Utility of the ammonia-free birch reduction of electron-deficient pyrroles: Total synthesis of the 20S proteasome inhibitor, clasto-lactacystin β-lactone

Article abstract of DOI:10.1002/chem.200401119

A new synthesis of the 20S proteasome inhibitor clasto-lactacystin β-lactone is described. Our route to this important natural product involves the partial reduction of an electron deficient pyrrole as a key step. By judicious choice of enolate counterion, we were able to exert complete control over the stereoselectivity of the reduction/aldol reaction. Early attempts to complete the synthesis by using a C-4 methyl substituted pyrrole are described in full, together with our attempts to promote regioselective elimination of a tertiary alcohol. The lessons learnt from this first approach led us to develop another, and ultimately successful, route that introduced the C-4 methyl group at a late stage in the synthesis. Our successful route is then described and this contains several highly stereoselective steps including a cis-dihydroxylation and an enolate methylation. The final synthesis proceeds in just 13 steps and in 15% overall yield making it an extremely efficient route to this valuable compound.

Full text of DOI:10.1002/chem.200401119

FULL PAPER
Utility of the Ammonia-Free Birch Reduction of Electron-Deficient Pyrroles:
Total Synthesis of the 20S Proteasome Inhibitor, clasto-Lactacystin b-Lactone
Timothy J. Donohoe,*[a] Herman O. Sintim,[a] Leena Sisangia,[a] Karl W. Ace,[b]
Paul M. Guyo,[b] Andrew Cowley,[a] and John D. Harling[c]
Abstract: A new synthesis of the 20S
proteasome inhibitor clasto-lactacystin
b-lactone is described. Our route to
this important natural product involves
the partial reduction of an electron de-
ficient pyrrole as a key step. By judi-
cious choice of enolate counterion, we
were able to exert complete control
over the stereoselectivity of the reduc-
tion/aldol reaction. Early attempts to
complete the synthesis by using a C-4
methyl substituted pyrrole are de-
scribed in full, together with our at-
tempts to promote regioselective elimi-
nation of a tertiary alcohol. The lessons
learnt from this first approach led us to
develop another, and ultimately suc-
cessful, route that introduced the C-4
methyl group at a late stage in the syn-
thesis. Our successful route is then de-
scribed and this contains several highly
stereoselective steps including a cis-di-
hydroxylation and an enolate methyla-
tion. The final synthesis proceeds in
just 13 steps and in 15% overall yield
making it an extremely efficient route
to this valuable compound.
Keywords: lactacystin
·
natural
products · pyrroles · total synthesis
Introduction
Proteasomes are large, hollow cylindrical protein struc-
tures (700–900 kD) composed of four stacked rings of seven
protein subunits and are indispensable to living cells.[3] All
chemical agents that specifically inhibit the proteasome
could be of great pharmacological relevance. In this regard,
the natural products lactacystin (3),[4] which is a prodrug of
clasto-lactacystin b-lactone (1),[5–8] salinosporamide A (2),[9]
and epoxomicin (4)[10] (Figure 1) are examples of potent and
selective inhibitors of the proteasome.
Proteolysis by ATP-dependent enzymes (proteasomes and
proteases) plays an important role in controlling levels of
key regulatory proteins and in the degradation of abnormal
polypeptides.[1] Intracellular protein degradation is a tightly
regulated process and is crucial for (amongst others) cell
cycle progression, apoptosis, antigen presentation and NF-
kB activation.[1] Regulatory proteasomes and proteases, such
as bleomycin hydrolase, tricon, HsIU and DegP are restrict-
ed to specific locations in the cell and can be accessed only
by polypeptides destined for destruction.[2]
[a] Prof. T. J. Donohoe, Dr. H. O. Sintim, Dr. L. Sisangia, Dr. A. Cowley
Department of Chemistry, University of Oxford
Chemistry Research Laboratory, Mansfield Road
Oxford, OX1 3TA (UK)
Fax : (+44)186-527-5708
E-mail: timothy.donohoe@chem.ox.ac.uk
[b] Dr. K. W. Ace, Dr. P. M. Guyo
Department of Chemistry, The University of Manchester
Oxford Road, Manchester, M13 9PL (UK)
[c] Dr. J. D. Harling
GlaxoSmithkline, Medicines Research Centre, Gunnels Wood
Road, Stevenage, SG1 2NY (UK)
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Figure 1. Examples of potent and selective proteasome inhibitors.
Chem. Eur. J. 2005, 11, 4227 – 4238
DOI: 10.1002/chem.200401119
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4227

Omura et al. reported the isolation and characterisation
of (+)-lactacystin (3)[4] in 1991 and there has been consider-
able interest among synthetic organic chemists and biolo-
gists ever since.[11] This is in part due to lactacystinꢁs inhibi-
tion of the 20S proteasome and its interesting and unusual
structure. (+)-Lactacystin (3) is now commercially available
and used as an indispensable tool in neuronal research. For
example, Yano et al. have used (+)-lactacystin (3) to investi-
gate the aggregation of heat-denatured proteins.[12] Sawada
et al. have also shown that proteasome inhibition by (+)-lac-
tacystin (3) blocks 1-methyl-4-phenylpyridinium ion
(MPP(+)) or rotenone-induced dopaminergic neuronal deg-
eration, thus implicating the 20S proteasome in neurodege-
nerative diseases such as Parkinsonꢁs.[13] As a consequence
of its relative scarcity, (+)-lactacystin (3) is expensive and
work towards a concise synthesis is a worthwhile endeavour.
In this paper, we report the evolution of the ammonia-
free reduction of electron-deficient pyrroles[14] into a strat-
egy for the total synthesis of (Æ)-clasto-lactacystin b-lactone
(1).[15]
(generated by reacting lithium with di-tert-butylbiphenyl 7
(DBB) in THF) provides the electrons, and bis(methoxyeth-
yl)-amine (11; BMEA) acts as an acid. A general ammonia
free reaction is shown in Scheme 2 with an aldehyde chosen
as the electrophile.
Utility of pyrroles as precursors to pyrrolidine synthesis:
When considering the prospects for reducing the pyrrole
ring it is clear that the chemistry of pyrroles is dominated by
the aromatic nucleus acting as a nucleophile in aromatic
substitution reactions. Obviously, the pyrrole nucleus is ex-
tremely electron-rich and, therefore, not easily reduced.
Moreover, the presence of the acidic NH (pKa ~17) of the
pyrrole presents the possibility of deprotonation by basic re-
ducing agents. In order to develop reduction methodology
that overcomes the nucleophilic reactivity of the pyrrole
ring we have shown that pyrroles must first be substituted to
render them electron-deficient. Thus, N-Boc protected pyr-
roles that are also substituted with acyl groups have been
shown to be good substrates for dissolving metal (Birch) re-
duction and they give rise to a variety of useful synthetic in-
termediates (Scheme 1).[16]
Scheme 2. Mechanism for the partial reduction reaction.
A major advantage of this ammonia-free protocol is its es-
pecial tolerance of the aforementioned set of reactive elec-
trophiles which gives the reaction sequence much more
scope for use in synthesis.
Comparison between clasto-lactacystin b-lactone (1) and
generic compound 14 reveals that it contains the requisite
functionalities at both C-2 and C-6 (if iPrCHO were the al-
dehyde electrophile) and also that the appropriate function-
al groups at C4 and C3 could be introduced easily. So, the
development of methodology to access clasto-lactacystin b-
lactone (1) in a short sequence from electron-deficient pyr-
roles became our target. The evolution of our synthetic
strategy is chronicled in this paper.
Results and Discussion
First-generation synthetic plan: We chose enone 16 as a key
retrosynthetic intermediate because we envisioned lots of
different ways of converting it into 15. A diastereoselective
reduction (hydrogenation) of enone 16 into advanced inter-
mediate 15 seemed very likely as it had the necessary direct-
ing groups (e.g. the hydroxy group on C-6) that could be
used to direct hydrogenation reagents plus the possibility of
a bulky protecting group PG1 sterically shielding one face of
the enone 16 (Scheme 3). Moreover, compound 16 could be
an ideal electrophilic intermediate for conjugate addition to
make a range of analogues of lactacystin 3.
Scheme 1. General sequence for the reductive alkylation of a pyrrole.
The use of ammonia as a solvent in the Birch reduction of
pyrroles restricts the number of electrophiles that can be
successfully trapped in situ; only alkyl halides and non-eno-
lisable aldehydes can be employed. Very reactive electro-
philes such as enolisable aldehydes, silyl halides, chlorofor-
mates and acid chlorides are incompatible with the nucleo-
philic solvent. To increase the repertoire of electrophiles
that can be successfully trapped under dissolving metal con-
ditions, an ammonia-free methodology was developed.[17] In
this new procedure, di-tert-butylbiphenyl radical anion 8
4-Methyl N-Boc pyrrole 21 was obtained following stan-
dard Boc protection of commercially available pyrrole 20
(Scheme 4). Subjecting 21 to the original ammonia-free
Birch conditions (Li, naphthalene, BMEA, iPrCHO) gave
4228
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238

Lactacystin
FULL PAPER
Scheme 3. First-generation synthetic plan.
Scheme 5. Attempted elimination of a tertiary alcohol: a) POCl3, pyri-
dine; b) Burgess reagent, Martin sulfurane or DAST.
the anti-aldol product 22 in 50% yield after column chroma-
tography; little or no trace of the syn-isomer was found (at
this point we made no attempt to optimise the yield of the
reaction). Alkene 22 was then subjected to the Upjohn dihy-
droxylation conditions (Scheme 4). In line with our expecta-
tions,[18] the oxidant (OsO4) approached alkene 22 anti to
the face bearing the free hydroxyl and bulky isopropyl
groups. Selective acetate protection of the two secondary
hydroxyl groups was achieved by employing catalytic
DMAP (0.03 equiv) in a mixture of acetic anhydride and
pyridine. Use of stoichiometric DMAP afforded the triace-
tate; the structure of compound 24 was proven by X-ray
crystal analysis.
outline mechanism for this (oxidative) transformation is
shown in Scheme 5.
Our postulated mechanism for the formation of lactam 25
from alcohol 24 proceeds via endocyclic olefin 27 which
would give reactive intermediate 28 after acetoxy elimina-
tion. Trapping of imminium 28 with water and a subsequent
(air?) oxidation of the resulting hemiaminal would then
give lactam 25. Not only was the elimination reaction diffi-
cult to effect but when it did eventually take place it pro-
ceeded with undesired regiochemistry and gave unstable in-
termediates.
Therefore, we attempted to prevent this unwanted endo-
cyclic elimination by using lactam intermediate 33 which
could potentially give the desired exocyclic olefin 34
(Scheme 6).
Scheme 4. Reductive aldol and oxidative manipulation reactions:
a) (Boc)2O, Et3N, MeCN, DMAP, RT; b) Li, naphthalene, BMEA, THF,
À788C; iPrCHO, then NH4Cl aq.; c) cat. OsO4, NMO, acetone/H2O, RT;
d) Ac2O, pyridine, cat. DMAP.
Next, we turned our attention to the dehydration of terti-
ary alcohol 24. Could we promote the reaction and also con-
trol the regioselectivity of the alkene formation to favour
the exocyclic alkene? Unfortunately, attempted dehydration
of tertiary alcohol 24 returned starting material under a va-
riety of different conditions. For example, Burgess re-
agent,[19] Martin sulfurane[20] and DAST[21] all failed to react
with alcohol 24. However, phosphoryl chloride did promote
a reaction but that of 24 into the undesired lactam 25. An
Scheme 6. Formation of a lactam ring: a) (Ac)2O, pyridine, cat. DMAP,
RT; b) CrO3, pyridine, CH2Cl2; c) TFA, CH2Cl2; d) cat. OsO4, NMO, qui-
nuclidine, acetone/H2O; e) Ac2O, pyridine, CH2Cl2, cat. DMAP.
Chem. Eur. J. 2005, 11, 4227 – 4238
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4229

