Formal synthesis of AB3217-A from anisomycin using a directed benzylic oxidation

Article abstract of DOI:10.1055/s-0030-1259010

A formal synthesis of the insecticidal natural product AB3217-A involving an unusual diastereoselective benzylic oxidation is described.

Full text of DOI:10.1055/s-0030-1259010

LETTER
2721
Formal Synthesis of AB3217-A from Anisomycin Using a Directed Benzylic
Oxidation
F
ormal Sy
u
nthesis of
A
B
l
3217-
i
A
e Toueg,a Christopher R. A. Godfrey,*a Jane E. Wibleyb
a
Syngenta Crop Protection Münchwilen AG, WST-820.1.15, Schaffhauserstrasse, 4332 Stein, Switzerland
E-mail: chris.godfrey@syngenta.com
b
Syngenta Crop Protection Jealott’s Hill International Research Centre, Bracknell, Berkshire, R42 6EY, UK
Received 9 September 2010
starting point, since it is commercially available and con-
tains much of the required functionality of AB3217-A,
with the exception of the benzylic hydroxy group.
Abstract: A formal synthesis of the insecticidal natural product
AB3217-A involving an unusual diastereoselective benzylic oxida-
tion is described.
Key words: natural product, anisomycin, AB3217-A, benzylic ox-
idation, insecticide
OBn
BnO
OH
O
HO
SPh
O
TfO
AB3217-A and its -B and -C congeners (Figure 1) were
isolated in 1992 from the fermentation broth of Strepto-
myces platensis and were shown to have marked activity
against two spotted spider mites as well as some herbicid-
al properties.1 These compounds have a unique structure,
consisting of deacetylanisomycin and b-D-xylofuranose
linked through glycosidic and ether bonds to form a nine-
membered ring containing three oxygen atoms.
2
O
O
+
OH
OTHP
OBn
OH
HN
MeO
AB3217-A
N
MeO
Cbz
1
18 steps
3.7%
OR
HO
Scheme 1 Synthetic plan proposed by Nakata et al.2
OAc
O
O
The key step of our synthesis was the application of the dia-
stereoselective benzylic oxidation developed by Ohfune
et al. (Scheme 2).5 In this reaction, a benzylic cation is
generated, which is then trapped intramolecularly by the
carbonyl group of the carbamate to release the tert-butyl
cation.
O
OH
HN
MeO
OH
HN
MeO
AB3217-A R = H
Anisomycin
AB3217-B R = C(O)(CH2)4C(OH)Me2
AB3217-C R = C(O)(CH2)2CHMe2
Figure 1 Structure of AB3217-A, -B, -C, and anisomycin
MeO
MeO
K2S2O8
CuSO4
To date, only one total synthesis of AB3217-A has been
published by Nakata et al.2 The retrosynthetic approach
adopted by this group is depicted below (Scheme 1). The
anisomycin derivative 1 was connected to the b-D-xylo-
furanose unit 2 via alkylation of the benzylic alcohol
followed by a diastereoselective intramolecular glycosy-
lation.
MeCN–H2O, 70 °C
R
R
R = CO2Me
55 %, dr = 49:1
R = CH2OAc 76%, dr = 37:1
NHBoc
O
NH
R = H
75%
O
Scheme 2 Benzylic oxidation developed by Ohfune et al.5
The synthesis of intermediate 1 proposed by this group,
starting from known (4R,5R)-4,5-bis(hydroxymethyl)-
2,2-dimethyl-1,3-dioxolane (a derivative of L-tartrate),3
comprises 18 steps with an overall yield of 3.7%. As we
were interested in synthesizing gram quantities of com-
pound 1, we decided to embark on an alternative synthe-
sis. We chose to explore the use of anisomycin4 itself as a
Even though this methodology has so far been applied
only to acyclic tyrosine and DOPA derivatives, we envis-
aged that it would be perfectly suited for our substrate
which already has the optimal substituents in place. To
that end, anisomycin was protected as its tert-butyl car-
bamate 3. It was then subjected to the oxidative cyclisa-
tion conditions, and the bicyclic product 4 was formed
in 62–65% yield with a 10:1 diastereoselectivity
(Scheme 3). p-Anisaldehyde formed by overoxidation
was identified as the major byproduct, but shortening the
reaction time did not result in a significant yield increase.
SYNLETT 2010, No. 18, pp 2721–2724
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x
.x
x
.2
0
1
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Advanced online publication: 22.10.2010
DOI: 10.1055/s-0030-1259010; Art ID: D24810ST
© Georg Thieme Verlag Stuttgart · New York

