Total synthesis of cryptophycin 3

Article abstract of DOI:10.1002/ejoc.200400558

The depsipeptide cryptophycin 3 (5) and the cryptophycin analogue 43 were prepared from the corresponding four subunits, The tripeptide analogue 34 was acquired from the starting amino ester 33, which contains fragments D and C. After extension at the car

Full text of DOI:10.1002/ejoc.200400558

FULL PAPER
Total Synthesis of Cryptophycin 3
Paulami Danner,[a] Matthias Bauer,[a] Prodeep Phukan,[a] and Martin E. Maier*[a]
Keywords: Alkylation / Amino acids / Natural products / Peptidomimetics
The depsipeptide cryptophycin 3 (5) and the cryptophycin
analogue 43 were prepared from the corresponding four sub-
in the presence of TBTU as condensing agent. This work fea-
tures a streamlined synthesis of the hydroxy ester 10, a short
units. The tripeptide analogue 34 was acquired from the synthesis of the amino acid 14 by enantioselective alkylation
starting amino ester 33, which contains fragments D and C.
After extension at the carboxyl function by esterification with
the hydroxy ester 10, the seco compounds 37 and 42 were
obtained. Ring closure was achieved by macrolactamization
of the glycinimine 21, and the use of the Fmoc protecting
group for the amino functions.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Cyclodepsipeptides are cyclic peptides containing at least
one hydroxy acid, resulting in the replacement of an amide
by an ester bond. As well as the hydroxy acid(s), cyclodepsi-
peptides often also contain unusual amino acids, such as
extended, N-methylated, hydroxylated, or halogenated ones.
The hydroxy acids frequently derive from the polyketide
pathway, so many cyclodepsipeptides are macrocyclic hy-
brid peptide/polyketide-like molecules. Compounds of this
type have quite recently been accessed by a chemoenzymatic
route.[1] Thanks to their modular natures and the presence
of peptide subunits, cyclodepsipeptides are ideal lead com-
pounds for the generation of libraries of natural product-
like compounds, compound collections of interest in the
context of chemical genetics and target discovery.[2] It might
also be argued that an organism, by producing cyclodepsi-
peptides, would have a flexible tool available for responding
to a possible hostile environment by simple combination of
post-translationally modified amino acids and one larger
building block from another biosynthetic pathway. A quite
prominent family of cyclodepsipeptides are the cryptophy-
cins. The first representative of these depsipeptides, crypto-
phycin 1 (1), was isolated in 1990 from a blue-green algae
(Figure 1).[3,4] Some time later, the isolation and structure
of cryptophycin 24 (3), also known as arenastatin A, was
described.[5] Initially, cryptophycin 1 was classified as an
antifungal agent, but it was later discovered that it also has
powerful antitumor activity caused by disruption of micro-
tubule assembly.[6] Of particular interest was the fact that
cryptophycin showed activity against some multiple drug
resistance (MDR) cell lines. Because of the interesting bio-
[a]
Institut für Organische Chemie, Universität Tübingen
Auf der Morgenstelle 18, 72076 Tübingen, Germany
Fax: (internat.) ϩ 49-7071-295137
E-mail: martin.e.maier@uni-tuebingen.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Figure 1. Structures of important cryptophycins
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DOI: 10.1002/ejoc.200400558
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317

P. Danner, M. Bauer, P. Phukan, M. E. Maier
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syntheses of the natural products[7,8,9,10] and their ana-
logues have been reported. Out of around 450 analogues,
cryptophycin 52 (4) has emerged as a promising clinical
candidate,[4] advancing even to Phase 2 clinical studies
(Table 1).[11] Because of steric hindrance around the ester
group, the analogue 4 is more stable towards hydrolysis, and
structure/activity studies also showed that variations in the
fragment A epoxide are tolerated well, even giving com-
pounds that are active against murine Panc-03 tumors at
much lower doses.[12] The chlorohydrin 7 is one example.
Compounds such as 5 or 6, lacking the epoxide ring, are
still quite active, which indicates that there is no covalent
bond-formation involved in binding to the tubulin. On the
other hand, fragment B has turned out to be rather sensitive
to modifications.[13] One of the most active compounds
from this series turned out to be the analogue 8.[14] The
triamide 9 is characterized by poor solubility and low bio-
availability but still shows reasonable activity.
While in vitro and in vivo studies with cryptophysin 52
were very promising, clinical studies revealed significant
neurological toxicity and only weak or no therapeutic re-
sponse. Nevertheless, from a chemical point of view, the ω-
hydroxy acid of cryptophycin should be an interesting
building block allowing restriction of the conformations of
tri- and tetrapeptides inserted between the hydroxy and car-
boxyl functions.
Table 1. IC50 values for some representative cryptophycins
Compound
IC50 [nM][a]
Cell type
1
2
3
4
5
6
7
8
9
0.0092
0.057
0.198
0.022
3.23
KB
KB
KB
CCRF-CEM
KB
2.15
KB
0.021
0.054
6.0
CCRF-CEM
CCRF-CEM
KB
[a] Data from references[4f] (compounds 1, 2, 3, 5, 9),[12] (compounds
4, 7),[3b] (compound 6), and[14] (compound 8); KB ϭ human naso-
pharyngeal carcinoma cell line, CCRF-CEM ϭ human leukemia
cell line.
a solid-phase assembly of a suitable seco compound. In this
paper we describe a formal total synthesis of cryptophycin
3 (5) in which all amino acids are Fmoc-protected and in
which the amino acid B was prepared by an enantioselective
alkylation. From a strategic point of view it seems advan-
tageous to combine a tripeptide unit such as 11 with a ω-
hydroxy ester 10 (Scheme 1).
The α-hydroxy ester 12 was prepared from isoleucine as
in the literature.[15] The synthesis of the β-amino acid 13
started from the tosylate 15, derived in turn from the Roche
ester (Scheme 2).[16] Substitution of the tosylate with azide,
followed by catalytic hydrogenation of the azide function,
Results and Discussion
In order to make a larger number of such macrocycles, provided the amine 17.[17] The amino group of 17 was then
an efficient synthesis of fragment A is required. In addition, immediately protected under SchottenϪBaumann con-
use of the Fmoc protecting group should in principle allow ditions, resulting in the Fmoc-protected ester 18. The hy-
Scheme 1. Retrosynthetic disconnection of cryptophycin 3 (5) to give the ω-hydroxy ester 10 and the building blocks 12, 13, and 14
318
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Total Synthesis of Cryptophycin 3
FULL PAPER
way, being oxidized to the aldehyde 27, which was then ex-
tended with (EtO)2P(O)CH2Ph (28) under WittigϪHorner
conditions to give the styrene derivative 29. After selective
cleavage of the primary silyl ether, resulting in alcohol 30,
one-pot oxidation and Wittig treatment[24] with Ph3Pϭ
CHCO2tBu[25] provided the unsaturated ester 31 in good
yield. Finally, removal of the silicon protecting group fur-
nished the key building block 10.
Scheme 2. Synthesis of the Fmoc-protected 3-amino-2-methylpro-
pionic acid 13 from the tosylate 15: a) NaN3, DMSO, 80 °C, 3 h
(80%); b) H2, Pd/C, MeOH, 23 °C, 15 h (90%); c) FmocCl, Na2CO3
(10%), 23 °C, 14 h (90%); d) HCl, AcOH, 100 °C, 15 h (67%)
drolysis of the ester function to give the amino acid 13 was
achieved under acidic conditions.[18]
The phenylalanine derivative (cf. 14), also called subunit
B, is usually prepared from d-tyrosine through chlorination
of the aromatic core. Since these conditions would probably
not be compatible with the Fmoc protecting group, a new
synthesis based on the enantioselective alkylation of the gly-
cine derivative 21 was developed (Scheme 3). Accordingly,
the methyl ether 19 was converted into the benzylic bromide
20 with N-bromosuccinimide. The enantioselective alky-
lation of the glycine imine[19] 21 with 20 was carried out
under basic conditions with use of the chiral ligand
22.[20Ϫ22] Hydrolysis of the imine 23 and protection of the
amine with (fluorenylmethoxy)carbonyl chloride provided
the fully protected amino acid 25. Treatment of 25 with
trifluoroacetic acid furnished the desired amino acid 14.