T. J. Donohoe et al.
The synthesis of lactam 33 began with acetate protection
of aldol adduct 22, followed by chromium trioxide allylic ox-
idation to afford Boc-protected lactam 30 in 66% yield after
two steps (Scheme 6). Unfortunately, compound 30 was re-
sistant to dihydroxylation under a variety of conditions and
it was postulated that this failure to oxidise was because of
the electron withdrawing Boc-protecting group. Consequent-
ly, removal of the Boc group and subjection of compound 31
to dihydroxylation conditions (cat. OsO4/NMO, quinuclidine
in acetone/H2O) gave diol 32 as a single diastereoisomer
(stereochemistry assigned by analogy to 23). Selective pro-
tection of the secondary alcohol with acetic anhydride in
pyridine and catalytic DMAP afforded acetate 33. Disap-
pointingly, several attempts to dehydrate compound 33
under a variety of conditions (e.g. Burgess reagent,[19]
Martin sulfurane,[20] Dast[21] and POCl3) all failed.
Scheme 8. Reductive aldol reaction on an electron deficient pyrrole:
a) (Boc)2O, DMAP, Et3N, CH2Cl2; b) Li, DBB, THF, À788C,
(MeOCH2CH2)2NH, MX, isobutyraldehyde.
enolate 41 in situ with various metals such as boron, magne-
sium, titanium and zinc. Of the metals that were screened,
MgBr2·Et2O was the most outstanding in terms of both
chemical yields and diastereoselectivity. Transmetalling lithi-
um enolate 41 with 1.1 equiv of MgBr2·Et2O (before
quenching with isobutyraldehyde) gave products 42 and 43
with greater than 20:1 diastereoselectivity and 74% chemi-
cal yield, in favour of the anti-diastereoisomer 42
(Scheme 8). Models to rationalise this diastereoselectivity
have been reported elsewhere.[14]
With anti-aldol product 42 in hand, we next investigated
its dihydroxylation reaction after a standard acetate protec-
tion (Scheme 9). Alkene 44 gave diol 45 in an average yield
of 65% after being subjected to catalytic OsO4 and NMO
(3 equiv) in acetone/water 4:1. This reaction was particularly
slow (over 24 h) and it was assumed that the moderate yield
was due to diol decomposition over the prolonged reaction
time. In our experience, dihydroxylation reactions employ-
ing Poli conditions (cat. OsO4, Me3NO·2H2O (3 equiv) in
CH2Cl2)[23] were usually completed faster than the cat.
OsO4/NMO system. Consistent with our observations, sub-
jecting 44 to the Poli conditions gave diol 45 in an excellent
yield of 95% and the reaction was complete in 3 h. X-Ray
crystal analysis of a derivative 46 (Figure 2) proved the ster-
At this point, it became clear that our initial idea of form-
ing the exocyclic olefin via elimination of a tertiary alcohol
was not viable partly because of the lack of reactivity of this
tertiary alcohol and also the realisation that endocyclic elim-
ination was favoured over exocyclic (Scheme 5).
Second-generation approach: The premise of our second
generation approach (Scheme 7) towards clasto-lactacystin
b-lactone 1, was a different disconnection from the key exo-
cyclic alkene 17, based on literature precedent whereby 1,1-
disubstituted olefins could be obtained via a standard Wittig
reaction on a ketone.[22] Thus, alkoxy ketone 35 became our
next target. This route differs from the first in that it does
not require a methyl group at the C-4 position of the start-
ing pyrrole 38.
Scheme 7. Second-generation synthetic plan.
MgBr2-catalysed aldol reaction of enolate 41 with isobutyr-
aldehyde—anti-aldol selectivity: The precursor to partial re-
duction, pyrrole 40, was prepared in one step from commer-
cially available 39 (Scheme 8). The aldol reaction between
enolate 41, generated under the ammonia-free conditions
(M = Li) afforded both syn- and anti-aldol products, the
ratio depending on the aldehyde used. Isopropylaldehyde
provided a ratio of 8:1 in favour of the anti-aldol product 42
(see 22, Scheme 4).
Figure 2. X-ray crystal structure of compound 46.
eochemistry of diol 45. As expected, the OsO4 reagent had
approached 44 from the face anti to the bulky isopropyl
group. This was not a surprising outcome as a similar facial
selectivity had been obtained before on a similar substrate
(compounds 22 and 31, Schemes 4 and 6).
In order to increase the diastereoselectivity in this reac-
tion, our effort focussed on transmetallation of the lithium
Selective silyl protection of the least hindered alcohol
within diol 45 was achieved by employing TBSOTf, 2,6-luti-
4230
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238

Lactacystin
FULL PAPER
The protecting group on the C-3 alcohol appeared irrele-
vant with respect to C-3 epimerisation. Swapping the MOM
group in ketone 50 with a TBDMS did not have any benefi-
cial effect in the olefination reaction, epimerisation still oc-
curred. Therefore, this route was deemed not viable and an-
other synthetic strategy was designed.
Scheme 9. Stereoselective dihydroxylation of the ring: a) Ac2O, pyridine,
DMAP; b) cat. OsO4, Me3NO·2H2O, CH2Cl2.
A third-generation synthetic strategy towards clasto-lacta-
cystin b-lactone 1 would have to take into account several
lessons learnt from the two previous approaches; these
were:
dine in dichloromethane at À788C (Scheme 10). The neo-
pentyl alcohol functionality within compound 47 was then
protected with a MOM group to give the fully protected
compound 48 in an excellent yield of 99% (Scheme 10).
Cleavage of the TBS protecting group with TBAF in dry
THF afforded the mono-MOM alcohol 49 in 84% yield; the
secondary alcohol was then oxidised with Dess–Martin peri-
odinane[24] to furnish ketone 50 as a white solid in 86%
yield. The X-ray crystal structure of ketone 50 provided ver-
ification of the regio- and stereochemistry up to this
stage.[25]
a) The facial bias of the alkene was predictable and re-
agents approached the dihydropyrrolidine ring anti to
the bulky isopropyl side chain.
b) Ketones on the pyrrolidine ring were not electrophilic,
and were easily epimerised.
c) The two hydroxyl groups of diol 45 can be differentiated,
with the C-4 OH being the more reactive.
With these lessons in mind, we designed a third-genera-
tion synthetic strategy (Scheme 12).
Scheme 10. Formation of a mono-protected cyclic ketone: a) TBSOTf,
2,6-lutidine, CH2Cl2, À788C; b) MOMCl, iPr2NEt, CH2Cl2, 508C;
c) TBAF, THF, RT; d) Dess–Martin periodinane, CH2Cl2, RT.
Scheme 12. Third-generation synthetic plan.
Unfortunately, all attempts at methylenation of ketone 50
failed. Amongst other things, reaction of compound 50 with
Tebbe reagent,[26] Petasis[27] or Peterson reagent[28] either re-
turned starting material or gave degradation, as confirmed
Third-generation synthetic strategy: Structure–activity rela-
tionship (SAR) requirements for proteasome inhibition by
clasto-lactacystin b-lactone are rather stringent.[29] The only
replaceable group in the molecule that retains biological ac-
tivity is the C-4 methyl group.[30] Significantly, our third-gen-
eration strategy introduces the methyl group at a late stage
and this holds promise for the production of analogues. Key
steps of this new strategy would be; i) selective deoxygena-
tion of the least hindered secondary alcohol within diol 36
(Scheme 12) and ii) diastereoselective methylation of lactam
53, taking advantage of the facial bias of the pyrrolidine
ring, see below.
1
by both TLC and H NMR analyses. Attempted Wittig olefi-
nation led to epimerisation at the stereocenter alpha to the
ketone (Scheme 11) to give diastereomer 51 and none of the
expected alkene 52. The lack of (standard) reactivity of
ketone 50 towards nucleophiles was further confirmed when
subjecting 50 to reaction with methylmagnesium bromide
only returned epimerised compound 51 (Scheme 11).
We decided to dispense with selective protection of the C-
3/4 diol. A regioselective Mitsunobu reaction of diol 45 led
to iodide 54 directly whereby the least hindered alcohol had
been displaced and the C-3 (neopentyl) alcohol remained
intact (Scheme 13). Dehalogenation of iodide 54 following
Inoueꢁs procedure[31] led to 55 in quantitative yield. Then,
standard protection of the C-3 hydroxyl functionality fol-
lowed by (cat.) RuO4 oxidation led to lactam 57. Initially,
Scheme 11. Attempted olefination reactions: a) PPh3CH3I, nBuLi, THF,
08C to RT or MeMgBr, THF, 08C to RT; b) Cp2TiCH2·AlMe2Cl, THF,
À408C to RT; or Cp2TiMe2, THF, RT to 708C; or CeCl3·7H2O, Me3Si-
CH2Li, TMEDA, THF, À788C to RT.
Chem. Eur. J. 2005, 11, 4227 – 4238
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4231

T. J. Donohoe et al.
the oxidation step proved capricious, however, it was real-
ised that desilylation of TES compound 56 in situ was re-
sponsible for the low and varied yields. Lowering the reac-
tion temperature to 08C and then slowly warming to room
temperature prevented this side reaction and lactam 57 was
obtained in a reproducible yield of 84%. Attempted methyl-
ation of TES compound 57 using LDA and methyl iodide
led, as expected, to elimination of the silyoxy group. There-
fore, we decided to deprotect 57 so that we could form the
dianion prior to the methylation step. Desilylation of the
TES group with HF·pyridine in THF furnished 58 in 94%
yield. The next key step in the synthesis was the diastereose-
lective methylation of 58.
mation with bis(2-oxo-3-oxazolidyl)phosphinic chloride
(BOPCl), to give (Æ)-clasto-lactacystin b-lactone 1 in only
13 steps and in 15% overall yield (Scheme 14). The spectro-
scopic data of lactone 1 (clasto-lactacystin b-lactone) was
identical to that reported in the literature.
Scheme 14. Completion of the synthesis: a) CF3CO2H, CH2Cl2; b) NaOH
(aq. 0.5m); c) BOPCl, Et3N, CH2Cl2.
Conclusion
Our synthetic studies on the Birch reduction of heteroaro-
matic compounds show that the methodology has broad ap-
plicability. In the last few years, we have used this methodol-
ogy to synthesise important natural products such as nemor-
ensic acid,[32] secosyrin 1[33] and 1-epi-australine.[34] In this
latest work, we have successfully applied this method to the
efficient (15% overall yield) total synthesis of the biologi-
cally active clasto-lactacystin b-lactone 1. Our route is note-
worthy for its concise nature, high levels of stereoselectivity
and late-stage introduction of the C-4 methyl group.
Scheme 13. Stereoselective enolate alkylation: a) PPh3, DBAD, MeI, ben-
zene; b) cat. InCl3, NaBH4, MeCN; c) TESCl, imidazole, DMAP,
CH2Cl2; d) cat. RuCl3·xH2O, m-NaIO4, CCl4/MeCN/H2O; e) HF·Py, THF,
pyridine; f) LDA, HMPA, MeI, THF.
Experimental Section
General: All reactions were carried out under an atmosphere of argon
unless otherwise stated. Solvents and reagents: THF was distilled from
sodium/benzophenone under an atmosphere of argon, CH2Cl2 from
CaH2 under an atmosphere of argon, triethylamine and BMEA from
CaH2, and isobutyraldehyde from 4 ꢂ molecular sieves. All distilled
chemicals were stored under an atmosphere of argon. All other reagents
were purified using standard procedures as required. Indium trichloride
was dried in vacuo at 1508C for 2 h prior to use. Analytical thin-layer
chromatography: Performed on Merck Kieselgel 60 aluminium-backed
plates and visualised with UV light (254 nm) and stained in p-anisalde-
hyde followed by gentle heating. Chromatography: Flash and gradient
column chromatography was carried out by using Merck silica gel 60
(particle size 40–63 mm). Petroleum ether (PE) refers to the fraction with
boiling range 40–608C. IR Spectroscopy: IR spectra were recorded as
evaporated films from chloroform using Perkin–Elmer 881 or Perkin–
Elmer Paragon 1000 Fourier transform instruments. Absorption maxima
(nmax) are quoted in wavenumbers (cmÀ1) and only the structurally signifi-
Deprotonation of 58 was effected with LDA (2 equiv) fol-
lowed by the addition of methyl iodide; HMPA was re-
quired in order for the lithium enolate to methylate in good
yield.
Significantly, the major alkylation adduct 59 had the de-
sired stereochemistry at C-4 and the facial selectivity exhib-
ited by the enolate was similar to that observed for the dihy-
droxylation step (see 44, Scheme 9). The structures of both
59 and 60 (the minor isomer) were proven by NOE experi-
ments: in compound 59, irradiation of 3-H led to an NOE
enhancement of 4-H, but not of the methyl group at C-4.
However, in compound 60 irradiation of the 3-H led to
NOE enhancements of both 4-H and the methyl group at C-
4. With the carbon skeleton intact and the stereochemistry
of compound 59 correct, the end-game was accomplished by
cleaving the tert-butoxycarbonyl group of lactam 59 with
TFA in CH2Cl2 followed by ester hydrolysis and lactone for-
1
cant peaks are listed. NMR Spectroscopy: H and 13C NMR spectra were
recorded in CDCl3 unless otherwise stated, on Varian Unity Inova 300
and Varian Gemini or Bruker AV400 or 500 spectrometers. All chemical
shifts are quoted in ppm relative to the internal CDCl3 standard. Signal
4232
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238

