Formal convergent synthesis of ivermectin aglycone - A synthetic approach to the C10-C25 subunit of avermectins 2b

Article abstract of DOI:10.1055/s-0029-1216954

A convergent, two-fragment synthesis of the C10-C25 northern moiety of avermectins has been developed. Along with our previous work in this area, the present contribution represents a formal synthesis of Ivermectin aglycone. Furthermore, according to a strategy leading to non y-pyranone adducts from, the condensation reaction between acetylacetone dianion and convenient aldehydes, 23-hydroxylated C10-C25 northern building blocks required for the synthesis of the avermectins series 2b were prepared. Subsequent unexpected kinetically favored unnatural (215)-spiro isomers were obtained under mild cyclization conditions.

Full text of DOI:10.1055/s-0029-1216954

PAPER
3477
Formal Convergent Synthesis of Ivermectin Aglycone – A Synthetic Approach
to the C10–C25 Subunit of Avermectins 2b
Convergent
S
ynthe
i
tic Ap
v
i
C10–C
e
25
S
ubuni
n
of
A
vermectins Henryon,a Jean-Pierre Férézou*b
a
Activation Chemical Process Research & Catalysis, 11, avenue Albert Einstein, 69100 Villeurbanne, France
Fax +33(4)78931964
b
Laboratoire de Syntèse Organique, DCSO, UMR CNRS 7652, Ecole Polytechnique, 91128 Palaiseau cedex, France
Fax +33(1)69335972; E-mail: ferezou@dcso.polytechnique.fr
Received 10 June 2009; revised 18 June 2009
was developed in the 1980s by Merck under the name
Abstract: A convergent, two-fragment synthesis of the C10–C25
northern moiety of avermectins has been developed. Along with our
previous work in this area, the present contribution represents a for-
mal synthesis of Ivermectin aglycone. Furthermore, according to a
strategy leading to non g-pyranone adducts from the condensation
reaction between acetylacetone dianion and convenient aldehydes,
23-hydroxylated C10–C25 northern building blocks required for
the synthesis of the avermectins series 2b were prepared. Subse-
quent unexpected kinetically favored unnatural (21S)-spiro isomers
were obtained under mild cyclization conditions.
Ivermectin (IVM; 1).2
Their unique broad-spectrum antihelminthic activity both
on endo and ecto-parasite infections made avermectins,
for more than 25 years, the most important class of pesti-
cides and veterinary drugs for livestock and companion
animals. Moreover, this class of microfilaricidal com-
pounds also found application in human medicine, initial-
ly for human onchocerciasis, and more recently against
other filariases. With the aim of developing new orally ef-
fective drugs against leishmaniasis, we recently success-
fully prepared semi-synthetic analogues of 1 exhibiting
promising antileishmanial activity.3 Huge synthetic ef-
forts towards avermectins have culminated in several total
syntheses of different members of this class at the end of
the last century.4 For our own part, we have described a
total synthesis of the aglycone of 1 according to a two-
subunit convergent strategy involving a C10–C11 discon-
nection.5
Key words: antibiotics, stereoselective synthesis, macrocycles,
spiro compounds, cyclizations
The avermectins, isolated from Streptomyces avermitilis
in the late 1970s, constitute a group of closely related 16-
membered macrocyclic lactones of high biological and
economical importance.1 To date, eight natural avermec-
tins have been isolated as fermentation products from
Streptomyces avermitilis (Figure 1). Only subtle structur-
al differences exist between them. A safer and more po-
tent mixture of semi-synthetic avermectin B1a and B1b,
hydrogenated at the level of the C22–C23 double bond,
Despite its high potency, several drawbacks progressively
appeared along with the intensive use of avermectin anti-
biotics, such as environmental soil, river and marine pol-
OH
23
23
22
H
H
H
R1O
R1O
R1O
O
O
O
O
21
17
13
O
25
O
O
H
H
H
19
R3
R3
R3
O
O
O
O
O
1
5
OH
OH
OH
8
3
7
6
8a
O
O
O
H
H
H
OR2
OR2
OH
Me (major)
H (minor)
Ivermectin
R3
=
1
avermectins 1-series
avermectins 2-series
R2
R3
R2
R3
R
1 = α-L-oleandrosyl-α-L-oleandrose:
MeO
MeO
Me
H
Me
H
Me
H
A1a
A1b
B1a
B1b
Me
Me
A2a
A2b
B2a
B2b
Me
Me
O
HO
Me
H
H
H
H
H
O
O
Figure 1 Eight natural avermectins and Ivermectin
SYNTHESIS 2009, No. 20, pp 3477–3487
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216954; Art ID: Z12109SS
© Georg Thieme Verlag Stuttgart · New York

3478
V. Henryon, J.-P. Férézou
PAPER
lution, or collateral toxicity effects, for example towards approach developed in the case of the C10–C25 stannane
soil invertebrates.6 Antihelmintic resistance also appears 2 used for the synthesis of IVM aglycone (Scheme 1).5
to be a major concern in the case of animal nematode
treatment,7 even though this is not yet the case for human
O
17
15
22
filariases.8 Continuing efforts towards developing new
molecules exhibiting higher potencies with an optimized
activity spectrum and improved safety profiles led to sev-
eral new semi-synthetic avermectin analogues, particular-
ly with regards to their optimized insecticidal and
acaricidal properties.9
14
12
SO2
Ph
H
Br
O
O3
18
3
O
OCb
Br
10
12
23
23
O
22
25
H
14
TBSO
O
13
12
TMSO
25
Furthermore, promising biological activities of avermec-
tins have also been recently reported in the field of antitu-
mor therapy. Based on the known inhibiting effect of
avermectins on P-glycoprotein, one key factor involved in
multidrug-resistance of tumors,10 Korustov’s group in
Russia demonstrated the beneficial effect of some aver-
mectin members when added to other antitumor drugs in
the treatment of multidrug-resistant cell tumors.11
17
18
15
10
OH
SnBu3
2
Scheme 1 Linear approach to the C10–C25 subunit of IVM 1
In order to develop a more convergent and practical ap-
Taken together, the scientific interest in the avermectin proach to the C10–C25 portion of avermectins, it was de-
class of antibiotics is in full renaissance in several aspects. cided to take advantage of the key diastereocontrolled
In a continuation of our program on avermectins, we aldol reaction occurring at the level of the condensation of
present here our results on the synthesis of avermectins of sulfonyl aldehyde 3 with the enolate of the bulky keto
the 2b-series for which little effort has so far been devot- acetal intermediate of type B (see 21, X–Y = CH2–CH2),
ed. To our knowledge, the only synthesis of the northern where R = triphenylethyl (see Scheme 2).13 An interesting
sub-unit of avermectin A2b, bearing the desired axial 23- 3:1 diastereoselectivity in favor of the expected chirality
OH, was reported by the group of E. J. Thomas: the key at C-17 was obtained, a bias tentatively explained by un-
hindered Re-face attack of the lithium enolate.5
step for installing this functional group involves a C22–
C23 epoxide ring-opening reaction by a dithiane anion at
C-21.12 The avermectin 2b series was chosen as key tar-
gets since they could potentially lead to all the other aver-
mectins through a dehydration reaction.
Therefore, a three-fragment convergent approach was en-
visioned as shown in Scheme 2, where a stereocontrolled
aldol reaction similar to that already described above was
expected to couple subunits of type A and B.
Two main goals were pursued during the present study.
We first wanted to develop a three-fragment disconnec-
tion allowing access to the C10–C25 northern subunit
in a more convergent manner than the previous linear
For the remaining steps of the total synthesis, which in-
volves a subsequent cross-coupling reaction between the
northern C10–C25 (E)-vinylstannane 4 and the corre-
Y
diastereoselective
aldol reaction
Y
H
X
HO
O
H
X
O
HO
O
O
O
A
OH
O
10
4
SnBu3
I
B
O
OH
OR
lactone
formation
Pd(0)
coupling
9
1
OH
O
C
H
O
(OH,OMe)
H
X–Y
C
(OH,OMe)
avermectin 1-series aglycones
avermectin 2-series aglycones
Ivermectin
CH=CH
CH-CH(α−OH)
CH2-CH2
HO
O
Y
X
H17
RO
O
25
+
4
O
18
10
SnBu3
B
A
Scheme 2 Three-fragment A–B–C disconnection for avermectins
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

PAPER
Convergent Synthetic Approach to the C10–C25 Subunit of Avermectins
3479
OH
OLi OLi
O
b
6
HO
21-R
OTBS
H
OTBS
O
O
OH
O
a
30%
(2 steps)
syn/anti 45:55
OH
[α]D –35.7
7
5
O
O
8
O
Ph3C
ROH =
Ph3CCH2OH
O
OPG
O
9
10
O
c
OTES
OH
d
MeO
MeO
25
MeOH
O
O
18
67%
(2 steps)
O
O
[α]D +142
11
12
Scheme 3 Reagents and conditions: (a) LDA (2 equiv), –78 °C, THF; (b) (i) TBAF, DMF, 60 °C, 1 h; (ii) Chromatography; (c) Mont. K10,
MeNO3, ROH, 5 min, r.t.; (d) TESCl, imidazole, DMF.
sponding southern vinyl iodide counterpart C followed by Protection of the secondary hydroxy by a triethylsilyl
the final macrolactonization step, it was decided to exploit group, afforded 12, which was ready to be condensed with
the route previously developed for 1.14
the C10–C17 subunit.
