Synthesis of the C26-C32 Oxazole Fragment of Calyculin C: A Test Case for Oxazole Syntheses

Article abstract of DOI:10.1021/jo971167m

The synthesis of the C₂₆-C₃₂ oxazole fragment 4 and its C₃₂ epimer 20 of serine/threonine protein phosphatase PP1 and PP2A inhibitor calyculin C is presented. The syn methyl arrangement in 4 was established through cyclic stereocontrol. Several methods for oxidizing the intermediate oxazolines 18 and 19 to the finished oxazole fragments were explored. The best results were obtained with oxidations proceeding through the corresponding ester enolate when the carbamate NH side chain was temporarily protected with a TMS group, or with CuBr₂/DBU/HMTA-based oxidations. The finished oxazole fragment 4 was obtained in 21% overall yield, starting from Boc-D-alaninal.

Full text of DOI:10.1021/jo971167m

92
J . Org. Chem. 1998, 63, 92-98
Syn th esis of th e C26-C32 Oxa zole F r a gm en t of Ca lycu lin C: A Test
Ca se for Oxa zole Syn th eses
Petri M. Pihko and Ari M. P. Koskinen*
Department of Chemistry, University of Oulu, Linnanmaa, FIN-90570 Oulu
Received J une 26, 1997X
The synthesis of the C26-C32 oxazole fragment 4 and its C32 epimer 20 of serine/threonine protein
phosphatase PP1 and PP2A inhibitor calyculin C is presented. The syn methyl arrangement in 4
was established through cyclic stereocontrol. Several methods for oxidizing the intermediate
oxazolines 18 and 19 to the finished oxazole fragments were explored. The best results were
obtained with oxidations proceeding through the corresponding ester enolate when the carbamate
NH side chain was temporarily protected with a TMS group, or with CuBr2/DBU/HMTA-based
oxidations. The finished oxazole fragment 4 was obtained in 21% overall yield, starting from Boc-
D-alaninal.
In tr od u ction
The calyculins are a class of highly cytotoxic metabo-
lites isolated from the marine sponge Discodermia calyx
by Fusetani and co-workers.1 To date, a total of 13
different calyculins have been described, the most abun-
dant being calyculins A (1) and C (2) (Figure 1), which
differ from each other only by methyl substitution at C32.
The remaining calyculins are either geometric isomers
of the calyculins A or C, having a different olefin
geometry at either the C2-C3 or at the C6-C7 double
bond,2 or close derivatives of calyculin A (e.g., calyculi-
namides,3 dephosphonocalyculin A4). The relative ster-
eochemistry of calyculin A was determined by X-ray
diffraction, and the structures of the other calyculins
have then been deduced from spectroscopic comparisons
with calyculin A. The absolute stereochemistry, however,
was ascertained only later (1991), by Shioiri et al., who
compared the synthetic C33-C37 amino acid fragment
with the one obtained by hydrolysis of the natural
product by Fusetani.5 Most of the initial synthetic efforts
toward the calyculins had therefore been directed at the
enantiomer of the natural product.6 The Evans group
reported their synthesis of ent-calyculin A7 in 1992, and
later (1994) Masamune et al. published the total synthe-
F igu r e 1.
sis of the natural enantiomer.8 Shioiri et al. have also
reported a formal total synthesis of calyculin A.9
The high cytotoxicity of the calyculins results from
their ability to selectively and efficiently inhibit protein
phosphatases 1 and 2A (PP1 and PP2A), two of the major
enzymes that dephosphorylate serine/threonine residues
of proteins in eukaryotic cells.10 Since a wide variety of
cellular events are regulated by reversible protein phos-
phorylation, protein phosphatase inhibitors have rapidly
gained an important position in the study of intracellular
processes.11 Other naturally occurring toxins known to
inhibit PP1 or PP2A include okadaic acid, the micro-
cystins, nodularin, motuporin, tautomycin, and canthari-
din.12 Of the commercially available PP1/PP2A inhibi-
tors, calyculin A displays both high activity for the
enzymes (the Ki values for PP1 and PP2A are 1.1 and
0.13 nM, respectively) and good cell permeability.13 X-ray
crystal structures are available for the catalytic subunit
X Abstract published in Advance ACS Abstracts, December 15, 1997.
(1) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Fujita,
S.; Furuya, T. J . Am. Chem. Soc. 1986, 108, 2780-2781.
(2) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Koseki,
K. J . Org. Chem. 1988, 53, 3930-3932.
(3) (a) Dumdei, E. J .; Blunt, J . W.; Munro, M. H. G.; Pannell, L. K.
J . Org. Chem. 1997, 62, 2636-2639. (b) Matsunaga, S.; Wakimoto, T.;
Fusetani, N. J . Org. Chem. 1997, 62, 2640-2642.
(4) Matsunaga, S.; Wakimoto, T.; Fusetani, N.; Suganuma, M.
Tetrahedron Lett. 1997, 38, 3763-3764.
(5) (a) Matsunaga, S.; Fusetani, N. Tetrahedron Lett. 1991, 32,
5605-5606. (b) Hamada, Y.; Tanada, Y.; Yokokawa, F.; Shioiri, T.
Tetrahedron Lett. 1991, 32, 5983-5986. (c) See also ref 18.
(6) For leading references to other synthetic approaches to the
calyculins, see: (a) Scarlato, G. R.; DeMattei, J . A.; Chong, L. S.;
Ogawa, A. K.; Lin, M. R.; Armstrong, R. W. J . Org. Chem. 1996, 61,
6139-6152. (b) Ogawa, A. K.; DeMattei, J . A.; Scarlato, G. R.; Tellew,
J . E.; Chong, L. S.; Armstrong, R. W. J . Org. Chem. 1996, 61, 6153-
6161. (c) Trost, B. M.; Flygare, J . A. Tetrahedron Lett. 1994, 35, 4059-
4062. (d) Smith, A. B., III; Salvatore, B. A. Tetrahedron Lett. 1994,
32, 1329-1333. (e) Barrett, A. G. M.; Edmunds, J . J .; Horita, K.;
Parkinson, C. J . J . Chem. Soc., Chem. Commun. 1992, 1236-1238.
(7) Evans, D. A.; Gage, J . R.; Leighton, J . L. J . Am. Chem. Soc. 1992,
114, 9434-9453.
(8) Tanimoto, N.; Gerritz, S. W.; Sawabe, A.; Noda, T.; Filla, S. A.;
Masamune, S. Angew. Chem., Int. Ed. Engl. 1994, 33, 673-675.
(9) Yokokawa, F.; Hamada, Y.; Shioiri, T. Chem. Commun. 1996,
871-872.
(10) For a review of protein phosphatases 1 and 2A, see: Wera, S.;
Hemmings, B. A. Biochem. J . 1995, 311, 17-29.
