Synthetic routes towards cryptophycin unit A diastereomers

Article abstract of DOI:10.1055/s-2007-1000868

Unit A of cryptophycin 1 is a δ-hydroxy acid with four stereogenic centres. Our unit A synthesis introduces the first two stereogenic centres by a catalytic, asymmetric dihydroxylation, whereas the remaining two stereogenic centres are established by dias

Full text of DOI:10.1055/s-2007-1000868

LETTER
273
Synthetic Routes towards Cryptophycin Unit A Diastereomers
Synthetic Rou
t
e
ards
C
rypto
f
phycin U
a
nit A Dias
n
tereomers Eißler,a Beate Neumann,b Hans-Georg Stammler,b Norbert Sewald*a
a
Department of Organic and Bioorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
Fax +49 (521) 106 8094; E-mail: norbert.sewald@uni-bielefeld.de
Department of Inorganic Chemistry, Bielefeld University, Universitätsstraße 25, 33615 Bielefeld, Germany
b
Received 29 August 2007
unit A
O
O
Abstract: Unit A of cryptophycin 1 is a d-hydroxy acid with four
stereogenic centres. Our unit A synthesis introduces the first two
stereogenic centres by a catalytic, asymmetric dihydroxylation,
whereas the remaining two stereogenic centres are established by
diastereoselective reactions. In this letter, we focus on the diaste-
reoselectivity of these reactions and discuss the accessibility of
cryptophycin unit A diastereomers.
O
unit B
O
O
HN
Cl
O
N
H
O
OMe
unit D
unit C
Key words: diastereoselectivity, addition reactions, oxidations,
cuprates, natural products
Figure 1 Structure of cryptophycin 1 (1)
respective hydroxy and amino acid building blocks, i.e.
units A–D (Figure 1). The synthesis of unit A with four
stereogenic centres stands in the focus of many publica-
tions on cryptophycin syntheses. In all syntheses of cryp-
tophycin unit-A precursors with four stereogenic centres,
the configuration of the future epoxide is established by
means of a syn-diol, which later in the synthesis is trans-
formed into the epoxide functionality by a three-step reac-
tion sequence with net retention of configuration.3
The cryptophycins are a family of sixteen-membered
macrocyclic depsipeptides isolated from blue-green algae
of the genus Nostoc.1 Cryptophycin 1 (1) as well as a num-
ber of related analogues attracted attention due to their po-
tent antitumour activity which surpasses the activity of
agents such as vinblastine and paclitaxel by up to three or-
ders of magnitude. Furthermore, biological activity is of-
ten maintained for multidrug-resistant tumour cell lines.2
Retrosynthetically, cryptophycins can be divided into the
We recently published a thirteen-step3e and a seven-step3f
1. AD
O
O
O
2. (MeO)2CMe2,
acetone, PTSA,
r.t.; separation
OEt
62%
OEt
O
2
3
O
O
1. LDA, TMSCl, THF, –78 °C
2. Pb(OAc)4, CH2Cl2, –78 °C
3. EtOH, NaOEt, r.t.; separation
hexane–Et2O, MeLi,
TMSCl, –78 °C to r.t.
OEt
72%
59%
O
4a
unit A precursor
O
O
O
O
7 steps
59%
OH
OH
O
OEt
O
6
5a
Ot-Bu
Scheme 1 Synthesis of cryptophycin unit A precursor 63e
unit A synthesis (Scheme 1). The former starts with di-
enoate 2, which is transformed by an asymmetric dihy-
droxylation into a mixture of the regioisomeric diols,
SYNLETT 2008, No. 2, pp 0273–0277
Advanced online publication: 26.12.2007
DOI: 10.1055/s-2007-1000868; Art ID: G27607ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

274
S. Eißler et al.
LETTER
Table 1 Reaction Conditions Leading to Diastereomeric Intermediates of the Cryptophycin Unit A Synthesis
Entry Conditions
R
–
Products
Ratio a/ba
Yield (%)
69b
A
B
1
2
3
4
5
hexane–Et2O (4:1), MeLi, TMSCl, –90 °C to –80 °C4
4a
4a
4a
4a
5a
4b
4b
4b
4b
5b
99
14
3
1
Me2CuLi, TMSCl, Et2O, –78 °C4
–
86
97
96
8
72b
Me2CuLi·LiCN, BF3·OEt2, Et2O, –50 °C
MeCu·LiI, BF3·OEt2, toluene–Et2O, –78 °C
–
(44)c,e
52b
–
4
1. LDA, TMSCl, THF, –78 °C to r.t.
2. CH2Cl2, Pb(OAc)4, –78 °C to r.t.
3. LiOH3e
H
92
59b
6
1. LDA, THF
H
5a
5b
18
82
59b
2. MoOPH, –78 °C to r.t.
7
8
NaHMDS, THF, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine, –78 °C
H
5a
7a
5b
7b
28
50
72
50
(99)b,d
80b
C
1. LDA, TMSCl, THF
Ac
2. CH2Cl2, Pb(OAc)4, –78 °C to r.t.
9
LDA, THF, MoOPH, –78 °C to r.t.