A second key strategic point was to apply our published The preparation of the C10–C17 aldehyde, depicted in
anti-Danishefsky spiroketal methodology, which allows Scheme 4, turned out to be straightforward. Attention
the construction of acetonyl tetrahydropyran subunits of only had to be paid to the choice of the aldehyde protect-
type B,15 instead of the usually expected g-pyranone of ing group at C-17, as some difficulties were encountered
type 9 (see Scheme 3).16
at the deprotection step. Forcing acidic conditions invari-
ably resulted in the production of the undesired C15–C17
conjugated aldehyde. The choice of the isopropyl acetal
protecting group, thanks to the mild conditions required
for its removal, solved this problem.18
The C18–C25 subunit was synthesized according to the
previously described strategy.14 Although the presence of
a bulky protecting group, such as a triisopropylsilyl group,
at the secondary hydroxy of 5 has been shown to favor for-
mation of the expected anti,anti-diastereomer, for practi- The sulfonyl diisopropyl acetal 14, derived from the
cal reasons, the less favorable tert-butyldimethylsilyl known 3-tosylpropanal 13, was condensed with 2-bro-
(TBS) group was selected. Therefore, the known, enan- mopent-3-ene to give a mixture of diastereomers that was
tiopure TBS-O-protected (2S,3R)-anti-aldehyde 5 was treated directly with ozone to yield, after triethylamine
chosen as a starting material, which represents the unique treatment, the conjugated (E)-aldehyde 15 according to an
source of asymmetry for the spiroketal unit.17 Condensa- Isobe sequence similar to that already successfully ap-
tion of 5 with the 2,4-pentanedione dianion 6 cleanly af- plied by us during the synthesis of 1.19 A Hoppe enantio-
forded the crude aldolization adduct as a 45:55 mixture of selective homoaldol reaction in the presence of (–)-
diastereomers, which was immediately treated with an ex- spartein20 between 16 and the (E)-butenyl-N,N-diisopro-
cess of tetrabutylammonium fluoride (TBAF) in N,N- pylcarbamate 17, furnished the anti-homoaldol 18 in ex-
dimethylformamide (DMF) at 60 °C to give, after purifi- cellent yield. 1H NMR analysis of the (R)-(+)-a-methoxy-
cation, the required hemiketal 8 in 30% yield from 5. No a-(trifluoromethyl)phenylacetyl ester of 18 (Mosher
trace of the g-pyranone 9 was detected. At this level, we ester)21 revealed a 93:7 enantiomeric ratio.
expected to be able to use a bulky ketal protecting group
Protection of the secondary hydroxy group using triiso-
to direct the subsequent aldol condensation with the C11–
propylsilyl triflate followed by treatment with an excess
C17 aldehyde. Unfortunately, all attempts to prepare a vo-
of s-BuLi gave the acetylenic derivative 19 in 76% yield.
Mild deprotection of the isopropyl acetal group delivered
the C10–C17 aldehyde 20, which was ready to be coupled
with the preceding C18–C25 subunit.
luminous ketal such as 10 failed. Strong stabilizing hydro-
gen bonds between the two axial hydroxy groups at C-21
and C-23 as well as with the carbonyl group at C-19, could
favor thermodynamically-controlled retro-condensation
of the bulky 2,2,2-triphenylethanol. Therefore, hemiketal
8 was subsequently transformed under our previously de-
scribed mild conditions into the protected methylketal 11.
In a preliminary approach to the final stage of the synthe-
sis of the C10–C25 subunit of Avermectin series 2b, the
viability of the novel C10–C17 + C18–C25 strategy was
tested using acetal 21, possessing the bulky 2,2,2-triphe-
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

3480
V. Henryon, J.-P. Férézou
PAPER
a
b
O
Ts
Ts
Oi-Pr
Oi-Pr
Oi-Pr
Oi-Pr
85%
78%
H
Ts
13
14
15
O
O
N(i-Pr)2
Oi-Pr
Oi-Pr
HO
Oi-Pr
Oi-Pr
17
O
c
d
H
84%
95%
18
(i-Pr)2N(CO)O
TIPSO
16
[α]D –10.5
Oi-Pr
Oi-Pr
TIPSO
O
g
17
e,f
H
76%
97%
10
[α]D +14.4
19
20
Scheme 4 Reagents and conditions: (a) i-PrOH, CH2Cl2, CSA, 3Å Sieves; (b) n-BuLi, THF, HMPA then 2-bromopent-3-ene; (c) O3, CH2Cl2,
Py (1%) then Et3N; (d) s-BuLi, (–)-spartein, Ti(OiPr)4; (e) TIPSOTf, CH2Cl2, 2,6-Lutidine; (f) s-BuLi (3.8 equiv), Et2O, –78 °C; (g) aq PTSA
(0.1 M), THF, 60 °C, 45 min.
H
RO
O
17R
25
RO
21R
O
O
OH
O
O
87%
10
O
22
Ph3C
(21R)-23
Ph3C
O
O
a
e
O
(dr = 4:1 )
21
H
RO
O
21S
O
O
RO
O
H
(21S)-23
20
OTES
d
(21S)-25
b
OTES
MeO
O
(dr = 1:1 )
23
O
H
RO
O
21S
12
O
OTES
O
(21S)-25
17R
RO
c
O
OTES
23
+
OH
O
MeO
64%
H
RO
O
21R
(17R)-24
36%
O
R = TIPS
O
(21R)-25
(4:1 mixture of 21S/21R)
Scheme 5 Reagents and conditions: (a) (i) LDA (1.1 equiv), –78 °C→r.t.; (ii) aq HCl work-up; (b) (i) LDA (1.1 equiv), –78 °C→r.t.;
(ii) chromatography; (c) PPTS, MeOH, r.t.; (d) (i) HF/Py; (ii) thiocarbonyldiimidazole, THF, reflux, 24 h; (iii) Bu3SnH, AIBN, toluene, reflux;
(e) HCl, CHCl3, r.t.
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

PAPER
Convergent Synthetic Approach to the C10–C25 Subunit of Avermectins
3481
nylethyl ketal protecting group previously developed for our previously described southern vinyl iodide C, fol-
the synthesis of the IVM 1 (Scheme 5). Besides providing lowed by a macrolactonization reaction would afford the
more convergent access to the C10–C25 subunit of this final macrolide. The present study demonstrates the via-
standard macrolide, this synthesis would provide a refer- bility of the synthesis of the whole family of avermectin
ence molecule that could be used to correlate the 23-hy- macrolides using a convergent approach to the fully func-
droxylated C10–C25 subunits of avermectins 2b.
tionalized spiroketal moiety of these molecules.
Condensation of the lithium enolate of 21 with aldehyde
20 afforded the crude aldol 22 as a 4:1 mixture of diaste-
reomers (Scheme 5). Subsequent acidic workup led to the
expected spiroketal subunit (21R)-23 as the major diaste-
reomer, the spectroscopic and physicochemical data of
which agreed completely with the analogous northern
spiroketal sub-units previously synthesized.5 Interesting-
ly, this new convergent route represents a marked im-
provement for the synthesis of this Ivermectin subunit.
Mass spectra were obtained on a Nermag R10-10B spectrometer via
either direct introduction by chemical ionization with ammonia (CI,
NH3) or electron impact (EI). Melting points were determined on a
Büchi 510 capillary apparatus and are uncorrected. 1H NMR spectra
were recorded on either a Cameca 250 or on a Bruker AM 400 in-
strument using CDCl3 as solvent. Chemical shifts (d) are expressed
in parts per million (ppm) downfield from tetramethylsilane (TMS)
or referenced to residual CHCl3 (7.27 ppm). 13C NMR spectra were
recorded on a Bruker AM 400 instrument at 100.57 MHz, the chem-
ical shifts are expressed in parts per million (ppm) downfield from
tetramethylsilane (TMS). When necessary, assignments were ob-
tained using J-modulation experiments. Infrared (IR) spectra were
obtained on a Perkin–Elmer 599 model instrument (wavelength are
given in cm–1). Optical rotations were determined on a Perkin-Elmer
241 instrument. Microanalyses were performed by the analytical
laboratory of the University of Pierre and Marie Curie, Paris. Sol-
vent distillation methods: THF and Et2O from sodium-benzophe-
none; CH2Cl2 and CHCl3 from CaH2; Et3N, DMF and pyridine from
CaH2; pentane, hexane and petroleum ether from phosphoric anhy-
dride; toluene from sodium-benzophenone. Thin Layer Chromatog-
raphy (TLC) was performed on pre-coated plates of silica gel 60
F254 (Merck, Art. 7735). Flash chromatography was performed on
silica gel Merck 60, 70–230 mesh (Art. 7736) or Merck 60, 230–400
mesh (Art. 9385). Medium pressure liquid chromatography
(MPLC) was carried out on Lobar column Merck Lichroprep R Si
60 (Art. 10401) or with Büchi MPLC column filled with silica gel
Merck 60, 230–400 mesh (Art. 9385) or Merck Lichroprep R Si 60
(Art. 139050 or 9336). Basic silica refers to NaHCO3-treated silica
gel Merck Art.7734. Preparation of a stock solution of LDA: To a
solution of diisopropylamine (58 mL, 415 mmol) in anhydrous THF
(65 mL, 800 mmol) at –70 °C, was added dropwise, n-BuLi (250
mL, 1.6 M in hexanes, 400 mmol). The mixture was warmed to 0 °C
for 30 min to give a solution of LDA (1.1 M), which was stored at
0 °C. IUPAC nomenclature was used for all compounds. For the de-
Turning to the 23-hydroxylated series, the lithium enolate
of methyl ketal 12 was condensed with aldehyde 20 to af-
ford a 1:1 mixture of C17-diastereomers that were sepa-
rated by column chromatography to give pure (17R)-24.
The latter aldol adduct was smoothly converted into a 4:1
mixture of spiroketals 25 under mild Lewis acid condi-
tions.
