Enantioselective total syntheses of (-)-clasto-lactacystin β-lactone and 7-epi-(-)-clasto-lactacystin β-lactone

Article abstract of DOI:10.1039/b516311k

An alkylidene carbene 1,5-CH insertion has been used as a key step in an efficient enantioselective total synthesis of (-)-clasto-lactacystin β-lactone, and its C7-epimer. An additional noteworthy feature of the synthesis is the use of a novel oxidative deprotection procedure, utilizing DMDO, for the conversion of a late-stage benzylidene acetal into a primary alcohol and a secondary benzoate ester. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b516311k

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Enantioselective total syntheses of (−)-clasto-lactacystin b-lactone
and 7-epi-(−)-clasto-lactacystin b-lactone†
Christopher J. Hayes,*a Alexandra E. Sherlocka and Matthew D. Selbyb
Received 16th November 2005, Accepted 24th November 2005
First published as an Advance Article on the web 9th December 2005
DOI: 10.1039/b516311k
An alkylidene carbene 1,5-CH insertion has been used as a
key step in an efficient enantioselective total synthesis of (−)-
clasto-lactacystin b-lactone, and its C7-epimer. An additional
noteworthy feature of the synthesis is the use of a novel
oxidative deprotection procedure, utilizing DMDO, for the
conversion of a late-stage benzylidene acetal into a primary
alcohol and a secondary benzoate ester.
lactone 2 has also served as a synthetic precursor to the natural
product 1 itself, and the enantioselective synthesis of 2 has become
an important synthetic challenge in its own right.
In 2002 we reported a formal synthesis of (+)-lactacystin 1,4
which used a highly stereoselective alkylidene carbene 1,5-CH
insertion reaction as a method to construct the key quaternary
stereocentre.5,6 In this first generation route we utilized TBS-
protecting groups during the CH-insertion step (vis 3 → 4, R =
TBS), but in order to mitigate unexpected problems during scale-
up we chose to explore an alternative protecting group strategy in a
second generation route to 1 and 2. As the TBS-protecting groups
on 3 (Scheme 1) created a highly hindered environment at the site
of CH-insertion, we chose to explore the possibility of protecting
the 1,3-diol moiety in 3 as a benzylidene acetal. During the
preparation of this manuscript, Wardrop independently reported
an alkylidene carbene 1,5-CH-insertion approach to 1,7 following
an identical approach to that outlined in Scheme 1, which also
uses a benzylidene acetal to protect the diol moiety in 3 and 4. We
now wish to report our own results in this area, which have led
to a second generation enantioselective total synthesis of clasto-
lactacystin b-lactone 2 as well as its C7-epimer 22.
(+)-Lactacystin 1 was isolated from the bacterial strain, Strepto-
˜
myces sp. OM-6519 by Omura in 1991 during a screening program
for small molecule mimics of nerve growth factors.1 Lactacystin
was later found to be a specific inhibitor of the 20S proteasome
found in mammalian and bacterial cells.2 The proteasome is
responsible for the normal turnover of cellular proteins and
degradation of damaged and mutated proteins, and 1 has played
a vital role in the study of its function. The remarkable biological
activity and intriguing structure of 1 has sparked continued
interest over the last 13 years and a number of syntheses have been
published to date.3 Lactacystin 1 spontaneously and reversibly
forms (−)-clasto-lactacystin b-lactone (also known as omuralide) 2
in the extracellular medium, and it is this b-lactone that penetrates
the cell and acylates an active site threonine residue, leading to
inhibition of the proteasome (Scheme 1). As well as serving as
the biologically active form of lactacystin 1, clasto-lactacystin b-
The key vinyl bromide CH-insertion precursor 7 was readily
prepared in 4 steps from epoxy alcohol 5 according to the route
shown below (Scheme 2).
Scheme 1
aSchool of Chemistry, University of Nottingham, University Park, Notting-
ham, UK NG7 2RD
bPfizer Global Research and Development, Ramsgate Road, Sandwich, Kent,
UK CT13 9NJ
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for 10, 11, 17, 18 and 23. See DOI:
10.1039/b516311k
Scheme 2 Reagents and conditions: (a) NaN3, B(OMe)3, DMF, 50 ◦C
(77%); (b) PhCH(OMe)2, PPTS, C6H6, reflux (78%); (c) H2, Lindlar cat.,
◦
˚
MeOH, 20 C (100%); (d) MnO2, 8, DCM, 4 A mol. sieves, reflux, then
NaCNBH3, AcOH, MeOH, 0 ◦C (75%); (e) KHMDS, THF, −30 ◦C (83%).
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Thus treatment of the known epoxide 5 under Miyashita’s
conditions8 gave 2-azido-1,3-diol 6 in 77% yield. Acetal protection
and hydrogenation next gave the amine 9 in good yield. One-pot
MnO2 oxidation, imine formation and reduction, as described
by Taylor,9 finally provided the (E)-vinyl bromide cyclisation
precursor 7 as a single isomer in 59% yield over 3 steps. After
careful optimization, exposure of 7 to an excess (2 equiv.) of
KHMDS in THF at −30 ◦C gave the desired 3-pyrroline 10 in
a very pleasing 83% isolated yield. The cyclisation of 7 to 10 was
