A new synthetic approach to (+)-lactacystin based on radical cyclisation of enantiopure α-ethynyl substituted serine derivatives to 4-methylenepyrrolidinones

Article abstract of DOI:10.1039/b806681g

Treatment of the acetylenic bromoamide 42c, derived from the enantiopure α-amino alcohol 40, with Bu₃SnH-AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone 43/44 (2: 1). Cleavage of the alkene bond in 43/

Full text of DOI:10.1039/b806681g

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
A new synthetic approach to (+)-lactacystin based on radical cyclisation of
enantiopure a-ethynyl substituted serine derivatives to
4-methylenepyrrolidinones†
Gerald Pattenden* and Gwenae¨lla Rescourio
Received 21st April 2008, Accepted 4th June 2008
First published as an Advance Article on the web 16th July 2008
DOI: 10.1039/b806681g
Treatment of the acetylenic bromoamide 42c, derived from the enantiopure a-amino alcohol 40, with
Bu3SnH–AlBN results in an efficient 5-exo dig radical cyclisation to the 4-methylenepyrrolidinone
43/44 (2 : 1). Cleavage of the alkene bond in 43/44, using O3–Me2S, next gave the corresponding
4-ketopyrrolidinone 45/46. a-Phenylsulfanylation of 45/46, using S-methyl-p-
toluenethiosulfonate–Et3N, proceeded in a stereoselective manner and led to the methylsulfanyl
derivative 48 (ca. 9 : 1 selectivity). Manipulation of the functionality in 48, using two separate
sequences, then led to the substituted pyrrolidinones 49b, 50 and 53 which are advanced intermediates
in a previous synthesis of (+)-lactacystin 1. In related studies, the acetylenic bromoamide 28a
containing all the carbon atoms in lactacystin was synthesised, but this substrate failed to undergo an
anticipated radical cyclisation to the 4-methylenepyrrolidinone 30, analogous to 43/44. Instead, only
the product of reduction of 28a, i.e. 28b, was produced, possibly resulting from adventitious
intramolecular hydrogen-abstraction processes from the carbon centred radical intermediate 29,
i.e. 32 to 33 and/or 31 to 34.
1. Introduction
Lactacystin 1 is one of the most important biologically active
pyrrolidinone-based natural products yet to be found in nature. It
was isolated from the culture broth of a Streptomyces in 1991,1
and since that time has generated an enormous interest as a
consequence of its highly selective and irreversible inhibition of the
20S proteasome.2 The 20S proteasome is involved in the turnover
of cellular proteins and in removing damaged, misfolded and
mistranslated proteins in cells.3 The b-lactone omuralide 2 (also
known as clasto-lactacystin b-lactone) is derived from lactacystin
in vivo, and is the actual biological agent that acts by acylation
of the amino terminal threonine residue of a proteasome unit.4
A more recently isolated pyrrolidinone-based inhibitor of the
In this paper we describe a synthetic approach to lactacystin
20S proteasome is salinosporamide A (3) found in the marine
which hinges on a radical cyclisation from a chiral a-ethynyl
bacterium Salinospora tropica.5 The three natural products 1, 2
substituted serine derivative, viz 4, as a key step to a functionalised
and 3, have become important compounds in studies of protein
pyrrolidinone, i.e. 5.11 The pyrrolidinone 5 is then elaborated to
biochemistry and cell biology, and to indicate that they have been
the derivative 6 from which the natural product can be obtained
attractive targets for synthetic and medicinal chemists would be
in a few steps using a documented procedure.
an understatement! Indeed, the first synthesis of lactacystin 1 was
described by Corey et al.6 as early as 1992, and since then a range
of ingenious synthetic approaches have been developed towards
this exciting target.7–10
School of Chemistry, The University of Nottingham, University Park,
Nottingham, England NG7 2RD
† Electronic supplementary information (ESI) available: Additional ex-
perimental procedures and data. CCDC reference number 226290. For
ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/b806681g
3428 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
moamide 17 en route to 4, 5 and 6, and beyond. In fact, a plethora
of methods are available for the synthesis of a,a-disubstituted
amino acid derivatives akin to 16, and we evaluated the scope for
several of these procedures.13 In these investigations, which were
carried out in parallel with our contemporaneous studies towards
the natural products oxazolomycin and neooxazolomycin,14 we
found that the procedure of Schmidt and Hatakeyama15 involving
the ring-opening of 3,3-disubstituted 2-trichloromethyloxazolines
derived from enantiopure 2-substituted glycidols (i.e. 2,3-epoxy-
1-propanols) was particularly convenient for the synthesis of the
2-ethynyl serine derivatives 16.
2. Results and discussions
2.1 Synthetic strategy
Our synthetic approach to the pyrrolidinone ring in lactacystin was
based on an initial 5-exo dig radical cyclisation of an acetylenic
amide radical, viz 7, leading to a 4-methylenepyrrolidinone, i.e.
8. We then envisaged an oxidative cleavage of the alkene bond
in 8, producing the corresponding 4-ketopyrrolidinone 9 for
subsequent elaboration to the 4-hydroxy derivative 10 and thence
onwards to lactacystin.
In our first synthetic approach to lactacystin we decided
to prepare the acetylenic bromoamide radical precursor 28a
containing all the carbon atoms in the natural product. In turn,
the bromoamide 28a was to be made from the a,a-disubstituted
amino alcohol derivative 25a using the aforementioned Schmidt–
Hatakeyama protocol (Scheme 1).
2.2 Radical approach to 4-methylenepyrrolidinones
The feasibility of the key radical cyclisation step 7 → 8 was
demonstrated several years ago in our laboratories using a number
of model acetylenic a-bromoamide substrates, i.e. 11, which
smoothly led to the corresponding 4-methylenepyrrolidinones 12
by way of 5-exo-dig radical cyclisations upon treatment with
Bu3SnH–AlBN in refluxing benzene.12 Furthermore, the reactions
and work-up procedures could be controlled such that only very
small amounts of the isomeric d-lactam products 14 were obtained
concurrently. Equally satisfying was the finding that careful
cleavage of the alkene bonds in the 4-methylenepyrrolidinones 12,
using ozone at −78 ◦C followed by reductive work-up at −78 ◦C to
room temperature with Ph3P or Me2S, allowed the isolation of the
corresponding 4-ketopyrrolidinones 13 with little contamination
by the isomeric tetramic acid derivatives 15.
Thus, 4-methylpent-2-yn-1-ol 1816 was first hydrostannylated in
a regio- and stereo-selective manner, under free radical conditions
(i.e. Bu3SnH–AlBN)17 leading to the Z-stannylpentenol 19 in 74%
yield. Exchange of tin for iodide in 19,18 followed by a coupling
reaction between the resulting iodide 20 and trimethylsilylacety-
lene under Sonogashira conditions19 next led to the Z-enynol
21a in excellent yield. Removal of the silyl protecting group in
21a, followed by epoxidation of the resulting 2-ethynylpropenol
21b using (+)-diethyl tartrate and tert-butyl hydroperoxide in the
presence of catalytic calcium hydride and silica gel at −40 ◦C
◦
to −18 C,20 next gave the corresponding epoxide 22 which was
obtained in 89% yield and with >95% ee (determined by 19F
NMR analysis of the corresponding Mosher ester derivative).
Acetamidation of the epoxy alcohol 22, using trichloroacetonitrile
in the presence of catalytic DBU then gave the acetamidate 23
which produced the corresponding oxazoline 24a on treatment
◦
with diethylaluminium chloride at 0–25 C.21 Protection of the
alcohol group in 24a as its silyl ether 24b followed by cleavage
of the oxazoline ring, using 1 M aqueous HCl now gave the a-
ethynyl amino alcohol 25a which was immediately converted into
its carbamate derivative 25b. Our plan now was to convert 25b
into the a-ethynyl amino acid ester 16b in readiness for elaboration
to 17b. However, although we were able to elaborate the primary
alcohol group in 25b to the corresponding methyl ester 26, we were
not able to remove the Boc protecting group in 26 leading to 16b.
We therefore altered our strategy at this point, and instead treated
the amino alcohol 25a with 2-bromopropionoyl chloride under
Schotten–Baumann22 conditions (i.e. NaHCO3–DCM) at pH 6.0–
6.5, which led to the substituted a-ethynyl bromoamide 27a in an
excellent 80% yield. Sequential oxidation of the primary alcohol
group in 27a, followed by esterification of the carboxylic acid
27c finally gave the methyl ester precursor 28a for our projected
2.3 Synthesis of a-ethynyl-aꢀ-substituted a-amino acids and the
proposed lactacystin precursor 28a
With the model radical cyclisations studies complete we now
required a practical synthetic route to an enantiopure a-ethynyl-a-
substituted amino acid derivative, viz 16, for elaboration to the bro-
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3428–3438 | 3429
©

View Article Online
2.4 Synthesis of the 4-methylene and 4-keto pyrrolidinones 43/44
and 45/46 respectively
We reasoned that the failure of the radical intermediate 29
produced from the acetylenic bromoamide 28a to undergo the
anticipated 5-exo-dig radical cyclisation to 30 was due, in part, to
a competing intramolecular 1,5-H abstraction process involving
the same radical intermediate from its amide rotamer, viz 32 → 33.
Indeed, on this basis, we might expect the resulting radical centre
33 with its proximal oxy-centre to be quite stable (captodative ef-
fects). Interestingly, in contemporaneous studies23 we showed that
the substrate 35 which lacked the isopropyl appendage present in
28a underwent a smooth 5-exo dig radical cyclisation when treated
with Bu3SnH–AlBN leading to the 4-methylenepyrrolidinone 36
in an excellent 80% yield. This contrasting result suggested that the
isopropyl substituent in the substrate 28a plays a significant role
in inhibiting the desired cyclisation of 29 to 30. Whether this effect
is steric in nature, or due to an additional and competing 1,6-H
abstraction process from 31 leading to the tertiary radical centre
34 is not clear. Whatever the rationale, we decided to capitalise on
the difference and synthesise the enantiopure amino alcohol 40,
corresponding to the isopropyl-substituted compound 25a, in an
alternative approach to lactacystin.
