 25.4, 20.0, 19.6, 17.5, 14.9, 12.5, 11.8. Anal. Calcd for
18.4, 17.5, 12.5, 11.7, 11.1, 9.2, 2.3 (3C), -4.5, -4.7. Anal.
C
6
41
H
66
O
10 (2-propanol solvate): C, 67.00; H, 9.05. Found: C,
6.83; H, 8.96.
3r-O-Mesyl-5-O-TBDMS-7-O-TMS-22,23-d ih yd r oa ver -
m ectin B Aglycon (9). A solution of crude alcohol 7 (31.3
Calcd for C46
9.34.
76 9 2
H O Si : C, 66.63; H, 9.24. Found: C, 66.64; H,
1
13â-Hyd r oxy-5-O-TBDMS-7-O-TMS-22,23-d ih yd r oa ver -
m ectin B Aglycon (15). A solution of propionate 13 (50 g,
1
1
g, 0.040 mol), (dimethylamino)pyridine (9.76 g, 0.08 mol), and
diisopropylethylamine (20.9 mL, 0.12 mol) in dichloromethane
0.06 mol) in i-PrOH (0.95 L) and titanium isopropoxide (56
mL, 0.188 mol) was heated at 80 °C for 12 h. The reaction
mixture was cooled to 25 °C, diluted with ethyl acetate (2.5
(125 mL) was cooled to -5 °C. Methanesulfonyl chloride (9.5
mL, 0.12 mol) was added, and the mixture was stirred at 0 °C
for 45 min. Hexanes (0.46 L) were added, the reaction mixture
was filtered through a silica-gel pad (15 g, 230-400 mesh),
and the cake was washed with hexanes (230 mL). The
L), and washed successively with 2% aqueous H
3
PO
4
(2 × 2.5
L), 10% aqueous NaCl (1 L), 5% NaHCO (2.5 L), and 10%
3
aqueous NaCl (2.5 L). The organic layer was dried over
magnesium sulfate (80 g), filtered, and concentrated in vacuo
to give 45 g of crystalline 13-epi-OH-7-O-TMS-5-O-TBS-22,23-
dihydroavermectin aglycon (15) in 95% yield (94.3 wt % assay,
HPLC). HPLC: gradient elution, A:B, 90:10 to 100:0 in 30
3
combined filtrates were mixed with 5% aqueous NaHCO (460
mL) and ethyl acetate (230 mL). The organic layer was
washed with 5% aqueous NaCl (460 mL), dried over sodium
sulfate (50 g), filtered, and concentrated in vacuo to afford 45
g of mesylate 9 as a yellow solid in 92% yield (69 wt % assay
min, t
R
(min) 13â-propionate 13 B1b, B1a 10.05, 11.21; 13-epi-
alcohol 15 B1b, B1a 4.87, 5.85.

Syntheses of 22,23-Dihydroavermectin B
1
Aglycons
J . Org. Chem., Vol. 62, No. 12, 1997 3993
Recr ysta lliza tion . Alcohol 15 (40 g, 94.3 wt % assay),
acetonitrile (795 mL), and water (34 mL) were heated to
dissolve at 80 °C for 15 min. The mixture was cooled slowly
to 70 °C, seeded with crystalline alcohol 15 (250 mg), further
cooled to 0 °C over 2 h, and then aged at 0 °C for 24 h. Product
(m, 1H), 3.38 (s, 3H), 3.22 (q, J ) 2.3, 1H), 3.15 (d, J ) 7.4,
1H), 2.44 (om, 2H), 2.30 (m, 2H), 1.78 (om, 4H), 1.62 (dd, J )
9.8, 2.2, 1H), 1.56-1.44 (om, 5H), 1.51 (s, 3H), 1.37 (m, 2H),
1.17 (d, J ) 6.5, 3H), 1.16 (om, 1H), 0.99-0.90 (om, 3H), 0.93
(s, 9H), 0.87 (om, 1H), 0.85 (d, J ) 6.8, 3H), 0.78 (m, 3H), 0.14
(s, 3H), 0.13 (s, 3H), 0.12 (s, 9H). C NMR: δ 170.7, 140.6,
138.2, 136.6, 134.2, 126.1, 123.8, 121.1, 120.3, 97.5, 92.8, 86.1,
83.4, 80.9, 77.0, 69.4, 69.1, 67.4, 67.2, 55.6, 47.3, 41.9, 40.4,
1
3
was filtered, washed with cold CH
3
CN:H
2
O (400 mL, 60:40),
and dried in vacuo (25 °C, 24 h), yielding alcohol 15 as a
crystalline white solid (30.4 g, 80% yield) with a purity of 99.15
wt % (HPLC assay), mp 192-194 °C. A second crop was
obtained by seeding the mother liquors and stirring for 24 h
at 0 °C, yielding an additional 6.57 g for a combined recovery
36.4, 35.6
18.4, 17.5, 12.5, 11.7, 10.8, 2.3 (3C), -4.5, -4.7.