Lactacystin
FULL PAPER
splittings are described as; singlet (s), doublet (d), triplet (t), quartet (q),
quintet (qt), sextet (st), septet (sp), multiplet (m), broad (br). Spectra
were assigned with the aid of COSY experiments. Multiple peaks are
present in the 1H and 13C NMR spectra of some compounds and due to
Boc rotamers. Mass Spectrometry: Mass spectra were recorded on either
Kratos MS25 or a VG Trio mass spectrometer. The modes of ionisation
were ESI, APCI and CI. Exact masses were measured on a Waters 2790-
Micromass LCT electrospray ionisation mass spectrometer operating at a
resolution of 5000 full width half height.
1H; N-CH), 3.39–3.33 (m, 1H; N-CH), 2.10 (s, 3H; COCH3), 1.97 (s,
3H; COCH3), 1.94–1.79 (m, 1H; CH(CH3)2), 1.44 (s, 9H; C(CH3)3),
1.33–1.27 (m, 6H; 2ꢃCH3), 1.02–0.92 ppm (m, 6H; 2ꢃCH3); 13C NMR
(100 MHz CDCl3): d=172.1, 172.0, 169.2, 169.0, 168.6, 168.4, 153.6, 152.4,
81.9, 81.3, 76.2, 76.0, 75.5, 74.9, 71.0, 70.9, 62.6, 62.5, 60.2, 59.4, 29.1, 28.2,
22.3, 22.0, 21.9, 21.8, 20.8, 20.7, 20.6, 18.3, 17.9, 13.9 ppm; IR (neat): n˜ =
3438, 2977, 2936, 2882, 1753, 1713, 1466, 1393, 1240, 1158, 1076,
1021 cmÀ1; MS (CI): m/z (%): 446 (100) [M ++H], 407 (58), 390 (58), 346
(70); HRMS (CI): m/z: calcd for C21H36NO9: 446.2390; found 446.2384.
4-Methyl N-Boc pyrrole 21: Di-tert-butyl dicarbonate (16.5 g, 86.3 mmol),
triethylamine (30 mL, 0.26 mol) and dimethylaminopyridine (88 mg,
0.86 mmol) were added to a solution of 20 (11 g, 72 mmol) in acetonitrile
(75 mL) under an atmosphere of nitrogen at 408C. The resulting solution
was stirred for 3 h by which time analysis of the reaction by TLC indicat-
ed complete consumption of the starting material. The crude mixture was
concentrated in vacuo and purification by flash column chromatography
eluting with iethyl ether/PE 85:15. This furnished the product 21 as a col-
ourless liquid (16.4 g, 90%); 1H NMR spectroscopic data was consistent
with that in the literature.[34]
Acetate protected aldol adduct 29: DMAP (cat.) was added to a solution
of 22 (2.28 g, 6.69 mol) in acetic anhydride (10 mL) and pyridine (10 mL)
at room temperature and under an inert atmosphere. The solution was
left to stir overnight and then the resulting crude mixture was evaporated
to dryness in vacuo. Purification by flash column chromatography eluting
with (5% acetone/PE) furnished 29 as a colourless oil (2.14 g, 83%).
3
1H NMR (400 MHz, CDCl3): d=5.72 (d, J(H,H)=3.6 Hz, 1H; CHOAc),
5.51–5.46 (m, 1H; C=C-H), 4.37–3.99 (m, 4H; N-CH2, CO2CH2CH3),
2.06, 2.05 (2ꢃs, 3H; COCH3), 2.03–1.88 (m, 1H; CH(CH3)2), 1.84, 1.82
(2ꢃs, 3H; CH3), 1.50–1.46 (m, 9H; C(CH3)3), 1.28–1.21 (m, 3H;
CO2CH2CH3), 0.95 (d, 3J(H,H)=6.9 Hz, 3H; CH3), 0.80 ppm (d, 3J-
(H,H)=6.9 Hz, 3H; CH3); 13C NMR (75 MHz CDCl3): d=171.3, 170.1,
169.8, 153.5, 138.8, 122.0, 121.8, 80.9, 80.0, 61.2, 61.1, 58.4, 58.2, 29.1, 28.9,
28.3, 28.1, 21.8, 21.6, 21.1, 17.1, 15.2, 14.1, 13.9 ppm; IR (neat): n˜ =
2977(s), 2935(s), 2917(s), 1790(s), 1746(s), 1708(s), 1392(s), 1237, 1160,
1025 cmÀ1; MS (CI): m/z (%): 370 (58) [M ++H], 331 (100), 314 (50), 270
(38); HRMS (CI): m/z: calcd for C19H32NO6: 370.2229; found 370.2227.
anti-Aldol adduct 22: Lithium (32.8 mg, 4.57 mmol) and naphthalene
(585 mg, 4.57 mmol) were dissolved in THF (20 mL) and sonicated for
1.5 h at RT under an atmosphere of argon. The resulting dark green solu-
tion was cooled to À788C and stirred for 10 min. The substrate 21
(245 mg, 0.91 mmol) and BMEDA (0.67 mL, 4.57 mmol) were premixed
and titrated into the green solution until a dark red solution formed. The
deep red solution was allowed to stir for a further 45 min before addition
of isobutyraldehyde (0.91 mL, 9.10 mmol). The light yellow solution that
formed was allowed to stir for another 50 min before finally quenching
with sat. NH4Cl. The solution was allowed to warm up to ambient tem-
perature before concentrating to dryness. Flash chromatography on
silica, eluting with acetone/PE 5:95 furnished 22 as a colourless oil
(158 mg, 50%). 1H NMR (300 MHz, CDCl3): d = 5.58 (brs, 1H; C=C-
N-Boc lactam 30: Pyridine (86.4 mL, 737 mmol) was added to a solution
of CrO3 (10.6 g, 105 mmol) in CH2Cl2 (80 mL) at 08C under an inert at-
mosphere. The mixture was stirred for 10 mins at 08C then allowed to
warm up to ambient temperature over 30 min. To the bright yellow com-
plex was added a solution of 29 (1.94 g, 5.27 mmol) in dichloromethane
(30 mL) dropwise. The resulting mixture was heated at 608C for 24 h.
The mixture was filtered through Celite and then concentrated in vacuo.
Purification of the crude material by flash chromatography eluting with
(100% Et2O) furnished 30 as a pale green viscous oil (1.61 g, 80%).
1H NMR (300 MHz, CDCl3): d=6.91 (q, 3J(H,H)=1.7 Hz, 1H; C=C-H),
5.95 (d, 3J(H,H)=3.15 Hz, 1H; CHOAc), 4.16 (m, 2H; CO2CH2CH3),
2.20 (s, 3H; OCOCH3), 1.89 (s, 3H; CH3), 1.81 (m, 1H; CH(CH3)2), 1.60
(s, 9H; C(CH3)3), 1.24 (t, 3J(H,H)=7.1 Hz, 3H; CO2CH2CH3), 0.95 (d, 3J-
(H,H)=7.0 Hz, 3H; CH3), 0.73 ppm (d, 3J(H,H)=7.0 Hz, 3H; CH3);
13C NMR (75 MHz, CDCl3): d=169.9, 169.7, 167.8, 139.7, 136.8, 84.1,
75.5, 71.7, 62.3, 28.6, 27.9, 21.7, 20.9, 17.2, 13.8, 10.9 ppm; IR (neat): n˜ =
2979, 2937, 2880, 1788, 1748 (br), 1717, 1393, 1370, 1329, 1235, 1156,
1025, 976, 779 cmÀ1; MS (CI): m/z (%): 384 (30) [M ++H], 331 (60), 284
(100); HRMS (CI): m/z: calcd for C19H30NO7: 384.2022; found 384.2021.
H), 4.43 (t, 3J(H,H)
= 3.0 Hz, 1H; CHOH), 4.36–3.61 (m, 5H;
CO2CH2CH3, C-NH2, C-OH), 1.83–1.79 (m, 4H; CH(CH3)2, CH3), 1.45
(s, 9H; C-(CH3)3), 1.29–1.22 (m, 3H; CO2CH2CH3), 1.06–0.86 ppm (m,
6H; 2ꢃCH3); 13C NMR (100 MHz CDCl3): d=174.9, 153.7, 138.4, 121.8,
80.6, 78.6, 76.3, 61.6, 58.4, 28.9, 28.4, 28.3, 22.2, 17.2, 14.3, 14.1 ppm; IR
(neat): n˜ =3538, 2976, 2930, 2868, 1706 (C=O), 1666, 1450 cmÀ1; MS
(ESI): m/z (%): 350 (100) [M ++Na], 294 (45), 250 (44); HRMS (ESI):
m/z: calcd for C17H29NO5Na: 350.1943; found 350.1965.
syn-Diol 23: NMO (367 mg, 3.13 mmol) and quinuclidine (87.0 mg,
0.78 mmol) were added to the substrate 22 (200 mg, 0.78 mmol) in ace-
tone (10 mL) and H2O (10 mL). The colourless solution was stirred for
2 min before addition of OsO4 (10 mg, 0.04 mmol). The brown solution
which formed was stirred for 28 h by which time analysis by TLC indicat-
ed complete consumption of the starting material. Silica gel was added
and the solution evaporated to dryness in vacuo. Purification of the
crude material by flash column chromatography eluting with methanol/
diethyl ether 1:99 furnished 23 as an orange foam (203 mg, 72%).
1H NMR (300 MHz, CDCl3): d=4.53–4.50 (m, 1H; CHOH), 4.47–4.45
(m, 1H; CHOH), 4.43–4.25 (m, 2H; O-CH2CH3), 4.16–3.83 (m, 1H; O-
H), 3.34 (dd, 3J(H,H)=12, 3J(H,H)=3.6 Hz, 2H; N-CH2), 3.16, 2.74 (2ꢃ
brs, 2H; 2ꢃO-H), 1.85–1.70 (m, 1H; CH(CH3)2), 1.49–1.42 (m, 9H; C-
(CH3)3), 1.42–1.35 (m, 6H; 2ꢃCH3), 1.10–0.96 ppm (m, 6H; 2ꢃCH3);
13C NMR (75 MHz, CDCl3): d=173.4, 81.2, 80.8, 78.6, 77.9, 75.6, 75.4,
75.2, 74.8, 74.4, 62.5, 58.9, 58.3, 28.6, 28.1, 22.5, 22.0, 21.6, 18.0, 17.3, 14.0,
13.9 ppm; IR (neat): n˜ =3940 (OH), 3451 (OH), 3244 (OH), 2974, 2933,
1704 cmÀ1 (C=O); MS (CI): m/z (%): 362 (100) [M ++H], 306 (40), 262
(20); HRMS (CI): m/z: calcd for C17H32NO7: 362.2179; found: 362.2171.
N-Deprotected lactam 31: TFA (1.0 mL) was added to a solution of 30
(632 mg, 1.65 mmol) in CH2Cl2 (2 mL) at RT under an inert atmosphere.
The reaction was stirred at room temperature for 30 min. The solution
was then evaporated to dryness in vacuo. The crude mixture was purified
by flash chromatography eluting with (20% acetone/PE) which furnished
31 as a colourless oil (458 mg, 98%). 1H NMR (300 MHz CDCl3): d=
6.56 (brt, 3J(H,H)=1.7 Hz, 1H; C=C-H), 6.20 (brs, 1H; N-H), 5.28 (d,
3J(H,H)=5.4 Hz, 1H; CHOAc), 4.17 (q, 3J(H,H)=7.1 Hz, 2H; O-
CH2CH3), 1.94 (s, 3H; COCH3), 1.88 (m, 1H; CH(CH3)2), 1.80 (s, 3H;
3
3
CH3), 1.25 (t, J(H,H)=7.1 Hz, 3H; O-CH2CH3), 0.89 ppm (d, J(H,H)=
6.7 Hz, 6H; 2ꢃCH3); 13C NMR (75 MHz, CDCl3): d=173.8, 170.3, 168.5,
139.8, 135.8, 75.9, 71.0, 62.5, 29.8, 20.4, 20.2, 18.0, 13.9, 10.4 ppm; IR
(neat): n˜ =2976, 2937, 2925, 2874, 1746 (C=O), 1735 (C=O), 1704, 1654,
1475, 1372, 1232, 1193, 1028 cmÀ1; MS (CI): m/z (%): 284 (100) [M +
+H], 169 (75), 123 (10); HRMS (CI): m/z: calcd for C14H22NO5:
284.1498; found 284.1492.
Monoacetate 24: DMAP (5 mg, 0.04 mmol) was added to the substrate
23 (464 mg, 1.29 mmol) in pyridine (5 mL) and acetic anhydride (5 mL).
The resulting solution was allowed to stir for 16 hr by which time analysis
by TLC indicated complete consumption of the starting material. The
crude mixture was evaporated to dryness and purification by flash
column chromatography eluting with (50% EtOAc/PE) furnished 24 as a
colourless solid (423 mg, 74%). 1H NMR (400 MHz, CDCl3): d = 5.78
(d, 3J(H,H)=7.5 Hz, 1H; CHOAc), 5.73–5.69 (m, 1H, CHOAc), 5.17,
4.75 (2ꢃbrs, 1H; OH), 4.41–4.15 (m, 2H; CO2CH2CH3), 4.10–3.92 (m,
syn-Diol 32: NMO (459 mg, 3.92 mmol) and quinuclidine (218 mg,
1.96 mmol) were added to compound 31 (554 mg, 1.96 mmol) in acetone
and H2O (3 mL). The colourless solution was stirred for 2 min before ad-
dition of OsO4 (10 mg, 0.20 mmol). The brown solution that formed was
stirred for 12 h and the solution evaporated to dryness in vacuo. Purifica-
tion of the crude material by flash column chromatography eluting with
(1% MeOH/Et2O) furnished 32 as a colourless solid (270 mg, 44%).
Chem. Eur. J. 2005, 11, 4227 – 4238
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4233