Thus, a Sharpless epoxidation of 2-ethynylpropenol 3724 using
(+)-diisopropyl tartrate, titanium tetraisopropoxide and cumene
hydroperoxide25 at −35 ◦C to −10 ◦C first gave the chiral epoxide
38a in 66% yield and with 86% ee (Scheme 2). Interestingly, our
attempts to epoxidise 37 applying the protocol used in the conver-
sion of 21b into 22 met with failure; this outcome reinforces the
important differences in ease of epoxidation of gem-disubstituted
and tri-substituted allylic alcohols using Sharpless procedures.26
The epoxide 38a was next converted into the oxazoline 39a via the
acetimidate 38b, which was then protected as the crystalline TBS
ether 39b. X-Ray crystallographic analysis of 39b, confirmed its
absolute stereochemistry.27 When the oxazoline 39b was carefully
treated with dilute (1 M) hydrochloric acid it was converted into
the amino alcohol 40, as its hydrochloride salt, which was reacted
immediately with 2-bromopropionoyl chloride in the presence of
sodium bicarbonate, to give the amide 41 as a 1 : 1 mixture of
diastereoisomers.
Scheme 1 ◦ Reagents and conditions: i) Bu3SnH, AIBN, 85 ◦C, 74%; ii) NIS,
The alcohol group in 41 was next converted into the correspond-
ing methyl ester 42c in three straightforward steps via the aldehyde
42a and the carboxylic acid 42b, in 62% overall yield. When a
solution of the bromoamide 42c in toluene under reflux was treated
over 30 min with a solution of Bu3SnH–AlBN, followed by heating
under reflux for a further 2 h, work-up and chromatography gave a
2 : 1 mixture of C3 methyl epimers of the 4-methylenepyrrolidinone
43/44 in a satisfying 60% yield. The stereochemistries of the
separated diastereoisomers 43 and 44 were established by NOE
≡
DCM, 0 C, 95%; iii) ◦Me3SiC CH, Pd(PPh3)4, CuI, Et2NH, RT, 91%;
iv) K2CO3, MeOH, 0 C, 89%; v) L-(+)-DET, Ti(OiPr)4, TBHP, DCM,
SiO2, CaH2,, −40 ◦C to −18 ◦C, 89%, >95% ee; vi) Cl3CCN, DBU, 0 ◦C,
85%; vii) Et2AlCl, DCM, 0 ◦C to RT, 79%; viii) TBSOTf, 2,6-lutidine,
DCM, 0 ◦C to RT, 93%; ix) 2 M HCl, THF, RT; x) (Boc)2O, NaHCO3,
DCM, 74% over 2 steps; xi) CH3CH(Br)COCl, NaHCO3, DCM, pH 6–6.5,
80% over 2 steps; xii) Dess–Martin periodinane, DCM, 0 ◦C; xiii) NaClO4,
NaH2PO4, t-BuOH, 2-methyl-2-butene, RT; xiv) Me3SiCHN2, MeO-
H–benzene, RT, 74% over 3 steps.
1
enhancement experiments in their H NMR spectra. These data
ascertained that the major diastereoisomer resulting from the 5-
exo dig radical cyclisation of 42c was the C3 a-Me epimer 43.
The 2 : 1 mixture 43/44 was next treated with ozone at −78 ◦C
followed by a reductive work-up of the ozonide intermediate with
dimethyl sulfide. This procedure led to a 2 : 1 mixture of a- and
b-methyl epimers of the 4-ketopyrrolidinone 45/46, in 75% yield,
with no evidence for the co-formation of the tautomeric tetramic
acid 47 (Scheme 3).28 The diastereoisomer 46, with a b-methyl at
C3, has the correct stereochemistry for elaboration to lactacystin,
radical cyclisation to the substituted 4-methylenepyrrolidinone 30,
en route to lactacystin.
Much to our frustration, treatment of 28a under standard
radical cyclisations conditions (i.e. slow addition of Bu3SnH
and catalytic AlBN in toluene) did not lead to the anticipated
4-methylenepyrrolidinone 30. Instead, a complex mixture of
products resulted, from which only the product of reduction of the
carbon-to-bromide bond in 28a, i.e. 28b, could be characterised.
3430 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
In one of their syntheses of lactacystin Corey et al.6d had prepared
the 3-methylsulfanyl derivative 53 as an advanced intermediate
and showed that it could be desulfurised in a selective manner,
using Raney nickel, producing the C3 b-methyl epimer of the
resulting pyrrolidinone 54 in an excellent 82% yield (Scheme 4). We
therefore treated the 2 : 1 mixture of diastereoisomers 45/46 with
S-methyl-p-toluenethiosulfonate30 in the presence of triethylamine
and we were pleased to find that this procedure led to largely one
diastereoisomer (ratio 87 : 13) of the C3 thiolated product 48 with
the methylsulfanyl group anti-to the bulky CH2OTBS group at
C5. After protection of the nitrogen centre in 48 with a PMB
group, deprotection of the primary alcohol group next led to the
pyrrolidinone 49b, which was found to undergo stereoselective
reduction6d to the corresponding C4 b-hydroxy compound 50
using sodium triacetoxyborohydride, in 88% yield.
Scheme 2 Reagents and conditions: i) L-(+)-DIPT, Ti(OiPr)4, cumene
hydroperoxide, DCM, −10 ◦C, 66%, 86% ee; ii) Cl3CCN, DBU, 0 ◦C, 66%;
iii) Et2AlCl, DCM, 0 ◦C to RT, 78%; iv) TBSOTf, 2,6-lutidine, DCM,
In a separate sequence, reduction of the 4-ketopyrrolidinone 48
with zinc borohydride in THF was also found to be stereoselective
leading to the C4 b-alcohol 51 in 79% yield. Protection of the
secondary alcohol and amine groups in 51 as their TBS and
PMB groups respectively, followed by deprotection of the primary
alcohol group in the product 52, then led to the substituted
pyrrolidinone 53. The substituted pyrrolidinones 49b, 50 and
53, are all intermediates in one of Corey’s total synthesis of
0
◦C to RT, 97%; v) 1 M HCl, THF, RT; vi) CH3CH(Br)COCl, NaHCO3,
DCM, RT, 76% over 2 steps.
and we were disappointed not to be able to produce further
quantities of this diastereoisomer by selective epimerisation of
the a-methyl diastereoisomer 45 using a range of conditions.29
1
lactacystin,6d and our synthetic 49b displayed H and 13C NMR
spectroscopic data which were identical to those reported in the
literature.
2.5 Elaboration of the 4-ketopyrrolidones 45/46 to the
3-methylsulfanyl derivatives 49 and 50, and completion of a formal
synthesis of (+)-lactacystin
3. Summary
With our failure to epimerise the C3 centre in 45 to the b-methyl
epimer 46 required for lactacystin, we decided to take advantage
of an observation made earlier by Corey et al. and first convert
45/46 into the corresponding C3 methylsulfanyl derivative, i.e. 48.
We have developed a new, formal, synthesis of (+)-lactacystin 1
which is distinguished from other syntheses by elaboration of the
pyrrolidinone ring system in the natural product via a novel 5-exo
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3428–3438 | 3431
©

View Article Online
Scheme 3 Reagents and conditions: i) Dess–Martin periodinane, DCM, 0 ◦C; ii) NaClO4, NaH2PO4, t-BuOH, 2-methyl-2-butene, RT; iii) Me3SiCHN2,
MeOH–benzene, RT, 62% over 3 steps; iv) Bu3SnH, AIBN, toluene, reflux, 60%; v) O3, MeOH, −78 ◦C, 15 min then Me2S, −78 ◦C to RT, 75%.
Scheme 4 Reagents and conditions: i) p-MeC6H4SO2Me, Et3N, DCM, RT, 78%; ii) PMBBr, NaH, DMF, THF, 0 ◦C to RT; iii) HF–pyridine, THF, RT,
37% over 2 steps; iv) NaBH(OAc)3, AcOH, RT, 88%. v) Zn(BH4)2 (4.4 M in THF), THF, 0 ◦C, 79%; vi) TBSOTf, 2,6-lutidine, DCM, 0 ◦C → RT, 80%;
vii) PMBBr, NaH, DMF, 0 ◦C → RT, 73%; viii) HF–pyridine, pyridine, THF, RT → 40 ◦C, 89%.
dig radical cyclisation from the acetylenic bromoamide 42c,
produced from the enantiopure a-amino alcohol 40, leading to
43/44. Manipulation of the functionality in 43/44 ultimately led
to the C3 methylsulfanyl derivative 48 which, by separate routes,
could be converted into the pyrrolidinones 49b, 50 and 53 used by
Corey et al.6d in their total synthesis of (+)-lactacystin 1.
for 2◦0 min, was added dropwise over 1◦min to the mixture at
−20 C. The mixture was stirred at −20 C for a further 10 min
and then cooled to −35 ◦C. Cumene hydroperoxide (4.39 ml,
24 mmol), which had been dried over a small amount of activated
˚
3 A molecular sieves at room temperature for 20 min, was added
dropwise over 10 min. The mixture was stirred at −35 ◦C for
30 min and then at −10 ◦C overnight. The progress of the reaction
was followed by 1H NMR spectroscopy, and when complete, the
mixture was quenched at −20 ◦C with citric acid monohydrate
(333 mg, 1.6 mmol) in a 1 : 10 mixture of acetone and diethyl ether
(47 ml), then allowed to warm to room temperature, and stirred for
30 min. The mixture was filtered through a pad of Celite and the
filtrate was concentrated in vacuo at 0 ◦C. The residue was purified
by flash chromatography on silica, using pentane–diethyl ether (3 :
2 then 1 : 1) as eluent, to give the epoxy alcohol (513 mg, 66%)
as a colourless liquid; [a]2D3 −24.2 (c 1.02, CHCl3); mmax/cm−1 (film)
3286, 1631; dH (360 MHz, CDCl3) 3.93 (1H, d, J 12.6, CHHO),
3.78 (1H, d, J 12.6, CHHO), 3.08 (1H, d, J 5.5, CHHOH), 3.05
4. Experimental
For general experimental details see ref. 31.
((S)-2-Ethynyl-oxiranyl)-methanol (38a)
L-(+)-Diisopropyl tartrate (437 ll, 2.1 mmol) was added dropwise
over 1 min to a stirred solution of titanium tetraisopropoxide
˚
(471 ll, 1.6 mmol) and activated 3 A molecular sieves (650 mg)
in dry dichloromethane (26 ml) at −20 ◦C under an argon
atmosphere, and the mixture was then stirred at −20 ◦C for 30 min.