Scheme 4. Synthesis of the 5-hydroxy ester 10: a) DMSO, (COCl)2,
Et3N, CH2Cl2, Ϫ78 °C, 1 h, NEt3, Ϫ70 to
0 °C, 3 h; b)
(EtO)2P(O)CH2Ph (28), nBuLi, THF, Ϫ78 °C, 1 h, add aldehyde,
Ϫ78 to 23 °C, 7 h (58%, 2 steps); c) PPTS, MeOH, 50 °C, 4 h
(85%); d) i) DMSO, (COCl)2, CH2Cl2, Ϫ78 °C, 1 h, then Et3N,
Ϫ78 to 0 °C, 3 h; ii) add Ph3PϭCHCO2tBu, 0 to 23 °C, 12 h (78%);
e) TBAF, THF, 0 to 23 °C, 2 h (73%)
The assembly of the tripeptide 11 began with ester forma-
Because of the use of the Fmoc strategy, the carboxyl tion between the secondary alcohol of 12 and the amino
group of the cyclization point has to be an ester that can acid 13 (Scheme 5). Use of DCC as a condensing agent pro-
be cleaved under non-basic conditions, so our original syn- vided an excellent yield of the depeptide analogue 32, and
thesis[23] of the subunit A was slightly modified (Scheme 4), treatment of compound 32 with diethylamine in THF
with the alcohol 26, obtained by the hydroboration path- caused cleavage of the Fmoc protecting group, resulting in
Scheme 3. Synthesis of the d-phenylalanine derivative 14 by enantioselective alkylation: a) NBS, AIBN (cat.), CCl4, reflux, 16 h (68%);
b) 50% KOH, toluene/CHCl3 (7:3), ammonium salt 22 (0.01 equiv.), 0 °C, 20 h (87%); c) citric acid (15%), THF, 23 °C, 16 h; d) FmocCl,
Na2CO3, 23 °C, 14 h (72%, 2 steps); e) TFA, CH2Cl2, 0 to 23 °C, 5 h (93%)
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P. Danner, M. Bauer, P. Phukan, M. E. Maier
FULL PAPER
the primary amine 33. This compound turned out to be
stable towards intramolecular amide formation. Coupling
of the amine 33 with the Fmoc-protected amino acid 14
in the presence of DCC/HOBt provided the d-C-B section,
compound 34, in good yield.
Scheme 6. Synthesis of desoxy cryptophycin 43: a) Fmoc-Phe-OH,
DCC, HOBt, 0 to 23 °C, 7 h (85%); b) TFA, CH2Cl2, 0 to 23 °C,
3 h; c) hydroxy ester 10, 2,4,6-Cl3C6H2COCl, iPr2NEt, DMAP,
THF, 23 °C, 2 h (75%); d) TFA, CH2Cl2, 0 to 23 °C; e) Et2NH,
THF, 0 to 23 °C, 3 h; f) TBTU, HOBt, iPr2NEt, DMF, 23 °C,
2 h (76%)
Scheme 5. Synthesis of desoxy cryptophycin 5 by the Fmoc strat-
egy: a) DCC, DMAP (cat.), CH2Cl2, 0 to 23 °C, 5 h (80%); b)
Et2NH, THF, 0 to 23 °C, 12 h (67%); c) 14, DCC, HOBt, 0 to 23
°C, 7 h (85%); d) TFA, CH2Cl2, 0 to 23 °C (79%); e) hydroxy ester
10, 2,4,6-Cl3C6H2COCl, iPr2NEt, DMAP, THF, 23 °C, 2 h (73%,
2 steps); f) TFA, CH2Cl2, 0 to 23 °C, 2 h; g) Et2NH, THF, 0 to 23
°C, 2 h; h) TBTU, HOBt, iPr2NEt, DMF, 23 °C, 2 h (42%, 3 steps);
Conclusion
To summarize, we have been able to demonstrate that the
Fmoc strategy is quite suitable for the production of the
cryptophycins 5 and 43 in a concise fashion. In particular,
this strategy is well suited with the enantioselective alky-
lation of the glycine derivative 21. Further work to bridge
the hydroxy acid 10 with tri- and tetrapeptides obtained by
solid-phase synthesis is underway in our laboratory.
TBTU
ϭ
2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate
The next stage in the plan was to form the ester bond
that connects A and D. Accordingly, treatment of the ester
34 with trifluoroacetic acid liberated the C-terminal car-
boxyl group, giving the acid 11. While the esterification of
11 with the hydroxy ester 10 in the presence of DCC was
low-yielding, esterification with the Yamaguchi reagent[26]
took place in high yield. For the generation of the seco com-
pound 37, the tert-butyl ester was first cleaved, followed
by removal of the Fmoc protecting group. Cyclization was
achieved with the reagent TBTU giving the macrocycle 5 in
good yield.
By replacement of the Fmoc-protected amino acid 14
with Fmoc-phenylalanine in the coupling with the amine
33, fragment 38 was obtained (Scheme 6). The subsequent
combination of the acid 39 with 10 provided the ester 40.
This compound could also be converted into the corre-
sponding cryptophycin 43 in good overall yield by cleavage
of the protecting groups and macrolactam formation.
Experimental Section
General: 1H and 13C NMR: Bruker Avance 400, spectra were re-
corded at 295 K in CDCl3; chemical shifts are calibrated to the
residual proton and carbon resonance of the solvent: CDCl3 (δH ϭ
7.25, δC ϭ 77.0 ppm), CD3OD (δH ϭ 4.78, 3.30, δC ϭ 49.0 ppm).
IR: Jasco FT/IR-430. Optical rotation: Jasco polarimeter P-1020,
reported in degrees [α]D {c [g/100 mL], solvent}; recorded at 298 K.
MS: Finnigan Triple-Stage-Quadrupole TSQ-70 (ionizing voltage
of 70 eV) or Intectra AMD 402 mass spectrometer. HRMS: Intec-
tra AMD MAT-711A (EI) or Bruker Daltonic APEX 2 (ESI).
Flash chromatography: J. T. Baker silica gel 43Ϫ60 µm. Thin-layer
chromatography MachereyϪNagel Polygram Sil G/UV254. All sol-
vents used in the reactions were distilled before use. Dry tetrahydro-
furan, and toluene were distilled from sodium and benzophenone,
320
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Total Synthesis of Cryptophycin 3
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whereas dry dichloromethane, dimethylformamide, and triethyl-
fluoroacetic acid (5 mL) at 0 °C. The reaction mixture was stirred
amine were distilled from CaH2. Petroleum ether with a boiling for 3 hours at room temperature. Toluene (5 mL) was then added,
range of 40Ϫ60 °C was used. Reactions were generally run under
argon. All commercially available compounds were used as received
unless stated otherwise.
and the mixture was concentrated in vacuo. This procedure was
repeated twice to give the crude acid, which was purified by flash
chromatography (5% MeOH in CH2Cl2 ϩ drops of AcOH), re-
sulting in acid 11 (82 mg, 79%) as a white solid. Rf ϭ 0.21. [α]2D4
ϭ
Cryptophycin 3 (5): Trifluoroacetic acid (5 mL) was added slowly
at 0 °C to a solution of the protected seco acid 35 (80 mg,
0.085 mmol) in CH2Cl2 (2 mL) and the mixture was stirred for 2
hours at room temperature. The solvent was removed in vacuo, and
toluene (5 mL) was added. After removal of the solvent, the residue
(the acid 36) was redissolved in THF (3 mL) and diethylamine
(3 mL) was added dropwise at 0 °C. The reaction mixture was again
stirred at room temperature for 2 hours, followed by the removal
of the solvents in vacuo. The crude amino acid 37 was dissolved in
dry DMF (15 mL), and TBTU (30 mg, 0.081 mmol), HOBT
(2 mg), and DIEA (33 µL, 0.19 mmol) were then added successively
at room temperature. The reaction mixture was stirred for 2 hours
at room temperature, saturated NaHCO3 solution (5 mL) was ad-
ded, and stirring was continued for 1 hour. The mixture was ex-
tracted with CH2Cl2 (15 mL), and the organic layer was dried with
MgSO4, filtered, and concentrated in vacuo. The crude product was
Ϫ34.87 (c ϭ 0.44, CH2Cl2). IR (neat): ν˜ ϭ 3416, 3310, 2850, 2051,
1
1700, 1630, 1502, 1180 cmϪ1. H NMR (400 MHz, CD3OD): δ ϭ
7.67Ϫ6.58 (m, 11 H), 4.86 (d, J ϭ 9.8 Hz, 1 H), 4.24Ϫ4.00 (m, 4
H), 3.58 (s, 3 H), 3.45Ϫ3.30 (m, 1 H), 3.08Ϫ2.89 (m, 1 H),
2.72Ϫ2.43 (m, 2 H), 1.73Ϫ1.51 (m, 3 H), 1.25Ϫ1.18 (m, 1 H), 1.04
(d, J ϭ 6.8 Hz, 3 H), 0.82 (d, J ϭ 6.3 Hz, 6 H) ppm. 13C NMR
(100 MHz, CD3OD): δ ϭ 174.0, 172.2, 156.6, 153.3, 142.5, 140.7,
131.3, 128.7, 128.1, 127.9, 126.2, 120.9, 114.8, 74.5, 63.1, 57.4, 55.5,
45.8, 44.7, 41.7, 38.2, 36.1, 23.7, 21.9, 16.8, 15.0 ppm. HRMS (FT-
ICR): calcd. for C35H39ClN2O8 [M ϩ Na]ϩ 674.1350 found
674.1343.
