Enantioselective total syntheses of omuralide, 7-epi-omuralide, and (+)-lactacystin

Article abstract of DOI:10.1021/jo7027695

(Chemical Equation Presented) An alkylidene carbene 1,5-CH insertion has been used as a key step in an enantioselective total syntheses of omuralide, its C7-epimer, and (+)-lactacystin. An additional noteworthy feature of the synthesis is the use of a nov

Full text of DOI:10.1021/jo7027695

Enantioselective Total Syntheses of Omuralide, 7-epi-Omuralide,
and (+)-Lactacystin
Christopher J. Hayes,*,† Alexandra E. Sherlock,† Martin P. Green,† Claire Wilson,†
Alexander J. Blake,† Matthew D. Selby,‡ and Jeremy C. Prodger§
School of Chemistry, UniVersity of Nottingham, UniVersity Park, Nottingham, NG7 2RD, UK,
Pfizer Global Research and DeVelopment, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK,
and GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, SteVenage,
Hertfordshire SG1 2NY, UK
chris.hayes@nottingham.ac.uk
ReceiVed December 31, 2007
An alkylidene carbene 1,5-CH insertion has been used as a key step in an enantioselective total syntheses
of omuralide, its C7-epimer, and (+)-lactacystin. 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.
Introduction
residue leading to inhibition of the proteasome. Other closely
related â-lactone-containing lactams have recently been isolated,
and synthetic interest in these molecules continues to grow due
to their therapeutic potential.4 In addition to serving as the
biologically active form of lactacystin 1, omuralide 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.
(+)-Lactacystin 1 was isolated from the bacterial strain
Streptomyces sp. OM-6519 by O˜ mura et al. 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 routine degradation of
cellular proteins and also the removal of damaged and mutated
proteins, and 1 has played a significant role in the study of its
function. The remarkable biological activity and intriguing
structure of 1 has stimulated much interest over recent years,
and a number of syntheses have been published to date.3
Lactacystin 1 spontaneously and reversibly forms omuralide 2
in the extracellular medium (Scheme 1), and it is this â-lactone
that penetrates the cell and acylates an active-site threonine
A variety of synthetic strategies have been employed in the
previous syntheses of lactacystin,3 and asymmetric construction
of the nitrogen-bearing quaternary stereocenter presents, perhaps,
the most significant challenge. Previous studies in our group
have demonstrated the utility of alkylidene carbene 1,5-CH
insertion reactions for the construction of 3-pyrrolines,5 and
furthermore, we have shown that the 3-pyrroline products can
be readily oxidized to the corresponding pyrrolinones under mild
conditions.6 We decided, therefore, to attempt an enantioselec-
tive synthesis of lactacystin 1 using this 1,5-CH insertion/
oxidation approach, proceeding through a suitably functionalized
pyrrolinone (e.g., 3). In 2002, we reported a formal synthesis
of (+)-lactacystin 13l by intercepting Baldwin’s route3v at lactam
3 (R1 ) R2 ) H), and this early success demonstrated the
† University of Nottingham.
‡ Pfizer Global Research and Development.
§ GlaxoSmithKline.
(1) O˜ mura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113.
(2) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J.;
Schreiber, S. L. Science 1995, 268, 726.
10.1021/jo7027695 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/21/2008
J. Org. Chem. 2008, 73, 2041-2051
2041

Hayes et al.
SCHEME 2. Scale-up of Route Used during 2002 Formal
SCHEME 1. Retrosynthetic Analysis of (+)-Lactacystin
Synthesis
report an extension of this work that has resulted in a new total
synthesis of (+)-lactacystin 1.
Results and Discussion
The first challenge in our second-generation approach to 1
was to develop a reliable, efficient, and scalable route to the
desired alkylidene carbene precursor 5 (Scheme 1). While the
methods used during our first formal synthesis (Scheme 2)3l
were adequate for providing small quantities of 5, it became
immediately obvious that simple scale-up of this chemistry
would not provide a viable long-term option for securing
multigram quantities of the key CH-insertion precursor. The
first problem was that the initial intramolecular epoxide-opening
reaction (7 f 9)7 routinely afforded a 5:1 ratio of 9/8, and the
desired major isomer could only be separated from the undesired
isomer 8 following extensive and tedious column chromatog-
raphy. In addition to the poor regioselectivity, the overall isolated
yield of the desired compound 9 varied considerably from batch
to batch (70-45%). The second problem was that alkylation
of the primary amine8 (6, R1 ) R2 ) TBS) with the allylic
bromide 11 (3:1, E/Z)9 was highly capricious (5-45% yield),
and despite much effort, we were not able to optimize this
reaction further. The highly hindered environment at the primary
amine, created by the two neighboring TBS-protecting groups
on 6 (R1 ) R2 ) TBS) (Scheme 1), appear to retard the desired
alkylation reaction, and we therefore decided to explore the use
of an alternative protecting group strategy during our revised
route.
validity of our overall synthetic approach. Due to unexpected
scale-up problems, however, accessing sufficient quantities of
3 with which to complete a new synthesis of 1 was difficult, so
we chose to explore a modified route to the pyrrolinone.
Fortunately, the second-generation route was successful, we
were able to complete a total synthesis of omuralide 2,3f and
we now wish to give a full account of this synthesis and also to
(3) (a) Legeay, J.-C.; Langlois, N. J. Org. Chem. 2007, 72, 10108. (b)
Yoon, C. H.; Flanigan, D. L.; Yoo, K. S.; Jung, K. W. Eur. J. Org. Chem.
2007, 37. (c) Gilley, C. B.; Buller, M. J.; Kobayashi, Y. Org. Lett. 2007,
9, 3631. (d) Balskus, E. P.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128,
6810. (e) Fukuda, N.; Sasaki, K.; Sastry, T. V. R. S.; Kanai, M.; Shibasaki,
M. J. Org. Chem. 2006, 71, 1220. (f) Hayes, C. J.; Sherlock, A. E.; Selby,
M. D. Org. Biol. Chem. 2006, 4, 193. (g) Donohoe, T. J.; Sintim, H. O.;
Sisangia, L.; Ace, K. W.; Guyo, P. M.; Cowley, A.; Harling, J. D. Chem.
Eur. J. 2005, 11, 4227. (h) Donohoe, T. J.; Sintim, H. O.; Sisangia, L.;
Harling, J. D. Angew. Chem., Int. Ed. 2004, 43, 2293.(i) Wardrop, D. J.;
Bowen, E. G. Chem. Commun. 2005, 5106. (j) Ooi, H.; Ishibashi, N.;
Iwabuchi, Y.; Ishihara, J.; Hatekeyama, S. J. Org. Chem. 2004, 69, 7765.
(k) Brennan, C. J.; Pattenden, G.; Rescourio, G. Tetrahedron Lett. 2003,
44, 8757. (l) Green, M. P.; Prodger, J. C.; Hayes, C. J. Tetrahedron Lett.,
2002, 43, 6609. (m) Iwama, S.; Gao, W. G.; Shinada, T.; Ohfune, Y. Synlett
2000, 1631. (n) Panek, J. S.; Masse, C. E. Angew. Chem., Int. Ed. 1999,
38, 1093. (o) Kang, S. H.; Jun, H. S. Chem. Commun. 1998, 1929. (p)
Kang, S. H.; Jun, H. S.; Youn, J. H. Synlett 1998, 1045. (q) Corey, E. J.;
Li, W. D.; Reichard, G. A. J. Am. Chem. Soc. 1998, 120, 2330. (r) Corey,
E. J.; Li, W. D.; Nagamitsu, T. Angew. Chem., Int. Ed. 1998, 37, 1676. (s)
Chida, N.; Takeoka, J.; Ando, K.; Tsutsumi, N.; Ogawa, S. Tetrahedron
1997, 53, 16287. (t) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.;
Sprengeler, P. A.; Smith, A. B. J. Am. Chem. Soc. 1996, 118, 3584. (u)
Chida, N.; Takeoka, J.; Tsutsumi, N.; Ogawa, S. J. Chem. Soc., Chem.
Commun. 1995, 793. (v) Uno, H.; Baldwin, J. E.; Russell, A. T. J. Am.
Chem. Soc. 1994, 116, 2139. (w) Sunazuka, T.; Nagamitsu, T.; Matsuzaki,
K.; Tanaka, H.; O˜ mura, S.; Smith, A. B. J. Am. Chem. Soc. 1993, 115,
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34, 6977. (y) Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114,
10677.
Our second-generation route started from the known Sharpless
epoxide 13 (Scheme 3),10 which was ring-opened in a regiose-
lective manner with azide using the recently reported conditions
(NaN3, B(OMe)3, DMF, 50 °C) of Miyashita et al.11 Under these
conditions, the desired azide 14 was produced in good yield
(75%) and good regioselectivity (C2/C3 opening, 14:1). The
minor 1,2-diol that resulted from C3-opening was removed by
treating the mixture with sodium periodate to give the pure
2-azido-1,3-diol 14 in 75% yield.
(4) (a) Ling, T.; Macherla, V. R.; Manam, R. R.; McArthur, K. A.; Potts,
B. C. M. Org. Lett. 2007, 9, 2289. (b) Ma, G.; Nguyen, H.; Romo, D. Org.
Lett. 2007, 9, 2143. (c) Mulholland, N. P.; Pattenden, G.; Walters, I. A. S.
Org. Biomol. Chem. 2006, 4, 2845. (d) Endo, A.; Danishefsky, S. J. J. Am.