T. J. Donohoe et al.
1H NMR (300 MHz, CD3SOCD3): d=8.50 (s, 1H; NH), 5.25 (d, 3J-
(H,H)=7.1 Hz, 1H; CHOH), 5.22 (d, 3J(H,H)=6.3 Hz, 1H; CHOAc),
5.13 (s, 1H; C(CH3)OH), 4.12 (q, 3J(H,H)=7.1 Hz, 2H; CO2CH2CH3),
3.64 (d, 3J(H,H)=7.1 Hz, 1H; CHOH), 2.07 (s, 3H; COCH3), 1.95 (sp, 3J-
(H,H)=6.3 Hz, 1H; CH(CH3)2), 1.20 (m, 6H; CO2CH2CH3, CH3), 0.84
(d, 3J(H,H)=6.9 Hz, 3H; CH(CH3)), 0.78 ppm (d, 3J(H,H)=6.9 Hz, 3H;
(H,H)=3.2, 3J(H,H)=0.8 Hz, 1H; OH), 1.90–1.70 (m, 1H; CHMe2),
1.44, 1.41 (2ꢃs, 9H; CMe3), 1.24, 1.21 ppm (2ꢃt, 3J(H,H)=7.6, 3J’-
(H,H)=7.2 Hz, 3H; OCH2Me), 0.97, 0.95 (2ꢃd, 3J(H,H)=6.8 Hz, 3H;
CHMe), 0.87, 0.84 ppm (2ꢃd, 3J(H,H)=6.8 Hz, 3H; CHMe); 13C NMR
(125 MHz CDCl3): d=174.8, 174.6, 154.3, 153.5, 129.0, 128.6, 128.5, 81.2,
80.6, 78.8, 78.4, 76.7, 76.0, 62.1, 61.9, 56.0, 55.9, 29.4, 29.0, 28.7, 22.6, 22.3,
17.7, 17.1, 14.5, 14.4 ppm; IR (neat): n˜ =3543 (br OH), 2974–2872 (CH),
1705 cmÀ1 (br C=O); MS (ESI): m/z (%): 214 (100) [M +ÀBoc], 336 (36)
[M ++Na]; HRMS (ESI): m/z: calcd for C16H27NO5Na: 336.1787; found
336.1787 [M ++Na].
CH(CH3)); 13C NMR (75 MHz, CD3SOCD3): d
= 176.5, 170.5, 170.4,
77.9, 75.6, 71.5, 70.6, 61.3, 29.7, 23.3, 21.1, 21.0, 19.3, 14.3 ppm; IR (neat):
n˜ =3464 (br OH), 3423 (br, OH), 2976 (s), 2936 (s), 1735 (C=O), 1709
(C=O), 1656, 1374, 1231, 1026, 824 cmÀ1; MS (CI): m/z (%): 318 (100)
[M ++H], 258 (20); HRMS (EI): m/z: calcd for C14H23NO7: 317.1474;
found 317.1470 [M +].
Acetate 44: DMAP (cat.), acetic anhydride (15 mL) and distilled pyri-
dine (15 mL) were added to the anti-aldol product 42 (4.33 g, 13.8 mmol)
and the mixture was stirred for 48 h. The reaction mixture was poured
into water (50 mL) and aqueous CuSO4 (20 mL), and then extracted with
Et2O (3ꢃ50 mL), dried (Na2SO4), filtered and evaporated under reduced
pressure. The product was purified by flash column chromatography
(eluting with 5% acetone/PE) to afford the acetate protected anti-aldol
product 44 (3.4 g, 72%) as a very pale yellow oil. 1H NMR (400 MHz,
CDCl3): d = 6.12–5.98 (m, 1H; CH=CH), 5.91–5.85 (m, 1H; CH=CH),
5.84, 5.77 (2ꢃd, 3J(H,H)=3.6, 3J’(H,H)=3.3 Hz, 1H; CHOAc), 4.51–
4.35 (m, 1H; NCH), 4.30–4.20 (m, 1H NCH), 4.14 (q, 3J(H,H)=7.1 Hz,
2H; OCH2Me), 2.14 (s, 3H; COMe), 2.08–1.92 (m, 1H; CHMe2), 1.50 (s,
9H; CMe3), 1.26 (t, 3J(H,H)=7.1 Hz, 3H; OCH2Me), 0.98 (d, 3J(H,H)=
6.9 Hz, 3H; CHMe), 0.83 ppm (d, 3J(H,H)=6.9 Hz, 3H; CHMe);
13C NMR (75 MHz; CDCl3): d=170.9, 170.1, 153.2, 129.1, 129.0, 128.3,
128.1, 81.1, 80.2, 61.4, 61.3, 55.5, 55.4, 30.9, 29.1, 29.0, 28.9, 28.4, 28.3,
28.2, 28.1, 21.9, 21.7, 21.1, 17.2, 16.9, 13.9 ppm; IR (neat): n˜ =2975 (CH),
1744 (C=O), 1707 cmÀ1 (C=O); HRMS (ESI): m/z: calcd for C18H30NO6:
356.2073; found 356.2077 [M ++H].
Monoacetate 33: Acetic anhydride (84.4 mL, 0.89 mmol) and DMAP
(cat.) was added to the substrate 32 (177 mg, 0.55 mmol) in pyridine
(1 mL) and CH2Cl2 (2 mL). The resulting solution was allowed to stir for
12 h and the crude mixture was then evaporated to dryness. Purification
by flash column chromatography eluting with (2% MeOH/CH2Cl2) fur-
1
nished 33 as a colourless oil (423 mg, 74%). H NMR (300 MHz, CDCl3):
3
d=6.8 (s, 1H; N-H), 5.43 (d, J(H,H)=6.2 Hz, 1H; CHOAc), 5.2 (s, 1H;
CHOAc), 4.34 (m, 2H; CO2CH2CH3), 3.2 (brs, 1H; OH), 2.19 (s, 3H;
COCH3), 2.14 (s, 3H; COCH3), 1.94 (sp, 3J(H,H)=6.2 Hz, 1H; CH-
(CH3)2), 1.51 (s, 3H; CH3), 1.38 (t, 3J(H,H)=7.1 Hz, 3H; CO2CH2CH3),
1.01 (d, 3J(H,H)=6.9 Hz, 3H; CH3), 0.96 ppm (d, 3J(H,H)=6.9 Hz, 3H;
CH3); 13C NMR (75 MHz, CDCl3): d=170.0, 169.9, 169.0, 75.8, 74.9, 72.3,
69.0, 62.8, 30.3, 22.8, 20.7, 20.4, 18.5, 14.0 ppm; IR (neat): n˜ =3404 (br),
2977 (s), 2938 (s), 1729 (br), 1714 (s), 1373 (s), 1225 cmÀ1; MS (CI): m/z
(%): 377 (65), 360 (100) [M ++H]; HRMS (EI): m/z: calcd for
C16H25NO8: 359.1678; found 359.1682.
N-Boc ethyl ester pyrrole 40: DMAP (cat.), distilled triethylamine
(4.2 mL, 30 mmol) and di-tert-butyl dicarbonate (3.1 g, 14 mmol) were
added to a stirred solution of ethyl ester pyrrole 39 (1.4 g, 10 mmol) in
distilled MeCN (10 mL). The mixture was then heated at 508C for 48 h.
The reaction mixture was poured into water (30 mL) and extracted with
Et2O (3ꢃ30 mL), dried (Na2SO4), filtered and evaporated under reduced
pressure. The product was purified by flash column chromatography
(eluting with 10% acetone/PE) to afford the N-Boc ethyl ester pyrrole
syn-Diol 45: Trimethylamine N-oxide (3 mmol) and osmium tetroxide
(cat.) was added to the acetate protected anti-aldol product 44 (1 g,
3 mmol) in CH2Cl2 (50 mL), and the reaction mixture was stirred for 4 h.
Saturated Na2SO3 (20 mL) was then added to the reaction mixture and
stirred for a further 0.5 h and then evaporated to dryness. The reaction
mixture was then extracted with CH2Cl2 (3ꢃ100 mL), dried (Na2SO4), fil-
tered and evaporated under reduced pressure. The product was purified
by flash column chromatography (eluting with 100% Et2O) to afford the
1
40 (2.2 g, 91%) as a pale yellow oil. H NMR (400 MHz, CDCl3): d=7.31
1
(dd, 3J(H,H)=3.6, 3J(H,H)=2.0 Hz, 1H; ArH), 6.83 (dd, 3J(H,H)=3.6,
3J(H,H)=1.6 Hz, 1H; ArH), 6.17 (t, 3J(H,H)=3.6 Hz, 1H; ArH), 4.31
diol 45 (1.08 g, 95%) as a clear oil. H NMR (400 MHz, CDCl3): d=5.82,
3
3
5.75 (2ꢃd, J(H,H)=4.8, J’(H,H)=4.4 Hz, 1H; CHOAc), 4.72, 4.64 (2ꢃ
t, 3J(H,H)=5.2 Hz, 1H; CHOHB), 4.41, 4.06 (2ꢃd, 3J(H,H)=11.6, 3J’-
(H,H)=12.4 Hz, 1H; OHA), 4.34–3.92 (m, 4H; OCH2Me, CHOHA,
NCH), 3.52, 3.48 (2ꢃdd, 2J(H,H)=8.4, 3J(H,H)=4.0 Hz, 1H; NCH),
3
3
(q, J(H,H)=7.2 Hz, 2H; OCH2Me), 1.59 (s, 9H; CMe3), 1.36 ppm (t, J-
(H,H)=7.2 Hz, 3H; OCH2Me); 13C NMR (125 MHz, CDCl3): d=160.9,
148.4, 126.5, 125.6, 120.6, 110.0, 84.7, 60.8, 27.6, 14.3 ppm; IR (neat): n˜ =
2982–2875 (CH), 1752 (C=O), 1725 cmÀ1 (C=O); HRMS (ESI): m/z:
calcd for C14H20N2O4Na: 303.1320; found 303.1320 [M ++CH3CN+Na].
3
3
2.97, 2.89 (2ꢃd, J(H,H)=7.6, J’(H,H)=6.8 Hz, 1H; OHB), 2.12, 2.10 (s,
3H; COMe), 1.90–1.75 (m, 1H; CHMe2), 1.44, 1.43 (2ꢃs, 9H; CMe3),
1.28 (t, 3J(H,H)=7.2 Hz, 3H; OCH2Me), 0.99 (d, 3J(H,H)=6.8 Hz, 3H;
CHMe), 0.89 ppm (d, 3J(H,H)=7.2 Hz, 3H; CHMe); 13C NMR
(100 MHz, CDCl3): d=173.4, 169.8, 153.0, 81.8, 81.1, 75.9, 75.8, 75.0, 72.9,
72.7, 71.0, 70.4, 62.6, 62.5, 54.8, 54.1, 30.9, 29.1, 28.2, 22.2, 21.9, 21.0, 20.9,
18.4, 18.0, 13.8 ppm; IR (neat): n˜ =3424 (br OH), 2976–2874 (CH), 1746
(C=O), 1710 cmÀ1 (C=O); MS (ESI): m/z (%): 412 (100) [M ++Na], 390
(28) [M ++H]; HRMS (ESI): m/z: calcd for C18H31NO8Na: 412.1947;
found 412.1944 [M ++Na].
anti-Aldol adduct 42: Small strips of lithium ribbon (119 mg, 17.0 mmol),
antibumping granules and di-tert-butylbiphenyl (4.5 g, 16.9 mmol) were
placed in a Schlenk tube which was then evacuated and purged with
argon several times. The mixture was ground with a magnetic stirrer until
all the lithium became a dark powder. Freshly distilled THF (50 mL) was
then added and the mixture was cooled down to À788C before a mixture
of N-Boc ethyl ester pyrrole 40 (1.1 g, 4.4 mmol) and bis-methoxyethyla-
mine (0.8 mL, 5.3 mmol) in freshly distilled THF (25 mL) was added
dropwise to the turquoise solution. The mixture was then stirred at
À788C for a further 15 min after which freshly prepared MgBr2 (1.0 g,
5.4 mmol) in THF (20 mL) was added and the mixture was stirred for a
further 30 min. Distilled isobutyraldehyde (0.7 mL, 7.0 mmol) was then
added and after 30 min the reaction mixture was quenched with saturated
NH4Cl (10 mL). Stirring was continued at À788C for a further 30 min
and then warmed to ambient temperature. The reaction mixture was
poured into aqueous HCl (1.0m, 50 mL) and extracted with Et2O (3ꢃ
60 mL), dried (Na2SO4), filtered and evaporated under reduced pressure.
The product was purified by gradient column chromatography (eluting
with neat PE to recover the DBB and then 5% acetone/PE) to afford
the anti-aldol 42 (1.07 g, 74%) as a colourless oil. 1H NMR (400 MHz,
CDCl3): d=5.98, 5.93, 5.91(dt, s, dt, 3J(H,H)=8.4, 3J(H,H)=2.0, 3J’-
(H,H)=8.4, 3J’(H,H)=2.4 Hz, 2H; CH=CH), 4.41, 4.38 (dd, dt, 3J-
(H,H)=5.6, 3J(H,H)=2.8, J’(H,H)=18.0, J’(H,H)=2.0 Hz, 1H;
CHOH), 4.34–4.00 (m, 4H; OCH2Me, NCH2), 3.89, 3.62 (2ꢃdd, 3J-
Cyclic sulfate 46: Triethylamine (1.1 mL, 7.9 mmol) was added to a stir-
red solution of the diol 45 (381 mg, 0.980 mmol) in distilled CH2Cl2
(2 mL) at 08C, followed by the dropwise addition of thionylchloride
(110 mL, 1.51 mmol) over 0.5 h. After 1 h the reaction mixture was
warmed to room temperature and stirred for 24 h. The reaction mixture
was then poured into water (30 mL), extracted with Et2O (3ꢃ40 mL) and
the combined organic extract was washed with brine (10 mL), dried
(Na2SO4), filtered and concentrated in vacuo to afford the cyclic sulfite
(355 mg, 84%) as a brown solid, which was taken straight through to the
next step without purification.
To the crude cyclic sulfite (355 mg, 0.820 mmol) were added MeCN
(2 mL), CCl4 (2 mL) and water (3 mL). The reaction mixture was then
cooled down to 08C, followed by the additon of ruthenium trichloride hy-
drate (cat.) and sodium m-periodate (279 mg, 1.30 mmol), and the mix-
ture was stirred for 1.5 h at room temperature. The dark brown reaction
mixture was then extracted with Et2O (3ꢃ40 mL) and the combined or-
4234
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238