also accompanied by the formation of the corresponding but-
2-ynyl-amine 11 (13% yield), but this byproduct could be easily
removed by column chromatography.
Although base-mediated epimerisation of the undesired di-
astereoisomer 16 proved difficult to achieve in high yield, we
found that 16 could be transformed into the 3-pyrrolinone 14 by
treatment with NaOMe–MeOH, hence providing a high yielding
(90%) method of recycling material through to the desired cis-
isomer 15.
Once we had access to 15, we were able to complete a formal
synthesis of 1 by conversion to the known triol 17 by standard
catalytic hydrogenation in 93% yield (Scheme 3). Whilst we were
pleased with this initial success, we were aware that 7 steps were
still required to convert 17 into the natural product 1, and we
therefore hoped to shorten this sequence by developing a selective
deprotection–oxidation strategy from lactam 15.
As we had access to both 15 and 16, we first decided to
investigate this new ‘end-game’ approach on the more abundant
trans-isomer 16 (Scheme 4). Thus, treatment of the benzylidene
acetal 16 with DMDO (dimethyldioxirane) caused a selective,
oxidative–deprotection to give the alcohol-ester 18, as a single
regioisomer, in quantitative yield.13 This remarkable deprotection
reaction gives both a free primary alcohol and protected secondary
alcohol in one convenient transformation. Selective oxidation of
the primary alcohol in 18 to the acid 19 was achieved using sequen-
tial Dess-Martin periodinane (63%) and sodium chlorite (81%)
oxidations. Deprotection of 19 and formation of the b-lactone
by treatment with BOPCl (bis(2-oxo-3-oxazolidinyl)phosphinic
chloride) finally afforded 7-epi-clasto-lactacystin b-lactone 22. The
spectroscopic data of 22 were identical to those reported by Corey
for this compound.14
Having secured an efficient route to the 3-pyrroline 10, we
next needed to install the additional oxygenation and remaining
stereocentres present in 1 and 2. Thus, oxidation with TPAP–
NMO, and then sodium chlorite first gave the N-chlorolactam 12
and treatment with sodium borohydride then provided the desired
3-pyrrolinone 14 in 76% over 3 steps.10 Dihydroxylation was then
accomplished using Sharpless’s modified UpJohn conditions11
which cleanly afforded the diol 13 as a single, crystalline di-
astereoisomer in 96% yield. Formation of the cyclic thiocarbonate,
n
followed by selective deoxygenation with Bu3SnH and AIBN12
then gave a separable 1 : 3.6 mixture of the 15 and 16 in 94%
combined yield (Scheme 3).
Scheme 4 Reagents and conditions: (a) DMDO (3 equiv., 0.06 M), acetone,
0
◦C (100%); (b) Dess-Martin periodinane, DCM, 20 ◦C (63%); (c)
NaClO2, NaH2PO4·2H2O, HOSO2NH2, BuOH, H2O, 20 ◦C (81%); (d)
t
NaOMe, MeOH, 20 ◦C (78%); (e) BOPCl, Et3N, DCM, 20 ◦C (38%).
˚
Scheme 3 Reagents and conditions: (a) TPAP, NMO, MeCN, 4 A mol.
Having completed the synthesis of 22, we then turned our
attention to repeating the same chemical steps on the correct
diastereoisomer isomer 15 required for the synthesis of (+)-
lactacystin 1 (Scheme 5). Thus, selective deprotection according
to our newly developed procedure cleanly gave the alcohol-ester
t
sieves (93%); (b) NaClO2, NaH2PO4·2H2O, 2-methyl-2-butene, BuOH,
H2O, 0 ◦C; (c) NaBH4, MeOH, 20 ◦C (84% over 2 steps); (d) K2OsO2(OH)4,
NMO, citric acid, BuOH–H2O (1 : 1), 20 ◦C (96%); (e) thiocarbonyl
t
diimidazole, THF, reflux (100%); (f) nBu3SnH, AIBN, toluene, reflux
(94%); (g) NaOMe, MeOH; (h) H2, Pd/C, HCl, MeOH (93%).
194 | Org. Biomol. Chem., 2006, 4, 193–195
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Acknowledgements
We thank the EPSRC and Pfizer Central Research for financial
support of this work.
References
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Scheme 5 Reagents and conditions: (a) DMDO (3 equiv. 0.06 M), acetone,
0 ◦C (90%); (b) Dess-Martin periodinane, DCM, 20 ◦C (35%); (c) NaClO2,
NaH2PO4·2H2O, HOSO2NH2, BuOH, H2O, 20 ◦C (95%); (d) NaOMe,
t
MeOH, 20 ◦C (74%); (e) BOPCl, Et3N, DCM, 20 ◦C (45%).
23 in 75% yield. Sequential Dess-Martin periodinane (35%) and
sodium chlorite (95%) oxidations then gave the acid 24. Pleasingly,
the ester 24 could be saponified to afford the previously reported
acid 26, which was then converted to clasto-lactacystin b-lactone
2 using the known procedure.15
In summary, we have developed a second generation synthesis
of 1 and 2 using an alkylidene carbene 1,5-CH insertion reaction
as a key step, and during this work we have also completed a
total synthesis of the recently described proteasome inhibitor 7-
epi-clasto-lactacystin b-lactone 22. In addition to developing novel
methodology for the construction of quaternary stereocentres, we
have also utilised a novel procedure for the selective oxidative
deprotection of benzylidene acetals using DMDO and we are
currently exploring the wider synthetic utility of this particular
transformation.
15 E. J. Corey, W. Li and G. A. Reichard, J. Am. Chem. Soc., 1998, 120,
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The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 193–195 | 195
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