H
H
H
H
H
7a
7a
7a
7a
7a
7b
7b
7b
7b
7b
33
3
67
97
89
94
93
71b
after crystallisation from n-hexane
41b
10
NaHMDS, THF, 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine, –78 °C
after crystallisation from n-hexane
11
6
(82)b,d
(50)b,d
(31)b,d,e
11
12
13
1. NaHMDS, THF, –78 °C
2. (+)-camphorsulfonyloxaziridine, –78 °C
7
1. NaHMDS, THF, –78 °C
2. (–)-camphorsulfonyloxaziridine, –78 °C
H
7a
8a
7b
8b
7
93
22
31b,e
62b
D
E
1. H2, Pd/C
Ac
78
2. LDA, TMSCl, THF, –78 °C to r.t.
3. CH2Cl2, Pb(OAc)4, –78 °C to r.t.
14
15
1. NaHMDS, THF, –78 °C
2. MoOPH, –78 °C to r.t.
8a
9a
8b
9b
45
78
55
22
41b,e
93b
TFA, H2O, MeCN, r.t.
–
a Determined by 1H NMR spectroscopy.
b Isolated yield of diastereomeric mixture.
c Conversion (FID-GC).
d Impurities.
e Incomplete conversion.
which after protection as the acetonides is separated by tively give the 3R-configured compound 4b5 (entries 2–
chromatography, and pure regioisomer 3 is obtained. 4). Within the methyl cuprate series, a severe separation
Conjugate addition of methyllithium gives diastereomer problem results from either moderate diastereoselectivity
4a selectively. The a-hydroxy group is introduced in a (entry 2) or incomplete turnover (entry 3). After changing
6
three-step reaction sequence. The trimethylsilylketene ac- to organocopper reagent MeCu·LiI, BF3·OEt2 (entry 4),
etal of 4a is treated with lead(IV)acetate providing the and toluene as solvent, we achieved complete conversion
corresponding a-acetoxy compound. Then the newly and excellent diastereoselectivity at –78 °C.
formed acetate is saponified yielding a-hydroxy acid 5a,
While addition of methyllithium (Table 1, entry 1) takes
place under nonpolar reaction conditions favouring che-
late control of reagent approach, there is usually no such
which is further converted into unit A precursor 6 in seven
steps.
We already described the selectivity of the conjugate ad- influence on diastereoselectivity for cuprate reagents.7
dition to 34 and took this as the starting point for some Nevertheless, there is no comprehensive explanation for
methodological studies. The results are summarised in the observed diastereoselectivities. The adaptation of the
Table 1. While the 1,4-addition of methyllithium to 3 se- Felkin–Anh model8 to a,b-unsaturated esters predicts the
lectively gives the 3S-configured diastereomer 4a wrong configuration for either nucleophile (Figure 2, A).
(Table 1, entry 1), various methylcopper reagents selec- The Yamamoto model7a correctly predicts the configura-
Synlett 2008, No. 2, 273–277 © Thieme Stuttgart · New York

LETTER
Synthetic Routes towards Cryptophycin Unit A Diastereomers
275
O
O
O
O
see Table 1, A
OEt
OEt
O
O
4a
4b
O
O
see Table 1, B
see Table 1, C
OEt
O
3
O
O
O
O
O
O
O
O
OR
OR
OR
OR
OEt
OEt
OEt
OEt
O
O
O
O
5a
5b
7a
7b
crystal structure determined
see Table 1, D
O
O
OH
OH
O
O
O
O
OR
OR
9b
see Table 1, E
+
OEt
OEt
O
O
8a
8b
O
O
OH
OH
9a
crystal structure determined
Scheme 2 Diastereoselective transformations of 3 leading to 5a/5b, 7a/7b and 8a/8b, respectively (for reaction conditions, see Table 1)
tion for the methyl cuprate addition, but cannot explain The basis for diastereoselectivity is the same in both cas-
the different stereochemical outcome of the methyllithi- es. The initial attack from the least hindered side leads to
um addition (Figure 2, B). A modified Felkin–Anh the final product 5b in case of MoOPH (entry 6) or oxazir-
model8 with the smallest substituent pointing towards the idine oxidation (entry 7). With lead(IV) acetate (entry 5),
same direction as the a,b-unsaturated ester would predict a cyclic plumbonium ion intermediate is initially formed
the correct stereochemistry for both the methyllithium and by addition of Pb(OAc)3+ to the silylketene acetal double
the methyl cuprate addition, but requires the nucleophile bond from the least-hindered side,10 and opened by the
to tolerate steric hindrance along the trajectory (Figure 2, rear attack of an acetate ion at the a-carbon atom leading
C). In our opinion, the Yamamoto model gives the best to the oppositely configured a-acetoxy compound, which
description for organocopper reagents. As to the methyl- after saponification leads to the corresponding a-hydroxy
lithium addition, we believe that the modified Felkin–Anh derivative. Oxidation with racemic 3-phenyl-2-(phenyl-
model gives the best rationale because the chelation-con- sulfonyl)-1,2-oxaziridine occurs in good yield and with a
trolled approach would put the steric hindrance along the slightly lower diastereoselectivity than MoOPH oxidation
trajectory into perspective.