2722
J. Toueg et al.
LETTER
hydroxy groups have an anti relationship.6 Moreover, a
minor byproduct was formed, which appeared to be the
deacylated ‘migrated’ compound 6 (Scheme 4).
OAc
a. Boc2O
NaHCO3
Anisomycin
OH
quant.
N
MeO
Boc
3
OBn
H
PMP
MeO
MeO
+
OAc
O
N
OAc
OAc
57%
b. K2S2O8
CuSO4
OAc
H
H
H
PMP
OH
OH
O
OH
NaH
62–65%
dr = 10:1
5
BnBr, TBAI
O
N
O
N
O
N
+
THF
OBn
O
4a
O
4b
0 °C to r.t., overnight
O
4
H
PMP
OH
Scheme 3 Benzylic oxidation leading to compound 4. Reagents and
conditions: (a) Boc2O (1.1 equiv), NaHCO3 (1.1 equiv), THF–H2O
(1:1), r.t., 3 h 30, quant.; (b) K2S2O8 (2 equiv), CuSO4 (0.2 equiv)
MeCN–H2O (1:1), 70 °C, 3.5 h, 62–65%.
10%
O
N
O
6
Scheme 4 Direct alkylation attempted on compound 4. Reagents
and conditions: BnBr (3 equiv), TBAI (0.1 equiv), NaH (1.1 equiv),
THF, 0 °C to r.t.
NOE experiments indicated that the undesired diastereo-
mer 4a was formed predominantly, and final confirmation
was achieved by X-ray crystallographic analysis of a later
derivative (see below). Following Ohfune’s rationale, the
selectivity of the reaction can be explained by considering
steric factors in the two possible transition states
(Figure 2). In the case of the minor diastereomer 4b, a dis-
favored interaction is apparent between the acetate and the
ortho proton of the aromatic ring, whereas no such inter-
action appears during the formation of the major diastere-
omer 4a. However, the acetate group might stabilise the
cation in both transition states, which could explain the
relatively low level of diastereoselectivity obtained for
substrate 3 compared to the acyclic examples described in
the literature.5
Compound 5 was hydrolyzed to compound 6, which was
purified by crystallization. X-ray crystallography
(Figure 3) confirmed the unexpected regioselectivity of
the alkylation as well as the proposed stereochemistry for
the benzylic position.7
MeO
AcO
OH
+
OAc
H
H
MeO
OH
H
N
H
Figure 3 Crystal structure of compound 6
O
N
O
Ot-Bu
favored
O
OAc
OH
4a
H
H
PMP
PMP
MeO
OH
OH
Ot-Bu
a. K2CO3, MeOH
77%
O
O
N
O
N
OAc
+
N
H
H
MeO
OH
O
O
H
H
4
7
O
N
AcO
dr = 10:1
single diastereomer
OH
disfavored
O
OTHP
b. Bu2SnO, BnBr, Et3N,
TBAI, toluene, reflux
c. DHP, CSA, CH2Cl2
4b
H
PMP
OBn
Figure 2 Possible transition states for the oxidative cyclisation
O
N
25%
O
The decision was taken to proceed with the diastereomeric
mixture and invert the stereochemistry of the benzylic
centre at a later stage, as described by Nakata.2 The next
step was thus to benzylate the free hydroxy residue on the
pyrrolidine ring. This reaction proved surprisingly chal-
lenging, as the acetyl group was observed to migrate prior
to alkylation under basic conditions, even though the two
8
Scheme 5 First synthesis of intermediate 8. Reagents and conditi-
ons: (a) K2CO3 (2 equiv), MeOH, r.t., 24 h, 77%; (b) Bu2SnO (2
equiv), Et3N (1.5 equiv), BnBr (1.1 equiv), TBAI (0.1 equiv), toluene,
reflux, overnight; (c) 3,4-dihydro-2H-pyran (DHP) (2 equiv), CSA
(0.1 equiv), CH2Cl2, r.t., 3 h, 25% over two steps.
Synlett 2010, No. 18, 2721–2724 © Thieme Stuttgart · New York