A solution of the allylic alcohol 3724 (650 mg, 7.9 mmol) in dry
dichloromethane (0.65 ml), which had been dried over a small
≡
(1H, d, J 5.5, CHHOH), 2.41 (1H, s, C CH), 2.01 (1H, br s,
CH2OH); dC (90 MHz, CDCl3) 79.8 (s), 73.3 (d), 62.9 (t), 51.1 (t),
amount of activated 3 A molecular sieves at room temperature
50.7 (s); m/z (EI) 98.0365 (M+, C5H6O2 requires 98.0368).
˚
3432 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
Mosher ester analysis of the epoxy alcohol (38a)
trichloroacetimidate 38b (2.29 g, 9.4 mmol) in dichloromethane
(75 ml) at 0 C under nitrogen atmosphere, and the mixture was
◦
a) R-(+)-Methoxytrifluoromethylphenylacetic acid (6 ll,
0.030 mmol) was added in a single portion to a stirred solution of
the epoxy alcohol 38a (2.7 mg, 0.027 mmol), triethylamine (9 ll,
0.065 mmol) and DMAP (2.6 mg, 0.022 mmol) in chloroform
(270 ll) at room temperature under a nitrogen atmosphere.
The mixture was stirred at room temperature for 3 h and
then concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (4 : 1)
as eluent, to give a 6 : 1 mixture of diastereoisomers of the (R)
Mosher ester (8 mg, 94%) as a colourless oil, which was not
separated; dH (360 MHz, CDCl3) 7.57 (2H, m, ArH), 7.44 (3H,
m, ArH), 4.75 (1H, d, J 12.1, CHHOCO), 4.35 (1H, d, J 12.1,
CHHOCO), 3.61 (3H, s, OCH3), 3.10 (1H, d, J 5.4, CHHO),
then stirred at 0 ◦C for 20 min. The mixture was allowed to
warm to room temperature and then stirred for a further 12 h.
The solution was diluted with diethyl ether (150 ml) and then
quenched with saturated aqueous sodium bicarbonate (75 ml).
The separated aqueous layer was extracted with diethyl ether
(3 × 75 ml) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica, using petrol–diethyl ether (4 : 1
then 7 : 3) as eluent, to give the oxazoline (1.77 g, 78%) as a
◦
colourless solid; mp 136–138 C (petrol–diethyl ether); [a]2D3 22.4
(c 1.00, CHCl3) (Found: C, 34.7; H, 2.5; N, 5.55; C7H6Cl3NO2
requires C, 34.7; H, 2.5; N, 5.8%); mmax/cm−1 (film) 3377, 3300,
1656; dH (360 MHz, CDCl3) 4.82 (1H, d, J 8.4, CHHO), 4.70 (1H,
d, J 8.4, CHHO), 3.97 (1H, dd, J 11.7, 6.0, CHHOH), 3.70 (1H,
≡
2.98 (1H, d, J 5.4, CHHO), 2.41 (1H, s, C CH); dF (376 MHz,
CDCl3) −72.17 (ee = 86%).
≡
dd, J 11.7, 8.4, CHHOH), 2.63 (1H, s, C CH), 2.45 (1H, dd, J
b) S-(−)-Methoxytrifluoromethylphenylacetic acid (4 ll,
0.021 mmol) was added in a single portion to a stirred solution
of the epoxy alcohol 38a (1.9 mg, 0.019 mmol), triethylamine
(6.3 ll, 0.046 mmol) and DMAP (1.85 mg, 0.015 mmol) in
chloroform (190 ll) at room temperature under a nitrogen
atmosphere. The mixture was stirred at room temperature for 3 h
and then concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (4 : 1) as
eluent, to give a 6 : 1 mixture of diastereoisomers of the (S) Mosher
ester (5.7 mg, 95%) as a colourless oil, which was not separated;
dH (360 MHz, CDCl3) 7.55 (2H, m, ArH), 7.42 (3H, m, ArH),
4.64 (1H, d, J 12.0, CHHOCO), 4.39 (1H, d, J 12.0, CHHOCO),
3.58 (3H, s, OCH3), 3.06 (1H, d, J 5.4, CHHO), 2.90 (1H, d, J
8.4, 6.0, CH2OH); dC (90 MHz, CDCl3) 165.2 (s), 85.9 (s), 81.0 (s),
77.9 (t), 75.7 (d), 70.0 (s), 66.7 (t); m/z (ES) 241.9537 (M + H+,
C7H7Cl3NO2 requires 241.9542).
Mosher ester analysis of the oxazoline alcohol (39a)
a) R-(+)-Methoxytrifluoromethylphenylacetic acid (3.2 ll,
0.017 mmol) was added in a single portion to a stirred solution
of the oxazoline 39a (3.7 mg, 0.015 mmol), triethylamine (5 ll,
0.036 mmol) and DMAP (1.5 mg, 0.012 mmol) in chloroform
(150 ll) at room temperature under a nitrogen atmosphere.
The mixture was stirred at room temperature for 3 h and
then concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (9 : 1 then
4 : 1) as eluent, to give a 6 : 1 mixture of diastereoisomers of the
(R) Mosher ester (6.6 mg, 96%) as a colourless oil, which was not
separated; dH (360 MHz, CDCl3) 7.49 (2H, m, ArH), 7.41 (3H, m,
ArH), 4.68 (1H, d, J 8.7, CHHO), 4.61 (1H, d, J 11.4, CHHOCO),
4.53 (1H, d, J 8.7, CHHO), 4.49 (1H, d, J 11.4, CHHOCO), 3.54
≡
5.4, CHHO), 2.35 (1H, s, C CH); dF (376 MHz, CDCl3) −72.24
(ee = 86%).
2ꢀ,2ꢀ,2ꢀ-Trichloro-acetimidic acid (R)-2-ethynyl-oxiranylmethyl
ester (38b)
Trichloroacetonitrile (1.25 ml, 12 mmol), followed by DBU
(187 ll, 1.2 mmol) were each added dropwise over 2 min to
a stirred solution of the epoxy alcohol 38a (1 g, 10 mmol) in
dichloromet◦hane (59.5 ml) at 0 ◦C, and the mixture was then
stirred at 0 C for 30 min. The mixture was diluted with diethyl
ether (60 ml) and then washed with water (45 ml). The separated
aqueous layer was extracted with diethyl ether (2 × 45 ml)
and the combined organic extracts were then dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography on silica, using petrol–diethyl ether (4 : 1) as
eluent, to give the trichloroacetimidate (1.60 g, 66%) as a colourless
liquid; [a]2D3 −22.2 (c 1.10, CHCl3) (Found: C, 34.8; H, 2.4; N, 5.3;
C7H6Cl3NO2 requires C, 34.9; H, 2.5; N, 5.8%); mmax/cm−1 (film)
1670; dH (360 MHz, CDCl3) 8.46 (1H, br s, NH), 4.60 (1H, d, J
12.0, CHHOC(NH)), 4.44 (1H, d, J 12.0, CHHOC(NH)), 3.13
(1H, d, J 5.5, CHHO), 3.10 (1H, d, J 5.5, CHHO), 2.41 (1H, s,
≡
(3H, s, OCH3), 2.66 (1H, s, C CH); dF (376 MHz, CDCl3) −72.00
(ee = 86%).
b) S-(−)-Methoxytrifluoromethylphenylacetic acid (3.2 ll,
0.017 mmol, 0.015 mmol) was added in a single portion to
a stirred solution of the oxazoline 39a (3.7 mg, 0.015 mmol),
triethylamine (5 ll, 0.036 mmol) and DMAP (1.5 mg, 0.012 mmol)
in chloroform (150 ll) at room temperature under a nitrogen
atmosphere. The mixture was stirred at room temperature for 3 h
and then concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (9 : 1 then
4 : 1) as eluent, to give a 6 : 1 mixture of diastereoisomers of the
(S) Mosher ester (6.5 mg, 94%) as a colourless oil, which was not
separated; dH (360 MHz, CDCl3) 7.51 (2H, m, ArH), 7.41 (3H, m,
ArH), 4.70 (1H, d, J 8.9, CHHO), 4.64 (1H, d, J 8.9, CHHO),
4.56 (1H, d, J 11.3, CHHOCO), 4.53 (1H, d, J 11.3, CHHOCO),
≡
C CH); dC (90 MHz, CDCl3) 162.3 (s), 90.8 (s), 79.1 (s), 73.2 (d),
≡
3.54 (3H, s, OCH3), 2.66 (1H, s, C CH); dF (376 MHz, CDCl3)
−72.12 (ee = 86%).
68.8 (t), 52.2 (t), 48.2 (s); m/z (CI) 242 (M + H+, C7H7Cl3NO2
requires 242).
((S)-4-Ethynyl-2-trichloromethyl-4,5-dihydro-oxazol-4-yl)-
(R)-4-(tert-Butyl-dimethyl-silanyloxymethyl)-4-ethynyl-2-
methanol (39a)
trichloromethyl-4,5-dihydro-oxazole (39b)
Diethylaluminium chloride (1 M in hexanes, 4.7 ml, 4.7 mmol)
was added dropwise over 10 min to a stirred solution of the epoxy
tert-Butyldimethylsilyl trifluoromethanesulfonate (1.13 ml,
4.95 mmol) was added dropwise over 2 min to a stirred solution
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3428–3438 | 3433
©

View Article Online
of the oxazoline alcohol 39a (0.8 g, 3.3 mmol) and 2,6-lutidine
(0.8 ml, 6.6 mmol) in dichloromethane (3.3 ml) at 0 C under a
(q), −5.4/−5.4 (q); m/z (ES) 364.0940 (M + H+, C14H27BrNO3Si
◦
requires 364.0944).
nitrogen atmosphere. The mixture was stirred at 0 ◦C for 30 min,
then allowed to warm to room temperature and stirred for a
further 4 h. The solution was diluted with dichloromethane
(10 ml) and then quenched with saturated aqueous sodium
bicarbonate (8 ml). The separated aqueous layer was extracted
with dichloromethane (2 × 10 ml), and the combined organic
extracts were then dried (MgSO4) and concentrated in vacuo.