(2R)-3-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-2-methylpropa-
noic Acid (13): A solution of the ester 18 (500 mg, 1.4 mmol) in
acetic acid (50 mL) was treated with concentrated HCl (5 mL), and
the mixture was then heated at 100 °C for 15 hours. After cooling
purified by flash chromatography (50% EtOAc in petroleum ether) it was poured into water (500 mL), and the colorless precipitate
to give compound 5 (22 mg, 42% from 35). Rf ϭ 0.31. [α]2D7
was collected by filtration. The colorless solid was purified by flash
ϩ24.68 (c ϭ 0.40, CHCl3) {ref.[7e] [α]2D2 ϭ ϩ29.5 (c ϭ 2.0, CHCl3)}. chromatography (5% MeOH in CH2Cl2) to provide the acid 13
IR (neat): ν˜ ϭ 3430, 3310, 2959, 1727, 1667, 1504, 1250, 1173 cmϪ1
(320 mg, 67%) as a colorless solid. Rf ϭ 0.38 (5% MeOH in CH2Cl2
1H NMR (400 MHz, CDCl3): δ ϭ 7.34Ϫ7.17 (m, 6 H), 7.04 (dd, ϩ 2 drops of AcOH). [α]2D5 ϭ Ϫ10.85 (c ϭ 0.273, CH2Cl2). IR
J ϭ 8.3, 1.8 Hz, 1 H), 6.96Ϫ6.91 (m, 1 H), 6.80 (d, J ϭ 8.3 Hz, 1 (neat): ν˜ ϭ 3344, 2360, 1715, 1520, 1450, 1247 cmϪ1 1H NMR
H), 6.65 (ddd, J ϭ 15.2, 9.8, 5.5 Hz, 1 H), 6.37 (d, J ϭ 15.9 Hz, 1 (400 MHz, CDCl3): δ ϭ 7.71Ϫ7.19 (m, 8 H), 5.16 (s, br, 1 H),
H), 5.97 (dd, J ϭ 15.8, 8.7 Hz, 1 H), 5.74 (d, J ϭ 15.4 Hz, 1 H), 4.46Ϫ4.14 (m, 3 H), 3.39Ϫ3.23 (m, 2 H), 2.72Ϫ2.69 (m, 1 H), 1.16
5.66 (d, J ϭ 8.6 Hz, 1 H), 5.08Ϫ4.93 (m, 1 H), 4.87Ϫ4.72 (m, 2
(d, J ϭ 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.8,
ϭ
.
.
H), 3.83 (s, 3 H), 3.51Ϫ3.41 (m, 1 H), 3.32-3-22 (m, 1 H), 3.10 (dd, 157.2, 144.2, 141.0, 128.1, 127.4, 125.4, 120.3, 67.1, 47.6, 43.5, 40.1,
J ϭ 14.4, 5.3 Hz, 1 H), 3.00 (dd, J ϭ 14.4, 7.0 Hz, 1 H), 2.71Ϫ2.62
(m, 1 H), 2.60Ϫ2.45 (m, 2 H), 2.41Ϫ2.28 (m, 1 H), 1.75Ϫ1.49 (m,
3 H), 1.38Ϫ1.26 (m, 1 H), 1.19 (d, J ϭ 7.0 Hz, 3 H), 1.10 (d, J ϭ
6.8 Hz, 3 H), 0.74 (d, J ϭ 6.3 Hz, 3 H), 0.69 (d, J ϭ 6.3 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.6, 170.9, 170.2, 165.4,
153.9, 141.4, 136.6, 131.8, 131.0, 130.3, 130.0, 129.7, 128.6, 127.5,
126.1, 125.1, 122.3, 112.1, 71.5, 56.1, 53.5, 42.2, 41.1, 39.5, 38.2,
36.4, 35.0, 24.4, 22.7, 21.1, 17.3, 14.0 ppm. HRMS (FT-ICR):
calcd. for C35H43ClN2O7 [M ϩ Na]ϩ 661.2651, found 661.2654.
15.0 ppm. HRMS (FT-ICR): calcd. for C19H19NO4 [M ϩ Na]ϩ
348.1206, found 348.1204.
3-Chloro-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-O-methyl-D-
tyrosine (14): The tert-butyl ester 25 (300 mg, 0.59 mmol) was dis-
solved in CH2Cl2 (5 mL), and trifluoroacetic acid (5 mL) was ad-
ded dropwise at 0 °C. After stirring at room temperature for 5
hours, the reaction mixture was concentrated in vacuo. Toluene
(5 mL) was added to the residue, and this mixture was again con-
centrated. The residue was purified by flash chromatography (5%
MeOH in CH2Cl2) to yield the Fmoc-protected acid 14 (245 mg,
tert-Butyl (2E,5S,6R,7E)-5-Hydroxy-6-methyl-8-phenylocta-2,7-di-
enoate (10): Tetra-n-butylammonium fluoride (1
0.87 mL, 0.87 mmol) was added at 0 °C to a solution of enoate 31
(110 mg, 0.26 mmol) in dry THF (4 mL) and the reaction mixture 1606, 1504, 1450, 1280, 1259, 1065 cmϪ1
m
in THF, 93%) as a white solid. Rf ϭ 0.25. [α]2D5 ϭ Ϫ20.71 (c ϭ 0.38,
CH2Cl2). IR (neat): ν˜ ϭ 3410, 3316, 3065, 2953, 2930, 1722, 1716,
1H NMR (400 MHz,
.
was stirred at room temperature for 3 hours. The mixture was
washed with brine, dried with MgSO4, filtered, and concentrated.
The residue was purified by flash chromatography (first 30% and
then 50% EtOAc in petroleum ether) to give the hydroxy ester 10
CDCl3): δ ϭ 7.76Ϫ7.18 (m, 9 H), 6.98 (d, J ϭ 8.0 Hz, 1 H), 6.80
(d, J ϭ 8.0 Hz, 1 H), 5.27 (d, J ϭ 7.0 Hz, 1 H, NH), 4.67Ϫ4.56
(m, 1 H), 4.47Ϫ4.29 (m, 2 H), 4.24Ϫ4.11 (m, 1 H), 3.84 (s, 3 H),
3.16Ϫ2.96 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.3,
(55 mg, 73%) as a colorless oil. Rf ϭ 0.29 (30% EtOAc in petroleum 156.2, 154.5, 144.0, 141.2, 131.4, 129.0, 128.1, 127.5, 125.4, 120.4,
ether). [α]2D5 ϭ ϩ40.0 (c ϭ 1.42, CH2Cl2). IR (neat): ν˜ ϭ 3444,
112.5, 67.5, 56.5, 54.1, 47.4, 37.0 ppm. HRMS (FT-ICR): calcd.
3025, 2976, 2931, 1712, 1652, 1494, 1361 cmϪ1 1H NMR for C25H22ClNO5 [M ϩ Na]ϩ 474.1079, found 474.1077.
.