LETTER
Formal Synthesis of AB3217-A
2723
A number of conditions were then tried to alkylate alcohol In conclusion, we have achieved the synthesis of the ad-
4 without migration, but all attempts were unsuccessful vanced intermediate 1 in 11 steps from anisomycin, with
(see Table 1 in Experimental Section). Benzylation at an an overall yield of 25.4%. This therefore represents a
earlier stage (on the Boc-protected anisomycin) also short and efficient formal total synthesis of the natural
failed.
product AB3217-A.
Table 1 Summary of the Different Attempts To Benzylate Interme-
diate 4 To Obtain Directly Compound 8 under Basic, Acidic, or
Neutral8 Conditions
In an alternative and ultimately successful approach, the
4-acetoxy group of intermediate 4 was hydrolyzed to give
the corresponding diol 7, which could be isolated as a sin-
gle diastereomer in 77% yield. It was envisioned that the
envelope shape of compound 7 would favour the regiose-
lective alkylation of the least hindered hydroxy group. At-
tempts using the usual basic conditions gave mixtures of
mono- and dibenzylated products. However, regioselec-
tive benzylation could be achieved using dibutyltin ester
methodology and subsequent protection of the remaining
alcohol as a tetrahydropyran (THP) ether afforded inter-
mediate 8, albeit in low overall yield (Scheme 5)
OAc
OAc
H
H
PMP
PMP
OH
OBn
O
N
O
N
O
O
4
8
Conditions
Comments
Basic conditions NaH, BnBr, TBAI, THF
migrated product
(57%)
Alternatively it was found that silylation with tert-bu-
tyldimethylsilylchloride in DMF in the presence of imida-
zole and catalytic amounts of DMAP took place
selectively at the least hindered hydroxy group. Subse-
quent formation of the THP ether of the remaining alco-
hol, deprotection, and benzylation afforded the protected
diol 8 (Table 1) in an improved overall yield of 82%
(Scheme 6).
Ag2O, BnBr, TBAI
complex mixture
Acidic conditions Cl3C(NH)OBn, TFA,
CH2Cl2, 0 °C
traces, mostly starting
material
Cl3C(NH)OBn, HBF4,
CH2Cl2, 0 °C
degradation
Cl3C(NH)OBn, BF3·OEt2, complex mixture
CH2Cl2, –20 °C to 0 °C
Opening of the cyclic carbamate was achieved by hydrol-
ysis under basic conditions, and subsequent re-protection
of the pyrrolidine nitrogen as a benzyl carbamate fur-
nished the intermediate alcohol 9. Disappointingly, at-
tempts to shorten the sequence by opening the carbamate
with benzyl alcohol9 to give the corresponding benzyl car-
bamate 9 failed, owing to the instability of the cyclic car-
bamate under the experimental conditions employed.
Cl3C(NH)OBn, TfOH,
CH2Cl2, –20 °C
complex mixture
Neutral
phenyl diazomethane, SnCl2no reaction
conditions8
benzyl triflate, 2,6-di-tert- 3% isolated product
butylpyridine, CH2Cl2,
