An enantiocontrolled synthesis of a key intermediate to (+)-lactacystin

Article abstract of DOI:10.1039/a804954h

An asymmetric synthesis of a key intermediate 16 to (+)-lactacystin 1 has been established starting from epoxide 2 via intramolecular mercurioamidation of allylic trichloroacetimidate 4 and concomitant addition-reduction of ester 13 by Pr(i) MgBr, in whic

Full text of DOI:10.1039/a804954h

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An enantiocontrolled synthesis of a key intermediate to (+)-lactacystin
Sung Ho Kang*† and Hyuk-Sang Jun
Department of Chemistry, Korea Advanced Institute of Science and Technology, Taejon. 305-701, Korea
An asymmetric synthesis of a key intermediate 16 to
(+)-lactacystin 1 has been established starting from epoxide
2 via intramolecular mercurioamidation of allylic tri-
chloroacetimidate 4 and concomitant addition-reduction of
ester 13 by Pri MgBr, in which reduction of the intermediate
ketone proceeded with complete stereoselectivity.
Owing to the inefficient Grignard addition, 11 was converted
into ester 13, [a]D +57.1 (c 1.70, CHCl3), in 90% yield.
21
Subjection of 13 to 1 equiv. of PriMgBr provided the
corresponding isopropyl ketone in 80% yield, the stereose-
lective reduction of which was attempted employing several
reducing agents such as oxazaborolidine,15 Ipc2Cl,16 sodium
triacetoxyborohydride,17 NaBH4 in the presence of diethylme-
thoxyborane,18 and so forth. However, the best stereoselectivity
turned out to be 5:1 in favor of 14 with NaBH4 in MeOH at
0 °C. Some experimentation revealed that an excess amount of
PriMgBr reduced the generated isopropyl ketone to the alcohol
14. Accordingly, 13 was treated with > 2 equiv. of PriMgBr to
give selectively only the desired diastereomeric alcohol 14,
[a]D20 +40.5 (c 1.20, CHCl3), in 91% yield. Acidic hydrolysis
of 14 yielded trihydroxy pyrrolidinone 16, mp 198–199 °C
Since neurotrophic factors are responsible for the survival and
function of neurons,1 they might be useful in the treatment of
various nerve diseases.2 Omura et al. screened a number of
microbial culture samples to isolate the first non-protein
neurotrophic agent (+)-lactacystin 1 from Streptomyces sp.
OM-6519.3 Its structure, elucidated by NMR spectroscopy and
X-ray crystallographic analysis, is composed of (R)-N-acet-
ylcysteine and a unique pyroglutamic acid via a thioester
linkage.4 (+)-Lactacystin inhibits cell proliferation, induces
neuritogenesis and increases the intracellular cAMP level
transiently in the Neuro 2A neuroblastoma cell line.3,5 Its
intriguing structural features as well as potential therapeutic
utility have engendered considerable interest in the fields of
synthetic and medicinal chemistry. Here we describe a
stereoselective synthetic route to (+)-lactacystin.6–9 The key
steps of our synthesis comprise tertiary amination of the olefinic
double bond in allylic trichloroacetimidate 4 via mercur-
ioamidation,10 facile differentiation of the hydroxymethyl
groups in 10 by ring formation and diastereoselective deriva-
tization of ester 13 into alcohol 14.
20
(decomp.), [a]D +16.2 (c 0.62, MeOH), quantitatively, the
spectroscopic data of which are identical to those reported in the
literature and which is a known intermediate to (+)-lactacystin
1.8,19
We have developed an enantioselective synthetic route to
(+)-lactacystin 1 via several crucial steps, including animo
hydroxylation of the olefinic double bond in 3, the hydrolytic
cyclization of 8, and the regio- and stereo-selective functional-
ization of one hydroxymethyl group in 10; these should have
versatility in the synthesis of its analogues.
20
The known epoxide 2,11 [a]D 224.7 (c 1.15, CHCl3), was
OH
treated with LDA to give allylic alcohol 3, [a]D21 +10.4 (c 1.44,
CHCl3), in 91% yield (Scheme 1). Only the primary hydroxy
group of 3 was functionalized to a trichloroacetimidate. The
crude monoimidate 4 was subjected to intramolecular mercur-
ioamidation using mercuric trifluoroacetate with K2CO3 to
furnish a 1:1 diastereomeric mixture of oxazolines 5 in 92%
overall yield after aqueous KBr work-up. Since oxidative
demercuration12 of 5 using O2 failed under a variety of reaction
conditions, it was attempted by exposing 5 to TEMPO in the
presence of LiBH4 to provide the oxidized products 6 in 78%
yield. The secondary hydroxy groups of 6 were protected with
MeOCH2Cl (MOMCl) and then the silyl groups were removed
to afford the corresponding primary alcohols in 84% overall
yield. While PDC oxidation of the alcohols in DMF was
sluggish, they were efficiently oxidized to carboxylic acids 8 in
78% yield by Swern oxidation13 followed by KMnO4 oxida-
tion.14 Complete hydrolysis and the ensuing cyclization were
effected by heating 8 at reflux with ethanolic HCl in AcOH. The
2,2,6,6-tetramethylpiperidyl (TEMP) groups of the generated
pyrrolidinones 9 were reductively cleaved in situ by adding zinc
to the hot reaction mixture to produce trihydroxy pyrrolidinone
10, [a]D19 +9.5 (c 0.95, MeOH), in 72% overall yield from 8.
For the appropriate elaboration of the a-hydoxymethyl
groups in 10, it was chemoselectively reacted with acetone
under acidic conditions to give a 7:1 mixture of acetonides 11
and 12 in 95% combined yield (Scheme 2). After chromato-
O
i
RO
ii
OTBDPS
HO
OTBDPS
R = H
3
4
R = C( NH)CCl3
iii
TEMPO
O
BrHg
OR
OH
iv
OTBDPS
OTBDPS
O
N
N
Cl3C
v
Cl3C
R = H
R = MOM
5
6
7
vi–viii
TEMPO
HO
OMOM
CO2H
ix
RO
HO
O
O
N
N
H
Cl3C
8
9
R = TEMP
R = H
10
Scheme 1 Reagents and conditions: i, LDA, THF, 0–24 °C; ii,Cl3CCN,
DBU, EtCN, 278 °C; iii, Hg(O2CCF3)2, K2CO3, THF, 0 °C, then aq. KBr;
iv, TEMPO, LiBH4, THF, 24 °C; v, MOMCl, Pri2NEt, CH2Cl2, 0–24 °C; vi,
20
graphic separation, the primary alcohol 11, [a]D +31.4 (c
1.10, CHCl3), was oxidized under Swern conditions and the
resulting aldehyde reacted with PriMgBr under various reaction
conditions to furnish a 1:1 mixture of alcohols 14 and 15 along
with an appreciable amount of the reduced starting alcohol 11.
Bu4NF, H2O, THF, 45 °C; vii, (COCl)2, DMSO, Et3N; viii, 1
1.25
Zn, reflux
M
KMnO4,
M
NaH2PO4, ButOH, 24 °C; ix, conc. HCl, EtOH, AcOH, reflux, then
Chem. Commun., 1998
1929