The residue was purified by flash chromatography on silica,
using petrol–diethyl ether (9 : 1 then 4 : 1) as eluent, to give
the silyl ether (1.14 g, 97%) as a colourless solid; mp 56–58 ◦C
(petrol–diethyl ether); [a]2D3 −1.81 (c 0.95, CHCl3) (Found: C,
43.5; H, 5.6; N, 3.8; C13H20Cl3NO2Si requires C, 43.8; H, 5.65; N,
3.9%); mmax (film)/cm−1 2126, 1660; dH (360 MHz, CDCl3) 4.85
(1H, d, J 8.1, CHHO), 4.61 (1H, d, J 8.1, CHHO), 3.94 (1H, d, J
10.4, CHHOTBS), 3.75 (1H, d, J 10.4, CHHOTBS), 2.56 (1H, s,
2-Bromo-N-[(S)-1ꢀ-(tert-butyl-dimethyl-silanyloxymethyl)-1ꢀ-
formyl-prop-2ꢀ-ynyl]-propionamide (42a)
Dess–Martin periodinane (550 mg, 1.3 mmol) was added portion-
wise over 5 min to a stirred solution of the alcohol 41 (400 mg,
1.1 mmol) in dry dichloromethane (5.65 ml) at 0 ◦C under a
nitrogen atmosphere, and the mixture was then stirred at 0 ◦C for
20 min. The mixture was allowed to warm to room temperature
and then stirred at this temperature for a further 3 h. The mixture
was quenched with saturated aqueous sodium bicarbonate (44 ml)
followed by a saturated solution sodium bisulfite (44 ml), then
diluted with diethyl ether (85 ml) and stirred at room temperature
for 30 min. The separated aqueous layer was extracted with diethyl
ether (2 × 90 ml) and the combined organic extracts were then
washed with saturated aqueous sodium bicarbonate (130 ml) and
brine (130 ml), dried (MgSO4) and concentrated in vacuo to leave a
1 : 1 mixture of diastereoisomers of the aldehyde (396 mg, 99%) as
a colourless solid (Found: C, 46.5; H, 6.5; N, 3.75; C14H24BrNO3Si
requires C, 46.4; H, 6.7; N, 3.9%); mmax (film)/cm−1 1734, 1688;
dH (400 MHz, CDCl3) 9.38/9.38 (1H, s, CHO), 7.32/7.32 (1H,
br s, NH), 4.45/4.43 (1H, q, J 7.1/7.1, CH(Br)CH3), 4.19/4.17
(1H, d, J 10.2/10.2, CHHOTBS), 4.09/4.08 (1H, d, J 10.2/10.2,
≡
C CH), 0.89 (9H, s, SiC(CH3)3), 0.10 (3H, s, SiCH3), 0.08 (3H, s,
SiCH3); dC (90 MHz, CDCl3) 164.2 (s), 86.2 (s), 81.6 (d), 77.5 (t),
75.0 (s), 70.1 (s), 67.1 (t), 25.9 (3 × q), 18.3 (s), −5.1 (q), −5.5 (q);
m/z (ES) 356.0393 (M + H+, C13H21Cl3NO2Si requires 356.0407).
The absolute stereochemistry of this protected oxazoline was
determined by X-ray crystallography.
2-Bromo-N-[(R)-1ꢀ-(tert-butyl-dimethyl-silanyloxymethyl)-1ꢀ-
≡
CHHOTBS), 2.60/2.59 (1H, s, C CH), 1.90/1.89 (3H, d, J
hydroxymethyl-prop-2ꢀ-ynyl]-propionamide (41)
7.1/7.1, CH(Br)CH3), 0.88/0.88 (9H, s, SiC(CH3)3), 0.08/0.08
(3H, s, SiCH3), 0.07/0.07 (3H, s, SiCH3); dC (100 MHz, CDCl3)
191.5/191.4 (d), 168.9/168.8 (s), 76.5/76.5 (d), 76.4/76.4 (s),
64.4/64.3 (t), 62.2/62.2 (s), 44.1/44.0 (d), 25.7/25.7 (3 × q),
22.9/22.8 (q), 18.2/18.2 (s), −5.4/−5.4 (q), −5.5/−5.5 (q); m/z
(ES) 362.0793 (M + H+, C14H25BrNO3Si requires 362.0787), and
was used without further purification.
Aqueous hydrochloric acid (1 M, 2.35 ml, 2.35 mmol) was added
in a single portion to a stirred solution of the oxazoline 39b
(840 mg, 2.35 mmol) in THF (13.6 ml) at room temperature.
The mixture was stirred at room temperature for 4 h and then
saturated aqueous sodium bicarbonate (∼ 2.83 ml) was carefully
added at room temperature until the pH = 7. The mixture
was evaporated to dryness in vacuo and the residue, which
consisted of the amino alcohol 40, was then diluted with water
(2.83 ml) and dichloromethane (1.49 ml). Saturated aqueous
sodium bicarbonate (10 ml) was added in a single portion at
room temperature and then 2-bromopropionyl chloride (242 ll,
2.35 mmol) was added dropwise over 1 min. The mixture was
stirred at room temperature for 2 h and then the separated aqueous
layer was extracted with dichloromethane (2 × 12 ml). The
combined organic extracts were dried (MgSO4) and concentrated
in vacuo. The residue was purified by flash chromatography on
silica, using petrol–diethyl ether (polarity increasing from 3 : 2
to 2 : 3) as eluent, to give a 1 : 1 mixture of diastereoisomers of
the acetylenic bromoamide (651 mg, 76%) as a colourless solid;
mp 66–68 ◦C (petrol–diethyl ether) (Found: C, 46.3; H, 7.0; N,
3.7; C14H26BrNO3Si requires C, 46.15; H, 7.2; N, 3.8%); mmax
(film)/cm−1 3327, 3307, 1663; dH (400 MHz, CDCl3) 7.14/7.14
(1H, br s, NH), 4.42/4.41 (1H, q, J 7.1/7.1, CH(Br)CH3),
4.02/3.99 (1H, d, J 9.8/9.8, CHHOTBS), 3.93/3.93 (1H, dd,
J 11.5/11.5, 4.9/4.9, CHHOH), 3.89/3.87 (1H, d, J 9.9/9.9,
CHHOTBS), 3.83/3.82 (1H, dd, J 11.5/11.5, 9.0/9.0, CHHOH),
3.31/3.28 (1H, dd, J 9.0/9.0, 4.9/4.9, CH2OH), 2.43/2.43 (1H, s,
(S)-2-(2ꢀ-Bromo-propionylamino)-2-(tert-butyl-dimethyl-
silanyloxymethyl)-but-3-ynoic acid (42b)
A freshly prepared solution of sodium chlorite (1.22 g, 11 mmol)
in aqueous sodium dihydrogen orthophosphate (20% w/v, 6.5 ml)
was added dropwise over 5 min to a stirred solution of the
t
aldehyde 42a (390 mg, 1.1 mmol) in BuOH (11.5 ml) and 2-
methyl-2-butene (6.5 ml) at room temperature. The mixture was
stirred vigorously at room temperature for 3 h and then diluted
with ethyl acetate (43 ml). The separated aqueous layer was
extracted with ethyl acetate (30 ml) and the combined organic
extracts were then dried (MgSO4) and concentrated in vacuo. The
oily residue was taken up in ethyl acetate (16 ml), washed with
aqueous sodium dihydrogen orthophosphate (8% w/v, 1.6 ml)
and the aqueous layer was extracted with ethyl acetate (2 ×
16 ml). The combined organic extracts were dried (MgSO4), and
concentrated in vacuo to leave a 1 : 1 mixture of diastereoisomers
of the acid (363 mg, 87%) as a colourless solid; mmax (film)/cm−1
3385, 3308, 1733, 1628; dH (400 MHz, CDCl3) 7.53/7.50 (1H,
br s, NH), 4.47/4.46 (1H, q, J 7.1/7.1, CH(Br)CH3), 3.82–
≡
≡
C CH), 1.90/1.90 (3H, d, J 7.1/7.1, CH(Br)CH3), 0.94/0.94
3.74 (2H, m, CHHOTBS), 2.54/2.54 (1H, s, C CH), 1.91/1.90
(9H, s, SiC(CH3)3), 0.14/0.13 (3H, s, SiCH3), 0.13/0.13 (3H, s,
SiCH3); dC (100 MHz, CDCl3) 169.4/169.3 (s), 80.5/80.5 (s),
73.8/73.8 (d), 66.5/66.5 (t), 66.3/66.1 (t), 56.9/56.9 (s), 45.1/45.0
(d), 25.9/25.9 (3 × q), 23.0/23.0 (q), 18.3/18.3 (s), −5.3/−5.3
(3H, d, J 7.1/7.1, CH(Br)CH3), 0.90/0.90 (9H, s, SiC(CH3)3),
0.12/0.11 (3H, s, SiCH3), 0.11/0.11 (3H, s, SiCH3); dC (100 MHz,
CDCl3) 170.1/170.0 (s), 169.7/169.7 (s), 77.3/77.3 (s), 74.4/74.4
(d), 66.1/66.0 (t), 58.4/58.3 (s), 44.4/44.2 (d), 25.7/25.7 (3 × q),
3434 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
23.0/22.8 (q), 18.2/18.2 (s), −5.4/−5.4 (q), −5.5/−5.5 (q); m/z
(ES) 378.0771 (M + H+, C14H25BrNO4Si requires 378.0736), and
was used without further purification.
3.03 gave an enhancement at dH 3.55 (0.28%); and ii, C3 a-methyl
epimer (120 mg, 38%) (eluted second) as a colourless oil; [a]D23
−19.0 (c 0.19, CHCl3), mmax (film)/cm−1 3230, 2954, 1714, 1662; dH
(400 MHz, CDCl3) 6.22 (1H, br s, NH), 5.45 (1H, app. d, J 2.9,
=
=
C CHH), 5.20 (1H, app. d, J 2.5, C CHH), 4.23 (1H, d, J 9.4,
CHHOTBS), 3.78 (3H, s, OCH3), 3.47 (1H, d, J 9.4, CHHOTBS),
3.08–3.02 (1H, m, CHCH3), 1.32 (3H, d, J 7.4, CHCH3), 0.86
(9H, s, SiC(CH3)3), 0.05 (6H, s, Si(CH3)2); dC (100 MHz, CDCl3)
177.0 (s), 171.3 (s), 145.3 (s), 111.5 (t), 70.0 (s), 69.7 (t), 53.1 (q),
40.3 (d), 25.7 (3 × q), 18.2 (s), 15.8 (q), −5.4 (q), −5.6 (q); m/z (ES)
355.2081 (M + H+ + CH3CN, C17H31N2O4Si requires 355.2053);
In an NOE experiment (400 MHz, CDCl3) irradiation at dH 3.47
gave an enhancement at dH 1.32 (0.40%) and irradiation at dH 1.32
gave an enhancement at dH 3.47 (0.14%).