In order to ascertain the stereochemistry at C-17 and at the
spirocenter C-21, the separated major cyclic epimer
(21S)-25 was subsequently submitted to a Barton–
McCombie deoxygenation reaction. To our surprise, the
deoxygenated spiroketal obtained through HF/Py mediat-
ed selective desilylation at C-23, followed by Bu3SnH/
AIBN treatment of the corresponding thioimidazolide,
was found to differ from (21R)-23 previously obtained
from 21. The milder conditions used to cyclise (17R)-24
compared with 22 (in order to avoid possible undesirable
formation of g-pyranone type adducts 9), were claimed to
be responsible for the major formation of the kinetically
controlled (21S)-25, spiroketal which was then deoxygen-
ated into the ‘unnatural’ spiroketal (21S)-23 as depicted in
Scheme 5. Treatment of the latter with HCl/CHCl3 result- scription of 1H NMR and 13C NMR spectra, avermectin numbering
ed in its total transformation into a product which was
is used.
shown to be completely identical to the thermodynamical-
ly more stable ‘natural’ spiroketal (21R)-23 that exhibits a
double reciprocal anomeric effect. Therefore the minor
isomer (21R)-25 was deduced to be the ‘natural’ northern
(2S,3R)-3-(tert-Butyldimethylsilyl)oxy-2,4-dimethylpentanal (5)
A solution containing pure (2S,3R)-3-(tert-butyldimethylsilyl)oxy-
2,4-dimethylpentan-1-ol (5 g, 20.3 mmol), DMSO (40 mL) and
Et3N (20 mL, 142 mmol, 7 equiv), was vigorously stirred at r.t.
while pyridine-SO3 complex (11 g, 71 mmol, 3.5 equiv) was added
portion-wise over 30 min. The reaction mixture was stirred for 30
min at r.t. and cooled to 0–5 °C (ice–water bath) before addition of
a mixture of 50% aq AcOH (100 mL) and crushed ice (100 g). Ex-
traction with pentane according to usual conditions (washings with
H2O) afforded a residue, which was diluted in pentane (5 mL) and
filtrated over a silica pad (elution with 50 mL Et2O). The solvent
was removed under reduced pressure to give pure aldehyde 5.
Yield: 4.6 g (93%); [a]D20 –35.7 (c 0.1, CH2Cl2) {Lit. [a]D –35.6 (c
0.1, CH2Cl2)}.
IR (film): 2980, 2940, 2900, 2840, 1730, 1470, 1390, 1260 cm–1.
moiety required for the synthesis of avermectins 2b.
The convergent A–B two-fragment synthesis of the
known northern precursor (21R)-23 of Ivermectin 1 using
the bulky ketal 21 represents a marked improvement to
the already published linear route. Thus, the present study
represents a formal synthesis of Ivermectin aglycone 1.
Dealing with the synthesis of the avermectins 2b series
from ketal 12, further transformation of the C10–C25 sub-
unit 25 into the genuine northern sub-unit of type 4 (cf.
Scheme 2) requires either successfully attempted or fully
described steps on similar substrates to those used in the
IVM 1 precedent: spiro-equilibration at C-21, stereoselec-
tive reduction at C-19 and hydrostannylation of the triple
bond. Subsequent Stille cross-coupling reaction of 4 with
1H NMR (250 MHz): d = 0.90, 0.93 [2 × d, J = 6.9 Hz, 6 H,
(CH3)2C-26], 1.11 (d, J = 7.1 Hz, 3 H, CH3C-24), 1.85 (m, 1 H, H-
26), 2.54 (m, 1 H, H-24), 3.68 (dd, J = 4.8, 4.2 Hz, 1 H, H-25), 9.8
(d, J = 2.5 Hz, 1 H, CHO).
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

3482
V. Henryon, J.-P. Férézou
PAPER
13C NMR: d = –4.3, –4.1 [(CH3)2Si], 11.9, 18.2, 18.7 [CH3C-24 and
(CH3)2C-26], 25.6 [(CH3)3C-Si], 25.9 [(CH3)3C-Si], 32.8 (C-26),
49.8 (C-24), 79.1 (C-25), 205.0 (CHO).
10 min, the reaction mixture was allowed to warm to 0 °C then, after
10 min, added to dilute aq Na2CO3 (100 mL). Usual work-up with
Et2O (washings with H2O and brine) followed by flash chromatog-
raphy on NaHCO3-treated silica (EtOAc–PE, 0:100→15:85), af-
forded the pure 23-O-silylated compound 12.
All data are in agreement with reported values.15,17b
(2R,4S,5S,6R)-2-Acetonyl-2,4-dihydroxy-6-isopropyl-5-meth-
yltetrahydropyran (8)
Yield: 1.88 g (67% for the 2 steps); [a]D20 +142 (c 2.7, CHCl3).
IR (film): 2960, 2900, 2880, 1720, 1460, 1350, 1100, 1010 cm–1.
(a) Aldol reaction: A solution of LDA (1.1 M in THF, 36.0 mL, 39.5
mmol, 2.1 equiv) was cooled to 0–5 °C (ice–water bath) under ni-
trogen, and 2,4-pentanedione (2.0 mL, 19.7 mmol, 1.05 equiv) was
added dropwise to the yellow solution. After 30 min at 0 °C, the re-
action mixture was cooled to –78 °C (dry ice–acetone bath) and a
solution of aldehyde 5 (4.6 g, 18.8 mmol) in THF (10 mL) was add-
ed slowly. The resulting mixture was stirred for another 30 min,
then hydrolyzed with sat. aq NH4Cl. Usual work-up with Et2O (suc-
cessive washings with H2O and brine) followed by silica flash chro-
matography (Et2O–PE, 0:1→1:1) afforded pure 7 as a mixture of
the two anti/syn diastereomeric adducts in a 45:55 ratio (6.33 g,
97% yield). This crude mixture was directly submitted to the subse-
quent cyclization step.
1H NMR (400 MHz): d = 0.58 [q, J = 7.6 Hz, 6 H, (CH3CH2)3Si],
0.81 (d, J = 6.6 Hz, 3 H, CH3C-24), 0.83 (d, J = 7.0 Hz, 3 H, CH3C-
26), 0.96 [t, J = 7.6 Hz, 9 H, (CH3CH2)3Si], 1.07 (d, J = 7 Hz, 3 H,
CH3C-26), 1.50 (dqd, J = 10.0, 7.0, 5.0 Hz, 1 H, H-24), 1.82 (sept
d, J = 6.6, 2.4 Hz, 1 H, H-26), 1.84 (m, 2 H, H2-22), 2.24 (s, 3 H,
CH3-18), 2.37, 2.95 (2 × d, J = 12.1 Hz, 2 H, H2-20), 3.21 (s, 3 H,
CH3O), 3.62 (dd, J = 10.0, 2.4 Hz, 1 H, H-25), 3.85 (ddd, J = 5.0,
3.3, 3.1 Hz, 1 H, H-23). Peaks were assigned with the aid of H,H-
COSY and HETCOR experiments.
13C NMR (100.57 MHz): d = 4.9 [(CH3CH2)3Si], 6.8 [CH3CH2)3Si],
13.6 (CH3C-24), 14.3, 20.3 [(CH3)2C-26], 28.4 (C-26), 32.0 (C-18),
36.3 (C-24), 39.4 (C-22), 47.3 (CH3O), 50.4 (C-20), 68.9 (C-23),
73.0 (C-25), 98.2 (C-21), 207.4 (C-19).
(b) Desilylation–cyclization of aldol mixture 7: To a solution of the
preceding mixture (6.33 g, 18.4 mmol) in DMF (180 mL) was add-
ed in one portion, TBAF trihydrate (36 g, 0.13 mol, 6 equiv). The
resulting solution was heated to 50 °C for 1 h, then allowed to cool
to r.t. and EtOAc and H2O were successively added. After decanting
and separation, the aqueous layer was extracted with EtOAc (2×).
The combined organic phases were treated as usual (washings with
brine) to give a crude dark-brown residue (7.62 g), which was dilut-
ed with EtOAc and filtered over a silica pad (25 g silica; EtOAc–
pentane, 4:1) to afford a mixture of diastereomers, which was sub-
sequently separated by Lobar MPLC silica chromatography
(EtOAc–PE, 1:40→4:1) to give, in order of elution: the required
lactol 8 and its (21S)-epimeric congener.
MS (CI, NH3): m/z = 344 (MH+ + NH3 – MeOH), 327, 195, 153,
132, 120.
Anal. Calcd. for C19H38O4Si: C, 63.64; H, 10.68. Found: C, 63.74;
H, 10.57.
1-(3,3-Diisopropoxypropane-1-sulfonyl)-4-methylbenzene (14)
Aldehyde 13 was synthesized according to the procedure of Cooper
and Dolby.22 To a solution of TsNa (98 g, 0.55 mol) in a mixture of
H2O (550 mL) and THF (275 mL), was added dropwise, at 0 °C,
AcOH (32 mL, 0.55 mol) over 1 h, then acrolein (33 mL, 0.5 mol)
in THF (138 mL). The reaction mixture was stirred for 24 h before
addition of H2O (1 L). Usual work-up with CH2Cl2 including wash-
ing with sat. aq NaHCO3 and brine, gave 3-(p-toluenesulfonyl)pro-
panal 13, which was sufficiently pure to be used in the next step
without purification.
(2R,4S,5S,6R)-2-Acetonyl-2,4-dihydroxy-6-isopropyl-5-meth-
yltetrahydropyran (8)
Yield: 1.32 g (30% over two steps); white solid; mp 66–67 °C
(Et2O–pentane); [a]D20 +68 (c 1.0, CHCl3).
Yield: 87.4 g (82%); colorless oil.
IR (film): 1725, 1600, 1500, 1450, 1400, 1300, 1175 cm–1.
All spectroscopic data were in full agreement with the same product
already described in the racemic series.15
1H NMR (400 MHz): d = 2.44 (s, 3 H, CH3Ar), 2.92 (t, J = 7.5 Hz,
2 H, H2-2), 3.40 (t, J = 7.5 Hz, 2 H, H2-3), 7.42, 7.80 (2 × d, J = 8.2
Hz, 2 × 2 H, 4 × Ar-H), 9.70 (s, 1 H, CHO).