(11) (a) Zhang, L.; Zhang, Z.; Long, F.; Lee, E. Y. C. Biochemistry
1996, 35, 1606-1611. See also: (b) Bagu, J . R.; Sykes, B. D.; Craig,
M. M.; Holmes, C. F. B. J . Biol. Chem. 1997, 272, 5087-5097.
(12) Holmes, C. F. B.; Boland, M. P. Curr. Opin. Struct. Biol. 1993,
3, 934-943.
(13) Takai, A.; Sasaki, K.; Nagai, H.; Mieskes, G.; Isobe, M.; Isono,
K.; Yasumoto, T. Biochem. J . 1995, 306, 657-665.
S0022-3263(97)01167-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/09/1998

Synthesis of the C26-C32 Oxazole Fragment of Calyculin C
J . Org. Chem., Vol. 63, No. 1, 1998 93
Sch em e 1
F igu r e 2.
Sch em e 2
of rabbit muscle PP1 complexed with microcystin LR,14
for human PP1, and its complex with tungstate.15 The
structural motifs responsible for the binding of micro-
cystin LR to the enzyme appear to be present in calyculin
A, okadaic acid, and tautomycin as well.16 In our
modeling studies, we have developed a spiroketal vector
model for the binding of calyculin A to PP1, proposing
that calyculin A binds to the enzyme in an extended
conformation.17
We have selected calyculin C as our prime synthetic
target. This decision reflects our strategy to utilize amino
acid chemistry for the construction of the northern half
(3) (C26-C37 fragment) of the molecule: the C33-C37
amino acid is derived from L-serine,18 and the C26-C32
oxazole fragment 4, in turn, is derived from D-alanine.19
The illustrated disconnection at C25-C26 parallels the
other published approaches to the calyculins6-9 and
conveniently divides the molecule into two comparably
complex fragments (Scheme 1). In this paper, we disclose
our approach to the C26-C32 oxazole fragment of calyculin
C.
and syn-isomers 8a and 8b in a quantitative yield. The
use of Pt/C instead of Pd/C, or changing the solvent, had
very little effect on the diastereomer ratio.23 Hydrolysis
with NaOH in aqueous THF/MeOH afforded a mixture
of the acids 9a and 9b, from which the pure anti isomer
9a was readily obtained by fractional recrystallization
in 61% yield. Single-crystal X-ray diffraction of 9a
provided a proof of the relative stereochemistry.24
The predominance of the anti-isomer could be rational-
ized on the basis of 1,3-allylic strain:25 the (E)-enoate
adopts a conformation where the si face is hindered by
the Boc group (Figure 2). Since the undesired anti
diastereomer was the major product obtained with the
(E)-enoate, the synthesis was then attempted via the
corresponding (Z)-enoate ent-12 (see Scheme 3), prepared
from Boc-L-alaninal through the Still-Gennari modifica-
tion26 of Horner-Emmons-Wadsworth reaction using
the phosphonate 11. To our surprise, hydrogenation of
ent-1227 over Pd/C gave the esters 8a and 8b in nearly
the same diastereomer ratio (5:3), with the undesired anti-
isomer predominating. In this case, a γ-turn type con-
Resu lts a n d Discu ssion
We initially explored the methodology for constructing
the correct stereochemistry at C30 with L-alanine derived
starting materials, leading to chirality opposite to the
natural product.19 Thus, the known amino aldehyde 520
was olefinated with the phosphorane 6 to afford the
known (E)-enoate 721 in 95% yield with an E:Z ratio 18:1
(Scheme 2). Attempts at hydrogenating the double bond
with the Pfaltz-type bisoxazoline, semicorrin, or pyridyl-
oxazoline ligands and Co(II)/NaBH4 proved unsuccess-
ful.22 Direct hydrogenation over Pd/C in EtOH, however,
cleanly afforded a 2:1 diastereomeric mixture of the anti-
(14) Goldberg, J .; Huang, H.; Kwon, Y.; Greengard, P.; Nairn, A.
C.; Kuriyan, J . Nature 1995, 376, 745-753.
(15) Egloff, M.-P.; Cohen, P. T. W.; Reinemer, P.; Barford, D. J . Mol.
Biol. 1995, 254, 942-959.
(16) Quinn, R. J .; Taylor, C.; Suganuma, M.; Fujiki, H. Bioorg. Med.
Chem. Lett. 1993, 3, 1029-1034.
(23) In a related case, the use of Pt/C instead of Pd/C led to a
remarkable improvement in selectivity: Kauppinen, P. M.; Koskinen,
A. M. P. Tetrahedron Lett. 1997, 38, 3103-3106.
(24) The authors have deposited atomic coordinates for this struc-
ture with the Cambridge Crystallographic Data Centre. The coordi-
nates can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ,
UK.
(17) Lindvall, M. K.; Pihko, P. M.; Koskinen, A. M. P. J . Biol. Chem.
1997, 272, 23312-23316.
(18) Koskinen, A. M. P.; Chen, J . Tetrahedron Lett. 1991, 32, 6977-
6980.
(19) Koskinen, A. M. P.; Pihko, P. M. Tetrahedron Lett. 1994, 35,
7417-7420.
(20) Narita, M.; Otsuka, M.; Kobayashi, S.; Ohno, M.; Umezawa,
Y.; Morishima, H.; Saito, S.; Takita, T.; Umezawa, H. Tetrahedron Lett.
1982, 23, 525-528.
(25) (a) J ohnson, F. Chem. Rev. (Washington, D.C.) 1968, 68, 375.
(b) Hoffmann, R. W. Chem. Rev. (Washington, D.C.) 1989, 89, 1841-
1860.
(21) Itaya, T.; Fujii, T.; Evidente, A.; Randazzo, G.; Surico, G.;
Iacobellis, N. S. Tetrahedron Lett. 1986, 27, 6349-6352.
(22) Leutenegger, U.; Madin, A.; Pfaltz, A. Angew. Chem. 1989, 101,
61-62.
(26) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-4408.
(27) ent-12 was prepared from 5 and 11 as described for 12 (Scheme
3) in 90% yield, see ref 19. In this paper, we report the optimized
procedure for the preparation of enantiomeric 12.

94 J . Org. Chem., Vol. 63, No. 1, 1998
Pihko and Koskinen
Sch em e 4
F igu r e 3.
Sch em e 3
Sch em e 5
Sch em e 6
formation (Figure 3), stabilized by the dipolar interaction
between the NH and the ester groups, could be invoked
to explain the poor selectivity. Allylic isomerization on
the surface of the catalyst can also lead to similar
results.28
A successful route to the desired syn isomer was then
found which involves cyclic stereocontrol, thereby impos-
ing better control over the stereochemistry of the hydro-
genation. The synthetic sequence is shown in Scheme
3, starting from the enantiomeric D-alaninal derivative
10. Cyclization of the (Z)-enoate 12 to the corresponding
lactam 13 under Ragnarsson-Grehn conditions,29 fol-
lowed by hydrogenation over Pd/C, afforded a 10:1
mixture of the syn and anti pyrrolidones 14a and 14b.