(S)-2-(2ꢀ-Bromo-propionylamino)-2-(tert-butyl-dimethyl-
silanyloxymethyl)-but-3-ynoic acid methyl ester (42c)
Trimethylsilyl diazomethane (2 M in hexanes, 380 ll, 0.76 mmol)
was added dropwise over 2 min to a stirred solution of the
acid 42b (263 mg, 0.69 mmol) in dry methanol (330 ll) and
anhydrous benzene (600 ll) at room temperature. The mixture
was stirred at room temperature for 20 min and then concentrated
in vacuo. The residue was purified by flash chromatography on
silica, using petrol–diethyl ether (polarity increasing from 9 : 1 to
7 : 3) as eluent, to give a 1 : 1 mixture of diastereoisomers of the
ester (194 mg, 72%) as a colourless solid; mp 57–59 ◦C (petrol-
diethyl ether) (Found: C, 46.0; H, 6.5; N, 3.4; C15H26BrNO4Si
requires C, 45.9; H, 6.7; N, 3.6%); mmax (film)/cm−1 1735, 1693;
dH (400 MHz, CDCl3) 7.44/7.42 (1H, br s, NH), 4.43/4.41
(1H, q, J 7.1/7.1, CH(Br)CH3), 4.25/4.22 (1H, d, J 9.7/9.7,
CHHOTBS), 4.04/4.03 (1H, d, J 9.7/9.7, CHHOTBS), 3.84/3.83
(5R,3S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-methyl-2,4-
dioxo-pyrrolidine -5-carboxylic acid methyl ester (45) and
(5R,3R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-methyl-2,4-
dioxo-pyrrolidine-5-carboxylic acid methyl ester (46)
A stream of ozone was bubbled through a stirred solution of the
2 : 1 mixture of pyrrolidinone diastereoisomers 43 and 44 (189 mg,
0.60 mmol) in dry methanol (8.5 ml) at −78 ◦C until a persistent
blue colour appeared (usually between 10 and 20 min). The
mixture was purged with oxygen to remove the excess of ozone and
then dimethyl sulfide was added. The mixture was stirred at −78 ◦C
for 1 h, then at room temperature for 1 h and evaporated to dryness
in vacuo. The oily residue was taken up in dichloromethane (5 ml)
and the solution was washed with water (4 ml). The separated
aqueous layer was extracted with dichloromethane (2 × 4 ml)
and the combined organic extracts were then washed with brine
(6 ml), dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography on silica, using petrol–diethyl
ether (polarity increasing from 1 : 1 to 1 : 4) as eluent, to give
a 2 : 1 mixture of diastereoisomers of the corresponding ketone
(142 mg, 75%) as a colourless oil which was not separated; mmax
(film)/cm−1 1784, 1741, 1666; dH (360 MHz, CDCl3) (b-methyl
epimer) 6.61 (1H, br s, NH), 4.15 (1H, d, J 10.2, CHHOTBS),
3.95 (1H, d, J 10.2, CHHOTBS), 3.80 (3H, s, OCH3), 2.80 (1H, q, J
7.8, CHCH3), 1.35 (3H, d, J 7.8, CHCH3), 0.83 (9H, s, SiC(CH3)3),
0.03 (6H, 2 s, SiCH3); (a-methyl epimer) 6.67 (1H, br s, NH), 4.05
(1H, d, J 10.2, CHHOTBS), 4.02 (1H, d, J 10.2, CHHOTBS),
3.80 (3H, s, OCH3), 2.96 (1H, q, J 7.6, CHCH3), 1.31 (3H, d,
J 7.6, CHCH3), 0.85 (9H, s, SiC(CH3)3), 0.04 (6H, s, SiCH3); dC
(90 MHz, CDCl3) (b-methyl epimer) 203.8 (s), 174.1 (s), 166.5 (s),
75.1 (s), 65.6 (t), 53.6 (q), 44.6 (d), 25.7 (3 × q), 18.2 (s), 11.0 (q),
−5.6 (2 × q); (a-methyl epimer) 203.0 (s), 173.7 (s), 166.5 (s), 75.3
(s), 65.1 (t), 53.6 (q), 44.3 (d), 25.7 (3 × q), 18.3 (s), 9.6 (q), −5.5
(q), −5.6 (q); m/z (ES) 316.1604 (M + H+, C14H26NO5Si requires
316.1580).
≡
(3H, s, OCH3), 2.50/2.49 (1H, s, C CH), 1.89/1.88 (3H, d, J
7.1/7.1, CH(Br)CH3), 0.86/0.86 (9H, s, SiC(CH3)3), 0.05/0.04
(3H, s, SiCH3), 0.03/0.03 (3H, s, SiCH3); dC (100 MHz, CDCl3)
168.5/168.4 (s), 168.2/168.1 (s), 77.5/77.5 (s), 73.7/73.7 (d),
66.3/66.1 (t), 58.8/58.8 (s), 53.8/53.8 (q), 44.6/44.4 (d), 25.6/25.6
(3 × q), 22.9/22.8 (q), 18.1/18.1 (s), −5.4/−5.5 (q), −5.6/−5.6 (q);
m/z (ES) 392.0916 (M + H+, C15H27BrNO4Si requires 392.0893).
(5S,3S)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-methyl-4-
methylene-2-oxo-pyrrolidine-5-carboxylic acid methyl ester (43)
and (5S,3R)-5-(tert-butyl-dimethyl-silanyloxymethyl)-3-methyl-4-
methylene-2-oxo-pyrrolidine-5-carboxylic acid methyl ester (44)
A solution of tri-butyltin hydride (291 ll, 0.98 mmol) and AIBN
(29 mg, 20 mol%) in anhydrous degassed toluene (30 ml) was
added dropwise over 30 min to a stirred solution of the ester 42c
(350 mg, 0.89 mmol) in anhydrous degassed toluene (280 ml) under
reflux, and the mixture was then stirred under reflux for 2.5 h.
The mixture was cooled and then evaporated to dryness in vacuo.
The residue was partitioned between acetonitrile (118 ml) and
hexane (82 ml), and the separated hexane layer was then extracted
with acetonitrile (41 ml). The combined acetonitrile extracts were
concentrated in vacuo to leave an oily residue which was purified
by flash chromatography on silica, using petrol–diethyl ether (1 :
1 then 1 : 4) as eluent, to give: i, the C3 b-methyl epimer (70 mg,
22%) (eluted first) as a colourless oil (C, 57.8; H, 8.5; N, 4.3;
C15H27NO4Si requires C, 57.5; H, 8.7; N, 4.5%) [a]2D3 +16.8 (c 0.15,
CHCl3), mmax (film)/cm−1 1715, 1662; dH (400 MHz, CDCl3) 6.18
=
(1H, br s, NH), 5.51 (1H, app. d, J 2.9, C CHH), 5.21 (1H,
app. d, J 2.4, C CHH), 4.16 (1H, d, J 9.4, CHHOTBS), 3.76
=
(3H, s, OCH3), 3.55 (1H, d, J 9.4, CHHOTBS), 3.06–3.00 (1H, m,
CHCH3), 1.32 (3H, d, J 7.4, CHCH3), 0.86 (9H, s, SiC(CH3)3),
0.05 (3H, s, Si CH3), 0.04 (3H, s, SiCH3); dC (100 MHz, CDCl3)
177.1 (s), 171.2 (s), 145.2 (s), 111.7 (t), 70.1 (s), 69.6 (t), 53.0 (q),
40.5 (d), 25.7 (3 × q), 18.2 (s), 16.5 (q), −5.4 (q), −5.6 (q); m/z (ES)
355.2018 (M + H+ + CH3CN, C17H31N2O4Si requires 355.2053);
In an NOE experiment (400 MHz, CDCl3) irradiation at dH 3.55
gave an enhancement at dH 3.03 (0.41%) and irradiation at dH
(5R,3R)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-3-methyl-3-
methylsulfanyl-2,4-dioxo-pyrrolidine-5-carboxylic acid methyl
ester (48)
Triethylamine (66 ll, 0.48 mmol) and S-methyl-p-
toluenethiosulfonate (80 mg, 0.40 mmol) were added successively
to a stirred solution of a 2 : 1 mixture of C3-Me epimers of 45
and 46 (125 mg, 0.40 mmol) in dichloromethane (1.24 ml) at
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3428–3438 | 3435
©

View Article Online
room temperature under a nitrogen atmosphere. The mixture
was stirred at room temperature overnight and then concentrated
in vacuo. The residue was purified by flash chromatography on
silica, using petrol–diethyl ether (polarity increasing from 4 : 1
to 2 : 3) as eluent, to give a 7 : 1 mixture of diastereoisomers
of the methylsulfanyl derivative (113 mg, 78%) as a colourless
oil (Found: C, 49.85; H, 7.35; N, 3.4; C15H27NO5SSi requires C,
49.8; H, 7.5; N, 3.9%); mmax (film)/cm−1 1731, 1713; dH (360 MHz,
CDCl3) (major a-methyl epimer) 6.54 (1H, br s, NH), 4.11 (1H,
d, J 10.0, CHHOTBS), 3.97 (1H, d, J 10.0, CHHOTBS), 3.82
(3H, s, OCH3), 2.08 (3H, s, SCH3), 1.50 (3H, s, CH3), 0.86 (9H, s,
SiC(CH3)3), 0.05 (6H, s, Si(CH3)2); (minor b-methyl epimer) 6.62
(1H, br s, NH), 4.35 (1H, d, J 9.6, CHHOTBS), 4.00 (1H, d, J
9.6, CHHOTBS), 3.83 (3H, s, OCH3), 2.16 (3H, s, SCH3), 1.53
(3H, s, CH3), 0.87 (9H, s, SiC(CH3)3), 0.08 (3H, s, SiCH3), 0.06
(3H, s, SiCH3); dC (90 MHz, CDCl3) (major a-methyl epimer)
195.7 (s), 171.0 (s), 166.5 (s), 73.5 (s), 66.3 (t), 53.6 (q), 50.4 (s),
25.7 (3 × q), 18.2 (s), 15.0 (q), 12.0 (q), −5.5 (q), −5.6 (q); m/z
(ES) 362.1461 (M + H+, C15H28NO5SSi requires 362.1457).