(400 MHz, CDCl3): δ ϭ 7.70Ϫ7.22 (m, 5 H), 6.89Ϫ6.81 (m, 1 H),
6.41 (d, J ϭ 15.9 Hz, 1 H), 6.06 (dd, J ϭ 15.9, 8.5 Hz, 1 H), 5.77
(d, J ϭ 15.6 Hz, 1 H), 3.61Ϫ3.56 (m, 1 H), 2.42Ϫ2.22 (m, 3 H),
1.41 (s, 9 H), 1.07 (d, J ϭ 6.8 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ ϭ 165.7, 143.9, 137.0, 131.9, 130.9, 128.5, 127.4, 126.1,
125.9, 80.2, 73.8, 43.2, 37.1, 28.1, 16.7 ppm. HRMS (FT-ICR):
calcd. for C19H26O3 [M ϩ Na]ϩ 325.1774, found 325.1775.
Methyl (2R)-3-Azido-2-methylpropanoate (16): A mixture of tosyl-
ate 15 (2.0 g, 7.3 mmol) and sodium azide (1.0 g, 15.3 mmol) in
DMSO (30 mL) was heated at 80 °C for 2Ϫ3 h. After the mixture
had cooled to room temperature, water (30 mL) was added and the
mixture was extracted with CH2Cl2 (3 ϫ 30 mL). The combined
extracts were dried with MgSO4, filtered, and concentrated in va-
cuo. The crude product was purified by flash chromatography with
20% EtOAc in petroleum ether to provide 16 (0.9 g, 85%) as a col-
orless oil. Rf ϭ 0.47. [α]2D2 ϭ Ϫ14.32 (c ϭ 0.99, CH2Cl2). IR (neat):
ν˜ ϭ 2982, 2103, 1732, 1463, 1381, 1199 cmϪ1. 1H NMR (400 MHz,
CDCl3): δ ϭ 3.68 (s, 3 H), 3.56Ϫ3.46 (m, 1 H), 3.35 (dd, J ϭ 12.1,
(2S)-2-{[(2R)-3-({3-Chloro-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-
O-methyl-D-tyrosyl}amino)-2-methylpropanoyl]oxy}-4-methyl-
pentanoic Acid (11): The tert-butyl ester 34 (100 mg, 0.14 mmol)
was dissolved in CH2Cl2 (5 mL), followed by the addition of tri-
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P. Danner, M. Bauer, P. Phukan, M. E. Maier
FULL PAPER
5.8 Hz, 1 H), 2.73Ϫ2.60 (m, 1 H), 1.28 (d, J ϭ 7.0 Hz, 3 H) ppm. (500 mg, 1.7 mmol) and chiral catalyst[20a] 22 (17.0 mg,
13C NMR (100 MHz, CDCl3): δ ϭ 174.7, 54.1, 52.9, 40.0,
15.1 ppm. HRMS (FT-ICR): calcd. for C5H9N3O2 [M ϩ Na]ϩ
166.0587, found 166.0585.
0.017 mmol) in toluene/chloroform (volume ratio ϭ 7:3, 10 mL).
The reaction mixture was cooled to 0 °C and treated with aqueous
KOH (50%, 2.5 mL). The mixture was stirred at room temperature
for approximately 20 hours (TLC monitoring). The suspension was
diluted with diethyl ether (100 mL) and washed with water (2 ϫ 50
mL), and the phases were separated. The organic layer was dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/diethyl ether,
2:1) to give the alkylation product 23 (0.65 g, 87%) as a colorless
oil. The ee was determined by HPLC on a chiral column (DAICEL
Chiral OB-H, 250 ϫ 2.6 mm; heptane/2-propanol, 98:02, flow
0.5 mL·minϪ1, tminor ϭ 8.82 min, tmajor ϭ 9.79 min) to be 96%.
Rf ϭ 0.29. [α]2D3 ϭ 155.41 (c ϭ 0.62, CH2Cl2). IR (neat): ν˜ ϭ 2975,
Methyl (2R)-3-{[(9H-Fluoren-9-ylmethoxy)carbonyl]amino}-2-meth-
ylpropanoate (18): A mixture of azide 16 (0.28 g, 2.0 mmol) and
Pd-C (10%, 140 mg) in MeOH (2 mL) was stirred under hydrogen
atmosphere at room temperature for 15 hours. The reaction mix-
ture was filtered through a pad of celite. Concentration of the fil-
trate gave the crude amine 17, which was immediately protected
without further purification. The crude amino ester 17 (300 mg,
2.5 mmol) was dissolved in THF (10 mL), and aqueous Na2CO3
(10%, 10 mL) was added, followed by FmocCl (1.0 g, 3.8 mmol).
The reaction mixture was stirred at room temperature for 14 hours.
The aqueous layer was extracted with EtOAc (2 ϫ 30 mL), and the
combined organic extracts were dried with MgSO4, filtered, and
concentrated. The residue was purified by flash chromatography
(20% EtOAc in petroleum ether) to provide the protected amine 18
(0.61 g, 90%) as a colorless solid. Rf ϭ 0.25. [α]2D2 ϭ Ϫ13.2 (c ϭ
0.962, CH2Cl2). IR (neat): ν˜ ϭ 3310, 2250, 1760, 1520, 1350, 1250
2928, 1731, 1622, 1502, 1445, 1256, 1150 cmϪ1 1H NMR
.
(400 MHz, CDCl3): δ ϭ 7.48 (d, J ϭ 7.0 Hz, 2 H), 7.30Ϫ7.16 (m,
6 H), 6.94Ϫ6.83 (m, 2 H), 6.70Ϫ6.58 (m, 3 H), 4.00 (dd, J ϭ 8.9,
4.4 Hz, 1 H), 3.72 (s, 3 H), 3.08Ϫ2.93 (m, 2 H), 1.35 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 171.0, 153.8, 139.8, 136.7, 131.7,
130.6, 129.5, 129.1, 128.8, 128.6, 128.3, 128.0, 122.2, 112.0, 81.6,
68.0, 56.5, 38.8, 28.4 ppm. HRMS (FT-ICR): calcd. for
C27H28ClNO3 [M ϩ Na]ϩ 472.5035, found 472.5030.
cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ 7.77Ϫ7.28 (m, 8 H),
.
5.43Ϫ5.33 (m, 1 H), 4.40 (d, J ϭ 6.3 Hz, 2 H), 4.22 (t, J ϭ 6.8 Hz,
1 H), 3.71 (s, 3 H), 3.46Ϫ3.29 (m, 2 H), 2.79Ϫ2.68 (m, 1 H), 1.20
(d, J ϭ 7.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 176.1,
156.8, 144.3, 141.7, 128.0, 127.4, 125.4, 120.3, 67.0, 52.2, 47.6, 43.7,
40.2, 15.1 ppm. HRMS (FT-ICR): calcd. for C20H21NO4 [M ϩ
Na]ϩ 362.3850, found 362.3855.
tert-Butyl 3-Chloro-O-methyl-d-tyrosinate (24): A solution of the al-
kylated imine 23 (500 mg, 1.1 mmol) in THF (10 mL) and aqueous
citric acid (15%, 5 mL) was stirred at room temperature for 14
hours. The mixture was then diluted with Et2O (10 mL) and ex-
tracted with HCl (1 m, 3 ϫ 10 mL). The combined aqueous layers
were washed with Et2O (10 mL), basified with solid K2CO3, and
then extracted with EtOAc (3 ϫ 15 mL). The organic extracts were
dried with MgSO4, filtered, and concentrated in vacuo to provide
the crude amino acid 24, which was used in the next step without
further purification.