Subsequent hydrolysis with lithium hydroperoxide30 gave
the open-chain acids 15a and 15b (Scheme 4), which were
directly carried over to the coupling with L-serine methyl
ester under mixed anhydride conditions31 to afford the
dipeptides 16a and 16b (Scheme 5). These were readily
separable by chromatography. The use of LiOH32 instead
of lithium hydroperoxide in the ring opening led to partial
epimerization at the C30 stereocenter, eroding the ratio
of 15a to 15b to 4:1.
Conversion of 16a to the oxazoline 18 was best ac-
34
complished with the Burgess reagent33,
(Scheme 6).
Thionyl chloride/pyridine also gave the oxazoline, but in
slightly lower yields (75%) and with ca. 5% epimerization
at the C30 stereocenter. The corresponding epi-C32 ox-
azoline 19 was similarly synthesized by coupling the acid
9a with L-serine methyl ester to give the dipeptide 17 in
79% yield after recrystallization (Scheme 5). Dehydra-
tion with the Burgess reagent afforded oxazoline 19 in
82% yield (Scheme 7).
(28) For a review, see: Siegel, S. in Comprehensive Organic Syn-
thesis; Trost, B. M., Series Ed.; Pergamon Press: 1991; Vol. 8, pp 417-
442.
(29) Grehn, L.; Ragnarsson, U. Angew. Chem. 1985, 97, 519-520.
(30) Evans, D. A.; Britton, T. C.; Ellman, J . A. Tetrahedron Lett.
1987, 28, 6141-6144.
(31) For a review, see: Albertson, N. F. Org. React. 1962, 12, 157-
355.
(32) For the use of LiOH in chemoselective hydrolysis of N-Boc
substituted pyrrolidones, see: Flynn, D. L.; Zelle, R. E; Grieco, P. A.
J . Org. Chem. 1983, 48, 2424-2426.
(33) Wipf, P.; Miller, C. P. Tetrahedron Lett. 1992, 33, 907-910.
(34) We eventually found that aqueous workup was necessary to
obtain a clean product. Direct silica gel chromatography of the reaction
mixture, according to the procedure described in ref 33, failed to remove
traces of the reagent.

Synthesis of the C26-C32 Oxazole Fragment of Calyculin C
J . Org. Chem., Vol. 63, No. 1, 1998 95
Sch em e 7
The CuBr2/HMTA/DBU oxidation has been proposed
to proceed via one-electron transfers from the copper
enolate of the oxazoline (Figure 4).39 The KHMDS/I2
oxidation also proceeds via the corresponding ester
enolate, and it is highly conceivable that similar one-
electron transfers accompanied with proton abstraction
by the base are also operating in this oxidation. Overall,
these two oxidation methods gave the cleanest reactions
and best yields.
Con clu sion
A successful route to the C26-C32 oxazole fragment 4
of calyculin C and its C32 epimer 20 has been developed.
For the syn isomer 4, the route involves seven steps
starting from Boc-D-alaninal (21% overall yield), and for
the anti isomer 20, six steps from Boc-L-alaninal (16%
overall yield). The oxidation of the sensitive oxazolines
18 and 19 to the corresponding oxazoles provided an
excellent test case for current oxidation methods. As the
route employed for 4 has provided us with a sufficient
supply of the required oxazole fragment in high purity,
studies toward the total synthesis of calyculin C are
ongoing and progress will be reported in due course.
Several novel methods for oxidizing oxazolines to the
oxazoles have been disclosed in recent years. We thus
began exploring them with high hopes. Table 1 sum-
marizes our results obtained with different oxidation
methods. Heterogeneous oxidants (activated MnO2,35
NiO236) led to poor and irreproducible yields, even in the
presence of added base.37 Copper(II) acetate-mediated
oxidation in the presence of tert-butyl perbenzoate38 led
to extensive fragmentation and poor yields. The best
results were obtained with either the CuBr2/HMTA/DBU
oxidation,39 or with our own method involving temporary
TMS protection of the carbamate nitrogen,40 deprotona-
tion of the oxazoline with KHMDS, and oxidation of the
intermediate enolate via the phenyl selenide7 or, even
more cleanly, directly with iodine.41 The use of TMS as
a temporary protecting group for the carbamate NH was
selected as all attempts to protect the oxazoline NH
effectively with either another Boc group or with more
bulkier silyl groups had failed (the use of LiHMDS at
higher temperatures led to decomposition of the oxazo-
line). Without the TMS protection step, all oxidation
methods involving proton abstraction from the oxazoline
with KHMDS (or LDA) led to poor yields, even with an
excess of the reagents.
The CuBr2/HMTA/DBU oxidation and the KHMDS/I2
oxidation gave nearly identical yields of the oxazoles 4
and 20. Both oxidation methods also yielded the same,
isomeric side products.42 We were able to improve the
combined yield of the product and the side product up to
82%, but the formation of the side products could not be
completely suppressed.43 The fact that the side products
were formed also with the KHMDS/I2 oxidation was
thought to be the result of an incomplete reaction at the
TMS protection step.44,45 However, all attempts at
improving this step (changing the temperature, the use
of TMSOTf instead of TMSCl, or the use of in situ quench
conditions46) failed.
Exp er im en ta l Section
Gen er a l. Melting points are uncorrected. Optical rotations
were measured at 22 °C. 1H and 13C NMR spectra were
(42) The structures of the side products have tentatively been
assigned as i and ii (both being mixtures of diastereomers due to the
presence of an additional chiral spiro atom):
Complete listings of 1H NMR, 13C NMR, and IR resonances as well as
the HRMS data are given in the Supporting Information. For i,
indicative long-range 1H-13C couplings and the corresponding 13C
chemical shifts are given below; similar correlations are also observed
for ii. The absence of N-H stretching in their IR spectra at 3400 cm-1
and their isomeric composition with the oxazoles 4 and 20 (as evidenced
by the HRMS data) are also indicative evidence for their structures.
(43) In contrast with the results obtained by Pen˜a and co-workers
(see ref 41), in our case all oxidations with iodine proceeded to
completion, with no traces of the starting oxazoline left. The CuBr2/
HMTA/DBU oxidations also proceeded to completion within 2-3 h.
(35) (a) Shin, C.; Nakamura, Y.; Okumura, K. Chem. Lett. 1993,
1405-1408. (b) Hamada, Y.; Shibata, M.; Sugiura; T.; Kato; S.; Shioiri,
T. J . Org. Chem. 1987, 52, 1252-1255.
(36) Evans, D. L.; Minster, D. K.; J ordis, U.; Hecht, S. M.; Mazzu,
A. L., J r.; Meyers, A. I. J . Org. Chem. 1979, 44, 497-501.
(37) Eastwood, F. W.; Perlmutter, P.; Yang, Q. Tetrahedron Lett.
1994, 35, 2039-2042.
(38) (a) Meyers, A. I.; Tavares, F. X. J . Org. Chem. 1996, 61, 8207-
8215. (b) Tavares, F. X.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
6803-6806.