13-â-O-MOM-22,23-Dih yd r oa ver m ectin B Aglycon (2).
3 7
, 35.5 , 34.5, 31.2, 28.1, 27.4, 25.9 (3C), 20.0, 19.5,
1
1
of 37.0 g (95% yield). H NMR: δ 5.84 (dd, J ) 14.9, 11.5,
A solution of 13â-O-MOM 16 (37.6 g, 0.046 mol) in MeOH (0.39
L), at 25 °C, was treated with 0.17 N methanolic HCl (13.4
mL) and stirred for 2.5 h at 25 °C. The reaction mixture was
1
H), 5.65 (dt, J ) 11.5, 2.4, 1H), 5.47 (q, J ) 1.6, 1H), 5.33
(
dd, J ) 14.9, 9.9, 1H), 5.29 (om, 1H), 4.79 (m, 1H), 4.68 (dd,
J ) 14.3, 2.4, 1H), 4.57 (dd, J ) 14.3, 2.4, 1H), 4.39 (m, 1H),
.80 (d, J ) 5.2, 1H), 3.77 (d, J ) 9.9, 1H), 3.62 (m, 1H), 3.23
q, J ) 2.4, 1H), 3.17 (d, J ) 7.5, 1H), 2.43-2.25 (om, 4H),
3
partitioned between 5% aqueous NaHCO (0.5 L) and ethyl
3
(
acetate (2.0 L), the phases were separated, and the aqueous
layer was reextracted with ethyl acetate (0.5 L). The combined
organic layers were washed with 5% aqueous NaCl (0.5 L) and
concentrated in vacuo to afford 29.3 g of L-694,554, 2, as an
amorphous solid in 98% yield. HPLC: gradient elution, A:B,
1
1
0
0
1
8
3
1
.79 (s, 3H), 1.76 (om, 1H), 1.63-1.42 (om, 7H), 1.61 (s, 3H),
.39 (m, 2H), 1.20-1.12 (om, 1H) 1.17 (d, J ) 6.7, 3H), 0.94-
.84 (om, 4H), 0.94 (s, 9H), 0.86 (d, J ) 6.7, 3H), 0.68 (m, 3H),
1
3
.14
0
(s, 3H), 0.13
7
(s, 3H), 0.12 (s, 9H). C NMR: δ 170.7,
60:40 to 80:20 in 18 min; 2.0 mL/min, t
B
R
(min) L-694,554 (2)
40.7, 140.2, 138.2, 134.2, 123.8, 123.7, 121.0, 120.3, 97.5, 83.7,
3.4, 80.8, 77.1, 69.4, 69.1, 67.4, 67.3, 47.3, 41.9, 41.6, 36.3,
1b, B1a 8.15, 9.91. 1H NMR: δ 5.81-5.76 (om, 2H), 5.43 (br
s, 1H), 5.40-5.21 (om, 3H), 4.70 (m, 2H), 4.66 (d, J ) 6.7, 1H),
4.44 (d, J ) 6.7, 1H), 4.30 (m, 1H), 3.97 (d, J ) 6.2, 1H), 3.96
(s, 1H), 3.64 (d, J ) 10.0, 1H), 3.61 (om, 1H), 3.38 (s, 3H), 3.28
(q, J ) 2.2, 1H), 3.17 (d, J ) 7.7, 1H), 2.44 (m, 1H), 2.36 (d, J
) 8.1, 1H), 2.33 (m, 2H), 2.02 (m, 1H), 1.88 (s, 3H), 1.72-1.60
(om, 2H), 1.58-1.37 (om, 7H), 1.50 (s, 3H), 1.32 (t, J ) 11.7,
1H), 1.15 (d, J ) 6.5, 3H), 0.96 (t, J ) 7.4, 3H), 0.90-0.84
5.6
7.5, 12.5, 11.7, 10.6, 2.3 (3C), -4.5, -4.7. Anal. Calcd for
Si : C, 66.80; H, 9.39. Found: C, 66.69; H, 9.45.