Lactacystin
FULL PAPER
ganic extract was washed with brine (10 mL) and saturated NaHCO3
(10 mL), dried (Na2SO4), filtered through a pad of charcoal and Celite
and concentrated in vacuo to afford the cyclic sulfate 46 (345 mg, 93%)
as a white solid. M.p. 133–1388C; 1H NMR (400 MHz, CDCl3): d=5.92,
5.82 (2ꢃd, 3J(H,H) = 3J’(H,H)=3.6 Hz, 1H; CHOAc), 5.76, 5.69 (2ꢃd,
3J(H,H)=6.8, 3J’(H,H)=7.2 Hz, 1H; CHOSO2), 5.43–5.34 (m, 1H;
NCH2CHOSO2), 4.35–4.01 (m, 4H; OCH2Me, NCH2), 2.14, 2.13 (2ꢃs,
3H; COMe), 1.93–1.82 (m, 1H; CHMe2), 1.47, 1.46 (2ꢃs, 9H; CMe3),
MOM protected diol 49: TBAF (2.40 mL, 2.40 mmol) was added drop-
wise to the bis-protected diol 48 (662 mg, 1.21 mmol) in distilled THF
(10 mL), and the mixture was stirred for 1 h. The reaction mixture was
quenched with saturated NH4Cl (10 mL) and stirred for a further 10 min
and then poured into water (30 mL) and extracted with Et2O (3ꢃ40 mL).
The combined organic extract was washed with brine (20 mL), dried
(Na2SO4), filtered and evaporated under reduced pressure. The product
was purified by flash column chromatography eluting with 20% EtOAc/
PE to afford the mono-MOM protected diol 49 (443 mg, 84%) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3): d=5.80, 5.76 (2ꢃd, 3J(H,H) =
3J’(H,H)=4.8 Hz, 1H; CHOAc), 4.83, 4.82 (2ꢃd, 3J(H,H)=6.8, 3J’-
(H,H)=6.4 Hz, 1H; OCHOMe), 4.71, 4.70 (2ꢃd, 3J(H,H) = 3J’(H,H)=
6.4 Hz, 1H, OCHOMe), 4.61, 4.27 (2ꢃd, 3J(H,H)=11.2, 3J(H,H)=
1.30, 1.26 (2ꢃt, J(H,H) = 3J’(H,H)=7.2 Hz, 3H; OCH2Me), 0.99 (d, J-
(H,H)=7.6 Hz, 3H; CHMe), 0.82 ppm (d, 3J(H,H)=6.8 Hz, 3H;
CHMe); 13C NMR (125 MHz CDCl3): d=170.1, 167.9, 152.9, 85.4, 84.5,
83.5, 79.7, 79.1, 75.2, 73.9, 63.3, 63.0, 53.1, 52.9, 29.7, 29.5, 28.6, 28.5, 21.6,
21.5, 17.9, 17.6, 14.2 ppm; IR (neat): n˜ =2977–2886 (CH), 1755 (C=O),
1694 cmÀ1 (C=O); MS (ESI): m/z (%): 474 (100) [M ++Na]; HRMS
(ESI): m/z: calcd for C18H29NO10SNa: 474.1414; found 474.1410 [M +
+Na].
3
3
3
3
11.6 Hz, 1H; OH), 4.51, 4.42 (2ꢃd, J(H,H)=4.4, J’(H,H)=4.8 Hz, 1H;
CHOMOM), 4.36–4.11 (m, 3H; OCH2Me, CHOH), 4.09, 3.94 (2ꢃd, 3J-
(H,H)=12.8, 3J’(H,H)=12.4 Hz, 1H; NCH), 3.48 (s, 3H; OCH2OMe),
3.43, 3.41 (2ꢃdd, 3J(H,H)=12.8, 3J(H,H)=3.6, 3J’(H,H)=12.4, 3J’-
(H,H)=3.6 Hz, 1H; NCH), 2.07, 2.05 (2ꢃs, 3H; COMe), 1.91–1.78 (m,
Monoprotected diol 47: Distilled 2,6-lutidine (0.76 mL, 6.50 mmol) was
added to the diol 45 (1.02 g, 2.62 mmol) in distilled CH2Cl2 (20 mL) and
the mixture was stirred at À788C for 0.5 h followed by dropwise addition
of tert-butyldimethylsilyl triflate (0.90 mL, 3.9 mmol). The reaction mix-
ture was then stirred at À788C for 1.5 h and then allowed to warm to
room temperature for 20 h. The mixture was poured into dilute HCl
(0.1m, 30 mL) and extracted with CH2Cl2 (3ꢃ40 mL), dried (Na2SO4), fil-
tered and evaporated under reduced pressure. The product was purified
by flash column chromatography (eluting with 10% acetone/PE) to
afford the mono-TBDMS protected diol 47 (1.2 g, 93%) as a pale yellow
3
1H; CHMe2), 1.45, 1.44 (2ꢃs, 9H; CMe3), 1.28, 1.26 (2ꢃt, J(H,H) = 3J’-
(H,H)=7.2 Hz, 3H; OCH2Me), 1.00, 0.99 (2ꢃd, 3J(H,H) = 3J’(H,H)=
6.8 Hz, 3H; CHMe), 0.89, 0.88 ppm (2ꢃd, 3J(H,H)=6.8, 3J’(H,H)=
6.4 Hz, 3H; CHMe); 13C NMR (100 MHz CDCl3): d=171.9, 169.5, 169.4,
153.8, 152.9, 96.5, 96.4, 81.7, 81.0, 80.6, 79.7, 76.0, 71.4, 71.2, 70.4, 69.9,
62.2, 62.1, 56.1, 55.7, 55.0, 30.9, 29.6, 28.9, 28.2, 28.1, 22.4, 22.2, 21.0, 20.9,
18.5, 18.2, 13.8 ppm; IR (neat): n˜ =3435 (br OH), 2973–2800 (CH), 1746
(C=O), 1710 cmÀ1 (C=O); MS (ESI): m/z (%): 456 (100) [M ++Na], 334
(53); HRMS (ESI): m/z: calcd for C20H36NO9: 434.2390; found 434.2386
[M ++H].
oil. 1H NMR (400 MHz, CDCl3): d=5.81, 5.77 (2ꢃd, 3J(H,H)
=
3J’-
(H,H)=4.0 Hz, 1H; CHOAc), 4.67, 4.49 (2ꢃt, 3J(H,H)=6.6, 3J’(H,H)=
6.2 Hz, 1H; CHOH), 4.36–4.26 (m, 1H; CHOTBS), 4.18–4.04 (m, 2H;
OCH2Me), 3.78–3.53 (m, 2H; NCH2), 3.33, 3.27 (2ꢃd, 3J(H,H) = 3J’-
(H,H)=6.8 Hz, 1H; OH), 2.14, 2.13 (2ꢃs, 3H; COMe), 1.94–1.83 (m,
1H; CHMe2), 1.45 (s, 9H; CMe3), 1.26 (t, 3J(H,H)=7.2 Hz, 3H;
OCH2Me), 0.97 (d, 3J(H,H)=6.8 Hz, 3H; CHMe), 0.92, 0.91 (2ꢃs, 9H;
OSiMe2CMe3), 0.86 (d, 3J(H,H)=7.2 Hz, 3H; CHMe), 0.14, 0.12 ppm
(2ꢃs, 6H; OSiMe2CMe3); 13C NMR (125 MHz CDCl3): d=170.3, 169.7,
153.5, 81.3, 76.2, 75.4, 74.7, 74.4, 73.6, 69.6, 68.8, 61.1, 61.0, 54.2, 54.0,
29.1, 28.8, 28.2, 28.1, 25.5, 22.0, 21.9, 21.1, 18.0, 17.6, 14.0, À4.8, À5.1,
À5.2 ppm; IR (neat): n˜ =3503 (br OH), 2963–2800 (CH), 1747 (C=O),
1706 cmÀ1 (C=O); MS (ESI): m/z (%): 526 (40) [M ++Na]; HRMS (CI):
m/z: calcd for C24H46NO8Si: 504.2993; found 504.2993 [M ++H].
MOM protected ketone 50: Dess–Martin periodinane (188 mg,
0.440 mmol) was added to the mono-MOM protected diol 49 (90 mg,
0.21 mmol) in distilled CH2Cl2 (4 mL) and the mixture was stirred for
1.5 h. Et2O (10 mL) was then added to the resulting cloudy white solution
followed by a 1:1 mixture of saturated NaHCO3 (2 mL) and saturated
Na2S2O3 (2 mL) and stirred for a further 1 h. The reaction mixture was
then poured into water (15 mL), extracted with Et2O (3ꢃ20 mL), dried
(Na2SO4), filtered and evaporated under reduced pressure. The product
was purified by flash column chromatography (eluting with 20% EtOAc/
PE) to afford the ketone 50 (77.2 mg, 86%) as a white solid. M.p. 80–
888C; 1H NMR (400 MHz, CDCl3): d=6.10, 6.04 (brs, d, 3J(H,H)=
2.8 Hz, 1H; CHOAc), 4.90 (d, 3J(H,H)=6.4 Hz, 1H; OCHOMe), 4.69
(d, 3J(H,H)=6.4 Hz, 1H; OCHOMe), 4.72–4.62 (m, 1H; CHOMOM),
4.28–4.04 (m, 3H; OCH2Me, NCH), 3.90 (d, 2J(H,H)=19.2 Hz, 1H;
NCH), 3.53 (s, 3H; OCH2OMe), 2.17–1.95 (m, 1H; CHMe2), 2.10 (s, 3H;
COMe), 1.48 (s, 9H; CMe3), 1.22 (t, 3J(H,H)=7.2 Hz, 3H; OCH2Me),
1.01 (d, 3J(H,H)=6.8, 3H; CHMe), 0.90 ppm (d, 3J(H,H)=7.2 Hz, 3H,
CHMe); 13C NMR (125 MHz CDCl3): d=205.3, 169.3, 168.8, 96.6, 82.6,
78.9, 74.8, 71.1, 61.5, 56.4, 52.8, 29.3, 28.0, 21.4, 20.9, 17.6, 13.9 ppm; IR
(neat): n˜ =2980–2922 (CH), 1778 (C=O), 1759 (C=O), 1711 cmÀ1 (C=O);
MS (ESI): m/z (%): 454 (48) [M ++Na]; HRMS (CI): m/z: calcd for
C20H34NO9: 432.2240; found 432.2234 [M ++H].
Diprotected diol 48: Diisopropylethylamine (5.0 mL, 28 mmol) was
added to the mono-TBDMS protected diol 47 (709 mg, 1.41 mmol) in dis-
tilled CH2Cl2 (10 mL) and the mixture was stirred for 45 min. Chloro-
methyl methoxy ether (1.61 mL, 21.2 mmol) was then added dropwise
and the mixture was heated at 508C for 21 h. The dark orange reaction
mixture was then quenched with saturated NH4Cl (5 mL) and the mix-
ture was stirred for a further 0.5 h, then poured into water (30 mL) and
extracted with Et2O (3ꢃ40 mL). The combined organic extract was
washed with brine (20 mL), dried (Na2SO4), filtered and evaporated
under reduced pressure. The product was purified by flash column chro-
matography (eluting with 10% acetone/PE) to afford the bis-protected
diol 48 (764 mg, 99%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3):
Epimerised MOM protected ketone 51: nBuLi (1.6m solution in hexane,
0.34 mL, 0.54 mmol) was added slowly at 08C to methyl triphenylphos-
phonium iodide (228 mg, 0.560 mmol) in distilled THF (2 mL), and the
reaction mixture was stirred for 1 h. Ketone 50 (117 mg, 0.270 mmol) in
distilled THF (5 mL) was then added dropwise to the orange solution,
which was stirred at room temperature for 1.5 h. The reaction mixture
was quenched with saturated NH4Cl (10 mL) and stirred for a further
15 min, then poured into water (20 mL) followed by extraction with Et2O
(3ꢃ30 mL). The combined organic extract was washed with brine
(15 mL), dried (Na2SO4), filtered and evaporated under reduced pressure.
The product was purified by flash column chromatography (eluting with
10% EtOAc/PE) to afford the ketone 51 (62.6 mg, 56%) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3): d=5.41 (s, 1H; CHOAc), 4.70,
d
=
5.80, 5.74 (2ꢃd, 3J(H,H)=4.0, 3J’(H,H)=3.6 Hz, 1H; CHOAc),
4.81, 4.78 (2ꢃd, 3J(H,H)=7.2, 3J’(H,H)=6.8 Hz, 1H; OCHOMe), 4.64–
4.60 (m, 1H; OCHOMe), 4.60, 4.50 (2ꢃd, 3J(H,H)=6.8, 3J’(H,H)=
5.2 Hz, 1H; CHOMOM), 4.28–3.98 (m, 3H; OCH2Me, CHOTBDMS),
3
3
3
3
3.77, 3.62 (2ꢃdd, J(H,H)=9.6, J(H,H)=6.8, J’(H,H)=10.0, J’(H,H)=
7.2 Hz, 1H; NCH), 3.48, 3.45 (2ꢃt, 3J(H,H) = 3J’(H,H)=9.6 Hz, 1H;
NCH), 3.35 (s, 3H; OCH2OMe), 2.14, 2.13 (2ꢃs, 3H; COMe), 1.99–1.84
(m, 1H; CHMe2), 1.45 (s, 9H; CMe3), 1.26, 1.23 (2ꢃt, 3J(H,H)=7.2, 3J’-
(H,H)=6.8 Hz, 3H; OCH2Me), 1.00, 0.98 (2ꢃd, 3J(H,H) = 3J’(H,H)=
6.8 Hz, 3H; CHMe), 0.91, 0.90 (2ꢃs, 9H; OSiMe2CMe3), 0.88, 0.84 (2ꢃd,
3J(H,H)
=
3J’(H,H)=6.8 Hz, 3H; CHMe), 0.12, 0.11, 0.10 ppm (3ꢃs,
6H; OSiMe2CMe3); 13C NMR (125 MHz CDCl3): d=170.3, 169.9, 169.5,
169.1, 153.7, 96.7, 81.3, 80.2, 77.7, 77.5, 75.5, 74.7, 74.5, 74.1, 70.4, 70.0,
61.0, 60.9, 56.0, 52.0, 51.6, 28.8, 28.4, 28.1, 26.1, 25.7, 22.3, 22.1, 21.0, 18.1,
18.0, 17.9, 13.8, À4.8, À5.0 ppm; IR (neat): n˜ =2961–2858 (CH), 1748 (C=
O), 1709 cmÀ1 (C=O); MS (ESI): m/z (%): 570 (47) [M ++Na]; HRMS
(CI): m/z: calcd for C26H50NO9Si: 548.3255; found 548.3255 [M ++H].
4.69 (2ꢃd, J(H,H)=6.4, J’(H,H)=6.8 Hz, 1H; OCHOMe), 4.64 (s, 1H;
CHOMOM), 4.58 (d, 3J(H,H)=6.8 Hz, 1H; OCHOMe), 4.46–4.02 (m,
3H; OCH2Me, NCH), 3.76, 3.74 (2ꢃd, 2J(H,H)=17.6, 2J’(H,H)=
18.8 Hz, 1H; NCH), 3.36 (s, 3H; OCH2OMe), 2.75, 2.69–2.57 (sp, m, 3J-
(H,H)=6.8 Hz, 1H; CHMe2), 1.91, 1.90 (2ꢃs, 3H; COMe), 1.47, 1.46
3
3
(2ꢃs, 9H; CMe3), 1.36, 1.32 (2ꢃt, 3J(H,H)
=
3J’(H,H)=7.6 Hz, 3H;
Chem. Eur. J. 2005, 11, 4227 – 4238
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4235