4-(Bromomethyl)-2-chloro-1-methoxybenzene (20): A mixture of 2-
chloro-1-methoxy-4-methylbenzene (19, 4.0 g, 25.5 mmol), NBS
(5.0 g, 28.1 mmol), and AIBN (190 mg, 1.15 mmol) in dry CCl4
(160 mL) was heated at reflux overnight. After being cooled to
room temperature, the mixture was washed with NaOH solution
(1.5 n, 75 mL) and water (75 mL). The organic layer was dried
with MgSO4, filtered, and concentrated in vacuo. The residue was
purified by flash chromatography (petroleum ether/diethyl ether,
3:1) to provide the benzyl bromide 20 (4.1 g, 68%) as a colorless
oil. Rf ϭ 0.52. IR (neat): ν˜ ϭ 2946, 1698, 1603, 1503, 1261, 1065
cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.40 (d, J ϭ 2.0 Hz, 1 H),
7.22 (dd, J ϭ 8.4, 2.1 Hz, 1 H), 6.85 (d, J ϭ 8.5 Hz, 1 H), 4.43 (s,
2 H), 3.86 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 155.7,
131.3, 129.0, 126.4, 122.8, 112.5, 56.6, 33.2 ppm. HRMS (FT-ICR):
calcd. for C8H8BrClO [M ϩ Na]ϩ 258.5050, found 258.5034.
tert-Butyl 3-Chloro-N-[(9H-fluoren-9-ylmethoxy)carbonyl]-O-methyl-
D-tyrosinate (25): The crude amino ester 24 (400 mg, 1.4 mmol) was
dissolved in THF (10 mL), and aqueous Na2CO3 (10%, 10 mL) was
added, followed by FmocCl (0.4 g, 1.5 mmol,). The reaction mix-
ture was stirred for 14 hours at room temperature, and the aqueous
layer was extracted with EtOAc (3 ϫ 10 mL), dried with MgSO4,
filtered, and concentrated in vacuo. The residue was purified by
flash chromatography (10% EtOAc in petroleum ether) to give 25
(510 mg, 72%) as a colorless oil. Rf ϭ 0.30. [α]2D5 ϭ Ϫ25.07 (c ϭ
1.22, CH2Cl2). IR (neat): ν˜ ϭ 3421, 3335, 3064, 2978, 2933, 1732,
1
1606, 1503, 1450, 1368, 1280 cmϪ1. H NMR (400 MHz, CDCl3):
tert-Butyl N-(Diphenylmethylene)glycinate (21): A solution of tert-
butyl 2-bromoacetate (7.0 g, 35.9 mmol) in acetonitrile (40 mL) was
treated with benzophenonimine (6.5 g, 35.8 mmol) and diisopropy-
lethylamine (6.2 mL, 4.6 g, 35.6 mmol), and the mixture was then
heated at reflux for 12 hours. After the system had cooled to room
temperature, most of the acetonitrile was removed in vacuo. The
residue was partitioned between water (40 mL) and diethyl ether
(60 mL) and the phases were separated. The organic layer was dried
with MgSO4, filtered, and concentrated in vacuo until the mixture
became turbid. Cooling in an ice bath provided a first fraction of
4.1 g. Concentration of all the filtrates resulted in another crop;
total yield 10.2 g (96%), slightly yellow solid. 1H NMR (400 MHz,
CDCl3): δ ϭ 7.71Ϫ7.20 (m, 10 H), 4.17 (s, 2 H), 1.44 (s, 9 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 171.3, 169.6, 139.2, 136.0, 132.2,
130.2, 129.9, 128.6, 128.4, 128.3, 128.1, 127.9, 127.5, 80.8, 56.2,
27.9 ppm.
δ ϭ 7.76 (d, J ϭ 7.3 Hz, 2 H), 7.61Ϫ7.17 (m, 7 H), 6.98 (d, J ϭ
8.0 Hz, 1 H), 6.81 (d, J ϭ 8.3 Hz, 1 H), 5.30 (d, J ϭ 7.8 Hz, 1 H),
4.53Ϫ4.41 (m, 2 H), 4.36Ϫ4.28 (m, 1 H), 4.21 (t, J ϭ 6.9 Hz, 1 H),
3.86 (s, 3 H), 3.05Ϫ2.96 (m, 2 H), 1.43 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ ϭ 170.3, 155.4, 154.0, 143.7, 141.2, 131.2,
128.7, 127.7, 127.0, 125.0, 122.1, 119.9, 111.9, 82.7, 66.9, 56.1, 55.0,
47.1, 37.1, 27.9 ppm. HRMS (FT-ICR): calcd. for C25H22ClNO5
[M ϩ Na]ϩ 474.1078, found 474.1077.
(2S,3S)-3,5-Bis{[tert-butyl(dimethyl)silyl]oxy}-2-methylpentanal
(27): Dimethyl sulfoxide (0.22 mL, 3.12 mmol) dissolved in CH2Cl2
(5 mL) was added dropwise at Ϫ78 °C to a solution of oxalyl chlo-
ride (0.139 mL, 1.6 mmol) in CH2Cl2 (10 mL). After 5 min, alcohol
26 (0.5 g, 1.3 mmol) in CH2Cl2 (10 mL) was added dropwise to the
reaction mixture, and stirring was continued at Ϫ78 °C for 1 hour.
Triethylamine (0.91 mL, 6.5 mmol) was then added dropwise, and
the mixture was warmed to room temperature over 3 hours. For
the workup the mixture was treated with water (15 mL) and the
layers were separated. The aqueous layer was extracted with
CH2Cl2 (2 ϫ 15 mL). The combined organic layers were washed
tert-Butyl 3-Chloro-N-(diphenylmethylene)-O-methyl-D-tyrosinate
(23): The benzyl bromide 20 (500 mg, 2.1 mmol) was added to a
stirred mixture of N-(diphenylmethylene)glycine tert-butyl ester 21
322
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 317Ϫ325

Total Synthesis of Cryptophycin 3
FULL PAPER
with brine (30 mL), dried with MgSO4, filtered, and concentrated
in vacuo to give the crude aldehyde 27, which was used for the next
step without further purification.
(c ϭ 0.95, CH2Cl2). IR (neat): ν˜ ϭ 3350, 2950, 2856, 1715, 1471,
1366, 1256 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.48Ϫ7.11 (m,
5 H), 6.78 (dt, J ϭ 15.0, 7.0 Hz, 1 H), 6.31 (d, J ϭ 15.9 Hz, 1 H),
6.11 (dd, J ϭ 15.9, 8.0 Hz, 1 H), 5.69 (d, J ϭ 15.6 Hz, 1 H),
3.72Ϫ3.64 (m, 1 H), 2.46Ϫ2.34 (m, 1 H), 2.31Ϫ2.19 (m, 2 H), 1.41
(s, 9 H), 1.04 (d, J ϭ 6.8 Hz, 3 H), 0.85 (s, 9 H), 0.0 (s, 6 H) ppm.
13C NMR (100 MHz, CDCl3): δ ϭ 165.7, 144.8, 137.6, 132.0, 130.3,
128.4, 127.0, 126.0, 125.0, 80.0, 75.1, 42.8, 37.2, 28.1, 25.8, 18.0,
16.0, Ϫ4.3 ppm. HRMS (FT-ICR): calcd. for C25H40O3Si [M ϩ
Na]ϩ 439.2639, found 439.2638.
[(1E,3R,4S)-4,6-Di{[tert-butyl(dimethyl)silyl]oxy}-3-methylhex-1-
enyl]benzene (29): A solution of diethyl benzylphosphonate 28
(0.77 mL, 3.71 mmol) in THF (15 mL) was treated at Ϫ78 °C with
nBuLi (2.5 m in hexane, 0.83 mL, 2.07 mmol). Stirring was con-
tinued at Ϫ78 °C for 1 hour, after which a solution of aldehyde 27
(from the previous step) in THF (7 mL) was added dropwise. After
having been stirred at Ϫ78 °C for 1 hour, the reaction mixture
was warmed gradually to room temperature over 6 hours. Aqueous tert-Butyl (2S)-2-[((2R)-3-{[(9H-Fluoren-9-ylmethoxy)carbonyl]-
NH4Cl solution (25 mL) was added, and the mixture was extracted
with Et2O (3 ϫ 40 mL). The combined organic layers were washed
with water (30 mL) and brine (30 mL), dried with MgSO4, filtered,
and concentrated. The residue was purified by flash chromatogra-
phy (5% EtOAc in petroleum ether) to give the styrene 29 (345 mg,
58%, 2 steps) as a colorless oil. Rf ϭ 0.55. [α]2D5 ϭ ϩ17.8 (c ϭ 1.00,
amino}-2-methylpropanoyl)oxy]-4-methylpentanoate (32): A solu-
tion of DCC (293 mg, 1.42 mmol) in CH2Cl2 (3 mL) was added
dropwise at 0 °C to a solution of hydroxy ester 12 (180 mg,
0.95 mmol), the amino acid 13 (373 mg, 1.14 mmol), and DMAP
(50 mg, 0.40 mmol) in CH2Cl2 (3 mL). The clear solution was
stirred for 30 min at 0 °C and then for 5 hours at room temperature.