13C NMR: d = 21.6 (CH3Ar), 36.6 (CH2CHO), 49.1 (CH2SO2),
128.0, 130.0 (2 × 2Ar-CH), 135.6 (CH3C-Ar), 145.1 (SO2C-Ar),
197.1 (CHO).
(2R,4R,5S,6R)-2-Acetonyl-2,4-dihydroxy-6-isopropyl-5-meth-
yltetrahydropyran
Yield: 1.22 g (28%); white solid; mp 86–87 °C (Et2O–pentane);
[a]D20 +6 (c 2.6, CHCl3).
All spectroscopic data were also in full agreement with the same
product already described in the racemic series.15
MS (CI, NH3): m/z = 213 [MH+], 124.
Anal. Calcd. for C10H12O3S: C, 56.59; H, 5.70. Found: C, 56.74; H,
5.82.
(2R,4S,5S,6R)-2-Acetonyl-6-isopropyl-2-methoxy-5-methyl-4-
(triethylsilyl)oxytetrahydropyran (12)
Aldehyde 13 (42 g, 0.2 mol) was added to a mixture containing
i-PrOH (100 mL, 1.3 mol), CH2Cl2 (200 mL) and CSA (1.5 g). The
reaction mixture was stirred under reflux for 3 h, then freshly acti-
vated 3Å molecular sieves were added and the mixture was stirred
at r.t. for 15 h. After addition of sat. aq NaHCO3, the mixture was
stirred another 2 h and filtered over a pad of Celite and decanted.
The aqueous phase was extracted with Et2O containing 1% Et3N,
and the combined organic phases were treated as usual to afford a
crude product that was subsequently purified on a preparative Lobar
MPLC column coated with silica Merck Lichroprep Si 60 (Art.
13905; Et2O–PE, 15:85→50:50) to give pure sulfonyl acetal 14.
To a solution of hemiketal 8 (1.8 g, 15.2 mmol) in a mixture of
MeOH (29 mL) and MeNO2 (49 mL), was added in one portion at
r.t., Montmorillonite K-10 (18 g). After 5 min, the reaction mixture
was quickly filtered through a pad composed of (from the top to the
bottom): sand, silica, K2CO3 and MgSO4 layers, each of which be-
ing of approximately equal thickness (eluent: EtOAc). The filtrate
was concentrated under reduced pressure (temperature of the heat-
ing bath should not exceed 30 °C) to give crude methyl ketal 11
(1.77 g, 87% yield) that was directly protected as a O-TES ether.
Spectroscopic data for this intermediate were in full agreement with
the same product already described in the racemic series.15
Yield: 53.4 g (85%); white solid.
To a solution of the preceding methyl ketal 11 (1.77 g, 7.25 mmol)
in DMF (30 mL) was added at r.t., imidazole (2.5 g, 36.2 mmol, 5
equiv). The resulting solution was cooled to –35 °C and TESCl
(2.73 g, 3.0 mL, 18.1 mmol, 2.5 equiv) was added dropwise. After
1H NMR (400 MHz): d = 1.13 (2 × d, J = 6.1 Hz, 12 H, 4 × CH3CH),
1.96 (m, 2 H, CH2CH), 2.46 (s, 3 H, CH3Ar), 3.19 (m, 2 H,
CH2SO2), 3.79 [hept, J = 6.2 Hz, 2 H, 2 × CH(CH3)2], 4.67 [t,
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

PAPER
Convergent Synthetic Approach to the C10–C25 Subunit of Avermectins
3483
J = 4.9 Hz, 1 H, CH(OiPr)2], 7.36, 7.79 (2 × d, J = 8.2 Hz, 2 × 2 H,
4 × Ar-H).
13C NMR: d = 10.1 (CH3C-14), 22.4 and 23.2 (4 × CH3CH), 35.6
(C-16), 68.4 [2 × OCH(CH3)2], 98.6 [CH(OiPr)2], 140.1 (C-15),
149.1 (C-14), 195.1 (CHO).
MS (CI, NH3): m/z = 232 [MH+ + 17], 155.
13C NMR: d = 21.4 (CH3-Ar), 22.2, 23.0 (2 × CH3CH), 28.8
(CH2CH2SO2), 51.6 (CH2SO2), 68.4 (2 × OCHCH3), 97.6 (CH-iPr),
127.8, 129.7 (2 × 2CH-Ar), 136.1 (CH3C-Ar), 144.4 (SO2C-Ar).
(–)-Vinyl-N,N-diisopropylcarbamate (18)
MS (CI, NH3): m/z = 332 [MH+ + 17], 315 [MH+], 255.
To a well stirred solution containing freshly distilled (–)-spartein
(5.94 g, 25.6 mmol, 1.1 equiv) in a mixture of pentane (81 mL) and
cyclohexane (11.6 mL), was successively added via cannula at
–78 °C, s-BuLi (1.3 M in cyclohexane–hexanes, 19.6 mL, 25.6
mmol) and the crotylcarbamate 17 (4.87 g, 24.5 mmol, 1.05 equiv)
in pentane (24.5 mL). After stirring 45 min at –90 °C, during which
time a white thick precipitate was formed, a pre-cooled solution of
titanium isopropoxide (30.5 mL, 102 mmol, 4 equiv/spartein) was
added dropwise via syringe. The reaction mixture became deep-red
and, after stirring a further 15 min, aldehyde 16 (4.98 g, 23.3 mmol)
in pentane (5 mL) was added via cannula at –90 °C. The reaction
mixture was stirred for 30 min at –78 °C, then at r.t. for 30 min be-
fore addition of ice-cold sat. aq NH4Cl (500 mL) and Et2O (500
mL). This slurry was filtrated on Celite (washings with Et2O) and
the filtrate decanted. Re-extraction of the aqueous phase and work-
Anal. Calcd. for C16H26O4S: C, 61.12; H, 8.33; Found: C, 61.03; H,
8.53.
1-(1,1-Diisopropoxy-4-methylhept-5-en-3-sulfonyl)-4-methyl-
benzene (15)
To a solution of sulfone 14 (32 g, 0.1 mol) in THF (350 mL), was
slowly added (30 min) at –78 °C under N2, n-BuLi (1.57 M in hex-
anes, 70 mL, 1.1 mol, 1.1 equiv). After being stirred for 30 min at
–78 °C, HMPA (18 mL) was carefully added, followed by freshly
prepared 4-bromopent-2-ene23 (17.9 g, 0.12 mol, 1.2 equiv). After 2
h at –78 °C, the reaction mixture was allowed to warm to 0 °C be-
fore being quenched with sat aq NaHCO3. After addition of Et3N (2
mL), usual work-up with Et2O afforded the crude material, which
was subsequently submitted to preparative silica MPLC chromatog-
raphy as above (Et2O–PE, 0:1→1:1) to give pure 15.
1
up as usual gave the crude anti-homoaldol product 18. H NMR
analysis revealed this product to be sufficiently pure for the next
step.
Yield: 30.4 g (78% yield); pale-yellow oil; 1:1 mixture of diastereo-
mers.
Yield: 9.10 g (95%); [a]D20 –10.5 (c 2.07, CHCl3).
IR (film): 3460, 2970, 1705, 770 cm–1.
1H NMR (400 MHz): d (1:1 mixture of diastereomers) = 1.0–1.2
(m, 15 H, 5 × CH3CH), 1.62 [t, J = 5.6 Hz, 3 H, CH3CH=], 1.83,
2.10 (2 × m, 2 H, CH2), 2.46 (s, 3 H, CH3Ar), 2.76 (m, 1 H,
CHCH=), 3.08, 3.19 (2 × m, 1 H, CHSO2), 3.75 [m, 2 H, 2 ×
CH(CH3)2], 4.65 [m, J = 4.9 Hz, 1 H, CH(OiPr)2], 5.32–5.48 (m,
2 H, 2 × CH=), 7.36, 7.77 (2 × d, J = 8.2 Hz, 2 × 2 H, 4 × Ar-H).
13C NMR: d (1:1 mixture of diastereomers) = 14.3, 17.8, 18.0, 18.8,
21.5, 22.0, 22.1, 22.8, 22.9, 23.3 and 23.3 (CH3), 30.3 and 31.2
(CH2CHSO2), 35.0 (CHCH=), 64.4 and 65.6 (CHSO2), 68.6, 68.8,
68.9 and 68.9 [2 × OCH(CH3)2], 98.6 and 98.6 [CH(OiPr)2], 125.3
and 126.5 (CHCH=), 128.5, 128.8, 129.6 and 129.7 (4 × Ar-CH),
130.4 and 133.2 (CH3CH=), 135.9 and 136.1 (CH3C-Ar), 144.3
(SO2C-Ar).
1H NMR (400 MHz): d = 0.88 (d, J = 6.8 Hz, 3 H, CH3CH-12),
1.14–1.23 [m, 24 H, 4 × (CH3)2CH], 1.65 (s, 1 H, CH3C-14), 2.38
(t, J = 6.25 Hz, 2 H, H2-16), 2.90 (m, 1 H, H-12), 3.67 (d, J = 9.1
Hz, 1 H, H-13), 3.88 [m, 2 H, 2 × OCH(CH3)2], 3.90, 4.26 {2 × br
m, 2 H, [(CH3)2CH]2N}, 4.55 (t, J = 8 Hz, 1 H, H-17), 4.65 (dd,
J = 9.9, 6.3 Hz, 1 H, H-11), 5.44 (t, J = 6.8 Hz, 1 H, H-15), 7.19 (d,
J = 6.3 Hz, 1 H, H-10).
