Total synthesis of (+)-lactacystin

Article abstract of DOI:10.1002/(SICI)1521-3773(19990419)38:8<1093::AID-ANIE1093>3.0.CO;2-U

A double stereodifferentiating crotylation between aldehyde 1 and silane (S)-2 to afford homoallylic alcohol 3 is the key diastereoselective step (anti:syn > 30:1) in an efficient asymmetric synthesis of (+)-lactacystin. This compound is a metabolite isol

Full text of DOI:10.1002/(SICI)1521-3773(19990419)38:8<1093::AID-ANIE1093>3.0.CO;2-U

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treatment of arthritis.[2] The equally potent b-lactone 2 acts by
selective acylation of the N-terminal threonine residue of a
protein subunit of the cylindrical 20S proteasome,[3] a result
confirmed by X-ray crystallographic studies at 2.4 Š resolu-
tion of the lactacystin inactivated proteasome.[4] Recent
mechanistic studies have shown that lactacystin hydrolyzes to
the inactive dihydroxy acid through its b-lactone 2. It is the b-
lactone species that subsequently acylates the proteasome and
results in its inactivation (Figure 1).[3b] The presence of intra-
cellular levels of glutathione (GSH) converts 2 into lacta-
thione, which is believed to act as a ªlactone reservoirº.[3c]
[10] a) N. Iwasawa, T. Ochiai, K. Maeyama, Organometallics 1997, 16,
Â
5137; b) J. Barluenga, M. Tomas, A. Ballesteros, J. Santamaría, R. J.
Â
Carbajo, F. Lopez-Ortiz, S. García-Granda, P. Pertierra, Chem. Eur. J.
1996, 2, 88. This migration was previously suggested: c) H. Fischer, T.
Meisner, J. Hofmann, Chem. Ber. 1990, 123, 1799; d) K. Dötz, C.
Christoffers, P. Knochel, J. Organomet. Chem. 1995, 489, C84.
[11] Alternatively, the regioselective formation of compounds of type 4 by
addition of allyl metal reagents to a,b-unsaturated carbonyl com-
pounds has not been definitively addressed. For elegant work on this
subject, see T. Ooi, T. Kondo, K. Maruoka, Angew. Chem. 1997, 109,
1231; Angew. Chem. Int. Ed. Engl. 1997, 36, 1183.
[12] a) Review: J. A. Marshall in Comprehensive Organic Synthesis, Vol. 3
(Eds.: B. M. Trost, I. Fleming, G. Pattenden), Pergamon, New York,
1991, p. 975; b) V. Rautenstrauch Chem. Commun. 1970, 4.
[13] An interesting case of C C bond for-
mation by sequential addition of pro-
pargyl alcohol to [ethoxy(phenylethy-
nyl)carbene]pentacarbonylchromium(0)
and Claisen rearrangement: A. Segun-
Â
Ä
do, J. M. Moreto, J. P. Vinas, S. Ricart,
Organometallics 1994, 13, 2467.
[14] I. Erden, F.-P. Xu, W.-G. Cao, Angew.
Chem. 1997, 109, 1557; Angew. Chem.
Int. Ed. Engl. 1997, 36, 1516.
[15] This study was also prompted by the
fact that undesired oxidation of the
carbene to a carbonyl group frequently
took place when working with Fischer
carbene complexes. The current results
suggest that nucleophilic addition/de-
metalation/hydrolysis processes might
be responsible rather than the routinely
invoked accidental oxidation by atmos-
pheric oxygen.
Figure 1. Mechanism of proteasome inhibition by (‡)-lactacystin.