The white precipitate was filtered off, and the filtrate was concen-
CH2Cl2). IR (neat): ν˜ ϭ 2955, 2928, 1471, 1463, 1256, 1067 cmϪ1
.
1H NMR (400 MHz, CDCl3): δ ϭ 7.39Ϫ7.10 (m, 5 H), 6.37 (d, trated. The residue was dissolved in Et2O and washed with HCl
J ϭ 15.9 Hz, 1 H), 6.18 (dd, J ϭ 15.6, 7.8 Hz, 1 H), 3.88Ϫ3.79 (m, (0.5 n, 10 mL), saturated NaHCO3 solution (10 mL), and brine
1 H), 3.74Ϫ3.59 (m, 2 H), 2.54Ϫ2.43 (m, 1 H), 1.65 (q, J ϭ 6.5 Hz, (10 mL). The ether layer was dried with MgSO4, filtered, and con-
2 H), 1.11 (d, J ϭ 7.0 Hz, 3 H), 0.95 (s, 9 H), 0.85 (s, 9 H), 0.11 centrated in vacuo. The residue was purified by flash chromatogra-
(s, 6 H), 0.00 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ
137.8, 132.8, 129.7, 128.4, 126.8, 126.0, 72.6, 60.1, 42.7, 36.7, 25.9,
phy (10% of EtOAc in petroleum ether) to give the ester 32
(378 mg, 80%) as a colorless oil. Rf ϭ 0.25. [α]2D4 ϭ Ϫ32.41 (c ϭ
18.1, 15.5, Ϫ4.5, Ϫ5.2 ppm. HRMS (FT-ICR): calcd. for 0.44, CH2Cl2). IR (neat): ν˜ ϭ 3366, 2958, 1732, 1522, 1450, 1369,
C25H46O2Si2 [M ϩ Na]ϩ 457.7920, found 457.7925.
1249, 1159 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.77Ϫ7.22 (m,
8 H), 6.03Ϫ5.92 (m, 1 H), 4.92 (dd, J ϭ 9.3, 4.5 Hz, 1 H),
4.38Ϫ4.26 (m, 2 H), 4.18 (t, J ϭ 7.3 Hz, 1 H), 3.59Ϫ3.50 (m, 1 H),
3.35Ϫ3.25 (m, 1 H), 2.83Ϫ2.73 (m, 1 H), 1.83Ϫ1.57 (m, 3 H), 1.47
(s, 9 H), 1.21 (d, J ϭ 7.0 Hz, 3 H), 0.94 (d, J ϭ 6.3 Hz, 3 H), 0.91
(d, J ϭ 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 174.3,
170.3, 156.5, 144.0, 141.2, 127.5, 126.9, 125.2, 119.8, 82.5, 71.3,
66.7, 47.1, 43.6, 40.8, 39.5, 27.9, 24.7, 23.0, 21.5, 14.5 ppm. HRMS
(FT-ICR): calcd. for C29H37NO6 [M ϩ Na]ϩ 518.2513, found
518.2511.
(3S,4R,5E)-3-{[tert-Butyl(dimethyl)silyl]oxy}-4-methyl-6-phenylhex-
5-en-1-ol (30): A solution of disilyl ether 29 (0.36 g, 0.85 mmol) and
pyridinium para-toluenesulfonate (70 mg, 0.27 mmol) in MeOH
(20 mL) was stirred for 4 hours at 50 °C. Most of the MeOH was
then removed under reduced pressure, and the mixture was par-
titioned between water and Et2O. The aqueous layer was extracted
with Et2O, and the combined organic layers were washed with satu-
rated NaHCO3 solution and brine, dried with MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash chroma-
tography (15% EtOAc in petroleum ether) to give the primary al-
cohol 30 (225 mg, 85%) as a colorless oil. Rf ϭ 0.25. [α]2D5 ϭ ϩ44.4
tert-Butyl (2S)-2-{[(2R)-3-Amino-2-methylpropanoyl]oxy}-4-methyl-
pentanoate (33): A solution of compound 32 (300 mg, 0.60 mmol)
(c ϭ 0.75, CH2Cl2). IR (neat): ν˜ ϭ 3352, 2955, 2930, 1465, 1378, in THF (85 mL) was treated at 0 °C with diethylamine (5 mL). The
1255, 1093 cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 7.26Ϫ7.06 (m, reaction mixture was stirred for 15 min at 0 °C and for 12 hours at
5 H), 6.27 (d, J ϭ 16.1 Hz, 1 H), 6.02 (dd, J ϭ 15.9, 7.5 Hz, 1 H),
room temperature. After evaporation of the solvent in vacuo, the
3.81Ϫ3.73 (m, 1 H), 3.68Ϫ3.57 (m, 2 H), 2.50Ϫ2.37 (m, 1 H), 1.84 residue was purified by flash chromatography (2% MeOH in
(s, br, 1 H), 1.61 (q, J ϭ 5.8 Hz, 2 H), 0.99 (d, J ϭ 6.8 Hz, 3 H), CH2Cl2) to give the amine 33 (110 mg, 67%) as a colorless liquid.
0.80 (s, 9 H), 0.00 (2 s, 6 H) ppm. 13C NMR (100 MHz, CDCl3):
The amine 33 was immediately used for the next step. Rf ϭ 0.19.
δ ϭ 137.5, 132.5, 130.0, 128.4, 127.0, 125.9, 74.5, 60.4, 42.6, 34.9, IR (neat): ν˜ ϭ 3286, 2959, 2872, 2285, 1738, 1651, 1556, 1369, 1141
25.8, 18.0, 14.7, Ϫ4.3, Ϫ4.5 ppm. HRMS (FT-ICR): calcd. for
cmϪ1. 1H NMR (400 MHz, CDCl3): δ ϭ 4.89 (dd, J ϭ 9.3, 4.5 Hz,
1 H), 2.98Ϫ2.90 (m, 1 H), 2.82Ϫ2.75 (m, 1 H), 2.62Ϫ2.53 (m, 1
H), 1.80Ϫ1.69 (m, 2 H), 1.66Ϫ1.54 (m, 1 H), 1.43 (s, 9 H), 1.18 (d,
J ϭ 7.0 Hz, 3 H), 0.94 (d, J ϭ 6.3 Hz, 3 H), 0.90 (d, J ϭ 6.3 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.0, 169.8, 81.9,
71.2, 45.5, 43.4, 39.6, 27.9, 24.7, 23.0, 21.5, 14.6 ppm. HRMS (FT-
ICR): calcd. for C14H27NO4 [M ϩ H]ϩ 274.2013, found 274. 2014.
C19H32O2Si [M ϩ Na]ϩ 343.5310, found 343.5314.
tert-Butyl (2E,5S,6R,7E)-5-{[tert-Butyl(dimethyl)silyl]oxy}-6-methyl-
8-phenylocta-2,7-dienoate (31): A solution of dimethyl sulfoxide
(0.086 mL, 1.2 mmol) in CH2Cl2 (5 mL) was added dropwise at
Ϫ78 °C to a stirred solution of oxalyl chloride (0.050 mL,
0.6 mmol) in CH2Cl2 (8 mL). After 10 min, a solution of the al-
cohol 30 (0.160 g, 0.50 mmol) in CH2Cl2 (5 mL) was added. After tert-Butyl (2S)-2-{[(2R)-3-({3-Chloro-N-[(9H-fluoren-9-ylmethoxy)-
having been stirred at Ϫ78 °C for 30 min, the reaction mixture was carbonyl]-O-methyl- -tyrosyl}amino)-2-methylpropanoyl]oxy}-4-
D
treated with Et3N (0.346 mL, 2.50 mmol) and warmed to 0 °C. At methylpentanoate (34): The amine 33 (150 mg, 0.54 mmol), the
this point tert-butyl (triphenylphosphoranylidene)acetate[25]
(0.546 g, 0.150 mmol) in CH2Cl2 (6 mL) was added and the mixture
was stirred at room temperature overnight. The reaction mixture
was poured into half-saturated NH4Cl solution (50 mL) and the
amino acid 14 (243 mg, 0.54 mmol), and HOBT (73 mg,
0.54 mmol) were dissolved in dry THF (3 mL), followed by ad-
dition of DCC (166 mg, 0.81 mmol), dissolved in THF (2 mL) at 0
°C. The mixture was stirred for 7 hours at room temperature, after
layers were separated. The organic layer was dried with MgSO4, which it was filtered and concentrated. The residue was diluted
filtered, and concentrated in vacuo. Purification of the residue by with Et2O and washed with water. The organic layer was dried with
flash chromatography (5% EtOAc in petroleum ether) gave the eno- MgSO4, filtered, and concentrated. The residue was purified by
ate 31 (180 mg, 78%) as a colorless oil. Rf ϭ 0.25. [α]2D4 ϭ ϩ50.1
flash chromatography (30% EtOAc in petroleum ether) to give the
Eur. J. Org. Chem. 2005, 317Ϫ325
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
323

P. Danner, M. Bauer, P. Phukan, M. E. Maier
FULL PAPER
tripeptide analogue 34 (325 mg, 84%) as a colorless oil. Rf ϭ 0.32.