Chem. Soc. 2005, 127, 8298. (e) Reddy, L. R.; Fournier, J.-F.; Reddy, B.
V. S.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 8974. (f) Reddy, L. R.;
Fournier, J.-F.; Reddy, B. V. S.; Corey, E. J. Org. Lett. 2005, 7, 2699. (g)
Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am. Chem. Soc. 2004, 126,
6230.
(5) Green, M. P.; Prodger, J. C.; Hayes, C. J.; Sherlock, A. E. Org. Lett.
2001, 3, 3377.
(6) Green, M. P.; Prodger, J. C.; Hayes., C. J. Tetrahedron Lett. 2002,
43, 2649.
(7) Hatakeyama, S.; Matsumoto, H.; Fukuyama, H.; Mukugi, Y.; Irie,
H. J. Org. Chem. 1997, 62, 2275.
(8) Salvatore, R. N.; Nagle, A. S.; Jung, K. W. J. Org. Chem. 2002, 67,
674.
(9) Walsh, R. A.; Bottini, A. T. J. Org. Chem. 1970, 35, 1086.
(10) (a) Kelkar, S. V.; Arbale, A. A.; Joshi, G. S.; Kilkarni, G. H. Synth.
Commun. 1990, 1, 839. (b) Gorthey, L. A.; Vairamani, M.; Djerassi, C. J.
Org. Chem. 1984, 49, 1511. (c) Caldwell, C. G.; Bondy, S. S. Synthesis
1990, 34. (d) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
(11) Sasaki, M.; Tanino, K.; Hirai, A.; Miyashita, M. Org. Lett. 2003,
5, 1789.
2042 J. Org. Chem., Vol. 73, No. 6, 2008

Syntheses of Omuralide, 7-epi-Omuralide, and (+)-Lactacystin
SCHEME 3. Second-Generation Route to Alkylidene
Carbene Precursor 19
FIGURE 1. X-ray crystal structure of the imine 18.
pure E-isomer from methacrylic acid 20 in three steps in 68%
overall yield (Scheme 4).13
A few methods to convert the alcohol 17 to the aldehyde
were examined (e.g., Dess-Martin periodane, TPAP/NMO),14
but the best method found was oxidation with activated
manganese dioxide.15 However, the aldehyde decomposed
quickly and needed to be used immediately. It was thought that
the one-pot allylic alcohol oxidation, imine formation, and
reduction procedure published by Taylor16 was a promising
method for this reductive amination. This method involved
stirring an allylic or benzylic alcohol in DCM with manganese
dioxide in the presence of an amine, 4 Å molecular sieves, and
sodium borohydride. Although this procedure seemed perfect
for our substrate, our initial attempts gave disappointing yields
of vinyl bromide 19. The 1H NMR of the crude material showed
that the imine 18 and the desired product 19 were present, but
no alcohol 17 or the corresponding aldehyde remained. Obvi-
ously, oxidation of 17 and condensation with 16 had occurred
efficiently, but reduction of the imine 18 was incomplete. Imine
18 could be isolated cleanly from the reaction of 16 and 17
with manganese dioxide as colorless crystals in 50% yield, and
an X-ray crystal structure was obtained, thus confirming all
regiochemical and stereochemical assignments (Figure 1).
In an attempt to optimize the one-pot oxidation/reductive
amination procedure, purified imine 18 was reduced with various
reducing agents. It was found that sodium triacetoxyborohydride
was ineffective, and sodium borohydride, even in the presence
of acetic acid, did not give a good conversion to the amine 19.
Fortunately, sodium cyanoborohydride in the presence of acetic
acid (1 equiv) proved to be an excellent reagent combination,
and this was adopted for the one pot procedure. It was important
to add the acetic acid last as it hindered the oxidation of the
alcohol if it was added at the start of the reaction, presumably
by deactivating the manganese dioxide. Hydrolysis of the imine
back to starting materials was observed if acetic acid was added
before the reducing reagent. Using these modified reduction
conditions, the vinyl bromide 19 was isolated in 75% yield as
a single isomer from the one-pot reductive alkylation (Scheme
2).
SCHEME 4. Stereoselective Synthesis of Vinyl Bromide 17
The next steps required were protection of the diol 14 and
reduction of the resulting azide 15a. Benzylidene acetal protec-
tion of the diol was chosen as it was hoped that tethering the
diol away from the resulting amine would reduce steric
hindrance and hence improve the yield of the subsequent
N-alkylation. Thus, treatment of 14 with benzaldehyde dimethyl
acetal in the presence of PPTS (6 mol %) in benzene with 4 Å
molecular sieves at reflux gave 15a and 15b as a 2:1 mixture
of isomers at the benzylic position. However, allowing the
system to equilibrate to the thermodynamic product (15a) by
not using molecular sieves increased this ratio to >25:1, and
azide 15a was isolated in 78% yield.
A few methods were found to reduce azide 15a to the
corresponding amine 16 (e.g., Ph3P/H2O; ZnBH4), but the most
reliable and convenient method was found to be catalytic
hydrogenation. Exposure of 15a to 10% Pd/C in MeOH gave
the amine 16 in 77% yield, but it was evident from TLC and
1H NMR of the crude material that a small amount of
benzylidene acetal deprotection had occurred.12 Instead, hydro-
genation in the presence of Lindlar’s catalyst in MeOH worked
very cleanly to give the desired product 16 in near-quantitative
yield.
As an alternative to the original N-alkylation (Scheme 1),
we decided to explore the use of a reductive amination procedure
for installation of the vinyl bromide-containing N-substituent
as this would avoid the preparation of the reactive allylic
bromide 11. First, it was necessary to prepare 3-bromoprop-2-
enal, and it was thought that the easiest route would be from
allylic alcohol 17. After some preliminary investigations, it was
found that the alcohol 17 could be made in high yield as the
(13) Dzierba, C. D.; Zandi, K. S.; Mollers, T.; Shea, K. J. J. Am. Chem.
Soc. 1996, 118, 4711.
(14) Ley, S. V.; Armstrong, A.; Diezmartin, D.; Ford, M. J.; Grice, P.;
Knight, J. G.; Kolb, H. C.; Madin, A.; Marby, C. A.; Mukherjee, S.; Shaw,
A. N.; Slawin, A. M. Z.; Vile, S.; White, A. D.; Williams, D. J.; Woods,
M. J. Chem. Soc., Perkin Trans. 1 1991, 667.
(15) Baker, R.; Castro, J. L. J. Chem. Soc., Perkin Trans. 1 1990, 47.
(16) Kanno, H.; Taylor, R. J. K. Tetrahedron Lett. 2002, 43, 7337.
(12) Smith, A. B.; Hale, K. J. Tetrahedron Lett. 1989, 30, 1037.
J. Org. Chem, Vol. 73, No. 6, 2008 2043

Hayes et al.
TABLE 1. Optimization of the Alkylidene Carbene 1,5-CH
Insertion Reaction for the Production of the 3-Pyrroline 22
entry
solvent
T (°C)
% yield of 22
% yield of 23
1
2
3
Et2O
THF
THF
23
23
-30
54
68
83
26
24
13
FIGURE 2. X-ray structure of 3-pyrrolinone 26.
SCHEME 6. Jao and Bogen’s Epoxidation of the
Electron-Deficient Alkene of 27
SCHEME 5. Oxidation of 3-Pyrroline 22 to 3-Pyrrolinone
26
SCHEME 7. Failed Epoxidation Attempt on Pyrrolinones
With a convenient route to vinyl bromide 19 in hand, it was
possible to investigate the key alkylidene carbene 1,5-CH
insertion reaction in some detail. The KHMDS-mediated17
R-elimination conditions used in our previous formal synthesis
route (Table 1, entry 1) gave 3-pyrroline 22 and acetylene 23
in 54% and 26% isolated yields respectively. This was already
an improvement on the yields obtained from insertion precursor
12 in our previous route.3l An extensive optimization study was
carried out in order to increase the yield of the desired
3-pyrroline 22 and minimize the formation of the unwanted
alkyne 23, which resulted from a competitive 1,2-alkyl shift of
the alkylidene carbene. A range of alternative solvents were
examined (e.g., DME, toluene, DMF, THF), and it was found
that THF gave the greatest improvement in isolated yield of 22
at room temperature (Table 1, entry 2). The best result, however,
was obtained when the reaction was conducted in THF at -30
°C, giving 22 in 83% isolated yield and 23 in a much reduced
13% yield. This considerable improvement in the yield of 22
meant that we could routinely access enough material with
which to complete the syntheses of 1 and 2.
be treated with sodium borohydride during the workup to
provide the desired 3-pyrrolin-2-one 26 in 93% yield over the
two steps. The relative stereochemistry of 26 was determined
by X-ray crystallography (Figure 2), and as the absolute
stereochemistry could be traced back from the X-ray structure
of imine 18, we could show that the 1,5-CH insertion had taken
place with retention of stereochemistry as expected.
A number of methods appeared available for installing the
C-6 alcohol, and the first to be examined was epoxidation
followed by reductive epoxide opening. Precedent for this
sequence was provided by Jao and Bogen, who had shown
previously that the hydroxylactams 29 and 30 could be accessed
from the pyrrolinone 27 using this approach (Scheme 6).18
Unfortunately, however, the pyrrolinone 26, and its protected
versions 31 and 32, failed to epoxidize under their conditions
(tBuOOH/Triton B, THF) and only recovered starting material
was observed (Scheme 7). Further epoxidation reactions with
t
m-CPBA,19 DMDO, and BuOOLi20 were also attempted, but
once again no epoxidation was observed.