(entry 7). A disadvantage using oxaziridines is the occur-
rence of side products, which are not always readily re-
moved by chromatography.
The stereoselective introduction of the a-hydroxyl group
by electrophilic acetoxylation or hydroxylation is
straightforward in case of diastereomer 4a and effectively In the case of diastereomer 4b, oxidation with MoOPH
gives either diastereomer 5a or 5b (Table 1, entries 5–7).3e predominantly gives syn-configured isomer 7b with only
low selectivity (entry 9), whereas oxidation of the
Synlett 2008, No. 2, 273–277 © Thieme Stuttgart · New York

276
S. Eißler et al.
LETTER
(A) adapted Felkin–Anh model
chelation
(B) Yamamoto model
non-chelation
emphasises the importance of the neighbouring methyl
substituent, which is the main though not the only influ-
ence, as indicated by the higher selectivity for the MoOPH
oxidation with 4a and the oxaziridine oxidation with 4b
(Table 1, entry 6, 10). For the oxidation with lead(IV) ac-
etate, there seems to be an additional, decisive influence
of the neighbouring dioxolane moiety, because 4a reacts
with high diastereoselectivity whereas 4b reacts without
any diastereoselectivity at all.
O
O
O
O
O
H
O
EtO
EtO
H
H
H
non-chelation
(C) modified Felkin–Anh model
The actual influence of the neighbouring methyl substitu-
ent on the electrophilic acetoxylation and hydroxylation
was examined for the corresponding demethyl com-
pounds. A moderate 3.5:1 selectivity in favour of the S-
configured diastereomer 8a is obtained for the
lead(IV)acetate oxidation of the corresponding silyl
ketene acetal (Table 1, entry 13). Instead, 4a gives the R-
configured diastereomer 5a with a higher diastereoselec-
tivity of 9:1 whereas 4b gives no diastereoselectivity at
all. The oxidation with MoOPH gives the R-configured
diastereomer 8b with low diastereoselectivity (1.2:1;
Table 1, entry 14) Under these conditions 4a gives the S-
configured compound 5b with a moderate diastereoselec-
tivity of 4:1 whereas 4b gives the R-configured compound
7b with a moderate diastereoselectivity of 2:1. Conse-
quently, for the lead(IV) acetate oxidation the presence of
a b-methyl group with S-configuration at the adjacent car-
bon leads to both an increase and reversion of diastereose-
lectivity, whereas a corresponding methyl group with R-
configuration at the adjacent carbon leads to a complete
loss of diastereoselectivity. With MoOPH, there is hardly
any diastereoselectivity in the absence of a neighbouring
methyl group, whereas in its presence diastereoselectivity
improves.
direction of approach
non-chelation
3R-isomer
from top
O
H
H
from bottom
3S-isomer
O
EtO
(D)
O
O
chelation
(E)
O
O
O
Ph
Ph
OR
RO
EtO
H
H
Me
H
H
Me
OEt
4a
4b
R = SiR'3, Na+, Li+, etc.
leads to α-S
oxidising agent
leads to α-R
oxidising agent
Figure 2 Models for the observed diastereoselectivities of the con-
jugate addition and the oxidation with MoOPH, oxaziridine-derived
reagents, and lead(IV) acetate. A fourth model for the conjugate addi-
tion has been suggested by Leonard et al.9 and is similar to B while
none of the residues is in exact anti-alignment to the enoate double
bond, but the alkoxy group is parallel to the enoate double bond.