13C NMR: d = 11.0 (CH3C-14), 17.4 (CH3C-12), 20.3 and 21.5 {br,
6 H, 2 × N[CH(CH3)2]}, 22.5, 22.6, 23.3 and 23.4 [2 × OCH(CH3)2],
34.2 (C-16), 34.5 (C-12), 45.7 and 46.9 {br, 2 × N[CH(CH3)2]},
67.7 and 67.8 [2 × OCH(CH3)2], 82.0 (C-13), 99.8 (C-17), 113.3 (C-
11), 124.1 (C-15), 136.6 (C-14), 137.0 (C-10), 152.8 (C=O).
MS (CI, NH3): m/z = 400 [MH+ + 17], 323, 167, 109.
MS (CI, NH3): m/z = 414 [MH+ + 17], 336, 128.
Anal. Calcd. for C21H34O4S: C, 65.93; H, 8.96. Found: C, 66.00; H,
9.05.
MTPA-ester of 18 (Steglich procedure):24 To a solution of DCC (50
mg, 0.24 mmol) and DMAP (2.4 mg, 0.014 mmol, 0.1 equiv) were
added, under nitrogen at r.t., crude 18 (80 mg diluted with 0.5 mL
CH2Cl2), then (R)-(+)-a-methoxy-a-(trifluoromethyl)phenylacetic
acid [(R)-(+)-MTPA; 56.7 mg, 0.24 mmol, 1.25 equiv). The reac-
tion mixture was stirred overnight, then pentane (2 mL) was added
and the mixture filtered. The filtrate was added to H2O and extracted
with CH2Cl2–pentane (1:1, 2×). Washings with sat. aq NaHCO3,
then H2O, followed by drying with MgSO4 and evaporation, deliv-
ered the crude product that was directly analyzed by 1H NMR.
(E)-5,5-Diisopropoxy-2-methylpent-2-enal (16)
Ozone enriched oxygen was gently bubbled at –78 °C through a so-
lution containing sulfone 18 (6.0 g, 16 mmol) in CH2Cl2 (160 mL)
containing 1% v/v of pyridine (1.6 mL) until a blue coloration per-
sisted. While still at –78 °C, the excess of ozone was flushed with a
nitrogen stream for 30 min. The temperature was then allowed to
warm to r.t. and Et3N (2.3 mL) added. After stirring overnight, the
orange-red reaction mixture was carefully evaporated in vacuo with
a rotavapor, behind a safety shield (CAUTION). The remaining
oily residue was diluted with pentane and partially purified on a
flash chromatography column (Et2O–PE, 0:100→70:30) to afford
impure material which was subsequently submitted to a MPLC pu-
rification step (CH2Cl2–PE, 40:60 with a Et2O gradient from
100:0→70:30) to furnished the expected pure (E)-aldehyde 16. This
aldehyde was immediately used for the subsequent homoaldol con-
densation.
(5E,3S,4S)-8,8-Diisopropoxy-3,5-dimethyl-4-[(triisopropyl-
silyl)oxy]-oct-5-en-1-yne (19)
To a solution of 21 (207 mg, 0.5 mmol) in CH2Cl2 (2 mL) was added
at 0 °C, 2,6-lutidine (0.14 mL, 1.2 mmol, 2.6 equiv), then dropwise,
triisopropylsilyl trifluoromethanesulfonate (0.17 mL, 0.65 mmol,
1.3 equiv). The reaction mixture was stirred for 10 min at 0 °C, then
quenched with H2O. Usual work-up including extraction with Et2O,
followed by MPLC silica column purification (Et2O–PE,
0:100→70:30) afforded the pure O-triisopropylsilyl-protected car-
bamate.
Yield: 2.82 g (84%); colorless oil.
IR (film): 2970, 2920, 1685, 1640, 1030 cm–1.
1H NMR (400 MHz): d = 1.20 (m, 12 H, 4 × CH3CH), 1.78 (d,
J = 1.0 Hz, 3 H, CH3C-14), 2.66 (t, J = 6.1 Hz, 2 H, H2-16), 3.89
[hept., J = 5.5 Hz, 2 H, 2 × OCH(CH3)2], 4.73 [t, J = 5.2 Hz, 1 H,
CH(OiPr)2], 6.58 (dq, J = 7.2, 1.0 Hz, 1 H, H-15), 9.44 (s, 1 H,
CHO).
Yield: 250 mg (91%); pale-yellow oil.
1H NMR (400 MHz): d = 0.99–1.17 [m, 48 H, 7 × (CH3)2CH, 3 ×
CHSi and CH3C-12], 1.70 (s, 1 H, CH3C-14), 2.48 (t, J = 6.1 Hz,
2 H, H2-16), 3.16 (m, 1 H, H-12), 3.64 and 3.93 {2 × br m, 2 H, 2 ×
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

3484
V. Henryon, J.-P. Férézou
PAPER
N[CH(CH3)2]}, 3.79 [sext, J = 6.1 Hz, 2 H, 2 × OCH(CH3)2], 4.07
(d, J = 7.4 Hz, 1 H, H-13), 4.61 (t, J = 5.4 Hz, 1 H, H-17), 4.73 (dd,
J = 9.9, 6.6 Hz, 1 H, H-11), 5.59 (t, J = 6.6 Hz, 1 H, H-15), 6.55 (d,
J = 7.6 Hz, 1 H, H-10).
13C NMR: d = 12.1 (CH3C-14), 12.4 and 12.6 [3 × SiCH(CH3)2],
17.6 (CH3C-12), 17.7, 18.2 and 18.2 [6 × Si(CHCH3], 20.5 and 21.5
{br, 2 × N[CH(CH3)2]}, 22.4, 22.6, 23.3 and 23.4 [2 × OCH(CH3)2],
34.2 (C-16), 35.7 (C-12), 45.7 and 46.8 {br, 2 × N[CH(CH3)2]},
67.5 and 67.6 [2 × OCH(CH3)2], 82.6 (C-13), 99.8 (C-17), 114.4 (C-
11), 122.7 (C-15), 134.8 (C-10), 138.1 (C-14), 153.0 (C=O).
and re-extraction of the aqueous phase with Et2O (3×), the com-
bined organic phases were washed with brine, diluted aqueous HCl,
then brine again before drying and evaporation under the usual con-
ditions. Silica MPLC purification (Et2O–hexanes, 0:100→15:85)
afforded the expected condensation adduct 23 (44 mg, 87% yield)
as a c.a. 4:1 mixture of epimers at C-17. The major isomer was thor-
oughly identified as [2R(2E,4S,5S),6R,8R,9S,10S]-2-[3,5-dimethyl-
4-(triisopropylsilyl)oxyhept-2-en-6-ynyl]-8-isopropyl-9-methyl-
1,7-dioxaspiro[5.5]undecan-4-one [(21R)-23] by comparison with
the northern spiroketal subunit of 22,23-dihydroavermectin B1b 1,
previously synthesized in our group.
1H NMR (400 MHz): d (4:1 mixture of isomers, only values for the
major isomer reported) = 0.81, 0.82, 0.90 [3 × d, J = 7.0 Hz, 9 H,
CH3C-24 and (CH3)2C-26], 1.07 [br m, 24 H, (iPr)3-Si and CH3C-
12], 1.40–1.80 (m, 5 H), 1.69 (s, 3 H, CH3C-14), 1.85 (sept d,
J = 7.0, 2.0 Hz, 1 H, H-26), 2.03 (d, J = 2.3 Hz, 1 H, H-10), 2.21
(dd, J = 14.3, 13.8 Hz, 1 H, Ha-18), 2.36 (m, 5 H), 2.64 (qint d,
J = 7.0, 2.4 Hz, 1 H, H-12), 3.08 (dd, J = 9.7, 2.0 Hz, 1 H, H-25),
3.94 (m, 1 H, H-17), 4.16 (d, J = 7.5 Hz, 1 H, H-13), 5.50 (br t,
J = 7.0 Hz, 1 H, H-15).
MS (CI, NH3): m/z = 587 [MH+ + 17], 336.
A solution of s-BuLi (1.28 M in cyclohexane/hexanes, 0.8 mL, 1
mmol, 3.8 equiv) was slowly added at –78 °C to a solution of the
above intermediate (150 mg, 0.26 mmol) in Et2O (2 mL). After 15
min at –78 °C, the temperature was allowed to reach 0 °C for 15
min, then the reaction mixture was quenched with sat. aq NH4Cl and
extracted as usual with Et2O. The crude product was purified on sil-
ica gel MPLC column coated with Lichroprep silica Merck Art.
9336 (hexane–Et2O, 100:0→85:15) to give the pure acetylenic de-
rivative 19.
MS (CI, NH3): m/z = 536 [MH+ + 17], 519 [MH+].
Yield: 102 mg (83%); [a]D20 +14.4 (c 2.0, CHCl3).
1H NMR (400 MHz): d = 0.95–1.20 [m, 36 H, 5 (CH3)2CH, 3 ×
CHSi and CH3C-12], 1.61 (s, 1 H, CH3C-14), 1.86 (d, J = 2.4 Hz,
1 H, H-10), 2.43 (t, J = 6.15 Hz, 2 H, H2-16), 2.67 (qd, J = 7.5 and
2.4 Hz, 1 H, H-12), 3.76 [m, 2 H, 2 × OCH(CH3)2], 4.24 (d, J = 7.7
Hz, 1 H, H-13), 4.56 (t, J = 5.4 Hz, 1 H, H-17), 5.61 (t, J = 7.1 Hz,
1 H, H-15).
13C NMR: d = 11.9 (CH3C-14), 12.6 [3 × SiCH(CH3)2], 17.2 (CH3C-
12), 18.2 and 18.2 [6 × Si(CHCH3], 22.4, 22.6, 23.4 and 23.4 [2 ×
OCH(CH3)2], 32.1 (C-12), 34.1 (C-16), 67.6 and 67.6 [2 ×
OCH(CH3)2], 69.3 (C-10), 81.7 (C-13), 87.9 (C-11) 99.7 (C-17),
123.6 (C-15), 137.0 (C-14).