diluted with dichloromethane (3.5 ml). The separated aqueous
layer was extracted with dichloromethane (2 × 3.5 ml), and the
combined organic extracts were then washed with brine (5 ml),
dried (MgSO4) and concentrated in vacuo. The residue was purified
by flash chromatography on silica, using pentane–diethyl ether
(polarity increasing from 3 : 2 to 2 : 3) as eluent, to give the alcohol
(5.4 mg, 92%) as a colourless oil; [a]2D1 +76.2 (c 0.15, EtOAc) (Lit.6d
[a]2D3 +94 (c 0.40, EtOAc)); dH (500 MHz, CDCl3) 7.36 (2H, d, J
8.6, ArH), 6.88 (2H, d, J 8.6, ArH), 5.20 (1H, d, J 15.2, PhCHH),
4.28 (1H, d, J 15.2, PhCHH), 4.19 (1H, dd, J 12.2, 9.1, CHHOH),
3.80 (3H, s, PhOCH3), 3.77 (1H, dd, J 12.2, 5.0, CHHOH), 3.73
(3H, s, OCH3), 2.14 (3H, s, SCH3), 1.56 (3H, s, CH3), 1.03 (1H,
dd, J 9.1, 5.0, CH2OH); dC (125 MHz, CDCl3) 198.8 (s), 172.1 (s),
165.7 (s), 159.7 (s), 129.8 (2 × d), 128.9 (s), 114.7 (2 × d), 77.7
(s), 61.9 (t), 55.4 (q), 53.4 (q), 49.6 (s), 44.3 (t), 16.8 (q), 12.4 (q);
m/z (ES) 390.0979 (M + Na+, C17H21NO6SNa requires 390.0987);
In an NOE experiment (400 MHz, CDCl3) irradiation at dH 4.19
gave an enhancement at dH 1.56 (1.57%) and irradiation at dH 3.73
gave an enhancement at dH 2.14 (0.11%).
(5R,3R)-5-Hydroxymethyl-1-(4-methoxybenzyl)-3-methyl-3-
methylsulfanyl-2,4-dioxo-pyrrolidine-5-carboxylic acid methyl
ester (49)
(5R,4S,3R)-4-Hydroxy-5-hydroxymethyl-1-(4-methoxybenzyl)-3-
methyl-3-methylsulfanyl-2-oxo-pyrrolidine-5-carboxylic acid
methyl ester (50)
A solution containing a 7 : 1 mixture of diastereoisomers of the
methylsulfanyl derivative 48 (10.2 mg, 0.028 mmol) in anhydrous
DMF (45 ll) was added dropwise to a stirred dispersion of
sodium hydride (60% in mineral oil, 1.4 mg, 0.034 mmol) in
anhydrous DMF (105 ll) at 0 ◦C under an argon atmosphere. The
mixture was stirred at 0 ◦C for 15 min and then p-methoxybenzyl
bromide (9 mg, 0.045 mmol) in anhydrous DMF (60 ll) was
Sodium triacetoxyborohydride (1.8 mg, 0.008 mmol) was added in
a single portion to a stirred solution of the 4-ketopyrrolidinone 49
(1.5 mg, 0.004 mmol) in acetic acid (100 ll) at room temperature.
The mixture was stirred at room temperature for 1 h and
then concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (polarity
increasing from 2 : 3 to 1 : 9) as eluent, to give the corresponding
alcohol (1.3 mg, 88%) as a colourless solid; [a]2D2 −42.0 (c 0.13,
CHCl3) (Lit.6d [a]D23 −41.8 (c 0.10, CHCl3)); dH (500 MHz, CDCl3)
7.31 (2H, d, J 8.6, ArH), 6.87 (2H, d, J 8.6, ArH), 5.16 (1H, d, J
15.3, PhCHH), 4.15 (1H, d, J 8.1, CHOH), 4.03 (1H, d, J 15.3,
PhCHH), 3.82–3.80 (2H, m, CHHOH), 3.80 (3H, s, PhOCH3),
3.79 (3H, s, OCH3), 3.63 (1H, d, J 8.1, CHOH), 2.16 (3H, s,
SCH3), 1.63 (3H, s, CH3), 1.06 (1H, dd, J 8.5, 5.7, CH2OH);
dC (125 MHz, CDCl3) 173.5 (s), 171.6 (s), 159.5 (s), 129.7 (s),
129.5 (2 × d), 114.6 (2 × d), 76.7 (d), 72.4 (s), 62.5 (t), 55.4 (q),
53.4 (s), 52.9 (q), 44.8 (t), 22.9 (q), 12.4 (q); m/z (ES) 370.1310
(M + H+, C17H24NO6S requires 370.1324); In an NOE experiment
(400 MHz, CDCl3) irradiation at dH 4.15 gave an enhancement at
dH 1.63 (3.47%), and irradiation at dH 1.63 gave an enhancement
at dH 4.15 (3.31%).
◦
added dropwise. The mixture was stirred at 0 C for 1.5 h, then
allowed to warm to room temperature and stirred overnight. The
mixture was quenched with glacial acetic acid (30 ll) and ice
water (0.25 ml), and then diluted with diethyl ether (0.4 ml).
The separated aqueous layer was extracted with diethyl ether
(3 × 0.4 ml) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica, using pentane and then pentane–
diethyl ether (polarity increasing from 9 : 1 to 7 : 3) as eluent, to
give the N-PMB derivative (5.4 mg, 40%) as a colourless oil; [a]D22
+21.0 (c 0.21, CHCl3); mmax (film)/cm−1 1738, 1704; dH (500 MHz,
CDCl3) 7.27 (2H, d, J 8.5, ArH), 6.83 (2H, d, J 8.5, ArH), 4.83
(1H, d, J 15.1, PhCHH), 4.41 (1H, d, J 15.1, PhCHH), 4.23 (1H,
d, J 10.8, CHHOTBS), 4.03 (1H, d, J 10.8, CHHOTBS), 3.79
(3H, s, PhOCH3), 3.48 (3H, s, OCH3), 2.16 (3H, s, SCH3), 1.55
(3H, s, CH3), 0.82 (9H, s, SiC(CH3)3), 0.00 (3H, s, SiCH3), −0.03
(3H, s, SiCH3); dC (125 MHz, CDCl3) 200.3 (s), 172.2 (s), 166.0
(s), 159.2 (s), 130.1 (2 × d), 128.3 (s), 113.9 (2 × d), 76.9 (s), 62.0
(t), 55.4 (q), 52.9 (q), 49.4 (s), 44.3 (t), 25.9 (3 × q), 18.4 (s), 17.2
(q), 12.5 (q), −5.6 (q), −5.7 (q); m/z (ES) Found 504.1834 (M +
Na+, C23H35NO6SSiNa requires 504.1852).
(5R,4R,3R)-5-(tert-Butyl-dimethyl-silanyloxymethyl)-4-hydroxy-
3-methyl-3-methylsulfanyl-2-oxo-pyrrolidine-5-carboxylic acid
methyl ester (51)
Zinc borohydride (4.4 M in THF, 14 ll, 0.062 mmol) was added
dropwise to a stirred solution of a 7 : 1 mixture of diastereoisomers
of the methylsulfanyl derivative 48 (22 mg, 0.061 mmol) in THF
Pyridine (0.2 ml) was added to a stirred solution of HF·pyridine
(0.12 ml) in anhydrous THF (0.49 ml) under a nitrogen atmosphere
and the mixture was then added to a stirred solution of the
above N-PMB derivative (8 mg, 0.016 mmol) in anhydrous THF
(0.79 ml) at room temperature under a nitrogen atmosphere. The
mixture was stirred overnight at room temperature, then carefully
quenched with saturated aqueous sodium carbonate (2.7 ml) and
◦
(0.6 ml) at 0 C under a nitrogen atmosphere. The mixture was
stirred at 0 ◦C for 40 min, and then quenched with water (60 ll).
The mixture was stirred for a further 40 min at 0 ◦C, then warmed
to room temperature and diluted with dichloromethane (1.2 ml)
and water (0.2 ml). The separated aqueous layer was extracted
with dichloromethane (3 × 0.5 ml) and the combined organic
3436 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©

View Article Online
extracts were then washed with brine (1.5 ml), dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash
chromatography on silica, using pentane–diethyl ether (polarity
increasing from 3 : 2 to 2 : 3) as eluent, to give: i, the secondary
alcohol (◦17.6 mg, 79%) (eluted first) as a colourless solid, mp
147–149 C (petrol–diethyl ether); [a]2D3 +30.1 (c 0.23, CHCl3); mmax
(film)/cm−1 3454, 3200, 1715, 1700; dH (400 MHz, CDCl3) 6.23
(1H, br s, NH), 4.22 (1H, d, J 9.7, CHHOTBS), 4.17 (1H, d, J
8.2, CHOH), 3.97 (1H, d, J 8.2, CHOH), 3.80 (3H, s, OCH3),
3.60 (1H, d, J 9.7, CHHOTBS), 2.13 (3H, s, SCH3), 1.56 (3H, s,
CH3), 0.86 (9H, s, SiC(CH3)3), 0.05 (3H, s, SiCH3), 0.03 (3H, s,
SiCH3); dC (100 MHz, CDCl3) 173.3 (s), 172.9 (s), 79.2 (d), 68.4 (t),
66.3 (s), 53.4 (s), 53.0 (q), 25.6 (3 × q), 21.1 (q), 18.1 (s), 11.7 (q),
−5.5 (q), −5.7 (q); m/z (ES) 364.1636 (M + H+, C15H30NO5SSi
requires 364.1614); In an NOE experiment (400 MHz, CDCl3)
irradiation at dH 3.97 gave enhancements at dH 3.60 (4.90%) and
dH 1.56 (3.77%), irradiation at dH 3.60 gave an enhancement at dH
3.97 (6.14%), and irradiation at dH 1.56 gave an enhancement at
dH 3.97 (2.29%); and ii, the minor b-methyl epimer (2.7 mg, 12%)
(eluted second) as a colourless solid; [a]2D3 +23.4 (c 0.14, CHCl3);
mmax (film)/cm−1 3479, 3300, 1735, 1689; dH (400 MHz, CDCl3) 6.11
(1H, br s, NH), 4.30 (1H, d, J 4.4, CHOH), 4.26 (1H, d, J 9.9,
CHHOTBS), 4.07 (1H, d, J 9.9, CHHOTBS), 3.80 (3H, s, OCH3),
3.02 (1H, d, J 4.4, CHOH), 2.19 (3H, s, SCH3), 1.53 (3H, s, CH3),
0.86 (9H, s, SiC(CH3)3), 0.06 (3H, s, SiCH3), 0.04 (3H, s, SiCH3);
dC (100 MHz, CDCl3) 173.3 (s), 172.6 (s), 78.4 (d), 68.4 (s), 65.7
(t), 54.9 (s), 53.0 (q), 25.7 (3 × q), 22.2 (q), 18.1 (s), 12.3 (q), −5.5
(q), −5.6 (q); m/z (ES) 364.1640 (M + H+, C15H30NO5SSi requires
364.1614); In an NOE experiment (400 MHz, CDCl3) irradiation
at dH 4.30 gave an enhancement at dH 1.53 (3.52%), irradiation at
dH 4.07 gave an enhancement at dH 2.19 (0.39%) and irradiation at
dH 1.53 gave an enhancement at dH 4.30 (3.20%).