Having successfully developed a reliable route to the key
3-pyrroline 22, our next task was to access the required
3-pyrrolinone (e.g., 3, Scheme 1). Pleasingly, this could be
achieved using our previously described procedure,6 which
involved conversion of 22 to the cyclic imine 24 using catalytic
TPAP/NMO (100%) followed by treatment of 24 with a buffered
solution of sodium chlorite (Scheme 5).
Undeterred by the resistance of 26 to epoxidation, we were
hopeful that dihydroxylation would be possible. Initially, 26 was
exposed to the Upjohn conditions,21 but this only resulted in a
low conversion and a poor isolated yield of the desired diol 35.
During a search for more forcing conditions, we were struck
by the recent work of the Sharpless group on the dihydroxylation
As we had observed in our earlier studies, the major product
from the sodium chlorite oxidation was the N-chlorolactam 25
but this did not present any problems as the crude material could
(18) Jao, E.; Bogen, S.; Saksena, A. K.; Girijavallabhan, V. Synthesis
2003, 2643.
(19) Camps, F.; Coll, J.; Messeguer, A.; Pujol, F. J. Org. Chem. 1982,
47, 5402.
(17) (a) Taber, D. F.; Christos, T. E.; Neubert, T. D.; Batra, D. J. Org.
Chem. 1999, 64, 9673.(b) Auty, J. M. A.; Churcher, I.; Hayes, C. J. Synlett
2004, 1443.
(20) Meth-Cohn, O.; Chen, Y. Tetrahedron Lett. 1999, 40, 6069.
(21) Vanrheenen, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
1973.
2044 J. Org. Chem., Vol. 73, No. 6, 2008

Syntheses of Omuralide, 7-epi-Omuralide, and (+)-Lactacystin
SCHEME 8. Formal Synthesis of (+)-Lactacystin via
Dihydroxylation and Deoxygenation of 26
SCHEME 9. Proposed Selective Oxidation of 38 and Partial
Deprotection of 34
(NaOMe/MeOH) gave a slightly improved ratio of 1:2 (34/37),
but no further improvements could be made to this equilibration
as both extended reaction times and increased reaction temper-
atures led to the production of the pyrrolinone 26, which
represents the thermodynamic sink of the reaction. In order to
avoid wasting precious material, the two isomers 34 and 37
were separated using reversed-phase HPLC, and the unwanted
isomer 37 was recycled to 26 via based mediated elimination
(NaOMe, MeOH) in quantitative yield. This material was then
used in subsequent rounds of dihydroxylation and deoxygenation
to produce more of the desired isomer 34. Our stereochemical
assignment of 34 was confirmed by removal of the benzylidene
acetal (H2, Pd/C, MeOH) to give the triol 38, which was a
known intermediate in Baldwin’s earlier synthesis of lactacystin.3v
Gratifyingly, our spectroscopic data for 38 were identical to
that reported, and hence, we had completed our second formal
synthesis of (+)-lactacystin. This new route to 38 proceeded in
11 synthetic steps from the known epoxide 13 in 26% overall
yield, and six further steps are required to access (+)-lactacystin
1 (i.e., 17 steps in total). This route is considerably shorter (by
9 steps) than our previous formal synthesis, and it also compared
well with Baldwin’s original route to 38, which was ac-
complished in 14 steps from (R)-glutamic acid.
of difficult substrates, including R,â-unsaturated amides.22
During these studies it was found that performing the Upjohn-
style dihydroxylation in a slightly acidic medium (e.g., citric
acid) gave much improved yields of diols from R,â-unsaturated
amides and we decided to apply these conditions to our
pyrrolinone 26. Under these conditions 26 underwent efficient
dihydroxylation and the diol 35 crystallized from the reaction
mixture as a single diastereoisomer in 88% yield (Scheme 8).
Furthermore, additional diol 35 could be isolated from the
aqueous filtrate giving a combined overall yield of 96%. This
dramatic improvement was a very pleasing result and we were
able to obtain a single-crystal X-ray structure of 35 to confirm
its relative stereochemistry (Figure 3).
As the desired stereochemistry at the C6-hydroxyl had been
obtained during the dihydroxylation reaction, all that was
required to complete functionalization of the lactam was
deoxygenation at C7. This transformation was readily achieved
by first treating 35 with thiocarbonyl diimidazole to produce
the thiocarbonate 36. Treatment of 36 with nBu3SnH and AIBN
in toluene using Baldwin’s procedure3v then gave the deoxy-
genated products 34 and 37 as a 1:3 mixture, respectively, in
95% yield.
Although we were delighted to have completed a synthesis
of the triol 38, we wished to move beyond this point and
complete our own synthesis of (+)-lactacystin. A brief examina-
tion of the known six-step route required to convert 38 into 1
reveals that four of the six steps involve protecting group
manipulations. It was hoped that a selective oxidation of the
primary alcohol 38 to either the aldehyde 39 or the known
carboxylic acid precursor to lactacystin 40 would remove the
need for protecting groups on the secondary alcohols and hence
reduce the number steps required to get to 1 (Scheme 9). A
number of selective oxidations of 38 to 39 were attempted (e.g.,
Dess-Martin periodinane, TEMPO/PhI(OAc)2),23 but these
reactions were unsuccessful due in large part to the highly polar
nature and low organic solubility of 38. The benzylidene acetal-
protected lactams 34 and 37, however, were soluble in a wide
range of organic solvents, with the aromatic ring presumably
playing a major role in the increased solubility. We therefore
decided to explore a selective deprotection strategy for 34 which
would lead to the formation of either the benzyl protected triol
41 by reductive cleavage or the benzoyl protected triol 42 by
oxidative cleavage (Scheme 9).
Attempted epimerization of the trans isomer 37 to the cis
isomer 34 using Baldwin’s previously described procedure
(22) Dupau, P.; Epple, R.; Thomas, A. A.; Pokin, V. V.; Sharpless, K.
B. AdV. Synth. Catal. 2002, 344, 421.
(23) DeMico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli,
G. J. Org. Chem. 1997, 62, 6974.
FIGURE 3. X-ray crystal structure of diol 35.
J. Org. Chem, Vol. 73, No. 6, 2008 2045

Hayes et al.
SCHEME 11. Total Synthesis of 7-epi-Omuralide 49
SCHEME 10. Exploratory Partial Deprotections of
Benzylidene Acetal 26
Common examples of reductive cleavage use a reducing agent
in combination with a Lewis acid, for example, LiAlH4/AlCl3,24
AlH3/AlCl3, NaCNBH3/TiCl4,25 and DIBAL.26 Under these
conditions, benzylidene acetals will usually cleave to reveal a
primary alcohol and a secondary benzyl ether. Our early results
using these reductive conditions on 3-pyrrolin-2-one 26 were
not promising (Scheme 10). No reaction occurred when 26 was
treated with DIBAL (2.5 equiv), and when the number of
equivalents was increased (10 equiv) only reduction to the
3-pyrroline 22 was observed. Based on these preliminary results,
it was felt that the reductive cleavage approach was not
appropriate for lactam 34 and that an alternative oxidative
approach might be more fruitful.
benzoates in the case of bipyridinium chlorochromate/m-CPBA).
During our earlier epoxidation studies on 26, we observed that
DMDO oxidized the benzylidene acetal to give the secondary
benzoate ester 44 as the major new product.38 At the time, this
was an unwanted and unexpected outcome, but if this same
oxidation could be performed on the acetal 34 then it could be
exploited in our new synthesis of (+)-lactacystin 1. In order to
conserve our supply of 34, we decided to perform the initial
exploratory experiments on its C7-epimer 37.
We were pleased to find that upon treatment with an excess
of DMDO (0.06 M, 3 equiv), the benzylidene acetal 37 gave
the corresponding secondary benzoate ester 45 as the only
isolable product (Scheme 11). Presumably, this reaction involves
oxidative CH-insertion into the benzylidene acetal methine to
produce a hemi-orthoester intermediate, which then collapses
to afford the benzoate ester and the primary hydroxyl in a
subsequent step. The origin of the high degree of selectivity
for the formation of the secondary, rather than the primary,
benzoate ester is not yet clear, and further work in our laboratory
is being directed to understanding the course of this reaction.
The selective oxidation of 45 with Dess-Martin periodinane
was successful, and aldehyde 46 was isolated in good yield.
Although the aldehyde was often clean enough to take onto the
next step, it was better to carry out column chromatography
prior to the next reaction as the subsequent products required
little or no chromatography and it was best to remove minor
impurities at this stage. Aldehyde 46 was cleanly converted into
the acid 47 in 81% yield by the use of sodium chlorite under
buffered conditions. Treatment of the acid 47 with a dilute
solution of sodium methoxide in methanol (0.1 M) for 3 days
gave the dihydroxy acid 48 in good yield. Using the procedure
developed by Corey, the acid 48 was finally converted into
7-epi-omuralide 49.39
There are numerous methods for performing oxidative
cleavage of benzylidene acetals. These include NBS,27 ozone,28
tBuOOH with Pd(II),29 Cu(II),30 PDC,31 or hypervalent iodine
species,32 KMnO4 and phase transfer catalyst,33 Oxone,34
bipyridinium chlorochromate/m-CPBA,35 NaBrO3/Na2S2O4,36
and O2/Co(II).37 Unfortunately, none of these methods are
particularly well suited to our needs as they either produce
unwanted functionality (i.e., alkyl bromides when NBS is used)
or the wrong regiochemistry (i.e., production of primary
(24) Eliel, E. L.; Badding, V. G.; Rerick, M. N. J. Am. Chem. Soc. 1962,
84, 2371; Eliel, E. L.; Pilato, L. A.; Badding, V. G. J. Am. Chem. Soc.