In summary, the diastereomers 5a/b and 7b13 were ob-
tained in synthetically useful amounts and purity. The rel-
ative configuration of 5a/b had already been proven,4
while the relative configuration of 7b was confirmed by
crystal structure analysis.14 The relative configuration of
8a/8b was proven by crystal structure analysis of 9a,14
which was obtained epimerisation-free from the main dia-
stereomer of a 3.5:1 mixture of 8a/8b (Table 1, entry 15,
diastereomers virtual inseparable). A direct access to pure
diastereomer 7a does not exist since the lead(IV) acetate
oxidation failed to be diastereoselective in case of 4b.
Both enantiomers of 3 are accessible depending on the
ligand of the asymmetric dihydroxylation, and so are the
enantiomers of 5a/b and 7b.
trimethylsilylketene acetal with lead(IV) acetate is not dia-
stereoselective at all (entry 8). A good syn/anti selectivity
of 9:1 is observed for oxidation with racemic 3-phenyl-2-
(phenylsulfonyl)-1,2-oxaziridine (entry 10), i.e. here the
oxaziridine oxidation is much more diastereoselective
than the oxidation with MoOPH. Interestingly, both chiral
oxidising agents (+)-camphorsulfonyloxaziridine (entry
11) and (–)-camphorsulfonyloxaziridine (entry 12) give
7b with the same excellent diastereoselectivity albeit in
low yield at –78 °C. These results indicate that the bulki-
ness of the reagent significantly hampers the reaction at
low temperatures, and that there is no matched/mis-
matched-pair relationship of the respective transition
states under these reaction conditions.
The oxaziridine-derived reagents and MoOPH give the
syn-configured compound in various degrees of selectivi-
ty. Similar selectivity has been observed by Hanessian et
al. in the synthesis of polypropionate building blocks of
rifamycin S with racemic 3-phenyl-2-(phenylsulfonyl)-
1,2-oxaziridine,11 and Morizawa et al. in the hydroxyla-
tion of b-trifluoromethyl ester enolates with MoOPH.12
The respective transition-state model (Figure 2, D and E)
References and Notes
(1) (a) Schwartz, R. E.; Hirsch, C. F.; Sesin, D. F.; Flor, J. E.;
Chartrain, M.; Fromtling, R. E.; Harris, G. H.; Salvatore, M.
J.; Liesch, J. M.; Yudin, K. J. Ind. Microbiol. 1990, 5, 113.
(b) Trimurtulu, G.; Ohtani, I.; Patterson, G. M. L.; Moore, R.
E.; Corbett, T. H.; Demchik, F. A. J. Am. Chem. Soc. 1994,
116, 4729. (c) Golakoti, T.; Ogino, J.; Heltzel, C. E.;
Husebo, T. L.; Jensen, C. M.; Larsen, L. K.; Patterson, G. M.
Synlett 2008, No. 2, 273–277 © Thieme Stuttgart · New York

LETTER
Synthetic Routes towards Cryptophycin Unit A Diastereomers
277
L.; Moore, R. E.; Mooberry, S. L.; Corbett, T. H.; Valeriote,
(8) (a) Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952,
74, 5828. (b) Cram, D. J.; Wilson, D. R. J. Am. Chem. Soc.
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1994, 35, 7969. For reviews, see: (f) Eißler, S.; Stončius,
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(g) Eggen, M.; Georg, G. I. Med. Res. Rev. 2002, 22, 85.
(h) Tius, M. A. Tetrahedron 2002, 58, 4343.
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J. H.; Wagner, M. M.; Williams, D. C. Mol. Cancer Ther.
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Eißler, S.; Stončius, A.; Stammler, H.-G.; Neumann, B.;
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Nahrwold, M.; Neumann, B.; Stammler, H.-G.; Sewald, N.
Org. Lett. 2007, 9, 817.
(13) Synthesis of 7b: NaHMDS (2 M, 0.68 mmol, 0.34 mL) in
THF (2.14 mL) was cooled to –78 °C, then a solution of (R)-
ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-
yl]butanoate (4b, 0.68 mmol, 0.200 g) in anhyd THF
(1.6 mL) was added over 15 min and the mixture was stirred
at –78 °C over 75 min. Then, racemic 3-phenyl-2-(phenyl-
sulfonyl)-1,2-oxaziridine (0.95 mmol, 0.248 g,) in anhyd
THF (1.6 mL) was added over 15 min and the mixture stirred
at –78 °C until the reaction was complete (approx. 1 h).