(3H, s, SiCH3), 0.04 (3H, s, SiCH3); dC (90 MHz, CDCl3) 174.0
(s), 169.9 (s), 79.6 (d), 69.1 (s), 67.9 (t), 53.0 (s), 52.3 (q), 25.7
(6 × q), 22.7 (q), 18.2 (2 s), 12.0 (q), −4.3 (q), −4.4 (q), −5.5 (q),
−5.6 (q); m/z (ES) 478.2504 (M + H+, C21H44NO5SSi2 requires
478.2479).
A solution of the TBS-ether (6.2 mg, 0.014 mmol) in anhydrous
DMF (22 ll) was added dropwise to a stirred dispersion of
sodium hydride (60% in mineral oil, 0.6 mg, 0.016 mmol) in
anhydrous DMF (53 ll) at 0 ◦C under an argon atmosphere. The
mixture was stirred at 0 ◦C for 15 min and then p-methoxybenzyl
bromide (4.2 mg, 0.021 mmol) in anhydrous DMF (30 ll) was
◦
added dropwise. The mixture was stirred at 0 C for 1.5 h, then
allowed to warm to room temperature and stirred overnight.
The mixture was quenched with glacial acetic acid (15 ll) and
ice water (0.2 ml), and then diluted with diethyl ether (0.3 ml).
The separated aqueous layer was extracted with diethyl ether
(3 × 0.3 ml) and the combined organic extracts were then dried
(MgSO4) and concentrated in vacuo. The residue was purified by
flash chromatography on silica, using pentane and then pentane–
diethyl ether (polarity increasing from 9 : 1 to 4 : 1) as eluent, to
give the N-benzyl derivative (6.1 mg, 73%) as a colourless oil; [a]D22
+12.0 (c 0.43, CHCl3); mmax (film)/cm−1 2954, 1737, 1694, 1523;
dH (400 MHz, CDCl3) 7.23 (2H, d, J 8.7, ArH), 6.80 (2H, d, J
8.7, ArH), 4.60 (1H, d, J 15.2, PhCHH), 4.29 (1H, s, CHOTBS),
4.24 (1H, d, J 15.2, PhCHH), 4.03 (1H, d, J 11.1, CHHOTBS),
3.90 (1H, d, J 11.1, CHHOTBS), 3.78 (3H, s, PhOCH3), 3.41
(3H, s, OCH3), 2.18 (3H, s, SCH3), 1.56 (3H, s, CH3), 0.90 (9H, s,
SiC(CH3)3), 0.86 (9H, s, SiC(CH3)3), 0.15 (3H, s, SiCH3), 0.10
(3H, s, SiCH3), 0.03 (3H, s, SiCH3), 0.00 (3H, s, SiCH3); dC
(100 MHz, CDCl3) 174.8 (s), 169.3 (s), 158.8 (s), 130.0 (2 × d),
129.3 (s), 113.7 (2 × d), 78.2 (d), 73.1 (s), 61.7 (t), 55.4 (q), 51.9 (s),
51.5 (q), 44.6 (t), 25.9 (3 × q), 25.8 (3 × q), 24.0 (q), 18.2 (2 × s),
12.3 (q), −4.0 (q), −4.4 (q), −5.5 (q), −5.6 (q); m/z (ES) Found
598.3051 (M + H+, C29H52NO6SSi2 requires 598.3054).
(5R,4R,3R)-4-(tert-Butyl-dimethyl-silanyloxy)-5-(tert-butyl-
dimethyl-silanyloxymethyl)-1-(4-methoxybenzyl)-3-methyl-3-
methylsulfanyl-2-oxo-pyrrolidine-5-carboxylic acid methyl
ester (52)
(5R,4R,3R)-4-(tert-Butyl-dimethyl-silanyloxy)-5-hydroxymethyl-
1-(4-methoxybenzyl)-3-methyl-3-methylsulfanyl-2-oxo-
pyrrolidine-5-carboxylic acid methyl ester (53)
tert-Butyldimethylsilyl trifluoromethanesulfonate (16.5 ll,
0.072 mmol) was added dropwise to a stirred solution of the
secondary alcohol 51 (6.7 mg, 0.018 mmol) and 2,6-lutidine
(17.5 ll, 0.144 mmol) in dichloromethane (70 ll) at 0 ◦C under a
nitrogen atmosphere, and the mixture was then stirred at 0 ◦C for
30 min. The mixture was allowed to warm to room temperature
and then stirred at this temperature for a further 18 h. The
solution was diluted with dichloromethane (0.5 ml) and then
quenched with saturated aqueous sodium bicarbonate (0.3 ml).
The separated aqueous layer was extracted with dichloromethane
(3 × 0.5 ml), and the combined organic extracts were then
washed with saturated copper sulfate (2 × 2 ml) and water (4 ×
1 ml), dried (MgSO4) and concentrated in vacuo. The residue was
purified by flash chromatography on silica, using petrol–diethyl
ether (polarity increasing from 7 : 3 to 1 : 1) as eluent, to give the
corresponding TBS-ether (6.9 mg, 80%) as a colourless oil; [a]D22
+6.5 (c 0.62, CHCl3); mmax (film)/cm−1 1738, 1706; dH (360 MHz,
CDCl3) 6.01 (1H, br s, NH), 4.18 (1H, d, J 9.4, CHHOTBS),
4.07 (1H, s, CHOTBS), 3.73 (3H, s, OCH3), 3.53 (1H, d, J 9.4,
CHHOTBS), 2.12 (3H, s, SCH3), 1.51 (3H, s, CH3), 0.95 (9H, s,
SiC(CH3)3), 0.86 (9H, s, SiC(CH3)3), 0.15 (6H, s, Si(CH3)2), 0.06
Pyridine (80 ll) was added to a stirred solution of HF·pyridine
(50 ll) in anhydrous THF (0.2 ml) under a nitrogen atmosphere,
and the resulting mixture was then added to a stirred solution of
the N-protected derivative 52 (4.3 mg, 0.007 mmol) in anhydrous
THF (0.31 ml) at room temperature under a nitrogen atmosphere.
The mixture was stirred at room temperature overnight, and
then pyridine (40 ll), followed by a solution of HF·pyridine
(25 ll) were each added dropwise and the mixture was stirred
at 40 ◦C for 4 h. The mixture was quenched carefully with
saturated aqueous sodium carbonate (2.6 ml) and then diluted
with dichloromethane (3.4 ml). The separated aqueous layer was
extracted with dichloromethane (2 × 3.4 ml), and the combined
organic extracts were then washed with brine (5 ml), dried
(MgSO4) and concentrated in vacuo. The residue was purified
by flash chromatography on silica, using pentane–diethyl ether
(polarity increasing from 7 : 3 to 1 : 1) as eluent, to give the
alcohol6d (3.0 mg, 89%) as a colourless oil; [a]2D3 −24.6 (c 0.28,
CHCl3); mmax (film)/cm−1 3410, 1737, 1674; dH (500 MHz, CDCl3)
7.31 (2H, d, J 8.5, ArH), 6.87 (2H, d, J 8.5, ArH), 5.20 (1H,
d, J 15.3, PhCHH), 4.36 (1H, s, CHOTBS), 3.83–3.76 (1H, m,
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 3428–3438 | 3437
©

View Article Online
CHHOH), 3.79 (3H, s, PhOCH3), 3.74 (1H, d, J 15.3, PhCHH),
3.72 (3H, s, OCH3), 3.67 (1H, dd, J 13.0, 4.8, CHHOH), 2.19
(3H, s, SCH3), 1.59 (3H, s, CH3), 0.93 (9H, s, SiC(CH3)3), 0.80
(1H, dd, J 10.6, 4.8, CH2OH), 0.15 (3H, s, SiCH3), 0.11 (3H, s,
SiCH3); dC (125 MHz, CDCl3) 174.9 (s), 169.5 (s), 159.5 (s), 129.9
(s), 129.5 (2 × d), 114.7 (2 × d), 77.7 (d), 74.3 (s), 61.4 (t), 55.4 (q),
55.2 (q), 51.7 (s), 44.8 (t), 25.8 (3 × q), 23.7 (q), 18.2 (s), 12.1 (q),
−4.2 (q), −4.5 (q); m/z (ES) 484.2203 (M + H+, C23H38NO6SSi
requires 484.2189).
9 For formal and partial syntheses of lactacystin see: S. H. Kang and
H.-S. Jun, Chem. Commun., 1998, 18, 1929–1930; S. H. Kang, H.-S.
Jun and J.-H. Youn, Synlett, 1998, 1045–1046; S. Iwama, W.-G. Gao,
T. Shinada and Y. Ohfune, Synlett, 2000, 1631–1633; Y. Ohfune and
T. Shinada, Bull. Chem. Soc. Jpn., 2003, 76, 1115–1129; P. C. B. Page,
A. S. Hamzah, D. C. Leach, S. M. Allin, D. M. Andrews and G. A.
Rassias, Org. Lett., 2003, 5, 353–355; P. C. B. Page, D. C. Leach, C. M.
Hayman, A. S. Hamzah, S. M. Allin and V. McKee, Synlett, 2003,
1025–1027; D. J. Wardrop and E. G. Bowen, Chem. Commun., 2005,
40, 5106–5108; J. -C. Legeay and N. Langlois, J. Org. Chem., 2007, 72,
10108–10113; C. B. Gilley, M. J. Buller and Y. Kobayashi, Org. Lett.,
2007, 9, 3631–3634; see also reference 11.