1962, 84, 2377.
(25) Adam, G.; Seebach, D. Synthesis 1988, 373.
(26) Takano, S.; Akiyama, M.; Sato, S.; Ogasawara, K. Chem. Lett. 1983,
1593.
(27) (a) Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1035. (b)
Hanessian, S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1045. (c) Hanessian,
S.; Plessas, N. R. J. Org. Chem. 1969, 34, 1053. (d) Hullar, T. L.; Siskin,
S. B. J. Org. Chem. 1970, 35, 225. (e) Binkley, R. W.; Goewey, G. S.;
Johnston, J. C. J. Org. Chem. 1984, 49, 992.
(28) (a) Deslongchamps, P.; Moreau, C.; Frehel, D.; Chenevert, R. Can.
J. Chem. 1975, 53, 1204. (b) Deslongchamps, P.; Moreau, C. Can. J. Chem.
1971, 49, 2465 and references therein.
(29) Hosokawa, T.; Imada, Y.; Murahashi, S. I. J. Chem. Soc., Chem.
Commun. 1983, 1245.
(30) Sato, K.; Igarashi, T.; Yanagisawa, Y.; Kawauchi, N.; Hashimoto,
H.; Yoshimura, J. Chem. Lett. 1988, 1699.
(31) Chidambaram, N.; Bhat, S.; Chandrasekaran, S. J. Org. Chem. 1992,
57, 5013.
(32) Sueda, T.; Fukuda, S.; Ochiai, M. Org. Lett. 2001, 3, 2387.
(33) Huang, N. J.; Xu, L. H. Synth. Commun. 1990, 20, 1563.
(34) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Synlett 1999,
777.
Having successfully developed a synthesis of 7-epi-omuralide
49 from the benzylidene acetal 37, attention was turned to
repeating the same chemical steps on acetal 34 in order to
complete total syntheses of omuralide 2 and (+)-lactacystin 1.
(35) Luzzio, F. A.; Bobb, R. A. Tetrahedron Lett. 1997, 38, 1733.
(36) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A. Tetrahedron
Lett. 1999, 40, 8439.
(37) (a) Chen, Y. S.; Wang, P. G. Tetrahedron Lett. 2001, 42, 4955.
(b) Karimi, B.; Rajabi, J. Synthesis 2003, 2373.
(38) This transformation has been reported previously: Akbalina, Z. F.;
Zlotskii, S. S.; Kabal’nova, N. N.; Grigor’ev, I. A.; Kotlyar, S. A.;
Shereshovets, V. V. Russ. J. Appl. Chem. 2002, 75, 1120.
(39) Reddy, L. R.; Saravan, P.; Fournier, J.-F.; Reddy, S. V.; Corey, E.
J. Org. Lett. 2005, 7, 2703.
2046 J. Org. Chem., Vol. 73, No. 6, 2008

Syntheses of Omuralide, 7-epi-Omuralide, and (+)-Lactacystin
SCHEME 12. Total Synthesis of Omuralide 2 Using
First-Generation Endgame
SCHEME 13. Model Study for Revised C6-Protection/
Oxidation Endgame
SCHEME 14. Completion of the Total Synthesis of
(+)-Lactacystin 1
These studies began well, with the acetal 34 being cleanly
oxidized to the secondary benzoate 42 using DMDO. Unfor-
tunately, however, treatment of 42 with Dess-Martin periodi-
nane only afforded a low yield (35%) of the corresponding
aldehyde. Furthermore, the aldehyde was formed as an insepa-
rable 2:1 mixture of diastereoisomers 50 and 51. The unwanted
C6-epimer 51 most likely forms via a retroaldol/aldol sequence
(via 52 or equivalent charged species). As it was particularly
difficult to purify this mixture of aldehydes by column chro-
matography, the 2:1 mixture was oxidized with buffered sodium
chlorite to give the acids 53 and 54 in excellent yield (95%) in
the same 2:1 ratio of R/â C6-epimers. The resulting mixture of
acids was treated with sodium methoxide for several days to
give dihydroxy acid 40 (2:1 ratio of C6-epimers). Pleasingly,
the 1H NMR and 13C NMR spectra of the major epimer matched
that previously reported for the dihydroxy acid 40.3s The 2:1
mixture of C6-epimers was then treated with BOPCl under
Corey’s conditions, and the major R-C6-epimer cyclized to
afford omuralide 2 (45%) (Scheme 12). The minor â-C6-epimer
of 40 is unable to form a â-lactone structure as its C6-hydroxyl
and C5-carboxylic acid are in a trans arrangement, and this
material could be separated at this stage.
Having achieved our first objective of synthesizing omuralide
2, we were very keen to go one step further and complete a
total synthesis of (+)-lactacystin 1. In order to provide material
for this task, a more efficient endgame from 34 had to be sought.
We reasoned that protection of the C6-secondary alcohol would
both increase the yield of the Dess-Martin oxidation of 42 and
also prevent the unwanted retroaldol reaction of 50. An acetate
protecting group was chosen as it could be introduced with ease,
and more importantly, it could be removed under the same
conditions that were already going to be used to remove the
benzoate later in the synthesis. This protection adds one extra
step to the synthesis, but the potential increase in overall yield
should provide adequate compensation for this effort.
acetate 55 in reasonable yield and gratifyingly the DMDO-
mediated acetal cleavage proceed smoothly to give alcohol 56
in excellent yield. Sequential oxidation with Dess-Martin
periodinane (81%) and then sodium chlorite gave the desired
acid 57 (77%) in good overall yield.
Having gained confidence in the revised protecting group
strategy, 34 was acetylated to give 58, and DMDO oxidation
of this material proceeded cleanly to give the primary alcohol
59 in excellent yield (88%). Sequential Dess-Martin periodi-
nane and sodium chlorite oxidations then gave the desired
carboxylic acid 60 in excellent yield and purity. Hydrolysis of
60 (0.2 M NaOH, 2 days) then gave the known dihydroxy acid
40 as a single diastereoisomer, and gratifyingly, the spectro-
scopic data matched that previously reported.3s Treatment of
40 with BOPCl then gave omuralide 2 (55%), and opening of
this â-lactone with N-acetyl-L-cysteine 61 according to Corey’s
procedure finally gave (+)-lactacystin 1 in 47% yield (Scheme
14).
In conclusion, we have successfully completed an enantiose-
lective total synthesis of (+)-lactacystin 1 in 16 steps using an
alkylidene carbene 1,5-CH insertion reaction to install the key
quaternary stereogenic center in high yield. Our route can readily
be adapted to provide analogues of lactacystin and omuralide
that have different sidechains at C7 and C5. We are currently
examining synthetic approaches to the salinosporamide family
of related natural products, and progress in this area will be
published in due course. During our synthesis, we have also
The lactam 37 was once again selected as a model system
with which to test the reaction conditions (Scheme 13). Thus,
exposure of 37 to Ac2O, DMAP, and Et3N in DCM gave the
J. Org. Chem, Vol. 73, No. 6, 2008 2047

Hayes et al.
for C17H22BrNO2: C, 57.96; H, 6.29; N, 3.98. Found: C, 57.96;
H, 6.29; N, 3.99.
shown that a regioselective DMDO-mediated oxidative cleavage
of a benzylidene acetal can be used to provide differentially
protected diol products. This transformation warrants further
study, and we hope to develop it into a general synthetic tool.
(5R,6S,8R)-6-Isopropyl-3-methyl-8-phenyl-7,9-dioxa-1-azaspiro-
[4.5]dec-3-ene (22) and But-2-ynyl(2R,4S,5R)-4-isopropyl-2-
phenyl-[1,3]-dioxan-5-yl)amine (23). KHMDS (0.5 M in toluene,
57.0 mL, 28.5 mmol) was added dropwise over 30 min to a stirring
solution of vinyl bromide 19 (5.00 g, 14.2 mmol) in THF (80 mL)
at -30 °C. The red solution was allowed to reach room temperature
over 6 h and then quenched with a saturated aqueous solution of
Na2CO3 (100 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (3 × 150 mL). The combined organic
layers were washed with brine (200 mL), dried over Na2SO4, and
concentrated in vacuo to give a yellow oil. The crude material was
purified by column chromatography using a pentane and EtOAc
(6:1) with 1% Et3N to give acetylene 23 (0.51 g, 13%) as a colorless
oil, and the polarity was increased to pentane and EtOAc (2:1) to
give 3-pyrroline 22 (3.20 g, 83%) as a colorless oil: 3-Pyrroline
Experimental Section
((E)-3-Bromo-2-methylallyl)-((2R,4R,5R)-4-isopropyl-2-phen-
yl-[1,3]-dioxan-5-yl)amine (19). A solution of alcohol 17 (3.79 g,
24.9 mmol) in DCM (100 mL) was added via cannula to a stirring
supension of MnO2 (22.0 g, 247 mmol) and powdered activated 3
Å molecular sieves (5.0 g) in DCM (50 mL) at room temperature
under Ar. This was followed by addition of a solution of amine 16
(6.0 g, 27 mmol) in DCM (100 mL) via cannula. The reaction
mixture was heated to reflux for 50 h and then cooled to 0 °C.