Condensation of Aldehyde (20) with (2R,4S,5S,6R)-2-Acetonyl-
6-isopropyl-2-methoxy-5-methyl-4-(triethylsilyl)oxytetrahy-
dropyran (12)
In a well-dried, round-bottomed flask, under nitrogen at –78 °C,
were successively introduced THF (20 mL), a solution of LDA
(1.05 M in THF, 5.54 mL, 5.54 mmol, 1.1 equiv) via a syringe and,
after 5 min, via cannula, a solution of acetal 12 (1.80 g, 5.04 mmol)
in THF (19 mL). After 5 min at 0 °C, the reaction mixture was
cooled to –78 °C and stirred for 15 min, then a solution of aldehyde
20 (2 g, 6.21 mmol, 1.2 equiv) in THF (14 mL) was added dropwise
via syringe. After 15 min, the reaction mixture was hydrolyzed with
sat. aq NH4Cl (15 mL) then allowed to warm to r.t. and poured into
a mixture of Et2O (100 mL) and sat. aq NH4Cl (100 mL). The aque-
ous layer was decanted and re-extracted twice with Et2O. Usual
work-up, including washings with brine, afforded the crude aldol
product which was shown to be a 1:1 mixture of diastereomers by
1H NMR analysis. Purification by silica MPLC (Et2O–PE,
0:1→1:1) gave, in order of elution: the less polar ‘natural’ diaste-
reomer (17R)-24 (1.23 g, 36%) then the more polar ‘unnatural’
epimer (17S)-24 (1.26 g, 37%).
MS (CI, NH3): m/z = 442 [MH+ + 17], 191.
(3E,5R,6S)-5-[(Triisopropylsilyl)oxy]-4,6-dimethyl-oct-3-en-7-
ynal (20)
To a solution of diisopropylacetal 19 (2.72 g, 6.41 mmol) in THF
(50 mL) was added in one portion an aqueous solution of TsOH
(0.1 M, 3.2 mL, 0.32 mmol, 0.05 equiv). The resulting solution was
heated to 55–60 °C for 45 min and then cooled to 0–5 °C (ice–water
bath) before addition of pentane (50 mL) and H2O (5 mL). After de-
canting and separation, the organic layer was quickly washed with
brine (2 × 100 mL) to give, after usual treatment, aldehyde 20. This
compound was fairly unstable; it could not be purified by chroma-
tography without extensive loss of material and was therefore im-
mediately used for the subsequent aldolization step.
[6E(2R,4S,5S,6R)4S,8S,9S]-7,9-Dimethyl-1-[6-isopropyl-2-
methoxy-5-methyl-4-(triethylsilyl)oxytetrahydropyran-2-yl]-4-
hydroxy-8-(triisopropylsilyl)oxyundec-6-en-10-yn-2-one
[(17R)-24]
[a]D20 +63 (c 1.2, CHCl3).
1H NMR (400 MHz): d = 0.58 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.81 (d, J = 6.9 Hz, 3 H, CH3C-24), 0.86 (d, J = 6.8 Hz, 3 H, CH3C-
26), 0.97 [t, J = 7.5 Hz, 9 H, (CH3CH2)3-Si], 1.07 [br m, 24 H,
(iPr)3-Si, CH3C-12 and CH3C-26], 1.52 (m, 1 H, H-24), 1.64 (s,
3 H, CH3C-14), 1.81 (m, 1 H, H-26), 1.83 (br d, J = 4.5 Hz, 2 H, H2-
22), 2.04 (d, J = 2.3 Hz, 1 H, H-10), 2.22 (m, 2 H, H2-16), 2.43 (d,
J = 12.4 Hz, 1 H, Ha-20), 2.64 (quint d, J = 7.0, 2.3 Hz, 1 H, H-12),
2.73 (m, 2 H, H2-18), 2.91 (d, J = 12.4 Hz, 1 H, Hb-20), 2.93 (d,
J = 6.2 Hz, 1 H, HOC-17), 3.18 (s, 3 H, CH3-O), 3.62 (dd, J = 10,
2.3 Hz, 1 H, H-25), 3.85 (q, J = 3.9 Hz, 1 H, H-23), 4.07 (m, 1 H,
H-17), 4.15 (d, J = 7.0 Hz, 1 H, H-13), 5.43 (br t, J = 6.2 Hz, 1 H,
H-15).
13C NMR: d = 4.9 [(CH3CH2)3Si], 6.8 [(CH3CH2)3Si], 12.2 (CH3C-
14), 12.5 {[(CH3)2CH]3Si}, 13.6 (CH3C-24), 14.4, 16.9, 20.3
[(CH3)2C-26 and CH3C-12], 18.1 {[(CH3)2CH]3Si}, 28.4 (C-26),
32.3 (C-12), 34.6 (C-16), 36.3 (C-24), 39.7 (C-22), 47.4 (CH3-O),
50.3, 50.5 (C-18 and C-20), 67.3 (C-17), 68.9 (C-23), 69.6 (C-10),
Yield: 2 g (97%); oil.
1H NMR (400 MHz): d = 1.08–1.12 [m, 24 H, 3 × (CH3)2CH, 3 ×
CHSi and CH3C-12], 1.67 (br s, 3 H, CH3C-14), 2.05 (d, J = 2.5 Hz,
1 H, H-10), 2.65 (qd, J = 7.2, 2.5 Hz, 1 H, H-12), 3.18 (d, J = 6.0
Hz, 2 H, H-16), 4.22 (d, J = 6.8 Hz, 1 H, H-13), 5.62 (br t, J = 7.2
Hz, 1 H, H-15), 9.66 (t, J = 2.0 Hz, 1 H, CHO). No trace of the cor-
responding a,b-conjugated aldehyde was found.
Condensation of Aldehyde (20) with (2R,5S,6R)-2-Acetonyl-6-
isopropyl-5-methyl-4-(triethylsilyl)oxy-2-(2,2,2-triphe-
nylethoxy)tetrahydropyran (21)
To a solution containing the known optically active bulky ketal 21
(47 mg, 0.1 mmol) in THF (12 mL), was added at –78 °C under ni-
trogen, LDA (1.05 M in THF, 0.105 mL, 1.1 equiv). After 30 min
at this temperature, optically active aldehyde 20 (46 mg, 0.14 mmol,
1.4 equiv) in THF (1 mL) was added, via cannula to the resulting an-
ion solution. After a further 30 min, the reaction mixture was
quenched with sat. aq NH4Cl and Et2O was added. After decanting
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

PAPER
Convergent Synthetic Approach to the C10–C25 Subunit of Avermectins
3485
73.2 (d, C-25), 81.0 (C-13), 87.6 (C-11), 98.2 (C-21), 123.5 (C-15),
138.1 (C-14), 209.9 (C-19).
(21R)-25
1H NMR (400 MHz): d = 0.63 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.79 (d, J = 7.0 Hz, 3 H, CH3C-26), 0.82 (d, J = 7.0 Hz, 3 H, CH3C-
24), 0.91 (d, J = 7.0 Hz, 3 H, CH3C-26), 1.00 [t, J = 7.5 Hz, 9 H,
(CH3CH2)3Si], 1.07 [br m, 24 H, (iPr)3Si, CH3C-12], 1.59 (dd,
J = 14.0, 4.3 Hz, 1 H, Ha-22), 1.60 (m, 1 H, H-24), 1.63 (s, 3 H,
CH3C-14), 1.76 (sept d, J = 7.0, 2.0 Hz, 1 H, H-26), 2.02 (dd,
J = 14.0, 3.0 Hz, 1 H, Hb-22), 2.03 (d, J = 2.3 Hz, 1 H, H-10), 2.16
(dd, J = 14.0, 11.0 Hz, 1 H, Ha-18), 2.34 (m, 5 H, H2-16, Hb-18 and
H2-20), 2.63 (quint d, J = 7.1, 2.3 Hz, 1 H, H-12), 3.58 (dd, J = 10.0,
2.0 Hz, 1 H, H-25), 3.90 (q, J = 3.1 Hz, 1 H, H-23), 3.98 (m, 1 H,
H-17), 4.16 (d, J = 7.1 Hz, 1 H, H-13), 5.52 (br t, J = 7.0 Hz, 1 H,
H-15).
MS (CI, NH3): m/z = 666, 649, 517, 410, 327, 239.
[6E(2R,4S,5S,6R)4R,8S,9S]-7,9-Dimethyl-1-[6-isopropyl-2-
methoxy-5-methyl-4-(triethylsilyl)oxytetrahydropyran-2-yl]-4-
hydroxy-8-(triisopropylsilyl)oxyundec-6-en-10-yn-2-one
[(17S)-24]
[a]D20 +93 (c 1.7, CHCl3).