10 For some syntheses of isomers and analogues of lactacystin see: E. J.
Corey and S. Choi, Tetrahedron Lett., 1993, 34, 6969–6972; E. J. Corey
and G. A. Reichard, Tetrahedron Lett., 1993, 34, 6973–6976; E. J. Corey
and W. Li, Tetrahedron Lett., 1998, 39, 7475–7478; H. Uno, N. Mizobe,
Y. Yamaoka and N. Ono, Heterocycles, 1998, 48, 635–640.
11 Preliminary communication: C. J. Brennan, G. Pattenden and G.
Rescourio, Tetrahedron Lett., 2003, 44, 8757–8760.
12 J. M. Clough, G. Pattenden and P. G. Wight, Tetrahedron Lett., 1989, 30,
7469–7472. For some other examples of 5-exo dig radical cyclisations
in synthesis, and in the synthesis of pyrrolidinones see under references
18 and 19 in reference 14a below.
Acknowledgements
We thank Pfizer Ltd. for financial support (scholarship to G. R.)
and Dr David Fox for his enthusiastic interest in this project. We
also thank Christopher J. Brennan for developing an approach to
racemic 2-ethynyl-2-amino alcohols and Drs Nathalie Cholleton
and Christopher J. Hayes for their contributions to the early part
of our work in this area.
13 C. Cativiela and M. D. Diaz-de-Villegas, Tetrahedron: Asymmetry,
1998, 9, 3517–3599.
14 (a) N. J. Bennett, J. C. Prodger and G. Pattenden, Tetrahedron, 2007,
63, 6216–6231; (b) C. J. Brennan, PhD Thesis, The University of
Nottingham, 2000.
15 (a) U. Schmidt, M. Respondek, A. Lieberknecht, J. Werner and P.
Fischer, Synthesis, 1989, 256–261; (b) S. Hatakeyama, H. Matsumoto,
H. Fukuyama, Y. Mukugi and H. Irie, J. Org. Chem., 1997, 62, 2275–
2279.
References
1 S. Omura, T. Fujimoto, K. Otoguro, K. Matsuzaki, R. Moriguchi,
H. Tanaka and Y. Sasaki, J. Antibiot., 1991, 44, 113–116; S. Omura,
K. Matsuzaki, T. Fujimoto, K. Kosuge, T. Furuya, S. Fujita and A.
Nakagawa, J. Antibiot., 1991, 44, 117–118.
2 M. Bogyo and E. W. Wang, Curr. Top. Microbiol. Immunol., 2002, 268,
185–208; D. H. Lee and A. L. Goldberg, Trends Cell Biol., 1998, 8,
397–403.
3 G. Fenteany, R. F. Standaert, G. A. Reichard, E. J. Corey and S. L.
Schreiber, Proc. Natl. Acad. Sci. U. S. A., 1994, 91, 3358–3362; A.
Craiu, M. Gaczynska, T. Akopian, C. F. Gramm, G. Fenteany, A. L.
Goldberg and K. L. Rock, J. Biol. Chem., 1997, 272, 13437–13445;
G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E. J. Corey and
S. L. Schreiber, Science, 1995, 268, 726–731; G. Fenteany and S. L.
Schreiber, J. Biol. Chem., 1998, 273, 8545–8548.
16 S. Aoyagi, T. C. Wang and C. Kibayashi, J. Am. Chem. Soc., 1993, 115,
11393–11409.
17 H. E. Ensley, R. R. Buescher and K. Lee, J. Am. Chem. Soc., 1982, 47,
404–408.
18 P. Gamez, C. Ariente, J. Gore and B. Cazes, Tetrahedron, 1998, 54,
14825–14834.
19 K. C. Nicolaou, R. E. Zipkin, R. E. Dolle and B. D. Harris, J. Am.
Chem. Soc., 1984, 106, 3548–3551.
20 Z. -M. Wang, W. -S. Zhou and G. -G. Lin, Tetrahedron Lett., 1985,
26, 6221–6224; Z.-M. Wang and W. -S. Zhou, Tetrahedron, 1987, 43,
2935–2944.
4 G. Fenteany, R. F. Standaert, W. S. Lane, S. Choi, E. J. Corey and S. L.
Schreiber, Science, 1995, 268, 726–731.
5 R. H. Feling, G. O. Buchanan, T. J. Mincer, C. A. Kauffman, P. R.
Jensen and W. Fenical, Angew. Chem., Int. Ed., 2003, 42, 355–357.
6 (a) E. J. Corey and G. A. Reichard, J. Am. Chem. Soc., 1992, 114, 10677–
10678; (b) E. J. Corey, G. A. Reichard and R. Kania, Tetrahedron Lett.,
1993, 34, 6977–6980; (c) E. J. Corey, W. D. Li and G. A. Reichard,
J. Am. Chem. Soc., 1998, 120, 2330–2336; (d) E. J. Corey, W. D. Li and
T. Nagamitsu, Angew. Chem., Int. Ed., 1998, 37, 1676–1679.
21 See reference 15b.
22 D. J. Chadwick, I. A. Cliffe, I. O. Sutherland and R. F. Newton, J. Chem.
Soc., Perkin Trans. 1, 1984, 1707–1717; M. C. Elliott and E. Kruiswijk,
J. Chem. Soc., Perkin Trans. 1, 1999, 3157–3166; N. S. Chandrakumar
and J. Hajdu, J. Org. Chem., 1983, 48, 1197–1202; A. Marchand, A.
Maxwell, B. Mootoo, A. Pelter and A. Reid, Tetrahedron, 2000, 56,
7331–7338.
7 For total syntheses of lactacystin see: T. Sunazuka, T. Nagamitsu, K.
Matsuzaki, H. Tanaka, S. Omura and A. B. Smith, J. Am. Chem. Soc.,
1993, 115, 5302; H. Uno, J. E. Baldwin and A. T. Russell, J. Am.
Chem. Soc., 1994, 116, 2139–2140; N. Chida, J. Takeoka, N. Tsutsumi
and S. Ogawa, J. Chem. Soc., Chem. Commun., 1995, 793–794; T.
Nagamitsu, T. Sunazuka, H. Tanaka, S. Omura, P. A. Sprengeler and
A. B. Smith, J. Am. Chem. Soc., 1996, 118, 3584–3590; N. Chida, J.
Takeoka, K. Ando, N. Tsutsumi and S. Ogawa, Tetrahedron, 1997, 53,
16287–16298; J. S. Panek and C. E. Masse, Angew. Chem., Int. Ed., 1999,
38, 1093–1095; F. Soucy, L. Grenier, M. L. Behnke, A. T. Destree, A. T.
McCormack, J. Adams and L. Plamondon, J. Am. Chem. Soc., 1999,
121, 9967–9976; H. Ooi, N. Ishibashi, Y. Iwabuchi, J. Ishihara and S.
Hatekeyama, J. Org. Chem., 2004, 69, 7765–7768; T. J. Donohoe, H. O.
Sintim, L. Sisangia and J. D. Harling, Angew. Chem., Int. Ed., 2004, 43,
2293–2296; T. J. Donohoe, H. O. Sintim, L. Sisangia, K. W. Ace, P. M.
Guyo, A. Cowley and J. D. Harling, Chem.–Eur. J., 2005, 11, 4227–4238;
C. J. Hayes, A. E. Sherlock and M. D. Selby, Org. Biomol. Chem., 2006,
4, 193–195; N. Fukuda, K. Sasaki, T. V. R. S. Sastry, M. Kanai and M.
Shibasaki, J. Org. Chem., 2006, 71, 1220–1225; E. P. Balskus and E. N.
Jacobsen, J. Am. Chem. Soc., 2006, 128, 6810–6812; C. H. Yoon, D. L.
Flanigan, D. L. Yoo and K. W. Jung, Eur. J. Org. Chem., 2007, 37–39;
C. J. Hayes, A. E. Sherlock, M. P. Green, C. Wilson, A. J. Blake, M. D.
Selby and J. C. Prodger, J. Org. Chem., 2008, 73, 2041–2051.
23 See reference 14.
24 K. C. Nicolaou, C. -K. Hwang, A. L. Smith and S. V. Wendeborn,
J. Am. Chem. Soc., 1990, 112, 7416–7418.
25 Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune and
K. B. Sharpless, J. Am. Chem. Soc., 1987, 109, 5765–5780.
26 A. Romero and C. -H. Wong, J. Org. Chem., 2000, 65, 8264–8268.
27 We thank Professor A. J. Blake of this School for the crystal structure
determination. The CIF has been deposited with the Cambridge
Crystallographic Data Centre as CCDC 226290.
28 For a synthesis of 47 starting from serine see: M. D. Andrews, A. G.
Brewster, K. M. Crapnell, A. J. Ibbett, T. Jones, M. G. Moloney, K.
Prout and D. Watkin, J. Chem. Soc., Perkin Trans. 1, 1998, 223–236.
29 For related epimerisation studies of 3-substituted pyrrolidinones, see:
J. -D. Charrier, J. E. S. Duffy, P. B. Hitchcock and D. W. Young, J. Chem.
Soc., Perkin Trans. 1, 2001, 2367–2371; C. M. Acevedo, E. F. Kogut and
M. A. Lipton, Tetrahedron, 2001, 57, 6353–6359; M. D. Andrews, A. G.
Brewster and M. G. Moloney, J. Chem. Soc., Perkin Trans. 1, 2002, 80–
90; H. Uno, J. E. Baldwin and A. T. Russell, J. Am. Chem. Soc., 1994,
116, 2139–2140.
30 J. H. Bateson, A. M. Quinn and R. Southgate, J. Chem. Soc.,
Chem. Commun., 1986, 1151–1152; For a synthesis of S-methyl-
p-toluenethiosulfonate and other thiosulfonates, see: K. Fujiki, N.
Tanifuji, Y. Sasaki and T. Yokoyama, Synthesis, 2002, 343–348.
31 G. Pattenden, N. J. Ashweek, C. A. G. Baker-Glenn, J. Kempson, G. M.
Walker and J. G. K. Yee, Org. Biomol. Chem., 2008, 6, 1478–1497.
8 For reviews see: E. J. Corey and W. -D. Z. Li, Chem. Pharm. Bull.,
1999, 47, 1–10; C. E. Masse, A. J. Morgan, J. Adams and J. S. Panek,
Eur. J. Org. Chem., 2000, 2513–2528.
3438 | Org. Biomol. Chem., 2008, 6, 3428–3438
This journal is
The Royal Society of Chemistry 2008
©