T. J. Donohoe et al.
OCH2Me), 1.04, 1.03 (2ꢃd, 3J(H,H) = 3J’(H,H)=7.2 Hz, 3H; CHMe),
0.78, 0.75 ppm (2ꢃd, 3J(H,H)=6.8, 3J’(H,H)=6.4 Hz, 3H; CHMe);
13C NMR (100 MHz CDCl3): d=204.5, 203.7, 169.5, 169.1, 153.0, 152.7,
97.4, 97.2, 82.5, 81.6, 70.5, 69.9, 62.0, 56.5, 56.3, 51.4, 50.9, 28.4, 28.3, 28.1,
23.0, 20.4, 17.0, 16.8, 14.0, 13.9 ppm; IR (neat): n˜ =2978–2810 (CH), 1782
(C=O), 1754 (C=O), 1707 cmÀ1 (C=O); MS (ESI): m/z (%): 454 (100)
[M ++Na], 449 (58) [M ++NH4]; HRMS (ESI): m/z: calcd for
C20H34NO9: 432.2234; found 432.2235 [M ++H].
(d, 3J(H,H)=6.8 Hz, 3H; CHMe), 0.96 (t, 3J(H,H)=8.0 Hz, 9H; OSi-
(CH2Me)3), 0.88 (d, 3J(H,H)=6.4 Hz, 3H; CHMe), 0.60, 0.59 ppm (2ꢃq,
3J(H,H)=8.0 Hz, 6H; OSi(CH2Me)3); 13C NMR (125 MHz, CDCl3): d=
170.1, 170.0, 153.9, 153.3, 80.9, 79.9, 76.1, 75.8, 75.4, 73.5, 72.8, 60.6, 60.4,
46.0, 45.4, 33.0, 32.3, 29.0, 28.9, 28.2, 28.1, 27.8, 22.3, 22.1, 21.0, 18.1, 17.9,
14.0, 6.6, 6.3, 4.9, 4.8 ppm; IR (neat): n˜ =2963–2878 (CH), 1749 (C=O),
1707 cmÀ1 (C=O); MS (ESI): m/z (%): 510 (100) [M ++Na], 488 (69)
[M ++H], 388 (81); HRMS (ESI): m/z: calcd for C24H46NO7Si: 488.3044;
found 488.3048 [M ++H].
Iodohydrin 54: Triphenylphosphine (4.19 g, 16.0 mmol) and di-tert-butyla-
zodicarboxylate (3.67 g, 15.9 mmol) were added to the diol 45 (1.0 g,
2.6 mmol) in distilled benzene (14 mL), and the reaction mixture was stir-
red for 20 min. Methyliodide (1.91 mL, 30.7 mmol) was then added drop-
wise and the mixture was heated at reflux at 808C for 34 h. The reaction
mixture was then poured into water (100 mL), extracted with dichloro-
methane (3ꢃ100 mL), dried (Na2SO4), filtered and evaporated under re-
duced pressure. The product was purified by flash column chromatogra-
phy (eluting with 5% acetone/PE) to afford the iodide 54 (1.04 g, 81%)
as a clear oil. 1H NMR (400 MHz, CDCl3): d=6.26 (brs, 1H; OH), 5.81,
TBS protected lactam 57: MeCN (17 mL), CCl4 (17 mL) and water
(26 mL) were added to the TES protected alcohol 56 (450 mg,
0.16 mmol), followed by the additon of sodium m-periodate (150 mg,
0.70 mmol) and ruthenium trichloride hydrate (33 mg, 0.16 mmol) at 08C.
The reaction mixture was stirred at 08C for 0.5 h and then warmed to
room temperature and stirred for 4 h. The reaction mixture was filtered
through a pad of Celite and evaporated under reduced pressure. The
product was purified by flash column chromatography (eluting with 5%
acetone/PE) to afford the lactam 57 (389 mg, 84%) as a pale yellow oil.
3
3
3
5.73 (2ꢃd, J(H,H)=4.8, J’(H,H)=4.4 Hz, 1H; CHOAc), 4.79, 4.73 (2ꢃ
dd, 3J(H,H)=9.8 Hz, 3J(H,H)=3.4, 3J’(H,H)=9.6, 3J’(H,H)=3.2 Hz,
1H; CHOH), 4.44–4.06 (m, 4H; OCH2Me, CHI, NCH), 3.61–3.46 (m,
1H; NCH), 2.12, 2.11 (2ꢃs, 3H; COMe), 1.98–1.82 (m, 1H; CHMe2),
1.44, 1.42 (2ꢃs, 9H; CMe3), 1.26, 1.22 (2ꢃt, 3J(H,H)=7.2 Hz, 3H;
OCH2Me), 1.00, 0.99 (2ꢃd, 3J(H,H)=6.8, 3J’(H,H)=7.2 Hz, 3H;
CHMe), 0.92, 0.91 ppm (2ꢃd, 3J(H,H)=6.8 Hz, 3H; CHMe); 13C NMR
(125 MHz, CDCl3): d=169.9, 169.8, 169.0, 155.6, 152.4, 83.2, 82.4, 81.9,
81.3, 81.2, 71.0, 61.6, 61.5, 54.1, 29.0, 28.1, 28.0, 27.8, 27.7, 22.0, 21.7, 20.9,
19.0, 18.6, 18.0, 17.7, 14.0, 13.9 ppm; IR (neat): n˜ =3337 (br OH), 2979–
2885 (CH), 1741 (C=O), 1708 cmÀ1 (C=O); HRMS (ESI): m/z: calcd for
C18H34N2IO7: 517.1400; found 517.1411 [M ++NH4].
1H NMR (400 MHz, CDCl3): d=5.94 (d, J(H,H)=3.6 Hz, 1H; CHOAc),
4.85 (dd, 3J(H,H)=8.8, 3J(H,H)=6.8 Hz, 1H; CHOTES), 4.19–4.08 (m,
2H; OCH2Me), 2.91, 2.87 (2ꢃd, 3J(H,H)=8.8 Hz, 1H; NCOCH), 2.70,
2.65 (2ꢃd, 3J(H,H)=6.4 Hz, 1H; NCOCH), 2.13 (s, 3H; COMe), 1.81,
1.80 (2ꢃsp, 3J(H,H)=6.8 Hz, 1H; CHMe2), 1.50 (s, 9H; CMe3), 1.24 (t,
3J(H,H)=7.2 Hz, 3H; OCH2Me), 0.98–0.92 (m, 12H; CHMe, OSi-
(CH2Me)3), 0.84 (d, 3J(H,H)=6.8 Hz, 3H; CHMe), 0.60 ppm (q, 3J-
(H,H)=8.0 Hz, 6H; OSi(CH2Me)3); 13C NMR (125 MHz; CDCl3): d=
172.1, 169.7, 168.3, 148.4, 84.4, 74.6, 74.2, 65.5, 61.2, 61.0, 40.9, 29.2, 27.7,
27.6, 25.0, 21.4, 21.0, 17.1, 13.9, 7.0, 6.6, 6.5, 6.3, 6.1, 4.7 ppm; IR (neat):
n˜ =2961–2879 (CH), 1798 (C=O), 1757 (C=O), 1725 cmÀ1 (C=O); MS
(ESI): m/z (%): 524 (100) [M ++Na], 424 (79); HRMS (ESI): m/z: cald
for C24H43NO8SiNa: 524.2656; found 524.2649 [M ++Na].
Mono-alcohol 55: A mixture of freshly dried indium trichloride (312 mg,
1.4 mmol) and sodium borohydride (102 mg, 2.8 mmol) in distilled
MeCN (6 mL) was stirred at À788C for 10 min. The heterogeneous solu-
tion was then warmed to ambient temperature and the iodide 54
(897 mg, 1.8 mmol) in distilled MeCN (14 mL) was added dropwise and
stirred for 2 h. The reaction mixture was then poured into water (40 mL)
and extracted with Et2O (3ꢃ50 mL). The combined organic extract was
washed with brine (20 mL), dried organic extract was washed with brine
(20 mL), dried (Na2SO4), filtered and concentrated in vacuo to afford the
alcohol 55 (658 mg, 98%) as a pale yellow oil. 1H NMR (400 MHz,
CDCl3): d=5.87, 5.79 (2ꢃd, 3J(H,H)=4.4, 3J’(H,H)=4.0 Hz, 1H;
CHOAc), 4.85, 4.78 (dd, t, 3J(H,H)=10.0, J = 7.6, J’ = 8.8 Hz, 1H;
CHOH), 4.29–4.07 (m, 2H; OCH2Me), 4.03–3.92, 3.90–3.81 (2ꢃm, 1H;
NCH), 3.34–3.22 (m, 1H; NCH), 2.22–2.09 (m, 2H; NCH2CH2), 2.13,
2.12 (2ꢃs, 3H; COMe), 2.00–1.80 (m, 1H; CHMe2), 1.45, 1.43 (2ꢃs, 9H;
Hydroxyl substituted lactam 58: Distilled pyridine (20 mL) and HF·pyri-
dine solution (20 mL) were added to the lactam 57 (850 mg, 1.70 mmol)
in distilled THF (100 mL) and the mixture was stirred for 15 min at 08C
before warming to room temperature. After 2 h NaHCO3 was added to
the reaction mixture until pH 7. The reaction mixture was poured into
water (20 mL) and extracted with EtOAc (3ꢃ150 mL). The combined or-
ganic extract was dried (Na2SO4), filtered and evaporated under reduced
pressure. The product was purified by flash column chromatography
(eluting with 10% acetone/PE) to afford the b-hydroxyketone 58
(617 mg, 94%) as a clear oil. 1H NMR(400 MHz, CDCl3): d=5.92 (d, 3J-
(H,H)=3.2 Hz, 1H; CHOAc), 4.90 (t, 3J(H,H)=9.0 Hz, 1H; CHOH),
4.23 (q, 3J(H,H)=7.2 Hz, 2H; OCH2Me), 2.92, 2.88 (2ꢃd, 3J(H,H)=9.6,
3J’(H,H)=8.8 Hz, 1H; NCOCH), 2.79, 2.75 (2ꢃd, 3J(H,H)=8.8, 3J’-
(H,H)=9.2 Hz, 1H; NCOCH), 2.16 (s, 3H; COMe), 2.14, 1.52 (2ꢃbrs,
1H; OH), 1.86, 1.85 (2ꢃsp, 3J(H,H)=6.8 Hz, 1H; CHMe2), 1.51 (s, 9H;
CMe3), 1.27 (t, 3J(H,H)=7.2 Hz, 3H; OCH2Me), 0.98 (d, 3J(H,H)=
6.8 Hz, 3H; CHMe), 0.89 ppm (d, 3J(H,H)=6.8 Hz, 3H; CHMe);
13C NMR (125 MHz, CDCl3): d=171.4, 168.9, 148.6, 84.6, 75.6, 73.6, 65.7,
61.8, 37.9, 29.6, 29.0, 27.7, 21.3, 20.9, 17.2, 13.9 ppm; IR (neat): n˜ =3489
(br OH), 2977–2855 (CH), 1790 (C=O), 1754 cmÀ1 (C=O); MS (ESI): m/
z (%): 310 (100); HRMS (ESI): m/z: calcd for C18H29NO8Na:410.1791;
found 410.1795 [M ++Na].
3
CMe3), 1.27, 1.23 (2ꢃt, J(H,H)=7.2 Hz, 3H; OCH2Me), 1.00, 0.99 (2ꢃd,
3J(H,H)=7.2, 3J’(H,H)=6.8 Hz, 3H; CHMe), 0.91, 0.90 ppm (2ꢃd, 3J-
(H,H)=6.8, 3J’(H,H)=7.2 Hz, 3H; CHMe); 13C NMR (100 MHz,
CDCl3): d=170.6, 170.5, 169.2, 169.0, 81.1, 80.3, 77.8, 75.6, 74.7, 72.1,
71.9, 61.2, 61.0, 45.4, 44.9, 30.8, 30.2, 29.7, 29.5, 29.2, 28.9, 28.1, 28.0, 27.8,
22.0, 21.7, 20.9, 18.2, 17.9, 14.0 ppm; IR (neat): n˜ =3490 (br OH), 2977–
2884 (CH), 1743 (C=O), 1703 cmÀ1 (C=O); HRMS (ESI): m/z: calcd for
C18H31NO7Na: 396.1998; found, 396.2004 [M ++Na].
TES protected alcohol 56: DMAP (226 mg, 1.85 mmol), imidazole
(1.26 g, 18.5 mmol) and triethylsilylchloride (1.86 mL, 11.1 mmol) were
added to a stirred solution of the alcohol 55 (1.38 g, 3.70 mmol) in distil-
led CH2Cl2 (25 mL). The reaction mixture was stirred for 24 h and then
poured into water (50 mL) and extracted with CH2Cl2 (3ꢃ100 mL). The
combined organic extract was washed with brine (50 mL), dried
(Na2SO4), filtered and evaporated under reduced pressure. The product
was purified by flash column chromatography (eluting with 5% acetone/
PE) to afford the TES protected alcohol 56 (1.8 g, 100%) as a pale
yellow oil. 1H NMR (400 MHz, CDCl3): d=5.84, 5.81 (2ꢃd, 3J(H,H)=
4.4 Hz, 1H; CHOAc), 4.85, 4.75 (2ꢃt, 3J(H,H)=7.8, 3J’(H,H)=7.4 Hz,
1H; CHOTES), 4.20–4.00 (m, 2H; OCH2Me), 4.00–3.91, 3.86–3.79 (2ꢃ
m, 1H; NCH), 3.33–3.22, 3.14–3.05 (2ꢃm, 1H; NCH), 2.13–2.04 (m, 2H;
NCH2CH2), 2.09 (s, 3H; COMe), 1.98–1.84 (m, 1H; CHMe2), 1.44, 1.43
(2ꢃs, 9H; CMe3), 1.24, 1.21 (2ꢃt, 3J(H,H)=7.2 Hz, 3H; OCH2Me), 0.97
Methylated lactam 59: nBuLi (1.6m in hexane, 1.56 mL, 2.5 mmol) was
added to a solution of distilled diisopropylamine (325 mL, 2.6 mmol) in
distilled THF (0.5 mL) at À788C and stirred for 15 min. Methyl iodide
(600 mL, 9.5 mmol) was then added followed by the dropwise addition of
a stirred solution of the alcohol 58 (400 mg, 1.03 mmol) and HMPA
(3 mL) in distilled THF (10 mL). The reaction mixture was stirred at
À788C for 6 h and then quenched with saturated NH4Cl (3 mL) and stir-
red for a further 10 min. The reaction mixture was then poured into
water (20 mL), extracted with Et2O (3ꢃ50 mL), dried (Na2SO4), filtered
and evaporated under reduced pressure. The product was purified by
flash column chromatography (eluting with 5–10% acetone/PE) to afford
the lactam 59 (261 mg, 63%) as a clear oil. 1H NMR (400 MHz, CDCl3):
d=5.91 (d, 3J(H,H)=3.6 Hz, 1H; CHOAc), 4.90 (d, 3J(H,H)=9.6 Hz,
1H; CHOH), 4.21 (q, 3J(H,H)=7.2 Hz, 2H; OCH2Me), 2.91 (dq, 3J-
(H,H)=9.6, 3J(H,H)=7.6 Hz, 1H; NCOCHMe), 2.16 (s, 3H; COMe),
4236
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238