1H NMR (400 MHz): d = 0.58 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.81, 0.82 (d, J = 6.8 Hz, 6 H, CH3C-24 and CH3C-26), 0.96 [t,
J = 7.5 Hz, 9 H, (CH3CH2)3Si], 1.07 (br m, 27 H, (iPr)3-Si, CH3C-
12 and CH3C-26), 1.48 (m, 1 H, H-24), 1.62 (s, 3 H, CH3C-14), 1.84
(sept d, J = 6.8, 2.2 Hz, 1 H, H-26), 1.86 (m, 2 H, H2-22), 2.04 (d,
J = 2.3 Hz, 1 H, H-10), 2.22 (br t, J = 6.2 Hz, 2 H, H2-16), 2.37 (d,
J = 12.3 Hz, 1 H, Ha-20), 2.60 (m, 1 H, H-12), 2.62 (dd, J = 15.3,
8.8 Hz, 1 H, Ha-18), 2.88 (dd, J = 15.3, 2.5 Hz, 1 H, Hb-18), 2.95
(d, J = 12.3 Hz, 1 H, Hb-20), 3.06 (d, J = 3.0 Hz, 1 H, HOC-17),
3.19 (s, 3 H, CH3-O), 3.61 (dd, J = 10.0, 2.2 Hz, 1 H, H-25), 3.85
(q, J = 3.1 Hz, 1 H, H-23), 4.05 (m, 1 H, H-17), 4.13 (d, J = 7.1 Hz,
1 H, H-13), 5.46 (br t, J = 7.0 Hz, 1 H, H-15).
13C NMR: d = 5.0 [(CH3CH2)3Si], 7.0 [(CH3CH2)3Si], 12.1 (CH3C-
14), 12.6 {[(CH3)2CH]3Si}, 13.5 (CH3C-24), 13.9, 20.3 [(CH3)2C-
26], 16.9 (CH3C-12), 18.1 {[(CH3)2CH]3Si}, 28.3 (C-26), 32.3 (C-
12), 32.8, 46.1, 52.3 (C-16, C-18 and C-20), 36.2 (C-24), 42.0 (C-
22), 68.3 (C-17), 68.9 (C-23), 69.5 (C-10), 72.5 (C-25), 81.1 (C-13),
87.6 (C-11), 99.1 (C-21), 123.0 (C-15), 137.9 (C-14), 206.3 (C-19).
MS (CI, NH3): m/z = 666 [MH+ + 17], 649 [MH+], 595, 517, 475,
319, 255, 223.
13C NMR: d = 4.9 [(CH3CH2)3Si], 6.8 [(CH3CH2)3Si], 12.1 (CH3C-
14), 12.5 {[(CH3)2CH]3Si}, 13.6, 14.4, 17.0, 20.3 [CH3C-24,
(CH3)2C-26, CH3C-12], 18.1 {[(CH3)2CH]3Si}, 28.4 (C-26), 32.2
(C-12), 34.5 (C-16), 36.3 (C-24), 39.6 (C-22), 47.4 (CH3-O), 50.1
(C-20), 50.4 (C-18), 67.5 (C-17), 68.9 (C-23), 69.5 (C-10), 73.2 (C-
25), 81.1 (C-13), 87.6 (C-11), 98.3 (C-21), 123.4 (C-15), 137.9 (C-
14), 209.0 (C-19).
Spiroketalisation Reaction of (17S)-24
For comparison studies, the ‘unnatural’ (17S)-epimer was also sub-
mitted to a spiroketalisation reaction using the above conditions.
From pure (17S)-24 (630 mg, 0.92 mmol), two epimeric spiroketal
adducts were obtained: a major less polar (21S)-epimer and a minor
(21R)-epimer.
MS (CI, NH3): m/z = 666, 649, 517, 327, 301, 285, 169.
[2S(2E,4S,5S),6S,8R,9S,10S]-2-[3,5-Dimethyl-4-(triisopropyl-
silyl)oxy-hept-2-en-6-ynyl]-8-isopropyl-9-methyl-4-(triethyl-
silyl)oxy-1,7-dioxaspiro[5.5]undecan-4-one] [(17S,21S)-
Spiroketal]
Spiroketalisation Reaction of (17R)-24
To a solution of (17R)-24 (~0.05 M, 550 mg, 0.81 mmol) in THF,
was added, at r.t., pyridinium p-toluenesulfonate (PPTS; 2 equiv).
The reaction mixture was stirred for 30 min, and then quenched with
sat. aq NaHCO3. Extraction with Et2O according to the usual work-
up, including washings with sat. aq CuSO4, afforded the crude
spiroketal adducts, which were subsequently separated by silica
MPLC chromatography (Et2O–PE, 0:1→3:7) to give, in order of
elution: the major less polar ‘unnatural’ spiro-epimer (21S)-25 (275
mg, 52% yield) and the minor ‘natural’ spiro-epimer (21R)-25 (64
mg, 12% yield).
Yield: 380 mg (64%); [a]D20 –19.3 (c 2.15, CHCl3).
1H NMR (400 MHz): d = 0.61 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.80 (d, J = 6.7 Hz, 3 H, CH3C-24), 0.82, 0.88 [2 × d, J = 6.9 Hz,
6 H, (CH3)2C-26], 0.97 [t, J = 7.5 Hz, 9 H, (CH3CH2)3Si], 1.07 [br
m, 24 H, (iPr)3Si, CH3C-12], 1.57 (m, 1 H, H-24), 1.63 (s, 3 H,
CH3C-14), 1.75 (m, 1 H, H-26), 1.76 (dd, J = 13.7, 3.7 Hz, 1 H, Ha-
22), 1.96 (dd, J = 13.7, 3.0 Hz, 1 H, Hb-22), 2.03 (d, J = 2.4 Hz,
1 H, H-10), 2.30 (m, 5 H, H2-16, H2-18 and Ha-20), 2.62 (quint d,
J = 7.0, 2.2 Hz, 1 H, H-12), 3.34 (d, J = 14.0 Hz, 1 H, Hb-20), 3.45
(dd, J = 10.0, 2.5 Hz, 1 H, H-25), 3.98 (q, J = 3.0 Hz, 1 H, H-23),
4.14 (d, J = 7.0 Hz, 1 H, H-13), 4.40 (m, 1 H, H-17), 5.45 (br t,
J = 6.0 Hz, 1 H, H-15).
13C NMR: d = 4.8 [(CH3CH2)3Si], 7.0 [(CH3CH2)3Si], 12.2 (CH3C-
14), 12.5 {[(CH3)2CH]3Si}, 13.3 (CH3C-24), 14.0, 20.3 [(CH3)2C-
26], 17.0 (CH3C-12), 18.1 {[(CH3)2CH]3Si}, 28.3 (C-26), 32.1 (C-
12), 34.2, 46.4 (C-18 and C-16), 36.3 (C-24), 43.5 (C-22), 49.0 (C-
20), 69.4 (C-17), 69.4 (C-10), 70.4 (C-23), 75.8 (C-25), 81.2 (C-13),
87.7 (C-11), 99.9 (C-21), 122.9 (C-15), 137.9 (C-14), 206.6 (C-19).
[2R(2E,4S,5S),6S,8R,9S,10S]-2-[3,5-Dimethyl-4-(triisopropyl-
silyl)oxy-hept-2-en-6-ynyl]-8-isopropyl-9-methyl-4-(triethyl-
silyl)oxy-1,7-dioxaspiro[5.5]undecan-4-one [(21S)-25]
[a]D20 –13.4 (c 1.9, CHCl3).
1H NMR (400 MHz): d = 0.62 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.80 (d, J = 6.9 Hz, 3 H, CH3C-24), 0.86, 0.88 [2 × d, J = 6.7 Hz,
6 H, (CH3)2C-26], 0.98 [t, J = 7.5 Hz, 9 H, (CH3CH2)3Si], 1.06 [br
m, 24 H, (iPr)3Si and CH3C-12], 1.60 (m, 1 H, H-24), 1.62 (s, 3 H,
CH3C-14), 1.75 (dd, J = 13.8, 3.1 Hz, 1 H, Ha-22), 1.78 (m, 1 H, H-
26), 1.90 (dd, J = 13.8, 3.3 Hz, 1 H, Hb-22), 2.00 (d, J = 2.4 Hz,
1 H, H-10), 2.40, 2.58 (br m, 4 H, H2-16 and H2-18), 2.59 (d,
J = 16.4 Hz, 1 H, Ha-20), 2.60 (m, 1 H, H-12), 3.38 (d, J = 16.4 Hz,
1 H, Hb-20), 3.39 (dd, J = 10.0, 2.5 Hz, 1 H, H-25), 3.99 (q, J = 3.0
Hz, 1 H, H-23), 4.12 (d, J = 7.3 Hz, 1 H, H-13), 4.15 (m, 1 H, H-
17), 5.46 (br t, J = 6.0 Hz, 1 H, H-15).
13C NMR: d = 4.8 [(CH3CH2)3Si], 7.0 [(CH3CH2)3Si], 12.1 (CH3C-
14), 12.5 {[(CH3)2CH]3Si}, 13.4 (CH3C-24), 14.2, 20.4 [(CH3)2C-
26], 17.1 (CH3C-12), 18.1 {[(CH3)2CH]3Si}, 28.0 (C-26), 32.0 (C-
12), 34.8, 44.1 (C-18 and C-16), 36.2 (C-24), 42.9 (C-22), 47.2 (C-
20), 69.4 (C-10), 70.4 (C-23), 71.0 (C-17), 76.5 (C-25), 81.3 (C-13),
87.6 (C-11), 99.6 (C-21), 123.0 (C-15), 137.9 (C-14), 207.2 (C-19).
MS (CI, NH3): m/z = 649 [MH+], 595, 517, 475, 319, 223.
(17S,21R)-Spiroketal
Yield: 56 mg (9%).
1H NMR (400 MHz): d = 0.61 [q, J = 7.5 Hz, 6 H, (CH3CH2)3Si],
0.80 (d, J = 6.8 Hz, 3 H, CH3C-26), 0.83 (d, J = 6.8 Hz, 3 H, CH3C-
24), 0.98 (d, J = 6.8 Hz, 6 H, CH3C-26), 0.99 [t, J = 7.5 Hz, 9 H,
(CH3CH2)3Si], 1.06 [br m, 24 H, (iPr)3Si, CH3C-12], 1.53 (dd,
J = 13.9, 3.3 Hz, 1 H, Ha-22), 1.60 (m, 1 H, H-24), 1.63 (s, 3 H,
CH3-14), 1.78 (sept d, J = 6.8, 2.0 Hz, 1 H, H-26), 1.99 (dd,
J = 13.9, 4.6 Hz, 1 H, Hb-22), 2.03 (d, J = 2.0 Hz, 1 H, H-10), 2.25–
2.45 (m, 2 H, H2-16), 2.45–2.65 (m, 4 H, H2-18, H2-20), 2.65 (m,
1 H, H-12), 3.85 (m, 2 H, H-23 and H-25), 4.02 (m, 1 H, H-17), 4.12
(d, J = 7.3 Hz, 1 H, H-13), 5.39 (m, 1 H, H-15).