(m, 2 H), 4.16Ϫ3.98 (m, 2 H), 3.69Ϫ3.55 (m, 1 H), 3.09Ϫ3.00 (m,
1 H), 2.95 (dd, J ϭ 13.7, 7.2 Hz, 1 H), 2.85Ϫ2.75 (m, 1 H),
[α]2D4 ϭ Ϫ21.93 (c ϭ 1.25, CH2Cl2). IR (neat): ν˜ ϭ 3317, 2950,
1
2152, 1738, 1670, 1504, 1257 cmϪ1. H NMR (400 MHz, CDCl3): 2.70Ϫ2.61 (m, 1 H), 1.69Ϫ1.40 (m, 3 H), 1.34 (s, 9 H), 1.06 (d, J ϭ
δ ϭ 7.74 (d, J ϭ 7.5 Hz, 2 H), 7.56Ϫ7.15 (m, 7 H), 7.03 (d, J ϭ 7.0 Hz, 3 H), 0.84 (d, J ϭ 6.3 Hz, 3 H), 0.81 (d, J ϭ 6.3 Hz, 3 H)
8.0 Hz, 1 H), 6.79 (d, J ϭ 8.3 Hz, 1 H), 5.61 (d, J ϭ 8.3 Hz, 1 H),
5.00Ϫ4.95 (m, 1 H), 4.51Ϫ4.38 (m, 2 H), 4.22Ϫ4.07 (m, 2 H), 3.81 141.2, 136.4, 129.2, 128.5, 127.6, 127.0, 125.0, 119.9, 82.9, 71.0,
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 173.7, 170.7, 155.6, 143.7,
(s, 3 H), 3.78Ϫ3.70 (m, 1 H), 3.13 (ddd, J ϭ 13.9, 10.1, 4.6 Hz, 1
66.9, 56.1, 47.0, 41.8, 40.5, 39.5, 39.1, 27.9, 24.7, 23.0, 21.5,
H), 3.04 (dd, J ϭ 13.9, 6.1, 1 H), 2.95 (dd, J ϭ 13.9, 6.8 Hz, 1 H), 14.7 ppm. HRMS (FT-ICR): calcd. for C38H46N2O7 [M ϩ Na]ϩ
2.82Ϫ2.70 (m, 1 H), 1.78Ϫ1.53 (m, 3 H), 1.43 (s, 9 H), 1.17 (d, J ϭ 665.3197, found 665.3202.
6.8 Hz, 3 H), 0.93 (d, J ϭ 6.3 Hz, 3 H), 0.90 (d, J ϭ 6.3 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 173.6, 171.8, 155.6, 153.8,
143.7, 141.2, 131.0, 129.5, 128.4, 127.6, 127.0, 125.0, 119.9, 112.1,
83.1, 71.0, 67.0, 60.3, 56.0, 47.0, 41.8, 40.6, 39.4, 38.0, 27.9, 24.8,
22.9, 21.4, 14.7, 14.1 ppm. HRMS (FT-ICR): calcd. for
C39H47ClN2O8 [M ϩ Na]ϩ 729.2913, found 729.2912.
tert-Butyl (2E,5S,6R,7E)-5-[(2S)-2-{[(2R)-3-({N-[(9H-Fluoren-9-yl-
methoxy)carbonyl]- -phenylalanyl}amino)-2-methylpropanoyl]oxy}-
4-methylpentanoyl)oxy]-6-methyl-8-phenylocta-2,7-dienoate (40):
Trifluoroacetic acid (7 mL) was added at 0 °C to a solution of the
fully protected amino acid 38 (230 mg, 0.35 mmol) in CH2Cl2
(7 mL), and the reaction mixture was then stirred for 3 hours at
D
tert-Butyl (2E,5S,6R,7E)-5-[(2S)-2-{[(2R)-3-({3-Chloro-N-[(9H- room temperature. Toluene (5 mL) was then added, and the mix-
fluoren-9-ylmethoxy)carbonyl]-O-methyl-
methylpropanoyl]oxy}-4-methylpentanoyl)oxy]-6-methyl-8-phenyl-
octa-2,7-dienoate (35): DIEA (35 µL, 0.201 mmol), 2,4,6-trichloro-
D
-tyrosyl}amino)-2-
ture was concentrated. This was repeated twice more. The crude
acid 39 was subjected to the next reaction without further purifi-
cation.
benzoyl chloride (27 µL, 0.173 mmol), and DMAP (2 mg) were ad- DIEA (45 µL, 0.40 mmol), 2,4,6-trichlorobenzoyl chloride (91 µL,
ded at room temperature to a solution of the amino acid 11 (90 mg,
0.153 mmol) in THF (3 mL). After 30 min, the alcohol 10 (25 mg,
0.374 mmol), and DMAP (2 mg) were added to a solution of the
N-protected amino acid 39 (200 mg, 0.34 mmol) in THF (3 mL).
0.082 mmol), dissolved in THF (1 mL), was added slowly in drop- After the system had been stirred for 30 min, the alcohol 10 (51 mg,
wise fashion. After the system had been stirred for an additional 2
hours, saturated aqueous NaHCO3 solution (5 mL) was added. The
layers were separated, and the aqueous layer was extracted with
CH2Cl2 (3 ϫ 20 mL). The combined organic layers were dried with
MgSO4, filtered, and concentrated in vacuo. The residue was puri-
fied by flash chromatography (30% EtOAc in petroleum ether) to
give the seco compound 35 (94 mg, 73%) as a colorless oil. Rf ϭ
0.23. [α]2D4 ϭ 1.19 (c ϭ 0.28, CH2Cl2). IR (neat): ν˜ ϭ 3566, 2925,
0.17 mmol), dissolved in THF (1 mL), was added slowly in a drop-
wise fashion. After 2 hours, saturated aqueous NaHCO3 solution
(5 mL) was added and the layers were separated. The aqueous layer
was extracted with CH2Cl2 (10 mL). The combined organic layer
was dried with MgSO4, filtered, and concentrated. The crude prod-
uct was purified by flash chromatography (30% EtOAc in petro-
leum ether) to give the protected seco compound 40 (231 mg, 75%).
Rf ϭ 0.21. [α]2D5 ϭ 1.88 (c ϭ 0.84, CH2Cl2). IR (neat): ν˜ ϭ 3318,
2900, 1750, 1730, 1353, 1506, 1456, 1258 cmϪ1
.
1H NMR 3063, 2959, 1735, 1600, 1545, 1450, 1254, 1152, 1081 cmϪ1
.