(‡)-Lactacystin (1) is a unique member of a class of
neurotrophic factors since it consists of a nonprotein g-lactam
thioester. Its compact array of five resident stereogenic
centers renders (‡)-lactacystin a significant target for syn-
thesis; a number of other syntheses of 1 have been reported.[5]
A critical issue relative to the synthesis of lactacystin is the
fact that most of the structural features of 1 are essential to
maintain its unique biological profile. The C4-carboxylic
moiety and the C6-hydroxyl group must be cis because of the
necessity for b-lactone formation to achieve proteasome
inactivation.[4] The absolute configuration of the C9-hydroxyl
and the isopropyl substituents are also essential for biological
activity.[5c] The C7-methyl group is critical to the activity and
stability of 1, although replacement of this group with either
ethyl or isopropyl groups does lead to a two- to threefold
increase in activity.[5c]
As a consequence of these strict structural and stereo-
chemical requirements any synthesis of 1 must not only be
efficient, but also highly selective for the introduction of each
of the stereogenic centers. Our approach to lactacystin nicely
compliments the synthesis by Smith and co-workers[5e]
through the use of the hydroxyleucine-derived oxazoline 5
to set the stage for the critical anti-crotylation reaction for the
installation of the C6 and C7 stereocenters.
Total Synthesis of (‡)-Lactacystin**
James S. Panek* and Craig E. Masse
(‡)-Lactacystin (1) is a metabolite isolated from Strepto-
myces sp. OM-6519 that exhibits significant neurotrophic
activity.[1a] The relative and absolute stereochemistry of (‡)-
1
lactacystin has been elucidated by H and 13C NMR spectro-
scopy, and single-crystal X-ray analysis.[1b] (‡)-Lactacystin has
been shown to be a potent proteasome inhibitor, and has led
to speculation that it may be therapeutically useful in the
[*] Prof. J. S. Panek, C. E. Masse
Department of Chemistry
Metcalf Center for Science and Engineering
Boston University, Boston, MA 02215 (USA)
Fax : (‡ 1)617-353-6466
E-mail: panek@chem.bu.edu
[**] This work was financially supported by the National Institutes of
Health (RO1GM55740). C.E.M. is grateful to the American Chemical
Society, Division of Medicinal Chemistry, and Hoechst Marion
Roussel for a pre-doctoral fellowship. We are grateful to Dr. Julian
Adams, Dr. Louis Plamondon, Mr. Louis Grenier, Mr. Francois Soucy,
and Mark Behnke of ProScript (Cambridge, MA.) for insightful
discussions.
Retrosynthetic analysis of the lactacystin skeleton
(Scheme 1) reveals two key operations: a) stereoselective
Supporting information for this article is available on the WWW
under http://www.wiley-vch.de/home/angewandte/ or from the author.
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Scheme 2. Preparation of oxazoline 5. Cbz ˆ ªcarbobenzoxyº ˆ benzyl-
oxycarbonyl, DME ˆ 1,2-dimethoxyethane.
raised to >99% by recrystallization (two times) from EtOH/
H2O (1/1). Subsequent transesterification to the methyl ester
[9]
in the presence of Ti(OiPr)4 and removal of the benzylox-
ycarbonyl group by hydrogenolysis afforded 6. Finally, treat-
ment of 6 with trimethylorthobenzoate in the presence of p-
toluenesulfonic acid[10] provided the trans-oxazoline 5. The
virtues of this approach are apparent from the concise nature
of the synthetic sequence, mild reaction conditions, and the
fact that either enantiomer can be prepared by the proper
choice of the alkaloid ligand.
The preparation of the heterocyclic aldehyde 4 was
accomplished according to a literature precedent established
by Smith et al.[5e] Oxazoline 5 was subjected to an aldol
condensation with formaldehyde according to the Seebach
protocol[11] to afford primary alcohol 10 as a single diaster-
eomer (Scheme 3). The topological bias for this ester enolate
was presumably controlled by the chirality of the oxazoline in
Scheme 1. Retrosynthetic analysis.