Synthesis 2009, No. 20, 3477–3487 © Thieme Stuttgart · New York

3486
V. Henryon, J.-P. Férézou
PAPER
13C NMR: d = 4.9 [(CH3CH2)3Si], 6.9 [(CH3CH2)3Si], 12.1 (CH3C-
14), 12.5 {[(CH3)2CH]3Si}, 13.2 (CH3C-24), 14.5, 20.6 [(CH3)2C-
26], 17.0 (CH3C-12), 18.1 {[(CH3)2CH]3Si}, 26.6 (C-26), 32.1 (C-
12), 34.9, 51.0 (C-18 and C-20), 36.5 (C-24), 40.8 (C-22), 44.0 (C-
16), 68.7 (C-23), 69.5 (C-10), 70.7 (C-17), 73.8 (C-25), 81.2 (C-13),
87.6 (C-11), 98.5 (C-21), 122.6 (C-15), 138.2 (C-14), 207.4 (C-19).
N. F., Ed.; The Royal Society of Chemistry, Special Edition:
London, 1985, 53. (b) Davies, H. G.; Green, R. H. Nat.
Prod. Rep. 1986, 3, 87. (c) Crimmins, M. T.; Hollis, W. G.
Jr.; O’Mahony, R. In Studies in Natural Products
Chemistry: Stereoselective Synthesis, Vol. 1; Atta-Ur-
Rahman, ., Ed.; Elsevier: Amsterdam, 1988, Part A, 435.
(d) Blizzard, T.; Fisher, M. H.; Mrozik, H.; Shih, T. L. In
Recent Progress in the Chemical Synthesis of Antibiotics;
Lukacs, G.; Ohno, M., Eds.; Springer-Verlag: New York,
1990, 65. (e) Davies, G. R.; Green, H. Chem. Soc. Rev. 1991,
20, 211. (f) Davies, G. R.; Green, H. Chem. Soc. Rev. 1991,
20, 271. (g) Blizzard, T. A. Org. Prep. Proceed. Int. 1994,
26, 617.
MS (CI, NH3): m/z = 666 [MH+ + 17], 649 [MH+], 517, 319, 304,
223, 172.
Correlation-Equilibration of the C-21 Spiro-Center: Prepara-
tion of a 23-Deoxy Derivative of (21S)-25
To a solution of pure (21S)-25 (45 mg, 0.07 mmol) in CH2Cl2 (2
mL), was added at 0 °C, HF–pyridine (~7:3, commercial) diluted in
THF (1:6, v/v). This solution was added portion-wise over 24 h (0.1
mL each portion) until total consumption of starting material was
observed. The reaction mixture was quenched with sat. aq NaHCO3
and extracted as usual to give, after silica MPLC purification
(Lichroprep Merck Art. 9336; Et2O–PE, 20:80→75:25), the corre-
sponding 23-O-desilylated adduct (35 mg, 95% yield). To this
material (30 mg, 0.056 mmol) in THF (2 mL) was added an excess
of 1,1¢-thiocarbonyldiimidazole (50 mg, 0.28 mmol, 5 equiv). The
reaction mixture was refluxed for 24 h. After cooling to r.t., usual
work-up followed by purification of the residue by flash chromatog-
raphy (Et2O–pentane, 0:1→2:3) gave the corresponding 23-thio-
imidazolide (19 mg, 53% yield). To the latter thioxanthate (18 mg,
0.025 mmol) dissolved in toluene (2 mL), were added Bu3SnH
(0.032 mL, 0.1 mmol, 4 equiv) and a trace of AIBN. The resulting
solution was refluxed for 2 h. After evaporation of the solvent, the
residue was purified by flash chromatography (Et2O–pentane,
0:1→3:2) to give the derivative (21S)-23 as the only observable
product.
(2) Omura, S. Int. J. Antimicrob. Agents 2008, 31, 91; and
references therein.
(3) Rouge dos Santos, A.; Falcão, C. A. B.; Muzitano, M. F.;
Kaiser, C. R.; Rossi-Bergmann, B.; Férézou, J.-P. Bioorg.
Med. Chem. 2009, 17, 496.
(4) For reports on avermectin B1a, see: (a) Hanessian, S.;
Ugolini, A.; Dubé, D.; Hodges, P. J.; André, C. J. Am. Chem.
Soc. 1986, 108, 2776. (b) Hanessian, S.; Ugolini, A.;
Hodges, P. J.; Beaulieu, P.; Dubé, D.; André, C. Pure Appl.
Chem. 1987, 59, 299. (c) Armstrong, A.; Ley, S. V. Synlett
1990, 323. (d) Diez-Martin, D.; Grice, P.; Kolb, H. C.; Ley,
S. V.; Madin, A. Synlett 1990, 326. (e) Armstrong, A.; Ley,
S. V.; Madin, A.; Mukherjee, S. Synlett 1990, 328. (f) Ley,
S. V.; Armstrong, A.; Diez-Martin, D.; Ford, M. J.; Grice, P.;
Knight, J. G.; Kolb, H. C.; Madin, A.; Marby, C. A.;
Mukherjee, S.; Shaw, A. N.; Slawin, A. M. Z.; Vile, S.;
White, A. D.; Williams, D. J.; Woods, M. J. Chem. Soc.,
Perkin Trans. 1 1991, 667. (g) White, J. D.; Bolton, G. L. J.
Am. Chem. Soc. 1990, 112, 1626. (h) For reports on
avermectin A1a, see: White, J. D.; Bolton, G. L.;
Dantanarayana, A. P.; Fox, C. M. J.; Hiner, R. N.; Jackson,
R. W.; Sakuma, K.; Warrier, U. S. J. Am. Chem. Soc. 1995,
117, 1908. (i) Danishefsky, S. J.; Armistead, D. M.;
Wincott, F. E.; Selnick, H. G.; Hungate, R. J. Am. Chem.
Soc. 1987, 109, 8117. (j) Danishefsky, S. J.; Armistead, D.
M.; Wincott, F. E.; Selnick, H. G.; Hungate, R. J. Am. Chem.
Soc. 1989, 111, 2967.
(5) Férézou, J.-P.; Julia, M.; Li, Y.; Liu, L. W.; Pancrazi, A.
Bull. Soc. Chim. Fr. 1995, 132, 428; and references therein.
(6) As a recent example, see: Kolar, L.; Erzen, N.; Logerwerf, ;
Van Gestel, C. A. M. Environ. Pollut. 2008, 151, 182.
(7) Kaplan, R. M. Trends Parasitol. 2004, 20, 477.
(8) (a) Prichard, R. Veterinary Parasitol. 2005, 133, 243.
(b) Prichard, R. Expert Opin. Drug Discovery 2007, 2, S41.
(9) Pitterna, T.; Cassayre, J.; Hüter, O. F.; Jung, P. M. J.;
Maienfisch, P.; Murphy Kessabi, F.; Quaranta, L.; Tobler,
H. Bioorg. Med. Chem. 2009, 17, 4085.
Yield: 8 mg (55%).
1H NMR (400 MHz): d = 0.81, 0.88 [2 × d, J = 7.0 Hz, 3 H + 6 H,
CH3C-24 and (CH3)2C-26], 1.06 [br m, 24 H, (iPr)3Si, CH3C-12],
1.20–1.80 (m, 5 H, H2-22, H2-23 and H-24), 1.63 (s, 3 H, CH3C-14),
1.80 (sept d, J = 7.0, 2.0 Hz, 1 H, H-26), 2.03 (d, J = 2.4 Hz, 1 H,
H-10), 2.30–2.65 (m, 4 H, H2-16 and H2-18), 2.56 (d, J = 15.8 Hz,
1 H, Ha-20), 2.60 (m, 1 H, H-12), 2.95 (dd, J = 9.7, 2.0 Hz, 1 H, H-
25), 2.98 (d, J = 15.9 Hz, 1 H, Hb-20), 4.13 (d, J = 7.2 Hz, 1 H, H-
13), 4.17 (m, 1 H, H-17), 5.46 (br t, J = 7.0 Hz, 1 H, H-15).
MS (CI, NH3): m/z = 536 [MH+ + 17], 519 [MH+], 475, 465, 345,
336, 327, 319.
Equilibration of (21S)-23 with HCl
To a solution of the preceding (17R,21S)-spiroketal (21S)-23 (5 mg)
in CDCl3 (0.5 mL) was added a trace of HCl gas. After 12 h, the 1H
NMR spectrum was directly recorded and showed that the starting
1
material was totally converted into a new product. The H NMR
data of this material, compared with those obtained for (21R)-23, re-
sulting from the cyclization of 22 under the same conditions, were
completely identical and in full agreement with the data previously
obtained for the same intermediate during the synthesis of the agly-
cone of 22,23-dihydroavermectin b1b (1).
(10) Didier, A.; Loor, F. Anticancer Drugs 1996, 745.
(11) (a) Korystov, Y.; Ermakova, N.; Kublik, L.; Levitman, M.;
Shaposhnikova, V.; Mosin, V.; Drinyaev, V.; Kruglyak, E.;
Novik, T.; Sterlina, T. Eur. J. Pharmacol. 2004, 493, 57.
(b) Drinyaev, V. A.; Mosin, V. A.; Kruglyak, E. B.; Novik,
T. S.; Sterlina, T. S.; Ermakova, N. V.; Kublik, L. N.;
Levitman, M. Kh.; Shaposhnikova, V. V.; Korystov, Y. N.
Eur. J. Pharmacol. 2004, 501, 19.
Acknowledgment
We are particularly grateful to Prof. Marc Julia for his continuous
interest as well as fruitful discussions in the area of Avermectin syn-
thesis.
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