3â-O-MOM-5-O-TBDMS-7-O-TMS-22,23-Dih yd r oa ver -
m ectin B Aglycon (16). A solution of chloromethylmethyl
4 9
, 35.5 , 34.5, 31.2, 28.1, 27.4, 25.9 (3C), 20.0, 19.3, 18.4,
C
43
H
72
O
8
2
1
1
1
5
ether (31.62 mL, 0.419 mol) and dichloromethane (116 mL)
was cooled to -10 °C. DIPEA (75.3 mL, 0.433 mol) was added,
and the solution was stirred at -10 °C for 45 min. The 13â-
alcohol 15 (35.9, 0.046 mol) in dichloromethane (116 mL) was
added at -10 °C, and the mixture was warmed to 25 °C and
stirred for 23 h. The reaction mixture was cooled to -10 °C,
1
3
(om, 1H), 0.86 (d, J ) 6.8, 3H), 0.80 (m, 3H). C NMR: δ
173.5, 140.3, 139.0, 137.9, 136.5, 125.8, 123.9, 120.4, 118.3,
97.5, 92.8, 85.8, 80.3, 79.4, 77.3, 68.7, 68.6, 67.7, 67.0, 55.7,
45.7, 41.4, 40.6, 36.7, 35.8, 35.5, 34.5, 31.3, 28.1, 27.5, 20.0,
+
19.1, 17.5, 12.6, 11.9, 10.7. HRMS: [M + H] ) 631.3839
5
% aqueous NaHCO
3
(0.5 L) was added, and the mixture was
(calculated ) 630.3846).
stirred for 30 min to destroy excess chloromethyl methyl ether.
Ethyl acetate (2 L) was added, the phases were separated, and
the aqueous layer was extracted with ethyl acetate (0.5 L).
The combined organic layers were washed with 5% aqueous
NaCl (0.5 L) and filtered through a silica gel pad (100 g, 230-
Ack n ow led gm en t. We would like to thank Drs.
Karst Hoogsteen and Richard G. Ball for X-ray analyses
of the crystalline MK-324 solvates.
4
3
00 mesh), and the eluent was concentrated in vacuo to afford
7.7 g of 13-â-MOM (16) in 98% yield with a purity of >99
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
area % by HPLC. HPLC: gradient elution, A:B, 90:10 to 100:0
and 13C NMR spectra of compounds 1, 2, 6, 7, 8, 9, 13, 15, and
in 30 min, t
R
(min) alcohol 15 B1b, B1a 5.39, 6.37; 13â-O-MOM
16 (18 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of this journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
1
1
1
6 B1b, B1a 11.42, 12.84. H NMR: δ 5.83 (dd, J ) 14.8, 1.4,
H), 5.66 (dt, J ) 11.4, 2.0, 1H), 5.46 (q, J ) 1.6, 1H), 5.32
(
om, 2H), 4.78 (m, 1H), 4.68 (dd, J ) 14.3, 2.2, 1H), 4.63 (d, J
6.7, 1H), 4.56 (dd, J ) 14.3, 2.1, 1H), 4.45 (d, J ) 6.7, 1H),
.39 (m, 1H), 3.79 (d, J ) 5.2, 1H), 3.68 (d, J ) 10.0, 1H), 3.61
)
4
J O970187L