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O
HO
O
3 S. Omura, T. Fujimoto, K. Otogurro, K. Matsuzaki, R. Moriguchi, H.
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i
O
10
+
O
O
N
H
N
H
O
HO
11
12
ii, iii
O
O
O
O
iv
O
O
N
H
N
MeO2C
H
X
8 H. Uno, J. E. Baldwin and A. T. Russell, J. Am. Chem. Soc., 1994, 116,
2139.
13
14
X = β-OH
9 N. Chida, J. Takeoka, N. Tsutsumi and S. Ogawa, J. Chem. Soc., Chem.,
Commun., 1995, 793.
15 X = α-OH
10 S. H. Kang and S. B. Lee, Chem. Commun., 1998, 761.
11 E. N. Jacobsen, I. Marko, W. S. Mungall, G. Schröder and K. B.
Sharpless, J. Am. Chem. Soc., 1988, 110, 1968; W. P. Griffith and S. V.
Ley, Aldrichim. Acta, 1990, 23, 13.
v
HO
HO
O
HO
12 C. L. Hill and G. M. Whitesides, J. Am. Chem. Soc., 1974, 96, 870.
13 A. J. Mancuso and D. Swern, Synthesis, 1981, 165.
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5551; E. J. Corey, R. K. Bakshi and S. Shibata, C.-P. Chen and V. K.
Singh, J. Am. Chem. Soc., 1987, 109, 7925.
HO2C
AcNH
S
O
O
N
N
H
H
OH
OH
1
16
Scheme 2 Reagents and conditions: i, TsOH, acetone, 24 °C; ii, Jones’
reagent, acetone, 0 °C; iii, CH2N2, THF, 0 °C; iv, PriMgBr, THF, 220 to
0 °C; v, TsOH, MeOH, 60 °C
16 J. Chandrasekharan, P. V. Ramachandran and H. C. Brown, J. Org.
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19 All new compounds showed satisfactory spectral data. Selected data for
16: dH(300 MHz, CD3OD) 0.94 (3H, d, J 6.7), 1.02 (3H, d, J 6.7), 1.11
(3H, d, J 7.5), 1.91–2.00 (1H, m), 2.79 (1H, p, J 7.5), 3.49 (1H, d, J 3.6),
3.78 (2H, s) and 4.40 (1H, d, J 7.5); dC(75.5 MHz, CD3OD) 9.5, 17.6,
22.7, 30.6, 42.6, 63.4, 70.7, 74.4, 79.1 and 181.6.
This work was supported by Creative Research Initiatives of
the Korean Ministry of Science and Technology.
Notes and References
† E-mail: shkang@kaist.ac.kr
1 F. Hefti and W. J. Weiner, Ann. Neurol., 1986, 20, 275; Y.-A. Barde,
Neuron, 1989, 2, 1525.
Received in Cambridge, UK, 29th June 1998; 8/04954H
1930
Chem. Commun., 1998