Sodium cyanoborohydride (4.71 g 74.9 mmol) in MeOH (50 mL)
was added via cannula over 30 min at 0 °C and then allowed to
reach room temperature, upon which acetic acid (1.50 mL, 24.7
mmol) was added. The mixture was stirred for 6 h and was then
filtered through Celite. The filtrate was concentrated in vacuo to
give a yellow solid. The solid was partitioned between Et2O (200
mL) and a saturated aqueous solution of Na2CO3 (100 mL). The
layers were separated, and the aqueous layer was extracted with
Et2O (2 × 200 mL). The combined organic layers were washed
with brine (200 mL), dried over Na2SO4, and concentrated in vacuo
to give a yellow solid. The crude material was purified by column
chromatography using petroleum ether/Et2O (2:1) to give Vinyl
bromide 19 (6.57 g, 18.6 mmol, 75%) as colorless crystals. A small
portion was further purified by recrystallization from petroleum
ether for analysis: mp 55-56 °C (petroleum ether); [R]26D -56.0
(c 0.51 in CHCl3); νmax/cm-1 (CHCl3) 2964, 1099; δH (400 MHz;
CDCl3) 7.51-7.48 (2H, m), 7.40-7. 34 (3H, m), 6.17 (1H, J 1.2),
5.46 (1H, s), 4.37 (1H, dd, J 10.6 and 4.8), 3.44 (1H, app t, J 10.6),
3.36 (1H, dd, J 9.6 and 2.0), 3.32 (1H, d, J 13.8), 3.26 (1H, d, J
13.8), 2.80 (1H, app td, J 10.0 and 4.8), 2.19 (1H, qqd, J 7.0, 6.9
and 2.0), 1.84 (3H, d, J 1.2), 1.09 (3H, d, J 7.0), 1.00 (3H, d, J
6.9); δC (100 MHz; CDCl3) 140.6 (C) 138.7 (C), 128.8 (CH), 128.3
(CH), 126.2 (CH), 104.2 (CH), 101.0 (CH), 85.7 (CH), 71.5 (CH2),
53.8 (CH2), 51.1 (CH), 28.0 (CH), 20.2 (CH3), 17.9 (CH3), 15.5
(CH3); m/z (CI, NH3) 356 (M + H+, 60), 354 (M + H+, 61), 248
(M + H+ - PhCHO, 13); C17H2581BrNO2 requires 356.1048, found
356.1044; C17H2579BrNO2 requires 354.1069, found 354.1062. Anal.
Calcd for C17H24BrNO2: C, 57.63; H, 6.83; N, 3.95. Found: C,
57.60; H, 6.84; N, 3.96.
22: [R]26 -8.47 (c 0.938 in CHCl3); νmax/cm-1 (CHCl3) 2960,
D
2840, 1666, 1382, 1096; δH (400 MHz; CDCl3) 7.5 -7.51 (2H,
m), 7.41-7.32 (3H, m), 5.82 (1H, m), 5.53 (1H, s), 3.90 (1H, d, J
10.4), 3.73 (1H, dq, J 15.1 and 1.0), 3.67 (1H, dq, J 15.1 and 1.0),
3.65 (1H, d, J 10.4), 3.39 (1H, d, J 4.4), 1.95 (1H, qqd, J 6.9, 6.8
and 4.4), 1.77 (3H, m), 1.45 (1H, br, s), 1.06 (3H, d, J 6.9), 1.01
(3H, d, J 6.7); δC (100 MHz; CDCl3) 138.9 (C), 137.2 (C), 128.7
(C), 128.3 (CH), 126.2 (CH), 125.4 (CH), 101.4 (CH), 89.2 (CH),
78.1 (CH2), 68.8 (C), 56.9 (CH2), 29.1 (CH), 22.0 (CH3), 18.5
(CH3), 14.3 (CH3); m/z (ES, +ve) 274 (M + H+, 100), 168 (M +
H+ - PhCHO, 80); C17H25NO2 requires 274.1807, found 274.1805.
Anal. Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found:
C, 74.51; H, 8.50; N, 4.82. Acetylene 23: [R]26D -56.3 (c 1.05 in
CHCl3); νmax/cm-1 (CHCl3) 2965, 2923, 2877, 1679, 1306, 1099;
δH (400 MHz; CDCl3) 7.53-7.50 (2H, m), 7.40-7.32 (3H, m),
5.47 (1H, s), 4.45 (1H, dd, J 10.7 and 4.8), 3.39 (1H, dd, J 10.7
and 10.0), 3.46 - 3.35 (3H, m), 3.05 (1H, app td, J 10.0 and 4.8),
2.18 (1H, qqd, J 6.9, 6.8 and 2.0), 1.83 (3H, s), 1.10 (3H, d, J 6.9),
1.05 (3H, d, J 6.8); δC (100 MHz; CDCl3) 138.7 (C), 128.7 (CH),
128.2 (CH), 126.1 (CH), 100.9 (CH), 85.3 (CH), 79.5 (C), 71.0
(CH2), 50.7 (CH), 36.8 (CH2), 27.8 (CH), 20.1 (CH3), 15.2 (CH3),
3.5 (CH3); m/z (ES, +ve) 274 (M + H+, 16), 168 (M + H+
-
PhCHO, 100); C17H25NO2 requires 274.1807, found 274.1821. Anal.
Calcd for C17H23NO2: C, 74.69; H, 8.48; N, 5.12. Found: C, 74.67;
H, 8.53; N, 5.09.
(5R,6S,8R)-6-Isopropyl-3-methyl-8-phenyl-7,9-dioxa-1-azaspiro-
[4.5]dec-3-en-2-one (26). A suspension of 3-pyrroline 22 (1.33 g,
4.87 mmol), TPAP (85.6 mg, 0.243 mmol), NMO (2.11 g, 18.0
mmol), and powdered 4 Å molecular sieves (625 mg) in MeCN
(16 mL) was stirred at room temperature for 4 h. The suspension
was filtered through Celite and then silica and eluted with EtOAc
to give imine 24 (1.32 g, 100%) as a black oil: [R]21D +4.1 (c 1.0
in MeOH); νmax/cm-1 (CHCl3) 2865, 1351, 1082, 975; δH (400
MHz; CDCl3) 7.99 (1H, s), 7.59-7.55 (2H, m), 7.47 (1H, s), 7.47-
7.35 (3H, m), 5.72 (1H, s), 4,48 (1H, d, J 10.5), 4.28 (1H, d, J
4.9), 3.28 (1H, d, J 10.5), 2.05 (3H, s), 1.48-1.37 (1H, qqd, J 6.8,
6.7 and 4.9), 0.86 (3H, d, J 6.7), 0.81 (3H, d, J 6.8); δC (400 MHz;
CDCl3) 169.4 (C), 150.8 (CH), 138.4 (C), 137.8 (C), 128.9 (CH),
128.3 (CH), 126.2 (CH), 102.0 (CH), 86.4 (CH), 84.0 (C), 74.2
(CH2), 29.7 (CH), 21.1 (CH3), 19.2 (CH3), 12.1 (CH3). A solution
of sodium chlorite (1.38 g, 12.3 mmol) and sodium dihydrogen
orthophosphate hydrate (1.53 g, 9.80 mmol) in water (12 mL) was
added dropwise to a stirring solution of imine 24 (1.32 g, 4.87
mmol) in tert-butyl alcohol (12 mL) and 2-methyl-2-butene (10
mL) at 0 °C. The solution was stirred for 18 h and then concentrated
in vacuo. The product was partitioned between water (50 mL) and
Et2O (50 mL). The layers were separated, and the aqueous layer
was extracted with Et2O (2 × 50 mL). The combined layers were
washed with brine (50 mL), dried over MgSO4, and concentrated
in vacuo to give a colorless solid. The crude material was dissolved
in MeOH (48 mL), and sodium borohydride (370 mg, 9.80 mmol)
was added slowly. The solution was stirred for 1 h and then
[(E)-3-Bromo-2-methylprop-2-en-(E)-ylidene]-(2R,4S,5R)-4-
isopropyl-2-phenyl-[1,3]-dioxan-5-yl)amine (18). A solution of
amine 16 (500 mg, 2.26 mmol) in DCM (10 mL) was added via
cannula to a stirring suspension of MnO2 (1.96 g, 22.5 mmol) and
3 Å molecular sieves (300 mg) in DCM (30 mL) at room
temperature under Ar, followed by a solution of alcohol 17 (330
mg, 2.2 mmol) in DCM (10 mL). The reaction mixture was heated
to reflux for 18 h and then cooled to room temperature, filtered
through Celite, and washed with DCM (50 mL). The organic
solvents were removed in vacuo to give a pale yellow solid. The
crude material was recrystallized from petroleum ether to give imine
18 (0.43 g, 56%) as a colorless crystalline solid, from which an
X-ray crystal structure was obtained (see Figure 1): mp 79-80
°C (petroleum ether); [R]30 -79.3 (c 0.91 in CHCl3); νmax/cm-1
D
(CHCl3) 2965, 1627 (CdN); δH (400 MHz; CDCl3) 7.96 (1H, s),
7.54 - 7.52 (2H, m), 7.41 - 7.33 (3H, m), 6.80 (1H, d, J 1.2),
5.60 (1H, s), 3.96 (1H, d, J 6.3), 3.95 (1H, d, J 9.1), 3.88 (1H, dd,
J 9.4 and 2.5), 3.46 (1H, app td, J 9.1 and 6.5), 2.00 (3H, d, J 1.2)
1.77 (1H, app septd, J 6.9 and 2.5), 1.05 (3H, d, J 6.9), 0.93 (3H,
d, J 6.9); δC (100 MHz; CDCl3) 162.9 (CH), 142.1 (C), 138.7 (C),
128.9 (CH), 128.3 (CH), 126.2 (CH), 120.5 (CH), 101.1 (CH), 84.3
(CH), 71.0 (CH2), 65.4 (CH), 28.8 (CH), 19.9 (CH3), 15.4 (CH3),
14.7 (CH3); m/z (CI) 352 (M + H+, 51), 354 (M + H+, 44);
C17H2379BrNO2 requires 352.0912, found 352.0901. Anal. Calcd
2048 J. Org. Chem., Vol. 73, No. 6, 2008

Syntheses of Omuralide, 7-epi-Omuralide, and (+)-Lactacystin
concentrated in vacuo to give a colorless solid. The product was
partitioned between water (50 mL) and Et2O (50 mL), the layers
were separated, and the aqueous layer was extracted with Et2O (2
× 50 mL). The combined layers were dried over MgSO4 and
concentrated in vacuo to give a colorless solid. The crude material
was purified by column chromatography using petroleum ether and
EtOAc (1:1) to give 3-pyrrolinone 26 (1.31 g, 93%) as a colorless
crystalline solid. The solid was recrystallized from EtOH, and an
X-ray crystal structure was obtained (see Figure 2): mp 157-159
4-Hydroxy-6-isopropyl-3-methyl-8-phenyl-7,9-dioxa-1-azaspiro-
[4.5]decan-2-one (34). A degassed solution of AIBN (57 mg, 0.37
mmol) in toluene (50 mL) was added in two portions over 2 h to
a degassed solution of thiocarbonate 36 (1.05 g, 2.89 mmol) and
nBu3SnH (1.3 mL, 5.78 mmol) in toluene (90 mL). The solution
was reluxed for 16 h and cooled to room temperature. The colorless
solution was treated with a 10% aqueous solution of KF (30 mL)
and a saturated aqueous solution of NaHCO3 (30 mL). The layers
were separated, and the extraction was repeated. The combined
aqueous layers was extracted with EtOAc (3 × 150 mL). The
combined organic layers were washed with brine (50 mL), dried
over MgSO4, and concentrated in vacuo to give a colorless oil.