(39) Barrish, J . C.; Singh, J .; Spergel, S. H.; Han, W.; Kissick, T.
P.; Kronenthal, D. R.; Mueller, R. H. J . Org. Chem. 1993, 58, 4494-
4496.
(40) Carstens, A. Ph.D. Dissertation, Christian-Albrechts-Univer-
sita¨t zu Kiel, 1993.
(41) Garey, D.; Ramirez, M.; Gonzales, S.; Wertsching, A.; Tith, S.;
Keefe, K.; Pen˜a, M. R. J . Org. Chem. 1996, 61, 4853-4856.
(44) Our failure to prevent
i and ii from forming despite our
attempts to improve the N-silylation step could also be explained if
they are formed as follows: intramolecular silyl transfer to the enolate
anion (Brook rearrangement), cyclization of the resulting carbamate
nitrogen-centered anion, and final loss of TMS from the ester. We
thank the anonymous reviewer for pointing out this possibility.
(45) The two methyl substituents are likely to considerably enhance
the rate of cyclization and thus favor the formation of the side product.
For an excellent discussion of this reactive rotamer effect, see: (a) J ung,
M. E.; Gervay, J . J . Am. Chem. Soc. 1991, 113, 224-232. For recent
studies of this effect with other than gem-dialkyl substituents, see:
(b) De Corte, F.; Nuyttens, F.; Cauwberghs, S.; De Clercq, P. Tetra-
hedron Lett. 1993, 34, 1831-1832. (c) Agami, C.; Couty, F.; Hamon,
L.; Venier, O. Tetrahedron Lett. 1993, 34, 4509-4512.
(46) Price, D. A.; Simpkins, N. S.; Macleod, A. M.; Watt, A. P. J .
Org. Chem. 1994, 59, 1961-1962.

96 J . Org. Chem., Vol. 63, No. 1, 1998
Pihko and Koskinen
Ta ble 1. Oxid a tion of Oxa zolin es 18 or 19 to th e Cor r esp on d in g Oxa zoles 4 or 20
entry
substrate
product
reagents and conditions
reaction time
18 h
48 h
10-20 h
9 h
yield (%)
reference
1
2
3
4
5
18
18
18
18
18
4
4
4
4
4
MnO2, PhH, cat. pyridine, 55 °C
NiO2, CH2Cl2, cat. DBU
NiO2, PhH, rfx
CuBr, Cu(OAc)2, t-BuOOBz, PhH, rfx
(1) (i) LiHMDS, (ii) TMSCl, (iii) KHMDS,
(iv) PhSeBr; THF, -78 °C; (2) H2O2, pyr,
CH2Cl2, 0 °C
(i) LiHMDS, (ii) TMSCl, (iii) KHMDS,
(iv) I2; THF, -78 to -60 °C (i-iv) to
0 °C (iv)
0a
35
27-39b
20-30c
27d
36, 37
36
38
(1) i-iv: 10-20
min each; (2): 2 h
42e
7, 40, this work
6
18
4
i-iii: 10-20
min each (iv):
30 min-4 h
3 h
42f
42g
40, 41, this work
7
19
20
CuBr2, DBU, HMTA; CH2Cl2, rt
39
a
b
d
The reaction fails also with activated MnO2. The yields were not reproducible. c Extensive decomposition observed. The product
was difficult to purify, and polymerization and decomposition of the starting material were also observed. e The use of LDA instead of
KHMDS gave 4 in a similar yield. f The side product i was also isolated in 26% yield. The side product ii was also isolated in 40% yield.
g
Prolonged reaction times led to loss of yield (20-25% instead of 42%).
minum hydride (162 mL, 1 M solution in toluene, 0.162 mol,
170 mol %) via cannula over a period of 45 min while
maintaining the internal temperature below -69 °C. The
mixture was stirred for 15 min, and precooled (-75 °C)
methanol (60 mL) was added via cannula. During the addi-
tion, the reaction mixture was maintained below -69 °C. The
mixture was then allowed to warm to 5 °C, and 200 g of ice
was added with heavy agitation, followed by 100 mL of 2 M
HCl. The cloudy, gellike mixture was extracted with EtOAc
(3 × 100 mL), and the combined extracts were washed with
brine (100 mL), dried (MgSO4), and concentrated. The crude
F igu r e 4.
product thus obtained was allowed to solidify and then washed
with cold hexane (20 mL) to give the first crop of 10.
recorded in CDCl3. s ) singlet, d ) doublet, t ) triplet, q )
quartet, m ) multiplet, br ) broad, app ) apparent.
Analytical thin-layer chromatography was performed on
Merck 0.25 mm silica gel 60 F plates. For visualization, UV
light and ninhydrin solution followed by heating were used.
Flash chromatography was performed on Merck silica gel 60
(230-400 mesh).
Concentration of the mother liquor and dry flash chromatog-
raphy (100 g of silica, 15% EtOAc:hexanes to 33% EtOAc:
hexanes) afforded a further crop of the aldehyde 10 as a white
crystalline solid; combined yield 11.06 g (71%). [R]D ) +36.2
(c ) 1.00, MeOH), mp 88 °C (lit.21 [R]18 ) +35.2 (c ) 1.00,
D
MeOH), mp 90-91 °C), 1H NMR (200 MHz) δ 9.57 (s, 1 H),
5.11 (m, 1 H), 4.25 (m, 1 H), 1.46 (s, 9 H), 1.34 (d, 1 H, J ) 7.2
Hz).
All reactions involving nonaqueous media were conducted
under a positive pressure of argon, and the solvents and
reagents were dried prior to use. Tetrahydrofuran was
distilled from sodium metal/benzophenone ketyl. N-Methyl
morpholine, toluene, and benzene were distilled from sodium
metal. Acetonitrile was distilled from phosphorus pentoxide.
Dichloromethane was distilled from calcium hydride. Ethyl
acetate was distilled from potassium carbonate. Methanol was
distilled from Mg(OMe)2. Triethylamine was distilled prior
to use. All other commercial reagents were used as received.
N-(ter t-Bu toxyca r bon yl)-D-a la n in a l (10). Acetyl chloride
(12.0 mL, 13.26 g, 0.169 mol, 167 mol %) was added dropwise
to dry methanol (200 mL) at 5 °C. To this was added D-alanine
(8.98 g, 0.101 mol, 100 mol %), and the mixture was heated to
reflux for 5 days. Concentration afforded the crude methyl
ester hydrochloride (14.2 g, 101% mass balance) as a white
solid, which was used in the next step without further
purification.
[2E,4S]-4-((ter t-Bu toxycar bon yl)am in o)-2-m eth yl-2-pen -
ten oic Acid , Meth yl Ester (7). To a solution of phosphorane
6 (1.92 g, 5.5 mmol, 110 mol %) in dichloromethane (10 mL)
at rt was added aldehyde 5 (0.87 g, 5.0 mmol, 100 mol %)
dissolved in CH2Cl2 (7 mL). An exothermic reaction ensued.