generation of the heterocyclic aldehyde 4 derived from a
3-hydroxyleucine derivative and b) an asymmetric crotylsi-
lane addition to aldehyde 4 to generate the fully elaborated
stereochemical core of the parent molecule 1. Earlier efforts
in this area[5e] have established that aldol surrogates such as
(E)-crotylboron or (E)-crotylchromium(ii) reagents exhibit
only modest levels of diastereoselection for the (6S)-isomer
(drˆ 2:1 !4:1). We anticipated that the chiral silane reagents
should be capable of providing enhanced levels of diaster-
eoselection for this double stereodifferentiating reaction since
Lewis acid promoted reactions involving allylsilanes proceed
through open transition structures.[6] These transition states
diminish the destabilizing effects associated with the steric
congestion of heterocyclic aldehyde 4. The first stage of the
synthesis involved the development of an efficient stereo-
selective synthesis of heterocyclic aldehyde 4 that contained
the C5 and C9 stereocenters of lactacystin. This required an
efficient route to oxazoline 5. Currently, the most efficient
approach to oxazoline 5 requires ten steps with an overall
yield of 60% from (E)-4-methyl-2-penten-1-ol.[5e]
Our first objective in the development of a more practical
synthesis of oxazoline 5 was to devise a concise and stereo-
selective synthesis of the hydroxyleucine unit. Numerous
approaches to the 3-hydroxyleucine synthon 6 have been
reported.[7] However, they either lack the flexibility to prepare
the various isomers, require the preparation of a chiral
catalyst system, or are prohibitively lengthy and impractical
for large scale preparation. Given those considerations, the
present synthesis of (2R,3S)-hydroxyleucine methyl ester (6)
employs commercially available materials and utilizes an
asymmetric catalytic aminohydroxylation of (p-bromo-
phenyl)-4-methyl-2-pentenoate.
Scheme 3. Completion of the synthesis of (‡)-lactacystin (1). LHMDS ˆ
lithium bis(trimethylsilyl)amide.
The asymetric aminohydroxylation (AA) of 7 using the
benzylcarbamate-based Sharpless reaction[8] and 1,4-bis(dihy-
droquininyl)anthraquinone (DHQ)2AQN) gave 9 with good
levels of regioselectivity (7:1) in favor of the a-amino ester
and high levels of enantioselectivity (87% ee, Scheme 2). The
ratio of regioisomers was determined by 1H NMR analysis of
the crude product and the initial ee value of 87% could be
which the bulky isopropyl group functions as the controller of
diastereoselectivity. Oxidation of the primary alcohol using
the Moffatt protocol (dicyclohexylcarbodiimide, DMSO,
pyridine, trifluoroacetic acid)[12] provided the desired hetero-
cyclic aldehyde 4. Any attempt to purify this product resulted
in deformylation, so this aldehyde was used without purifica-
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Jung, Tetrahedron Lett. 1989, 30, 6636 ± 6640; e) D. A. Evans, E. B.
Sjogren, A. E. Weber, R. E. Conn, Tetrahedron Lett. 1987, 28, 39 ± 43.
For an earlier approach to the hydroxyleucine synthon developed in
our laboratories, see J. S. Panek, C. E. Masse, J. Org. Chem. 1998, 63,
2382 ± 2384.
tion. The critical anti-selective crotylation reaction was then
carried out to establish the relative configuration at the C6
and C7 centers. This double stereodifferentiating[13] reaction
was readily accomplished with TiCl4 to afford homoallylic
alcohol 11 with high levels of diastereoselectivity (anti:syn
>30:1) and in 50 ± 60% yield. This anti-bond construction was
presumably achieved through simultaneous coordination of
the aldehyde oxygen atom and the nitrogen atom in the
oxazoline ring. The 1,3-relationship of the heteroatoms ideally
predisposes the more Lewis basic nitrogen atom relative to
the aldehyde carbonyl group to generate a 5-membered
chelate with TiCl4 via the illustrated synclinal transition state
(Scheme 3).[14] Oxidative cleavage of (E)-olefin 11 under
standard ozonolysis conditions and subsequent oxidation with
sodium chlorite[15] furnished carboxylic acid 3.
The completion of (‡)-lactacystin was initiated by catalytic
transfer hydrogenation of the oxazoline moiety with Pd-black
to give the g-lactam methyl ester after cyclization. Saponifi-
cation of the methyl ester under mild conditions afforded the
dihydroxy acid, which was directly converted into b-lactone 2
by treatment with bis(2-oxo-3-oxazolidinyl)phosphinic chlor-
ide (BOPCl). We employed the lactone opening strategy
developed by Corey et al. to attach the N-acetyl-l-cysteine
side chain.[5b] Treatment of 2 with N-acetyl-l-cysteine/Et3N
furnished synthetic (‡)-1 identical in all respects to the
natural product (1H and 13C NMR, IR spectroscopies, HR-
MS, optical rotation, and TLC).[5b]
[8] B. Tao, G. Schlingloff, K. B. Sharpless, Tetrahedron Lett. 1998, 39,
2507 ± 2510; G. Li, H. H. Angert, K. B. Sharpless, Angew. Chem. 1996,
108, 2995 ± 2999; Angew. Chem. Int. Ed. Engl. 1996, 35, 2837 ± 2841.