The crude material was purified by column chromatography using
petroleum ether and EtOAc (1:1) to give a lactams 34 and 37 (839
mg, 95%) as a mixture of isomers (cis/trans, 1:3.6). The epimers
were separated by reversed-phase HPLC using MeOH and water
(65:35) to give trans-lactam 37 and cis-lactam 34 as colorless solids.
trans-Lactam 37: mp 63-66 °C (DCM); [R]D27 -57.2 (c 0.870 in
CHCl3); νmax/cm-1 (CHCl3) 3564, 3484, 2966, 1704 (CdO), 1101;
δH (500 MHz; CDCl3) 7.48-7.45 (2H, m), 7.42-7.37 (3H, m),
7.35 (1H, br, s), 4.46 (1H, d, J 11.4), 4.40 (1H, d, J 7.3), 3.71 (1H,
d, J 11.4), 3.53 (1H, d, J 8.3), 3.09 (1H, br, s), 2.66 (1H, app quin
J 7.3), 2.08 (1H, dqq, J 8.3, 6.8 and 6.6), 1.34 (3H, d, J 7.3), 1.13
(3H, d, J 6.6), 0.95 (3H, d, J 6.8); δc (126 MHz; CDCl3) 177.7
(C), 137.4 (C), 129.3 (CH, ArH), 128.5 (CH), 126.0 (CH), 101.5
(CH), 87.1 (CH), 76.0 (CH), 71.6 (CH2), 57.3 (C), 44.1 (CH), 29.0
(CH), 20.8 (CH3), 20.3 (CH3), 13.7 (CH3); m/z (ES, +ve) 328 (M
+ Na+, 26), 306 (M + H+, 100); C17H24NO4 requires 306.1705,
found 306.1710). cis-Lactam 34: [R]30D -37.6 (c 0.585 in CHCl3);
°C (EtOH); [R]25 -30.2 (c 1.00 in CHCl3); νmax/cm-1 (CHCl3)
D
2966, 1649 (CdO), 1099; δH (400 MHz; CDCl3) 7.86 (1H, br, s),
7.54-7.51 (2H, m), 7.43-7.51 (3H, m), 7.26 (1H, s), 5.61 (1H,
s), 4.09 (1H, d, J 10.9), 3.81 (1H, d, J 5.6), 3.79 (1H, d, J 10.9),
1.93 (3H, s), 1.80-1.68 (1H, qqd, J 6.8, 6.7 and 5.6), 0.94 (3H, d,
J 6.7), 0.93 (3H, d, J 6.8); δC (400 MHz; CDCl3) 174.7 (C), 144.5
(C), 137.8 (C), 134.7 (C), 129.1 (CH), 128.3 (CH), 126.1 (CH),
101.7 (CH), 86.3 (CH), 74.3 (CH2), 61.3 (C), 28.9 (CH), 21.2 (CH3),
19.0 (CH3), 10.9 (CH3); m/z (ES, +ve) 288 (M + H+, 100); C17H22-
NO3 requires 288.1600, found 288.1591. Anal. Calcd for C17H21-
NO3: C, 71.06; H, 7.37; N, 4.87. Found: C, 70.85; H, 7.23; N,
5.01.
(3R,4R,5S,6S,8R)-3,4-Dihydroxy-6-isopropyl-3-methyl-8-phenyl-
7,9-dioxa-1-azaspiro[4.5]decan-2-one (35). Citric acid (597 mg,
2.84 mmol), potassium osmate dihydrate (103 mg, 0.280 mmol),
and NMO (367 mg, 3.12 mmol) were added successively to a
suspension of 3-pyrrolinone 26 (816 mg, 2.84 mmol) in tert-butyl
alcohol (2.8 mL) and water (2.8 mL) at room temperature. The
resulting olive green solution was stirred for 48 h. The product
precipitated out of solution and was filtered and washed with water
(50 mL) to give pure diol 35 (523 mg) as a colorless powder. The
filtrate was treated with solid sodium sulfite and extracted with
EtOAc (3 × 100 mL). The combined organic layers were washed
with brine (50 mL), dried over MgSO4, and concentrated in vacuo
to give diol (110 mg) as a single diastereoisomer. The products
were combined to give diol 35 (878 mg, 96%) as a colorless powder.
A small sample was recrystallized from EtOH, and an X-ray crystal
structure was obtained (see Figure 3): mp 228-230 °C (tBuOH/
ν
max/cm-1 (CHCl3) 3590, 3418, 2964, 1705 (CdO), 1097; δH (500
MHz; CDCl3) 7.49-7.47 (2H, m), 7.42-7.37 (3H, m), 6.23 (1H,
br, s), 5.56 (1H, s), 4.72 (1H, d, J 7.6), 4.45 (1H, d, J 11.0), 3.67
(1H, d, J 11.0), 3.47 (1H, d, J 7.9), 2.72 (1H, dq, J 7.6 and 7.5),
2.46 (1H, br, s), 1.95 (1H, dqq, J 7.9, 6.6 and 6.6), 1.27 (3H, d, J
7.5), 1.07 (3H, d, J 6.6), 1.01 (3H, d, J 6.6); δc (126 MHz; CDCl3)
179.1 (C), 137.6 (C), 129.3 (CH), 128.5 (CH), 126.0 (CH), 101.7
(CH), 87.9 (CH), 71.9 (CH2), 69.5 (CH), 60.6 (C), 41.7 (CH), 29.0
(CH), 21.8 (CH3), 20.0 (CH3), 9.1 (CH3); m/z (ES, +ve) 328 (M
+ Na+, 75), 306 (M + H+, 100); C17H24NO4 requires 306.1705,
found 306.1720. Anal. Calcd for C17H23NO4: C, 66.86; H, 7.59;
N, 4.59. Found: C, 66.70; H, 7.66; N, 4.49.
H2O); [R]23 -32.0 (c 0.513 in MeOH); νmax/cm-1(solid) 3428,
D
3306, 1703 (CdO); δH (400 MHz; CD3OD) 7.51-7.49 (2H, m),
7.38-7.33 (3H, m), 5.53 (1H, s), 4.64 (1H, d, J 11.5), 4.24 (1H,
s), 3.66 (1H, d, J 11.5), 3.53 (1H, d, J 8.0), 2.10-2.03 (1H, dqq,
J 8.0, 6.8 and 6.5), 1.36 (3H, s), 1.11 (3H, d, J 6.5), 0.96 (3H, d,
J 6.8); δC (400 MHz; CD3OD) 177.3 (C), 139.7 (C), 129.8 (CH),
129.0 (CH), 127.4 (CH), 102.7 (CH), 87.4 (CH), 74.9 (C), 74.4
(CH), 72.7 (CH2), 57.9 (C), 30.2 (CH), 22.4 (CH3), 21.0 (CH3),
20.7 (CH3); m/z (ES, +ve) 322 (M + H+,100); C17H24NO5 requires
322.1654, found 322.1657. Anal. Calcd for C17H23NO5: C, 63.54;
H, 7.21; N, 4.36. Found: C, 63.22; H, 7.46; N, 4.12.