1H
NMR (400 MHz, CDCl3): δ ϭ 7.65 (d, J ϭ 7.6 Hz, 2 H), 7.47Ϫ7.02
(m, 16 H), 6.97Ϫ6.90 (m, 1 H), 6.83Ϫ6.74 (m, 1 H), 6.23 (d, J ϭ
(400 MHz, CDCl3): δ ϭ 7.74 (d, J ϭ 7.3 Hz, 2 H), 7.57Ϫ7.16 (m,
12 H), 7.11 (dd, J ϭ 8.5, 2.0 Hz, 1 H), 7.08Ϫ7.02 (m, 1 H),
6.82Ϫ6.73 (m, 2 H), 6.14 (d, J ϭ 8.6 Hz, 1 H), 6.00 (dd, J ϭ 15.9, 15.6 Hz, 1 H), 6.03 (dd, J ϭ 15.9, 8.4 Hz, 1 H), 5.81 (d, J ϭ 8.4 Hz,
8.5 Hz, 1 H), 5.81 (d, J ϭ 15.9 Hz, 1 H), 5.12Ϫ4.88 (m, 2 H), 1 H), 5.76Ϫ5.69 (m, 1 H), 5.04Ϫ4.79 (m, 2 H), 4.52Ϫ4.26 (m, 2
4.57Ϫ4.29 (m, 2 H), 4.21Ϫ3.97 (m, 2 H), 3.78 (s, 3 H), 3.74Ϫ3.61 H), 4.13Ϫ3.85 (m, 2 H), 3.69Ϫ3.57 (m, 1 H), 3.30Ϫ3.20 (m, 1 H),
(m, 1 H), 3.29Ϫ3.06 (m, 2 H), 3.01Ϫ2.85 (m, 1 H), 2.82Ϫ2.30 (m,
3.13Ϫ2.93 (m, 2 H), 2.70Ϫ2.23 (m, 4 H), 1.76Ϫ1.43 (m, 3 H), 1.41
4 H), 1.80Ϫ1.52 (m, 3 H), 1.44 (s, 9 H), 1.15 (d, J ϭ 7.1 Hz, 3 H), (s, 9 H), 1.06 (d, J ϭ 7.0 Hz, 3 H), 0.72 (d, J ϭ 6.3 Hz, 3 H), 0.67
1.10 (d, J ϭ 7.1 Hz, 3 H), 0.80 (d, J ϭ 6.3 Hz, 3 H), 0.74 (d, J ϭ (d, J ϭ 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 173.5,
6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 173.6, 171.5,
171.1, 165.3, 153.8, 144.0, 144.2, 136.9, 129.9, 128.5, 127.6, 127.0,
171.2, 171.0, 165.9, 156.0, 144.0, 141.1, 136.6, 131.7, 129.3, 128.5,
127.5, 127.0, 126.0, 125.0, 119.8, 80.5, 70.6, 67.0, 56.5, 47.1, 42.0,
126.0, 125.1, 122.1, 119.9, 112.0, 80.5, 70.7, 67.0, 55.9, 47.1, 44.3, 39.4, 38.5, 34.8, 28.1, 24.6, 22.8, 21.2, 16.8, 14.5 ppm. HRMS (FT-
42.1, 41.0, 37.5, 33.8, 28.1, 24.6, 21.4, 17.5, 14.5 ppm. HRMS (FT-
ICR): calcd. for C54H63ClN2O10 [M ϩ Na]ϩ 957.4063, found
957.4061.
ICR): calcd. for C53H62N2O9 [M
893.4344.
ϩ
Na]ϩ 893.4347, found
Cryptophycin (43): Trifluoroacetic acid (5 mL) was added slowly at
0 °C to a solution of 40 (100 mg, 0.11 mmol) in CH2Cl2 (3 mL),
and the mixture was stirred at room temperature for 2 hours. The
tert-Butyl (2S)-2-{[(2R)-3-({N-[(9H-Fluoren-9-ylmethoxy)carbonyl]-
D-phenylalanyl}amino)-2-methylpropanoyl]oxy}-4-methylpentanoate
(38): A mixture of the amine 33 (150 mg, 0.54 mmol), the Fmoc- solvent was removed in vacuo, and toluene (5 mL) was added.
protected d-phenylalanine (212 mg, 0.54 mmol), and HOBT
(50 mg, 0.37 mmol) in dry THF (3 mL) was treated at 0 °C with
After removal of the solvent in vacuo, the residue was dissolved in
THF (3 mL), and diethylamine (3 mL) was added dropwise at 0 °C.
DCC (166 mg, 0.81 mmol), dissolved in THF (2 mL). The reaction The reaction mixture was stirred for 2 hours at room temperature
mixture was stirred for 7 h at room temperature, filtered, and con- followed by removal of the solvents in vacuo. The crude amino acid
centrated. The residue was diluted with Et2O, and the resulting 37 was dissolved in dry DMF (15 mL) and the mixture was treated
mixture was washed with water. The organic layer was dried with
MgSO4, filtered, and concentrated. The residue was purified by
flash chromatography (30% EtOAc in petroleum ether) to give the
successively with TBTU (60 mg, 0.16 mmol), HOBT (2 mg), and
DIEA (66 µL, 0.38 mmol) at room temperature. The reaction mix-
ture was stirred for 2 hours at room temperature, after which satu-
tripeptide analogue 38 (280 mg, 81%) as a colorless oil. Rf ϭ 0.33. rated NaHCO3 solution (10 mL) was added and stirring was con-
[α]2D4 ϭ Ϫ23.63 (c ϭ 1.25, CH2Cl2). IR (neat): ν˜ ϭ 3064, 2957,
tinued for 1 hour. The mixture was extracted with CH2Cl2 (3 ϫ
2341, 1732, 1665, 1539, 1450, 1246, 1106 cmϪ1 1H NMR 15 mL) and the combined organic layers were dried with MgSO4,
(400 MHz, CDCl3): δ ϭ 7.65 (d, J ϭ 7.3 Hz, 2 H), 7.51Ϫ6.95 (m, filtered, and concentrated. The residue was purified by flash chro-
11 H), 5.49 (d, J ϭ 8.0 Hz, 1 H), 4.91Ϫ4.84 (m, 1 H), 4.45Ϫ4.27 matography (50% EtOAc in petroleum ether) to provide macrocycle
.
324
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 317Ϫ325

Total Synthesis of Cryptophycin 3
FULL PAPER
43 (47 mg, 74%) as a slightly yellow oil. Rf ϭ 0.29. [α]2D4 ϭ 7.04
(c ϭ 0.32, CH2Cl2). IR (neat): ν˜ ϭ 3271, 2960, 1744, 1714, 1675,
M. Kobayashi, W. Wang, N. Ohyabu, M. Kurosu, I. Kitagawa,
[8b]
Chem. Pharm. Bull. 1995, 43, 1598Ϫ1600.
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7792Ϫ7799.
1540, 1457, 1341, 1175 cmϪ1 1H NMR (400 MHz, CDCl3): δ ϭ
.
7.34Ϫ7.13 (m, 10 H), 7.06Ϫ6.99 (m, 1 H), 6.66 (ddd, J ϭ 15.1,
10.0, 4.9 Hz, 1 H), 6.36 (d, J ϭ 15.9 Hz, 1 H), 5.97 (dd, J ϭ 15.9,
8.8 Hz, 1 H), 5.70 (d, J ϭ 15.6 Hz, 1 H), 5.62 (d, J ϭ 8.3 Hz, 1 H),
5.05Ϫ4.94 (m, 1 H), 4.86Ϫ4.74 (m, 2 H), 3.26Ϫ3.22 (m, 2 H), 3.18
(dd, J ϭ 14.1, 5.3 Hz, 1 H), 3.08 (dd, J ϭ 14.4, 7.3 Hz, 1 H),
2.70Ϫ2.60 (m, 1 H), 2.57Ϫ2.44 (m, 2 H), 2.39Ϫ2.26 (m, 1 H),
1.67Ϫ1.54 (m, 2 H), 1.43Ϫ1.36 (m, 1 H), 1.20 (d, J ϭ 8.0 Hz, 3
H), 1.09 (d, J ϭ 6.8 Hz, 3 H), 0.71 (d, J ϭ 6.3 Hz, 3 H), 0.68 (d,
J ϭ 6.3 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ ϭ 175.9,
171.1, 170.8, 165.3, 141.6, 136.7, 131.8, 130.1, 129.2, 128.6, 127.5,
126.9, 126.1, 125.0, 71.1, 53.7, 42.3, 40.8, 39.5, 38.1, 35.9, 24.4,
22.7, 21.2, 17.3, 14.2 ppm. HRMS (FT-ICR): calcd. for
C34H42N2O6 [M ϩ Na]ϩ 597.2935, found 597.2934.
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Acknowledgments
Financial support by the Deutsche Forschungsgemeinschaft (grant
MA 1012/13Ϫ1) and the Fonds der Chemischen Industrie is
gratefully acknowledged. P. Phukan thanks the Alexander von
Humboldt Stiftung for a postdoctoral fellowship.
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For total syntheses of cryptophycin 24 (arenastatin), see:
Eur. J. Org. Chem. 2005, 317Ϫ325
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
325