Lactacystin
FULL PAPER
1.96 (brs, 1H; OH), 1.85–1.82 (m, 1H; CHMe2), 1.52 (s, 9H; CMe3), 1.33
(d, 3J(H,H)=7.6 Hz, 3H; NCOCHMe), 1.27 (t, 3J(H,H)=7.2 Hz, 3H;
[1] For a review, see: M. Groll, T. Clausen, Curr. Opin. Struct. Biol.
2003, 13, 665.
OCH2Me), 0.98 (d, 3J(H,H)=6.8 Hz, 3H; CHMe), 0.86 ppm (d, J
=
6.8 Hz, 3H; CHMe); 13C NMR (100 MHz, CDCl3): d=176.0, 169.6, 169.4,
84.6, 75.5, 74.3, 66.8, 61.9, 40.7, 29.2, 27.8, 21.5, 21.1, 17.2, 13.9, 10.5,
6.7 ppm; IR (neat): n˜ = 3491 (br OH), 2977–2882 (CH), 1786 (C=O),
1752 cmÀ1 (C=O); MS (ESI): m/z (%): 424 (100) [M ++Na], 302 (84),
324 (72); HRMS (ESI): m/z: calcd for C19H31NO8Na: 424.1947; found
424.1935 [M ++Na].
[2] For a review, see: C. N. Larsen, D. Finley, Cell 1997, 91, 431.
[3] For a review, see: A. Hershko, A. Ciechanover, Annu. Rev. Bio-
chem. 1998, 67, 425.
[4] a) S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi,
H. Tanaka, Y. Sasaki, J. Antibiot. 1991, 44, 113; b) S. Omura, K.
Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya, S. Fujita, A. Nakaga-
wa, J. Antibiot. 1991, 44, 117.
Free acid 61: Trifluoroacetic acid (2 mL) was added dropwise to the
lactam 59 (250 mg, 0.62 mmol) in distilled CH2Cl2 (4.0 mL) at 08C, and
the mixture was stirred for 10 min and then warmed to room tempera-
ture. After 1 h the reaction mixture was evaporated under reduced pres-
sure. The product was purified by flash column chromatography (eluting
with 25% acetone/PE) to afford the amine 61 (190 mg, 100%) as a white
solid. M.p. 135–1428C; 1H NMR (400 MHz, CDCl3): d=8.01 (brs, 1H;
NH), 5.56 (d, 3J(H,H)=6.0 Hz, 1H; CHOAc), 4.40–4.29 (m, 2H,
OCH2Me), 4.26 (d, 3J(H,H)=6.0 Hz, 1H; CHOH), 2.63 (appqt, 3J-
(H,H)=6.8 Hz, 1H; NCOCHMe), 2.10 (s, 3H; COMe), 1.94 (sp, 3J-
(H,H)=6.7 Hz, 1H; CHMe2), 1.37 (t, 3J(H,H)=7.2, 3H; OCH2Me), 1.17
(d, 3J(H,H)=8.0 Hz, 3H, NCOCHMe), 0.93 ppm (t, 3J(H,H)=7.0 Hz,
6H; CHMe2); 13C NMR (125 MHz, CDCl3): d=179.3, 171.2, 170.0, 78.2,
76.3, 74.7, 62.5, 61.0, 40.8, 30.2, 20.8, 19.6, 18.0, 13.9, 7.8 ppm; IR (neat):
n˜ = 3321 (br OH), 2980–2884 (CH), 1730 (C=O), 1698 cmÀ1 (C=O); MS
(ESI): m/z (%): 324 (100) [M ++Na], 302 (46) [M ++H]; HRMS (ESI):
m/z: calcd for C14H24NO6: 302.1604; found 302.1607 [M ++H].
[5] G. Fenteany, R. F. Standaert, G. A. Reichard, E. J. Corey, S. L.
Schreiber, Proc. Natl. Acad. Sci. USA 1994, 91, 3358.
[6] G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E. J. Corey, S. L.
Schreiber, Science 1995, 268, 726.
[7] M. Groll, L. Ditzel, J. Lowe, D. Stock, M. Bochtler, H. D. Bartunik,
R. Huber, Nature 1997, 386, 463.
[8] L. R. Dick, A. A. Cruikshank, L. Grenier, F. D. Melandri, S. L.
Nunes, R. L. Stein, J. Biol. Chem. 1996, 271, 7273.
[9] R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A. Kauffman, P. R.
Jensen, W. Fenical, Angew. Chem. 2003, 115, 369; Angew. Chem. Int.
Ed. 2003, 42, 355.
[10] M. Elofsson, U. Splittgerber, J. Myung, R. Mohan, C. M. Crews,
Chem. Biol. 1999, 6, 811.
[11] Total syntheses of lactacystin 3: a) E. J. Corey, G. A. Reichard, J.
Am. Chem. Soc. 1992, 114, 10677; b) T. Sunazuka, T. Nagamitsu, K.
Matsuzaki, H. Tanaka, S. Omura, A. B. Smith III, J. Am. Chem. Soc.
1993, 115, 5302; c) H. Uno, J. E. Baldwin, A. T. Russell, J. Am.
Chem. Soc. 1994, 116, 2139; d) N. Chida, J. Takeoka, N. Tsutsumi, S.
Ogawa, J. Chem. Soc. Chem. Commun. 1995, 793; e) J. S. Panek,
C. E. Masse, Angew. Chem. 1999, 111, 1161; Angew. Chem. Int. Ed.
1999, 38, 1093; f) F. Soucy, L. Grenier, M. L. Behnke, A. T. Destree,
T. A. McCormack, J. Adams, L. Plamondon, J. Am. Chem. Soc.
1999, 121, 9967; for formal syntheses of lactacystin see: g) M. P.
Green, J. C. Prodger, C. J. Hayes, Tetrahedron Lett. 2002, 43, 6609;
h) C. J. Brennan, G. Pattenden, G. Rescourio, Tetrahedron Lett.
2003, 44, 8757.
[12] M. Yano, Y. Koumoto, Y. Kanesaki, X. Wu, H. Kido, Biomacromol-
ecules 2004, 5, 1465.
[13] H. Sawada, R. Kohno, T. Kihara, Y. Izumi, N. Sakka, M. Ibi, M. Na-
kanishi, T. Nakamizo, K. Yamakawa, H. Shibasaki, N. Yamamoto,
A. Akaike, M. Inden, Y. Kitamura, T. Taniguchi, S. Shimohama, J.
Biol. Chem. 2004, 279, 10710.
[14] a) T. J. Donohoe, D. House, Tetrahedron Lett. 2003, 44, 1095; b) T. J.
Donohoe, D. House, K. W. Ace, Org. Biomol. Chem. 2003, 3749.
[15] T. J. Donohoe, H. O. Sintim, L. Sisangia, J. D. Harling, Angew.
Chem. 2004, 116, 2343; Angew. Chem. Int. Ed. 2004, 43, 2293.
[16] T. J. Donohoe, P. M. Guyo, R. L. Beddoes, M. Helliwell, J. Chem.
Soc. Perkin Trans. 1 1998, 667.
[17] T. J. Donohoe, D. House, J. Org. Chem. 2002, 67, 5015.
[18] T. J. Donohoe, P. R. Moore, M. J. Waring, N. J. Newcombe, Tetrahe-
dron Lett. 1997, 38, 5027.
[19] E. M. Burgess, H. R. Penton, E. A. Taylor, J. Am. Chem. Soc. 1970,
92, 5224.
[20] J. C. Martin, R. J. Arhart, J. Am. Chem. Soc. 1971, 93, 4327.
[21] K. Ramesh, M. S. Wolfe, Y. Lee, D. V. Velde, R. T. Borchardt, J.
Org. Chem. 1992, 57, 5861.
(Æ)-Lactacystin b-lactone 1: a) Cold (08C) aqueous NaOH (0.5m, 10 mL)
was added to lactam 61 (120 mg, 0.40 mmol) and left in the fridge for
6.5 d at 48C. Aqueous HCl (1.0m) was then added dropwise to the reac-
tion mixture until a pH of 1 was obtained, and the mixture was concen-
trated in vacuo. Hot THF (100 mL) was added to the residue and the in-
soluble inorganic salt was filtered. The filtrate was concentrated in vacuo
to afford crude dihydroxyacid 15 (95 mg) as a white solid that was used
in the next step without purification.
b) A suspension of crude dihydroxyacid 15 (20 mg) in CH2Cl2 (2 mL) was
treated with Et3N (36 mL, 0.26 mmol) and bis(2-oxo-3-oxazolidinyl)phos-
phinic chloride (BOPCl, 33 mg, 0.13 mmol) at ambient temperature.
After 1 h of stirring at room temperature, water (2 mL) was added to the
reaction mixture and extracted with EtOAc (3ꢃ5 mL). The combined or-
ganic phases were dried (Na2SO4) and concentrated in vacuo. The solid
residue was recrystallised from EtOAc/hexane to give lactacystin b-lac-
tone 1 (14.6 mg, 81% over two steps). Both 1H and 13C NMR matched
1
those reported in the literature. M.p. 182–1838C (lit:[36] 1858C); H NMR
(500 MHz, [D5]pyridine): d=10.37 (s, 1H; NH), 7.76 (brs, 1H; OH), 5.65
(d, 3J(H,H)=6.1 Hz, 1H; CHOCO), 4.35–4.31 (m, 1H; OCHCH), 3.02
(dq, J1 = 6.1, J2 = 7.3 Hz, 1H, CHMe), 2.14–2.05 (m, 1H; CH(Me)2),
1.45 (d, 3J(H,H)=7.6 Hz, 3H; CHMe), 1.11 (d, 3J(H,H)=6.7 Hz, 3H;
CH(Me)2), 0.99 ppm (d, 3J(H,H)=6.7 Hz, 3H; CH(Me)2); 13C NMR
(125 MHz, [D5]pyridine): d=177.3, 172.4, 80.5, 77.0, 70.6, 38.9, 29.8, 20.4,
16.5, 8.8 ppm; HRMS (Cl, NH3): m/z: calcd for C10H19N2O4: 231.1344;
found, 231.1349 [M ++NH4].
Literature NMR data, see ref. [36].
1H NMR (500 MHz, [D5]pyridine): d=10.50 (s, 1H; NH), 7.85 (d, 3J-
(H,H)=6.8 Hz, 1H; OH), 5.68 (d, 3J(H,H)=6.1 Hz, 1H; CHOCO), 4.33
(dd, 3J(H,H)=3.6, 3J(H,H)=6.7 Hz, 1H; OCHCH), 3.03 (dq, 3J(H,H)=
6.1, 3J(H,H)=7.4 Hz, 1H; CHMe), 2.09 (m, 1H; CH(Me)2), 1.45 (d, 3J-
(H,H)=7.5 Hz, 3H; CHMe), 1.10 (d, 3J(H,H)=6.8 Hz, 3H; CH(Me)2),
0.98 (d, 3J(H,H)=6.8 Hz, 3H; CH(Me)2); 13C NMR (125 MHz, [D5]pyri-
dine): d=177.4, 172.4, 80.5, 77.0, 70.6, 38.9, 29.8, 20.4, 16.5, 8.8 ppm.
[22] R. O. Martin, M. O. Saavedra, F. Xie, L. Liu, S. Picasso, P. Vogel, H.
Kizu, N. Asano, Bioorg. Med. Chem. 2001, 9, 1269.
[23] G. Poli, Tetrahedron Lett. 1989, 30, 7385.
[24] a) D. B. Dess, J. C. Martin, J. Am. Chem. Soc. 1991, 113, 7277;
b) D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[25] CCDC-252399 (24), -252400 (46), -252401 (50) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif
Acknowledgements
We thank the EPSRC, Rhꢄne-Poulenc Rorer and GlaxoSmithkline for
funding this project. In addition, we would also like to thank AstraZene-
ca, Pfizer, Novartis and Merck for generous unrestricted financial sup-
port.
[26] F. N. Tebbe, G. W. Parshall, G. S. Reddy, J. Am. Chem. Soc. 1978,
100, 3611.
Chem. Eur. J. 2005, 11, 4227 – 4238
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4237