(3R,4S,5R,1′S)-4-Hydroxy-5-hydroxymethyl-5-(1′-hydroxy-2-
methylpropyl)-3-methylpyrrolidin-2-one (38).3v A suspension of
lactam 34 (2.3 mg, 7.5 µmol), Pd (10% on C, 2.9 mg), and
concentrated HCl (15 µL) in MeOH (1.2 mL) was stirred under a
H2 atmosphere at room temperature for 17 h. Solid NaHCO3 (31
mg) was added, and the suspension was filtered through a pad of
Celite and washed with MeOH (50 mL). The filtrate was concen-
trated in vacuo to give a colorless solid. The crude material was
purified by column chromatography using CHCl3 and MeOH (4:
(3R,4R,5S,6S,8R)-6-Isopropyl-3-methyl-8-phenyl-7,9,11,13-tet-
raoxa-12-thiocarbonyl-1-azaspiro[4.5]decan-2-one (36). A yellow
solution of diol 35 (587 mg, 1.83 mmol) and thiocarbonyl
diimidazole (814 mg, 2.74 mmol) in THF (9 mL) was heated to
reflux for 6 h. The solution was cooled to room temperature and
concentrated in vacuo to give a brown oil. The residue was purified
by column chromatography using petroleum ether and EtOAc (1:
2) to give thiocarbonate 36 (637 mg, 96%) as a colorless foam:
mp 176-179 °C; [R]28D +60.6 (c 0.500 in CHCl3); νmax/cm-1 3404,
3198, 2968, 1726 (CdO), 1314 (CdS); δH (400 MHz; CDCl3) 7.85
(1H, br, s), 7.52-7.48 (2H, m), 7.42-7.38 (3H, m), 5.60 (1H, s),
5.30 (1H, s), 4.26 (1H, d, J 11.5), 3.80 (1H, d, J 11.5), 3.59 (1H,
d, J 8.4), 1.79 (3H, s), 1.76-1.69 (1H, dqq, J 8.4, 6.6 and 6.5),
1.10 (3H, d, J 6.5), 0.99 (3H, d, J 6.6); δc (100 MHz; CDCl3) 188.5
(C), 170.2 (C), 137.0 (C), 129.4 (CH), 128.4 (CH), 126.2 (CH),
102.0 (CH), 88.7 (C), 86.5 (CH), 85.1 (CH), 70.7 (CH2), 60.1 (C),
28.7 (CH), 21.6 (CH3), 19.9 (CH3), 18.3 (CH3); m/z (ES, +ve) 386
(M + Na+, 100), 364 (M + H+, 42); C18H22NO5S requires
364.1219, found 364.1223.
1) to give triol 38 (1.3 mg, 79%): [R]22 -9.7 (c 1.0 in MeOH)
D
(lit.3v [R]22D -9.7 (c 1.0 in MeOH)); νmax/cm-1 (film) 3358, 2962,
1673 (CdO); δH (270 MHz; CD3OD) 4.40 (1H, d, J 7.6), 3.78
(2H, s), 3.51 (1H, d, J 3.4), 2.81 (1H, app quin, J 7.6), 2.01-1.90
(1H, qqd, J 6.9, 6.7 and 3.4), 1.10 (3H, d, J 7.6), 1.03 (3H, d, J
6.9), 0.95 (3H, d, J 6.7); δC (67 MHz; CD3OD) 181.7 (C), 79.0
(CH), 74.4 (CH), 70.0 (C), 68.3 (CH2), 42.7 (CH), 30.6 (CH), 22.7
(CH3), 17.6 (CH3), 9.5 (CH3); m/z (ES, +ve) 218 (M + H+, 100).
The data were identical to that reported by Baldwin.3v
(3S,4S,5R,6S)-6-Isopropyl-3-methyl-2-oxo-8-phenyl-7,9-dioxa-
1-azaspiro[4.5]dec-4-yl Acetate (58). Acetic anhydride (15 µL,
0.16 mmol) was added to a stirring solution of lactam 34 (33.0
mg, 0.108 mmol), DMAP (1.3 mg, 0.010 mmol), and triethylamine
(23 µL, 0.17 mmol) in DCM (1 mL) under Ar at 30 °C. The solution
was stirred for 1 h and then diluted with DCM (2 mL). HCl (2 M,
3 mL) was added, and the layers were separated. The aqueous layer
was extracted with DCM (3 × 3 mL). The organic layers were
combined, washed with a saturated aqueous solution of NaHCO3
(3 mL) and brine (3 mL), dried over MgSO4, and concentrated in
(3S,4R,5S,6S,8R)-4-Hydroxy-6-isopropyl-3-methyl-8-phenyl-
7,9-dioxa-1-azaspiro[4.5]decan-2-one (37) and (3R,4R,5S,6S,8R)-
J. Org. Chem, Vol. 73, No. 6, 2008 2049

Hayes et al.
t
vacuo to give a colorless solid. The crude material was purified by
column chromatography using petroleum ether and EtOAc (1:2)
to give acetate 58 (25.3 mg, 68%) as a colorless foam: mp 60-62
mmol) in BuOH/H2O (1.7 mL, 1:1) at room temperature. The
resulting green solution was stirred for 18 h and then concentrated
to give a colorless solid. The solid material was partitioned
betweenwater (4 mL) and EtOAc (4 mL), and the layers were
separated. The aqueous layer was extracted with EtOAc (3 × 4
mL) and the combined organic layers were washed with brine (4
mL), dried over MgSO4, and concentrated in vacuo to give a
colorless solid. The crude product was purified by column chro-
matography using 20% MeOH in EtOAc to give acid 60 (29.5 mg,
°C (CHCl3); [R]25 +3.8 (c 0.64 in CHCl3); νmax/cm-1 (CHCl3)
D
3420 (N-H), 3210, 2912, 1744 (s) (CdO), 1704 (s) (CdO); δH
(500 MHz; CDCl3) 7.43-7.35 (5H, m), 6.01 (1H, d, J 7.5), 5.46
(1H, s), 4.34 (1H, d, J 11.1), 3.66 (1H, d, J 11.1), 3.42 (1H, d, J
7.6), 2.81 (1H, dq, J 7.5 and 7.4), 1.95 (1H, dqq, J 7.6, 6.6 and
6.5), 1.95 (3H, s), 1.68 (1H, br, s) 1.16 (3H, d, J 7.4), 1.04 (3H, d,
J 6.5), 1.00 (3H, d, J 6.6); δC (126 MHz; CDCl3) 178.6 (C), 169.7
(C), 137.7 (C), 129.2 (CH), 128.4 (CH), 126.5 (CH), 102.6 (CH),
87.6 (CH), 71.2 (CH), 69.9 (CH2), 60.0 (C), 41.1 (CH), 29.0 (CH),
21.7 (CH3), 20.7 (CH3), 19.9 (CH3), 9.3 (CH3); m/z (ES, +ve) 370
(M + Na+, 100), 348 (M + H+, 82); C19H25NNaO5 requires
370.1630, found 370.1631.
General Procedure A: Oxidative Cleavage of Benzylidene
Acetals with DMDO. Benzylidene acetal was treated with a
solution of DMDO (0.06 M in acetone, 3 equiv) and stirred at 0-3
°C for 18 h. The solution was allowed to reach room temperature,
dried over MgSO4, and concentrated in vacuo. The product of the
reaction was clean enough to be taken onto the next step without
further purification unless otherwise stated.
93%) as a colorless solid: mp 223-227 °C (MeOH/EtOAc); [R]21
D
+63.5 (c 0.400 in CHCl3); νmax/cm-1 (CHCl3) 3751, 1743, 1601;
δH (500 MHz; CD3OD) 8.05-8.02 (2H, m), 7.69-7.65 (1H, m),
7.55-7.51 (2H, m), 5.71 (1H, d, J 6.4), 5.62 (1H, d, J 6.4), 2.60
(1H, qd, J 7.4 and 6.4), 2.09 (1H, qqd, J 6.9, 6.7 and 6.4), 1.02
(3H, d, J 6.9), 0.96 (3H, d, J 6.7), 0.88 (3H, d, J 7.4); δC (126
MHz; CD3OD) 179.9 (C), 171.3 (C), 170.8 (C), 166.9 (C), 135.1
(CH), 130.8 (CH), 130.3 (C), 130.1 (CH), 80.9 (CH), 76.1 (CH),
73.8 (C), 41.3 (CH), 31.4 (CH), 20.7 (CH3), 20.4 (CH3), 18.9 (CH3),
9.1 (CH3); m/z (ES, +ve) 400 (M + Na+, 100), 378 (M + H+,
27); C19H24NO7 requires 378.1553, found 378.1546.