After 1 h at rt, the reaction mixture was concentrated and then
triturated with EtOAc:hexanes (1:5, 30 mL) to induce crystal-
lization. Filtration (3 × 10 mL 1:5 EtOAc:hexanes rinse),
concentration, and purification of the residue by flash chro-
matography (4 × 5 cm silica, gradient of 17% EtOAc:hexanes
to 33% EtOAc:hexanes) afforded the crude product as a solid
(1.15 g, 95%). Recrystallization from hexanes afforded the
pure (E)-isomer 7 (985 mg, 81%): mp 79 °C (lit.21 mp 79-80
°C), 1H NMR (200 MHz) δ 6.52 (dq, 1 H, J ) 8.7, 1.4 Hz), 4.52
(m, 2 H), 3.74 (s, 3 H), 1.92 (d, 3 H, J ) 1.4 Hz), 1.43 (s, 9 H),
1.22 (d, 3 H, J ) 6.5 Hz).
[2S/R,4S]-4-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h yl-
p en ta n oic Acid , Meth yl Ester (8a /8b). To a solution of
ester 7 (10.49 g, 43.1 mmol) in ethyl acetate (300 mL) was
added 10% Pt/C (0.44 g), and the flask was then flushed with
argon and finally with hydrogen. The reaction mixture was
hydrogenated under atmospheric pressure at rt for 14 h, after
which it was filtered through a pad of Celite (3 × 40 mL EtOH
rinse) and concentrated. Trituration with isooctane (50 mL)
induced solidification, yielding, after drying, the product as a
The crude ester obtained above was dissolved in a mixture
of dichloromethane (200 mL) and methanol (10 mL), and the
mixture was cooled to 5 °C. To this was added triethylamine
(17.4 mL, 12.7 g, 0.125 mol, 125 mol %) and di-tert-butyl
dicarbonate (22.04 g, 0.101 mol, 100 mol %). The mixture was
allowed to warm to rt. After 1 h, the mixture was warmed to
35 °C and stirred at that temperature overnight. After
concentration, the mixture was partitioned between 7% citric
acid solution (150 mL) and diethyl ether (300 mL). The
aqueous layer was extracted twice more with 50-mL portions
of diethyl ether. The combined extracts were washed with
saturated NaHCO3 (2 × 40 mL) and brine, dried (MgSO4), and
concentrated to afford the protected ester (19.39 g, 95%) as a
solid, which was employed in the next step without further
purification.
2:1 diastereomer mixture of 8a /8b (10.54 g, 100%): [R]D
)
+17.3 (c ) 1.78, MeOH); mp 41-49 °C; IR (CDCl3) 3442, 2979,
1708, 1503, 1455, 1367, 1251, 1163 cm-1; major diastereomer
8a : 1H NMR (200 MHz) δ 4.30 (m, 1 H), 3.72 (m, 1 H), 3.67 (s,
3 H), 2.52 (app dq, 1 H, J ) 7.0 Hz), 1.78 (m, 1 H), 1.48 (m, 1
H), 1.42 (s, 9 H), 1.16 (d, 3 H, J ) 7.1 Hz), 1.10 (d, 3 H, J )
6.6 Hz); minor diastereomer 8b 1H NMR δ 4.30 (m, 1 H), 3.72
(m, 1 H), 3.66 (s, 3 H), 2.52 (app dq, 1 H, J ) 7.0 Hz), 1.78 (m,
2 H), 1.42 (s, 9 H), 1.17 (d, 3 H, J ) 6.9 Hz), 1.12 (d, 3 H, J )
The crude protected ester obtained above (18.30 g, 90 mmol,
100 mol %) was dissolved in toluene (200 mL) and cooled to
-80 °C. To this was added precooled (-70 °C) diisobutylalu-

Synthesis of the C26-C32 Oxazole Fragment of Calyculin C
J . Org. Chem., Vol. 63, No. 1, 1998 97
6.6 Hz). Anal. Calcd for C12H23NO4: C, 58.75; H, 9.45; N, 5.71.
Found: C, 58.80; H, 9.82, N, 5.76.
H, J ) 6.1 Hz), 2.59-2.33 (m, 2 H), 1.54 (s, 9 H), 1.39 (d, 3 H,
J ) 6.1 Hz), 1.25 (d, 3 H, J ) 6.9 Hz), 1.25 (m, 1 H); 13C NMR
(50 MHz) δ 177.1, 150.5, 82.7, 52.2, 37.6, 34.5, 28.1, 22.1, 16.4.
HRFABMS calcd for MH+ (C11H20NO3) 214.1443, found:
214.1436, ∆ ) 3.3 ppm.
[2S,4S]-4-((ter t-Bu toxyca r bon yl)a m in o)-2-m eth ylp en -
ta n oic Acid (9a ). To a solution of ester 8a /8b (2:1 mixture
of two diastereomers) (2.36 g, 9.36 mmol, 100 mol %) in 1:1
THF/methanol (40 mL) at rt was added 1 M NaOH (14.4 mL,
14.4 mmol, 154 mol %), and the resulting clear solution was
stirred at rt for 16 h. The solution was cooled in ice, acidified
with 1 M HCl (20 mL), and extracted with EtOAc (4 × 20 mL).
The combined extracts were dried (MgSO4) and concentrated.
The clear oil thus obtained solidified in high vacuum, yielding
the crude product as a white solid (2.22 g, 100%). The major
product 9a was obtained by recrystallization from Et2O:
hexanes (1:1) as a white crystalline solid (1.36 g, 61%): mp
112-114 °C, [R]D ) +21.5 (c ) 1.00, MeOH); IR (CDCl3) 3437,
2980, 1744, 1708, 1513, 1455, 1368, 1252, 1163 cm-1; 1H NMR
(400 MHz) δ 4.53 (m, 1 H), 3.77 (m, 1 H), 2.53 (m, 1 H), 1.79
(m, 1 H), 1.45 (m, 1 H), 1.45 (s, 9 H), 1.19 (d, 3 H, J ) 6.8 Hz),
1.15 (d, 3 H, J ) 6.5 Hz); 13C NMR (100 MHz) δ 179.1, 156.7,
[2S/R,4R]-4-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h yl-
p en ta n oic Acid (15a /15b). Hydrogen peroxide (30% solution,
7.0 mL, 400 mol %) and lithium hydroxide monohydrate (1.45
g, 34.6 mmol, 200 mol %) were added to a solution of
pyrrolidones 14a /14b (3.67 g, 17.2 mmol, 100 mol %, 10:1
mixture of diastereomers) in 4:1 THF:water (125 mL) at 0 °C.
The resultant cloudy mixture was stirred at 0 °C for 12 h.
Saturated Na2SO3 (50 mL) and 1 M NaOH (100 mL) were then
added, and the solution was washed with CH2Cl2 (2 × 200 mL).