See also P. OꢁBrien, Angew. Chem. 1999, 111, 339 ± 342; Angew. Chem.
Int. Ed. 1999, 38, 326 ± 329.
[9] D. Seebach, E. Hungerbühler, R. Naef, P. Schnurrenberger, B.
Weidmann, M. Züger, Synthesis 1982, 138 ± 141.
[10] R. A. Moss, T. B. K. Lee, J. Chem Soc. Perkin Trans. 1 1973, 2778 ±
2781.
[11] D. Seebach, J. D. Aebi, Tetrahedron Lett. 1983, 24, 3311 ± 3314.
[12] K. E. Pfitzner, J. G. Moffatt, J. Am. Chem. Soc. 1965, 87, 5661 ± 5669.
[13] S. Masamune, W. Choy, J. S. Peterson, L. R. Sita, Angew. Chem. 1985,
97, 1 ± 31; Angew. Chem. Int. Ed. Engl. 1985, 24, 1 ± 30.
[14] For similar bond constructions of the silane reagents with oxazoles, see
P. Liu, J. S. Panek, Tetrahedron Lett. 1998, 39, 6143 ± 6146.
[15] E. J. Corey, A. G. Myers, J. Am. Chem Soc. 1985, 107, 5574 ± 5576.
Aerobic Oxidation of Primary Alcohols by a
New Mononuclear CuII-Radical Catalyst**
Phalguni Chaudhuri,* Martina Hess,
Thomas Weyhermüller, and Karl Wieghardt*
Received: October 20, 1998 [Z12551]
Recently we reported[1] a dinuclear CuII-phenoxyl radical
complex, which catalyzes efficiently the aerobic oxidation of
primary and secondary alcohols to the corresponding alde-
hydes and ketones or to 1,2-glycols by oxidative C ± C
coupling with concomitant formation of H2O2. This complex
together with that of Stack et al.[2] are the first reported
functional models for the enzyme galactose oxidase (GO).[3]
We report here a new mononuclear CuII-iminosemiquinone
catalyst that selectively transforms primary alcohols (e.g.
ethanol but not methanol) with O2 to aldehydes and H2O2;
secondary alcohols are not at all substrates for the catalyst.
The trifluoroacetate salt of the cation N,N-bis(2-hydroxy-
3,5-di-tert-butylphenyl)ammonium [H4(L3)](CF3CO2) was
prepared through the condensation of 3,5-di-tert-butylcate-
chol with NH3 in n-heptane and subsequent acidification with
trifluoroacetic acid. It is known[4] that the diamagnetic
trianion (L3)3 (Scheme 1), present as a tridentate ligand in
complexes, can be easily oxidized to the radical dianion (L2)2
and then to the diamagnetic monoanion (L1)1 in two
successive one-electron oxidation steps. Speier and Pierpont
et al. have, for example, described the complexes [CuII(L1)2]
German version: Angew. chem. 1999, 111, 1161 ± 1163
Keywords: asymmetric synthesis
´ enzyme inhibitors ´
lactacystin ´ lactones ´ total synthesis
[1] a) S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi, H.
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[*] Priv.-Doz. Dr. P. Chaudhuri, Prof. Dr. K. Wieghardt, M. Hess,
Dr. T. Weyhermüller
Max-Planck-Institut für Strahlenchemie
Stiftstrasse 34 ± 36, D-45470 Mülheim an der Ruhr (Germany)
Fax: (‡49)208 ± 306 ± 3952
E-mail: chaudh@mpi-muelheim.mpg.de
wieghardt@mpi-muelheim.mpg.de
[**] This work was supported by the Degussa AG, Frankfurt, and the
Fonds der Chemischen Industrie.
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