Then, sat. NH4Cl solution (1.5 mL) was added over 15 min
at –78 °C and the mixture allowed to reach r.t. Afterwards,
Et2O (50 mL) and H2O (10 mL) were added, the layers
separated and the aqueous layer extracted three times with
Et2O (50 mL). The combined organic layers were washed
twice with H2O (25 mL) and sat. NaCl solution (25 mL),
dried over Na2SO4, and the solvent was evaporated under
vacuum. The residue was purified twice by chromatography
(silica gel 60, hexane–EtOAc, 4:1) to obtain reasonably pure
(2R,3R)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-di-
oxolan-4-yl]-2-hydroxybutanoate (7b, 0.56 mmol, 0.173 g,
82% yield, 77% de). Crystallisation from n-hexane gives a
diastereomerically enriched material (0.104 g, 0.34 mmol,
50%, 88% de); [a]D22 –4.44 (c 1.1, MeOH). 1H NMR (500
MHz, CDCl3): d = 7.25–7.45 (m, 5 H), 4.73 (d, J = 8.1 Hz, 1
H), 4.61 (dd, J = 5.0, 2.2 Hz, 1 H), 4.27 (m, 2 H), 4.02 (dd,
J = 8.4, 8.4 Hz, 1 H), 2.94 (d, J = 5.0 Hz, 1 H), 2.24 (qdd,
J = 8.7, 6.9, 1.9 Hz, 1 H), 1.56 (s, 3 H), 1.51 (s, 3 H), 1.31 (t,
J = 7.1 Hz, 3 H), 0.59 (d, J = 7.1 Hz, 3 H). 13C NMR (126
MHz, CDCl3): d = 174,5, 138.3, 128.6, 128.5, 127.9, 109.0,
83.5, 83.2, 71.2, 61.7, 40.2, 27.4, 27.3, 14.3, 10.2. IR (neat):
3437, 3065, 3029, 2983, 2933, 2902, 1729, 1496, 1456,
1383, 1306, 1248, 1225, 1173, 1156, 1132, 1096, 1053,
1034, 924, 880, 814, 754, 697. ESI-MS: m/z calcd for
C17H24O5Na+: 331.15 [M + Na]+; found: 331.0; m/z calcd for
C34H48O10Na+ 639.31 [2 M + Na]+; found: 638.7.
(4) Stončius, A.; Mast, C. A.; Sewald, N. Tetrahedron:
Asymmetry 2000, 11, 3849.
(5) Synthesis of 4b
Copper(I) iodide (25.34 mmol, 4.826 g) was dried for 2 h in
high vacuum at 100 °C, deoxygenated three times with
argon and suspended in anhyd toluene (52 mL). The mixture
was cooled to –78 °C, then MeLi (1.4 M) in Et2O (18.1 mL)
was added over 20 min. While the reaction mixture was
warmed to –40 °C for 15 min, the suspension turned bright
yellow. The mixture was cooled to –78 °C again and
BF3·OEt2 (25.2 mmol, 3.58 g, 3.10 mL) was added dropwise
and the mixture was stirred for 15 min at –78 °C. Then a
solution of (E)-ethyl 3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-
dioxolan-4-yl]acrylate (3, 7.24 mmol, 2.000 g) in anhyd
toluene (5 mL) was added dropwise and after the addition
was complete, the reaction mixture was stirred for 16 h at
–78 °C. A 9:1 mixture of aq NH4Cl solution and 25% aq
NH4OH solution (6 mL) was added over 30 min at –78 °C,
and the cooling bath was removed. Then, H2O (50 mL) and
hexane (200 mL) were added to the reaction, and the mixture
was filtered through a pad of Celite®. The layers of the
filtrate were separated, the aqueous phase was extracted
three times with hexane (50 mL) and the combined organic
layers were washed with sat. NaCl solution (30 mL) and
dried over Na2SO4. The solvent was removed under vacuum
(50 °C). The crude product was purified by flash
chromatography (hexane–EtOAc, 12:1) yielding (R)-ethyl
3-[(4R,5R)-2,2-dimethyl-5-phenyl-1,3-dioxolan-4-
yl]butanoate (4b, 1.106 g, 52%, 92% de) as a slightly yellow,
highly viscous oil. For the analytical data see ref. 4.
(6) Yamamoto, Y.; Maruyama, K. J. Am. Chem. Soc. 1978, 100,
3240.
(14) CCDC 668175 (7b) and 668176 (9a) contain the
supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(7) (a) Yamamoto, Y.; Chounan, Y.; Nishii, S.; Ibuka, T.;
Kitahara, H. J. Am. Chem. Soc. 1992, 114, 7652.
(b) Dorigo, A. E.; Morokuma, K. J. Am. Chem. Soc. 1989,
111, 6524.
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