After acidification to pH ) 2 with 0.5 M phosphoric acid, the
mixture was extracted with EtOAc (5 × 100 mL). The
combined EtOAc extracts were dried (Na2SO4) and concen-
trated to afford acid 15a /15b as a clear oil, which solidified to
a white crystalline mass (3.65 g, 92%): [R]D ) +1.8 (for the
mixture of diastereomers 15a and 15b, c ) 1.00, MeOH), mp
73 °C (for an isolated crystal of 15a ); IR (CDCl3) 3438, 2979,
1708, 1504, 1455, 1393, 1368, 1248, 1163, 1072 cm-1; 1H NMR
(200 MHz) δ 11.19 (br s, 1 H), 4.41 (m, 1 H), 3.72 (m, 1 H),
2.48 (m, 1 H), 1.82 (m, 1 H), 1.50-1.36 (obs m, 1 H), 1.41 (s,
9 H), 1.22-1.13 (m, 3 H), 1.10 (d, 3 H, J ) 6.6 Hz); HRFABMS
calcd for MH+ (C11H22NO4): 232.1549, found: 232.1531, ∆ )
7.8 ppm. Anal. Calcd for C11H21NO4: C, 57.12; H, 9.15; N,
6.06. Found: C, 56.81; H, 9.27; N, 6.05.
[2S,2(2S,4R)]-Meth yl 2-[4-((ter t-Bu toxycar bon yl)am in o)-
2-m eth yl-1-oxopen tyl)am in o]-3-h ydr oxypr opion ate (16a).
To a solution of acid 15a /15b (4.22 g, 18.2 mmol, 100 mol %,
10:1 mixture of diastereomers) in THF (120 mL) at -25 °C
was added N-methylmorpholine (2.05 mL, 1.88 g, 18.6 mmol,
105 mol %), followed by isobutyl chloroformate (2.41 mL, 2.54
g, 18.6 mmol, 105 mol %). The resultant cloudy mixture was
stirred at -25 °C for 10 min, and L-serine methyl ester
hydrochloride (2.90 g, 18.6 mmol, 105 mol %) was then added,
followed by N-methylmorpholine (2.35 mL, 2.16 g, 21.4 mmol,
120 mol %). The mixture was allowed to gradually warm to
rt. After 16 h, the mixture was quenched with 7% NaHCO3
solution (300 mL) and extracted with EtOAc (5 × 150 mL).
The combined extracts were dried (Na2SO4) and concentrated
to afford a viscous oil which was purified by flash chromatog-
raphy (6 × 20 cm of silica, linear gradient of 17% acetone:
CHCl3 to 30% acetone:CHCl3) to yield diastereomerically pure
16a as a white, crystalline solid (4.89 g, 81%): [R]D ) +16.0
(c ) 1.38, MeOH); mp 124 °C; IR (CDCl3) 3442, 2979, 1745,
1684, 1506, 1369, 1249, 1163, 1077 cm-1; 1H NMR (200 MHz)
δ 6.92 (d, 1 H, J ) 7.7 Hz), 4.70 (m, 2 H), 4.21 (app t, 1 H, J
) 7.0 Hz), 3.99 (m, 2 H), 3.79 (s, 3 H), 3.60 (m, 1 H), 2.44 (ddq,
1 H, J ) 4.9, 7.0, 10.2 Hz), 1.92 (app ddd, 1 H, J ) 4.9, 10.2
Hz), 1.44 (m, 1 H), 1.42 (s, 9 H), 1.24 (d, 3 H, J ) 6.9 Hz), 1.16
(d, 3 H, J ) 6.6 Hz); 13C NMR δ 175.5, 171.1, 155.7, 80.0, 63.0,
54.7, 52.5, 45.2, 41.6, 39.2, 28.4, 20.3, 18.8. Anal. Calcd for
C15H28N2O6: C, 54.20; H, 8.49; N, 8.43. Found: C, 53.97; H,
8.42; N, 8.33.
80.4, 45.0, 42.8, 36.8, 28.3, 21.5, 17.7. Anal. Calcd for C11H21
-
NO4: C, 57.12; H, 9.15; N, 6.06. Found: C, 57.37; H, 9.49; N,
6.12.
[2Z,4R]-4-((ter t-Bu t oxyca r b on yl)a m in o)-2-m et h yl-2-
p en ten oic Acid , Meth yl Ester (12). Potassium carbonate
(29.59 g, 0.214 mol, 600 mol %) and 18-crown-6 (18.86 g, 71.4
mmol, 200 mol %) were stirred at rt in toluene (100 mL) and
acetonitrile (10 mL) for 1 h, and the mixture was cooled to
-12 °C. To this was added a solution of aldehyde 10 (6.18 g,
35.7 mmol, 100 mol %) and phosphonate 11 (11.85 g, 35.7
mmol, 100 mol %) in toluene (45 mL). The reaction mixture
was stirred at -12 °C for 5 h and then quenched with 200 mL
of 25% citric acid solution. Extraction with EtOAc (3 × 150
mL), followed by washing of the combined extracts with brine
(100 mL), drying (MgSO4), and concentration afforded an oil
which was purified by flash chromatography (5 × 20 cm of
silica, 18% EtOAc:hexanes) to afford the ester 12 as a white,
crystalline solid (8.37 g, 96%): [R]D ) -66.9 (c ) 1.00, MeOH);
mp 49-50 °C; IR (CDCl3) 3445, 2981, 1712, 1497, 1454, 1368,
1
1230, 1156, 1048 cm-1; H NMR (200 MHz) δ 5.80 (br d, 1 H,
J ) 8.3 Hz), 4.95 (m, 1 H), 4.56 (m, 1 H), 3.75 (s, 3 H), 1.90 (d,
3 H, J ) 1.3 Hz), 1.45 (s, 9 H), 1.24 (d, 3 H, J ) 6.8 Hz); 13C
NMR (50 MHz) δ 187.9, 155.1, 145.0, 126.7, 79.3, 51.5, 45.9,
28.4, 20.8, 20.4. Anal. Calcd for C12H21NO4: C, 59.24; H, 8.70;
N, 5.76. Found: C, 59.09; H, 8.66; N, 5.75.
[5R]-N-(ter t-Bu toxyca r bon yl)-3,5-d im eth yl-3-p yr r olin -
2-on e (13). To a solution of ester 12 (1.92 g, 7.89 mmol, 100
mol %) in acetonitrile (15 mL) were added 4-(dimethylami-
no)pyridine (116 mg, 0.95 mmol, 12 mol %) and di-tert-butyl
dicarbonate (1.90 g, 8.70 mmol, 110 mol %). The solution was
stirred for 48 h at rt, during which time it gradually turned
red. More 4-(dimethylamino)pyridine (60 mg, 0.49 mmol, 6
mol %) and di-tert-butyl dicarbonate (1.32 g, 6.05 mmol, 77
mol %) were added, and the mixture was stirred for a further
72 h at rt. Concentration followed by purification of the
residue by flash chromatography (4 × 18 cm silica, 1:4 EtOAc:
hexanes) afforded the lactam 13 as a crystalline solid (1.40 g,
84%): [R]D ) -117.1 (c ) 1.00, MeOH); mp 67-68 °C; IR
[2S,2(2S,4S)]-Meth yl 2-[4-((ter t-Bu toxycar bon yl)am in o)-
2-m eth yl-1-oxop en tyl)a m in o]-3-h yd r oxyp r op ion a te (17).