(3R,4S,5R)-4-Hydroxy-5-[(1′S)-1′-hydroxy-2′-methylpropyl]-
3-methyl-2-pyrrolidinone-5-carboxylic Acid (40).3q,3s An aqueous
solution of NaOH (0.2 M, 1.0 mL, 0.20 mmol) was added to acid
60 (26.1 mg, 0.689 mmol) at room temperature. The solution was
stirred for 3 days at room temperature and then acidified with 2 M
HCl. The solution was concentrated in vacuo to give a colorless
solid, and the crude material was purified by column chromatog-
raphy using CHCl3/MeOH (1:1) to give dihydroxy acid 40 (9.7
mg, 61%) as a colorless solid: mp 234 °C dec (lit.3y mp 240 °C
dec); [R]24 +20.4 (c 0.265 in MeOH); (lit.3v [R]21 +18.5 (c 1.0
(S)-1-((2R,3S,4R)-3-Actetoxy-2-hydroxymethyl-4-methyl-5-oxo-
pyrrolidin-2-yl)-2-methylpropyl Benzoate (59). Using general
procedure A: Lactam 58 (49.3 mg, 0.142 mmol) and DMDO
solution (8.4 mL, 0.56 mmol) gave alcohol 59. The material was
purified by column chromatography using EtOAc to give alcohol
59 (45.2 mg, 88%) as a colorless foam: mp 56-58 °C; [R]24
D
-16.2 (c 0.520 in CHCl3); νmax/cm-1 (CDCl3) 3603, 3418, 2935,
1711 (s)(CdO); δH (500 MHz; CHCl3) 8.07-8.04 (2H, m), 7.64-
7.60 (1H, m), 7.51-7.47 (2H, m), 6.32 (1H, br, s), 5.80 (1H, d, J
8.2), 5.30 (1H, d, J 5.2), 3.71 (1H, d, J 12.1), 3.67 (1H, d, J 12.1),
2.90 (1H, dq, J 8.2 and 7.6), 2.21 (1H, app septd, J 7.0 and 5.2),
2.01 (3H, s), 1.10 (3H, d, J 7.6), 1.07 (3H, d, J 7.0), 1.06 (3H, d,
J 7.0); δC (126 MHz; CHCl3) 177.3 (C), 167.0 (C), 166.7 (C),
133.9 (CH), 130.1 (CH), 129.1 (C), 128.9 (CH), 77.1 (CH), 72.4
(CH), 66.5 (C), 63.4 (CH2), 39.9 (CH), 29.0 (CH), 22.2 (CH3),
20.5 (CH3), 18.7 (CH3), 10.0 (CH3); m/z (ES, +ve) 386 (M + Na+,
100), 364 (M + H+, 86); C19H26NO6 requires 364.1760, found
364.1761.
D
D
in MeOH)); δH (500 MHz; CD3OD) 4.43 (1H, d, J 5.9), 3.96 (1H,
d, J 6.4), 2.98 (1H, dq, J 7.5 and 5.9), 1.73 (1H, qqd, J 6.8, 6.7
and 6.4), 1.07 (3H, d, J 7.5), 0.97 (3H, d, J 6.7), 0.93 (3H, d, J
6.8); δC (126 MHz; CD3OD) 182.2, 175.0, 79.9, 79.5, 76.8, 42.6,
32.3, 20.9, 18.8, 8.8; m/z (ES, -ve) 230 (M - H, 100). The data
were identical to that reported by Chida.3s
Omuralide (2).3q Using the method described by Corey: BOPCl
(23.9 mg, 94.1 µmol) was added to a stirring suspension of
dihydroxy acid 40 (14.5 mg, 62.7 µmol) and triethylamine (26 µL,
190 µmol) in DCM (0.9 mL) at room temperature. The suspension
was stirred for 30 min, and then water (0.5 mL) was added. The
aqueous layer was extracted with EtOAc (3 × 2 mL). The combined
organic layers were washed with brine (2 mL), dried over MgSO4,
and concentrated in vacuo to give a colorless solid. The crude
material was purified by column chromatography using CHCl3/
MeOH (50:1) to elute BOPCl residues and then EtOAc to give
(2R,3S,4R)-3-Acetoxy-2-((S)-1-benzoyloxy-2-methylpropyl)-
4-methyl-5-oxopyrrolidine-2-carboxylic Acid (60). Dess-Martin
periodinane (73.2 mg, 0.173 mmol) was added to a stirring solution
of alcohol 59 (40.0 mg, 0.110 mmol) in “moist” DCM (0.55 mL,
10 µL of H2O in 10 mL of dry DCM) at room temperature. The
resulting suspension was stirred for 2 h and then diluted with Et2O
(3 mL). A saturated aqueous solution of sodium thiosulfate (1 mL)
and a saturated aqueous solution of NaHCO3 (1 mL) were added,
and the mixture was stirred until both layers had become clear.
The layers were separated, and the aqueous layer was extracted
with Et2O (4 × 3 mL). The combined organic layers were washed
with brine (3 mL), dried over MgSO4, and concentrated in vacuo
to give a colorless oil. The crude material was purified by column
chromatography using petroleum ether/EtOAc (1:1) to give the
omuralide 2 (7.4 mg, 55%): [R]25 -73 (c 0.09 in MeCN) (lit.3q
D
[R]21 -93.9 (c 0.53 in MeCN)); νmax/cm-1(CHCl3) 1840, 1723;
D
δH (500 MHz; C5D5N) 10.4 (1H, br, s), 7.84 (1H, br, s), 5.69 (1H,
d, J 6.1), 4.37 (1H, s), 3.06 (1H, qd, J 7.5 and 6.1), 2.15-2.11
(1H, m), 1.48 (1H, d, J 7.5), 1.14 (1H, d, J 6.9), 1.02 (1H, d, J
6.7); m/z (ES, +ve) 214.1064 (C10H16NO4 requires 214.1079). The
data were identical to those reported.3q
(+)-Lactacystin (1).3q Using the method described by Corey:
N-Acetyl-L-cysteine 61 was added to a stirring solution of omuralide
2 (6.3 mg, 29.5 µmol) and Et3N (12 µmol, 86 µL) in DCM (600
µL) at room temperature under Ar. The solution was stirred for 18
h and then concentrated in vacuo. Pyridine (2 mL) was added and
then removed by rotary evaporation under reduced pressure. The
azeotropic distillation was repeated twice. The free acid was
regenerated by treatment with THF/AcOH (5:1, 2 mL), and then
the solvent was removed by rotary evaporation under reduced
pressure. The azeotropic distillation was repeated twice to give a
colorless solid. The crude material was purified by column
chromatography using CHCl3/MeOH/AcOH (10:2:1) to give (+)-
aldehyde (33.0 mg, 0.091 mmol, 83%) as a colorless oil: [R]27
D
+76.1 (c 0.305 in CHCl3); νmax/cm-1 (CHCl3) 3428, 2973, 1722
(s)(CdO); δH (500 MHz; CDCl3) 9.66 (1H, s), 8.06-8.03 (2H,
m), 7.65-7.61 (1H, m), 7.51-7.48 (2H, m), 6.58 (1H, br, s), 5.80
(1H, d, J 6.5), 5.69 (1H, d, J 5.5), 2.77 (1H, qd, J 7.0 and 6.5),
2.09 (1H, qqd, J 7.0, 6.8 and 5.5), 1.00 (3H, d, J 6.8,), 0.99 (6H,
d, J 7.0); δC (126 MHz; CDCl3) 195.7 (CH), 177.8 (C), 169.6 (C),
165.6 (C), 134.0 (CH), 130.1 (CH), 129.0 (CH), 128.8 (C), 77.4
(CH), 75.3 (CH), 73.8 (C), 39.9 (CH), 30.2 (CH), 21.1 (CH3), 20.4
(CH3), 18.3 (CH3), 8.9 (CH3); m/z (ES, +ve) 362 (M + H+, 100);
C19H24NO6 requires 362.1604, found 362.1596.
Sulfamic acid (49.0 mg, 0.505 mmol), sodium dihydrogen
orthophosphate dihydrate (52.5 mg, 0.337 mmol), and sodium
chlorite (80%, 57.1 mg, 0.505 mmol) were added sequentially to a
stirring solution of the aldehyde (prepared above) (30.4 mg, 0.084
lactacystin 1 (5.2 mg, 47%): [R]24 +31 (c 0.13 in MeOH) (lit.3v
D
[R]21 +75 (c 0.28 in MeOH)); δH (500 MHz; C5D5N) 9.92 (1H,
D
br, s), 5.48-5.41 (1H, m), 5.37 (1H, d, J 7.1), 4.62 (1H, J 7.0),
4.09 (1H, dd, J 13.5 and 4.7), 3.86 (1H, dd, J 13.5 and 6.6), 3.50
2050 J. Org. Chem., Vol. 73, No. 6, 2008

Syntheses of Omuralide, 7-epi-Omuralide, and (+)-Lactacystin
(1H, qd, 7.6 and 7.1), 2.27 (1H, dqq, J 7.0, 6.8 and 6.6), 2.13 (1H,
br, s), 2.06 (3H, s), 1.60 (3H, d, J 7.6), 1.28 (3H, d, J 6.6), 1.21
(3H, d, J 6.8); δC (126 MHz; C5D5N) 203.4, 181.7, 173.4, 170.6,
81.8, 80.4, 76.4, 53.5, 42.3, 32.5, 32.0, 23.5, 21.9, 20.4, 10.7.3q
Andrew J. P. White at Imperial College for their help with
collecting the X-ray diffraction data for compound 35.
Supporting Information Available: Experimental procedures
for the preparation of 6, 9-12, 14-17, 21, 42, 45-49, and 53-
56, CIF files for X-ray structures of 18, 26, and 35, and copies of
1H NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank Pfizer Ltd., GlaxoSmithKline,
and the EPSRC (GR/M74696) for their financial support of this
work. We also thank Neil Brooks at Oxford Diffraction and
JO7027695
J. Org. Chem, Vol. 73, No. 6, 2008 2051