T. J. Donohoe et al.
[27] N. A. Petasis, S. P. Lu, E. I. Bzowej, D. K. Fu, J. P. Staszewski, I. Ak-
ritopoulouzanze, M. A. Patane, Y. H. Hu, Pure Appl. Chem. 1996,
68, 667.
[31] K. Inoue, A. Sawada, I. Shibata, A. Baba, J. Am. Chem. Soc. 2002,
124, 906.
[32] T. J. Donohoe, J. -B. Guillermin, D. S. Walter, J. Chem. Soc. Perkin
Trans. 1 2002, 1269.
[33] T. J. Donohoe, J. W. Fisher, P. J. Edwards, Org. Lett. 2004, 6, 465.
[34] T. J. Donohoe, H. O. Sintim, Org. Lett. 2004, 6, 2003.
[35] D. H. R. Barton, J. Kervagoret, S. Z. Zard, Tetrahedron 1990, 46,
7587.
[28] C. R. Johnson, B. D. Tait, J. Org. Chem. 1987, 52, 281.
[29] a) E. J. Corey, W.-D. Z. Li, Tetrahedron, 1999, 55, 3305; b) E. J.
Corey, W.-D. Z. Li, Tetrahedron Lett. 1998, 39, 8043; c) E. J. Corey,
W.-D. Li, Tetrahedron Lett. 1998, 39, 7475; d) E. J. Corey, W. Li, T.
Nagamitsu, Angew. Chem. 1998, 110, 1784; Angew. Chem. Int. Ed.
1998, 37, 1676; e) E. J. Corey, S. Choi, Tetrahedron Lett. 1993, 34,
6969; f) E. J. Corey, G. A. Reichard, Tetrahedron Lett. 1993, 34,
6973; g) E. J. Corey, D.-H. Lee, S. Choi, Tetrahedron Lett. 1992, 33,
6735.
[36] E. J. Corey, W. Li, G. A. Reichard, J. Am. Chem. Soc. 1998, 120,
2330.
[30] For a review, see: C. E. Masse, A. J. Morgan, J. Adams, J. S. Panek,
Eur. J. Org. Chem. 2000, 2513.
Received: November 5, 2004
Published online: May 2, 2005
4238
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 4227 – 4238