Following the procedure given for 16a , acid 9a (4.22 g, 18.3
mmol, 100 mol %) afforded, after recrystallization of the
product from Et2O-hexanes, the dipeptide 17 as a crystalline
solid (4.79 g, 79%): [R]D ) +6.4 (c ) 1.01, MeOH); mp 126 °C;
IR (CDCl3) 3434, 3303, 2980, 1748, 1672, 1513, 1456, 1437,
1368, 1249, 1161, 1085 cm-1; 1H NMR (400 MHz) δ 7.91 (br d,
1 H, J ) 7.0 Hz), 4.50 (m, 2 H), 4.06-3.91 (m, 3 H), 3.76 (s, 3
H), 3.20 (unresolved t, 1 H, J ) 5.9 Hz), 2.40 (m, 1 H), 1.78
(app ddd, 1 H, J ) 2.7, 11.3, 14.0 Hz), 1.43 (s, 9 H), 1.30 (app
t, 1 H, J ) 11.5 Hz), 1.16-1.12 (two overlapping doublets, 6
H, J ) 6.7, 8.6 Hz); 13C NMR (100 MHz) δ 176.3, 170.8, 156.8,
80.1, 63.0, 55.4, 52.4, 44.8, 43.9, 37.1, 28.4, 22.2, 17.9. Anal.
Calcd for C15H28N2O6: C, 54.20; H, 8.49; N, 8.43. Found: C,
54.33; H, 8.63; N, 8.42.
(CDCl3) 2982, 1771, 1721, 1371, 1350, 1330, 1282, 1161 cm-1
;
1H NMR (200 MHz) δ 6.72 (dq, 1 H, J ) 1.7, 2.1 Hz), 4.47 (dq,
1 H, J ) 2.1, 6.6 Hz), 1.66 (t, 3 H, J ) 1.7 Hz), 1.56 (s, 9 H),
1.39 (d, 3 H, J ) 6.6 Hz); 13C NMR (100 MHz) δ 169.9, 149.6,
144.8, 133.5, 82.6, 56.0, 28.1, 18.3, 10.8. Anal. Calcd for
C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.47; H,
7.80; N, 6.44.
[3S/R,5R]-N-(ter t-Bu toxyca r bon yl)-3,5-d im eth yl-2-p yr -
r olid on e (14a /14b). To a solution of lactam 13 (1.79 g, 8.47
mmol) of in 50 mL of EtOH was added 10% Pd/C (110 mg),
and the round-bottomed flask was then flushed with argon
and finally with hydrogen. The mixture was hydrogenated
at atmospheric pressure for 24 h, filtered through Celite
(followed by 4 × 15 mL EtOH rinse), and concentrated to give
the pyrrolidones 14a /14b as a 10:1 mixture of diastereomers
(GC) (1.82 g, 100%): colorless oil, [R]D ) -55.2 (c ) 1.00,
MeOH); IR (CDCl3) 2979, 2936, 1775, 1714, 1457, 1370, 1343,
[4S,2(1S,3R)]-2-[3-((ter t-Bu toxyca r bon yl)a m in o)-1-m e-
th ylbu tyl]-2-oxa zolin e-4-ca r boxylic Acid , Meth yl Ester
(18). To dipeptide 16a (2.49 g, 7.49 mmol, 100 mol %)
1
1292, 1257, 1154 cm-1; H NMR (200 MHz) δ 4.03 (app dq, 1

98 J . Org. Chem., Vol. 63, No. 1, 1998
Pihko and Koskinen
dissolved in THF (100 mL) at 0 °C was added Burgess reagent
(2.05 g, 8.61 mmol, 115 mol %) over a period of 10 min, and
the resulting solution was stirred for a further 15 min at 0
°C. The solution was then heated to reflux for 2 h, allowed to
cool, and stirred at rt for 8 h. Evaporation of the solvent left
a residue which was partitioned between saturated NH4Cl (75
mL) and benzene (75 mL). The layers were separated, and
the aqueous layer was extracted with benzene (2 × 75 mL).
The combined organic extracts were dried (Na2SO4) and
concentrated. The resulting oil was purified by flash chroma-
tography (5 × 19 cm silica, 70% EtOAc:hexanes), giving 1.97
g (84%) of oxazoline 18 as a colorless oil: [R]D ) +109.8 (c )
1.28, MeOH); IR (CDCl3) 3439, 2979, 1740, 1706, 1653, 1506,
gradient of 30% EtOAc:hexanes to 35% EtOAc:hexanes),
yielding the side product i as a colorless oil (500 mg, 26%),
followed by oxazole 4 as a solid (840 mg, 42%): [R]D ) +35.4
(c ) 1.00, MeOH); mp 55-56 °C (Et2O/hexanes) (lit.47 for ent-
4: [R]27 ) -30.6 (c ) 0.9, MeOH); mp 50-53 °C); IR (CDCl3)
D
3438, 2979, 1708, 1597, 1503, 1440, 1368, 1326, 1246, 1159,
1
1112 cm-1; H NMR (400 MHz) δ 8.13 (s, 1 H), 4.24 (m, 1 H),
3.88 (s, 3 H), 3.75 (m, 1 H), 3.10 (app dq, 1 H, J ) 6.7 Hz),
1.94 (ddd, 1 H, J ) 6.2, 9.6, 14.0 Hz), 1.68 (m, 1 H), 1.39 (s, 9
H), 1.36 (d, 3 H, J ) 7.0 Hz), 1.12 (d, 3 H, J ) 6.5 Hz); 13C
NMR (100 MHz) δ 169.2, 161.7, 155.2, 143.6, 133.0, 79.1, 52.0,
44.4, 42.2, 31.0, 28.3, 22.0, 18.2. Anal. Calcd for C15H24N2O5:
C; 57.68, H; 7.74; N; 8.97. Found: C; 57.91, H; 7.85, N, 9.06.
[4S,2(1S,3S)]-2-[3-((ter t-Bu toxyca r bon yl)a m in o)-1-m e-
th ylbu tyl]-2-oxazole-4-car boxylic Acid, Meth yl Ester (20).
To a suspension of CuBr2 (721 mg, 3.23 mmol, 400 mol %) in
degassed CH2Cl2 (20 mL) at rt was added hexamethylenetet-
ramine (453 mg, 3.23 mmol, 400 mol %) as a solid, followed
by addition of DBU (483 mL, 492 mg, 3.23 mmol, 400 mol %).