–78 °C to 0 °C
Final inversion of the benzylic alcohol in compound 9 was
achieved in 65% yield using the oxidation–reduction pro-
tocol described by Nakata et al.2
AgOTf, BnBr, 2,6-di-tert- degradation
butylpyridine (solvent), r.t.
MeO
OH
d. TBSCl, Im, DMAP, DMF
e. DHP, CSA, CH2Cl2
f. TBAF, THF
OAc
OAc
H
H
PMP
a. Boc2O, NaHCO3
b. K2S2O8, CuSO4
c. K2CO3
MeOH
OH
OH
g. BnBr, NaH, TBAI, THF
OH
O
N
O
N
HN
62–65%
dr = 10:1
77%
82% over 4 steps
MeO
PMP
single diastereomer
O
O
Anisomycin
OTHP
4
7
OH
OH
OTHP
OTHP
OBn
H
h. NaOH aq, EtOH
i. CbzCl, NaHCO3, dioxane
j. DMSO, (COCl)2, Et3N
k. DIBAL-H, toluene
OBn
OBn
O
N
quantitative over
2 steps
65%
N
N
MeO
MeO
Cbz
Cbz
O
8
9
1
11 steps
25.4%
Scheme 6 Synthesis of 1 from anisomycin. Reagents and conditions: (a) Boc2O (1.1 equiv), NaHCO3 (1.1 equiv), THF–H2O (1:1), r.t., 3.5 h,
quant.; (b) K2S2O8 (2 equiv), CuSO4 (0.2 equiv), MeCN–H2O (1:1), 70 °C, 3.5 h, 62–65%; (c) K2CO3 (2 equiv), MeOH, r.t., 24 h, 77%; (d)
TBSCl (1.1 equiv), DMAP (0.3 equiv), imidazole (2 equiv), DMF, r.t., 24 h, 86%; (e) 4-dihydro-2H-pyran (DHP) (2 equiv), CSA (0.1 equiv),
CH2Cl2, r.t., 3 h, 86%; (f) TBAF (2 equiv), THF, r.t., 3 h, 95%; (g) BnBr (2 equiv), TBAI (0.1 equiv), NaH (1 equiv), THF, r.t., 2 h, quant.; (h)
8 M aq NaOH (8 equiv), EtOH, reflux, 2 h; (i) benzyl chloroformate (1.1 equiv), 1 M aq NaHCO3 (4 equiv), dioxane, r.t., quant. over 2 steps;
(j) (COCl)2 (2 equiv), DMSO (4 equiv), Et3N (6 equiv), CH2Cl2, –78 °C to 0 °C, quant.; (k) DIBAL-H (2 equiv), toluene, –78 °C, 45 min, 65%.
Synlett 2010, No. 18, 2721–2724 © Thieme Stuttgart · New York

2724
J. Toueg et al.
LETTER
(5) (a) Shimamoto, K.; Ohfune, Y. Tetrahedron Lett. 1988, 29,
5177. (b) For a recent example see: Bulman Page, P. C.;
Buckley, B. R.; Rassias, G. A.; Blacker, A. J. Eur. J. Org.
Chem. 2006, 803.
(6) For precedents for trans intramolecular acetyl migration,
see: (a) Deng, S.; Chang, C.-W. T. Synlett 2006, 756.
(b) Markad, S. D.; Schmidt, R. R. Eur. J. Org. Chem. 2009,
5002.
Acknowledgment
The authors thank Dr. R. Beaudegnies, Dr. A. De Mesmaeker and
Prof. S. V. Ley for helpful discussions. J.T. is also grateful to Syn-
genta Crop Protection for funding.
References and Notes
(7) The hypothesis that the migration of the acetate proceeds via
formation of an epoxide was ruled out. If an epoxide was
formed and re-opened by the acetate, the stereochemistry of
the two hydroxy groups on the pyrrolidine moiety would be
inverted, which is not the case as can be observed on the
crystal structure of 6 (Figure 3).
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Synlett 2010, No. 18, 2721–2724 © Thieme Stuttgart · New York

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