The reaction mixture turned dark brown. After cooling to 0
°C, a solution of oxazoline 19 (254 mg, 0.808 mmol, 100 mol
%) in degassed CH2Cl2 (10 mL) was added via cannula. The
reaction mixture was allowed to gradually warm to rt. After
3.5 h, a 1:1 solution of saturated NH4Cl and 25% aqueous NH3
(50 mL) was added, and the blue mixture was extracted with
EtOAc (3 × 50 mL). The combined organic extracts were
washed with brine (30 mL), dried (Na2SO4), and concentrated.
The crude product thus obtained was purified by flash chro-
matography (3 × 17 cm, linear gradient of 30% EtOAc:hexanes
to 35% EtOAc:hexanes) to afford the side product ii as a solid
mass (100 mg, 40%), followed by oxazole 20 as a colorless oil
(105 mg, 42%): [R]D ) +42.5 (c ) 0.84, MeOH); IR (CDCl3)
3442, 2980, 1708, 1587, 1502, 1440, 1367, 1326, 1161, 1113
1
1438, 1367, 1216, 1161 cm-1; H NMR (400 MHz) δ 4.71 (dd,
1 H, J ) 10.7, 7.8 Hz), 4.45 (t, 1 H, J ) 8.6 Hz), 4.42 (m, 1 H),
4.39 (dd, 1 H, J ) 8.6, 10.7 Hz), 3.78 (s, 3 H), 3.72 (m, 1 H),
2.59 (app dq, 1 H, J ) 7.0 Hz), 1.83 (ddd, 1 H, J ) 7.0, 10.2,
13.7 Hz), 1.54 (m, 1 H), 1.41 (s, 9 H), 1.21 (d, 3 H, J ) 7.0 Hz),
1.12 (d, 3 H, J ) 6.4 Hz); 13C NMR (100 MHz) δ 174.4, 171.8,
155.3, 79.0, 69.3, 67.8, 52.6, 44.6, 41.4, 30.8, 28.4, 22.1, 17.7;
HRFABMS calcd for MH+ (C15H27N2O5): 315.1920, found
315.1877, ∆ ) 14 ppm.
[4S,2(1S,3S)]-2-[3-((ter t-Bu toxyca r bon yl)a m in o)-1-m e-
th ylbu tyl]-2-oxa zolin e-4-ca r boxylic Acid , Meth yl Ester
(19). Following the procedure given for 18, dipeptide 17 (1.00
g, 3.01 mmol) similarly afforded oxazoline 19 as a colorless
oil (0.78 g, 82%): [R]D ) +104.4 (c ) 1.62, MeOH); IR (CDCl3)
3443, 2979, 1740, 1707, 1656, 1503, 1438, 1367, 1216, 1174
1
cm-1; H NMR (400 MHz) δ 4.71 (dd, 1 H, J ) 7.8, 10.5 Hz),
4.45 (m, 1 H), 4.44 (t, 1 H, J ) 8.6 Hz), 4.38 (dd, 1 H, J ) 8.6,
10.5 Hz), 3.76 (s, 3 H), 3.70 (m, 1 H), 2.64 (m, 1 H), 1.80 (m, 1
H), 1.60 (m, 1 H), 1.41 (s, 9 H), 1.18 (d, 3 H, J ) 7.0 Hz), 1.11
(d, 3 H, J ) 6.7 Hz); 13C NMR (100 MHz) δ 173.8, 171.7, 155.1,
79.0, 69.2, 67.9, 52.5, 44.8, 40.7, 30.5, 28.4, 20.8, 17.9; HR-
FABMS calcd for MH+ (C15H27N2O5): 315.1920, found 315.1917,
∆ ) 1.0 ppm.
1
cm-1; H NMR (400 MHz) δ 8.14 (s, 1 H), 4.29 (m, 1 H), 3.90
(s, 3 H), 3.68 (m, 1 H), 3.14 (app dq, 1 H, J ) 7.0 Hz), 2.00
(ddd, 1 H, J ) 5.9, 8.3, 14 Hz), 1.75 (m, 1 H), 1.40 (s, 9 H),
1.35 (d, 3 H, J ) 7.0 Hz), 1.11 (d, 3 H, J ) 6.7 Hz); 13C NMR
(100 MHz) δ 168.9, 161.8, 155.0, 143.6, 133.1, 79.1, 52.0, 44.7,
41.8, 30.9, 28.3, 21.0, 18.8; HRFABMS calcd for MH+
(C15H25N2O5): 313.1763, found 313.1747, ∆ ) 5.1 ppm.
[4S,2(1S,3R)]-2-[3-((ter t-Bu toxyca r bon yl)a m in o)-1-m e-
th ylbu tyl]-2-oxa zole-4-ca r boxylic Acid , Meth yl Ester (4).
A solution of lithium hexamethyldisilazide in THF was
prepared as follows: To a solution of hexamethyldisilazane
(1.45 mL, 1.11 g, 6.89 mmol, 110 mol %) in THF (15 mL) at
-78 °C was added n-butyllithium (2.35 M solution in hexanes,
2.95 mL, 6.89 mmol, 110 mol %), and the resulting clear
solution was then warmed to 0 °C for 30 min and recooled to
-78 °C. This solution was then added, via cannula, to a
solution of oxazoline 18 (1.97 g, 6.27 mmol, 100 mol %) in THF
(20 mL) held at -78 °C. After 15 min at -78 °C, trimethylsilyl
chloride (835 mL, 715 mg, 6.58 mmol, 105 mol %) was added
to the reaction mixture, and the solution was allowed to warm
to -60 °C over a period of 10 min and then recooled to -78
°C. Upon addition of solid potassium hexamethyldisilazide
(1.56 g, 7.83 mmol, 125 mol %), the solution turned pale yellow.
After 20 min, a solution of iodine (1.99 g, 7.83 mmol, 125 mol
%) in THF (15 mL) was added via cannula, resulting in
immediate decolorization at first and then gradual darkening
of the reaction mixture. The solution was allowed to warm to
-20 °C over a period of 4 h. Saturated NH4Cl (150 mL) and
10% Na2S2O3 (50 mL) were then added, and the mixture was
extracted with EtOAc (3 × 100 mL). The organic extracts were
dried (Na2SO4) and concentrated to afford an oil which was
purified by flash chromatography (4 × 18 cm of silica, linear
Ackn owledgm en t. Financial support from the Acad-
emy of Finland and the Ministry of Education is
gratefully acknowledged. We also thank Ms. Pa¨ivi
J oensuu, University of Oulu, for the MS analyses, the
Trace Element Laboratory of the University of Oulu for
elemental analyses, and professor Kari Rissanen, Uni-
versity of J yva¨skyla¨, for the X-ray analysis of 9a . In
addition, we thank the professors Reinhard W. Hoff-
mann and Takayuki Shioiri for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of new compounds and characterization data for the side
products i and ii (23 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O971167M
(47) Yokokawa, F.; Hamada, Y.; Shioiri, T. Synlett 1992, 151-152.