A new magnesium-catalyzed doubly diastereoselective anti-aldol reaction leads to a highly efficient process for the total synthesis of lactacystin in quantity

Article abstract of DOI:10.1021/ja973444c

A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling of a chiral tertiary α-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product. The metal requirement is strict, since of se

Full text of DOI:10.1021/ja973444c

2330
J. Am. Chem. Soc. 1998, 120, 2330-2336
A New Magnesium-Catalyzed Doubly Diastereoselective anti-Aldol
Reaction Leads to a Highly Efficient Process for the Total Synthesis
of Lactacystin in Quantity
E. J. Corey,* Weidong Li, and Gregory A. Reichard
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
ReceiVed October 2, 1997
Abstract: A new process is described for metal-catalyzed doubly diastereoselective Mukaiyama aldol coupling
of a chiral tertiary R-amino aldehyde and an achiral silyl enol ether to form selectively an anti-aldol product.
The metal requirement is strict, since of several salts tested only MgI2 functions as an effective catalyst. The
MgI2-catalyzed aldol greatly facilitates the total synthesis of lactacystin (1) and the corresponding â-lactone
(2), microbial products which are potent and selective inhibitors of proteasome function, cell cycle progression,
and gene regulation. The method also allows the synthesis of analogues of 1 in which the 7â-methyl group
of lactacystin is replaced by higher alkyl or aralkyl groups. Detailed experimental procedures are presented
for the optimized synthesis of lactacystin on the scale required to meet the current needs of many hundreds of
biological laboratories.
Lactacystin (1) is a microbial product which was obtained
by Ohmura et al. as a result of the screening of several thousand
microbial cultures for the capacity to induce differentiation of
the neuro 2A (neuroblastoma) cell line.1,2 It was originally
thought that lactacystin might be a small molecular mimic of
nerve growth factor.3-6 Stimulated by the unusual structure of
1, the remarkable biological activity, and the scarcity of natural
material, several research groups undertook the total syntheses.7-10
The first total synthesis of 1, in these laboratories in 19927 (and
a subsequent modified version11), made available 1 (and
radiolabeled 1) and was instrumental in research which dem-
onstrated that the biological activity of lactacystin is due to
potent, highly selective, and irreversible inhibition of protea-
some-mediated peptidase activity.12 Conclusive evidence was
obtained that the â-lactone 212,13 is the effective agent and that
it acts by acylation of the amino terminal threonine residue of
a proteasome subunit. This result was confirmed by X-ray
crystallographic studies at 2.4 Å resolution.14,15 Proteasomes
are large, hollow cylindrical protein structures (mass 700-900
kD, length roughly 150 Å, and diameter roughly 100 Å)
composed of four stacked rings of seven protein subunits (Figure
1). They occur in prokaryotes and eukaryotes and serve as
machines for the degradation of ubiquitin-conjugated proteins.16
Proteasomes thus mediate the turnover of various proteins
including misfolded or denatured proteins17 and many other
proteins including those involved in cell cycle progression18 and
the regulation of gene transcription.19 In consequence, lacta-
cystin and the â-lactone 2 have emerged as important new tools
for the study of protein biochemistry and cell biology. Synthetic
lactacystin has been in use in many hundreds of biological
laboratories. The rapidly growing demand for lactacystin has
provided an incentive for a more efficient and economical
(1) Ohmura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi,
R.; Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113.
(2) Ohmura, S.; Matsuzaki, K.; Fujimoto, T.; Kosuge, K.; Furuya, T.;
Fujita, S.; Nakagawa, A. J. Antibiot. 1991, 44, 117.
(3) Levi-Montalcini, R. Science 1987, 237, 1154.
(4) McDonald, N. Q.; Lapatto, R.; Murray-Rust., J.; Gunning, J.;
Wlodawer, A.; Blundell, T. L. Nature 1991, 354, 411.
(5) Bothwell, M. Cell 1991, 65, 915.
(6) Rosenberg, S. Annu. Rep. Med. Chem. 1992, 27, 41.
(7) Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114, 10677.
(8) (a) Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.; Ohmura,
S.; Smith, A. B., III. J. Am. Chem. Soc. 1993, 115, 5302. (b) Nagamitsu,
T.; Sunazuka, T.; Tanaka, H.; Ohmura, S.; Sprengeler, P. A.; Smith, A. B.,
III. J. Am. Chem. Soc. 1996, 118, 3584.
(14) Groll, M.; Ditzel, L.; Lo¨we, J.; Stock, D.; Bochtler, M.; Bartunik,
H. D.; Huber, R. Nature 1997, 386, 463.
(9) Uno, H.; Baldwin, J. E.; Russel, A. T. J. Am. Chem. Soc. 1994, 116,
2139.
(10) Chida, N.; Takeoka, J.; Tsutsumi, N.; Ogawa, S. J. Chem. Soc.,
Chem. Commun. 1995, 793.
(11) Corey, E. J.; Reichard, G. A.; Kania, R. Tetrahedron Lett. 1993,
34, 6977.
(12) Fenteany, G.; Standaert, R. F.; Lane, W. S.; Choi, S.; Corey, E. J.;
Schreiber, S. L. Science 1995, 268, 726.
(13) (a) Fenteany, G.; Standaert, R. F.; Reichard, G. A.; Corey, E. J.;
Schreiber, S. L. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 3358. (b) See also:
Dick, L. R.; Cruikshank, A. A.; Grenier, L.; Melandri, F. D.; Nunes, S. L.;
Stein, R. L. J. Biol. Chem. 1996, 271, 7273.
(15) See also: Bogyo, M.; McMaster, J. S.; Gaczynska, M.; Tortorella,
D.; Goldberg, A. L.; Ploegh, H. Proc. Natl. Acad. Sci. U.S.A. 1997, 94,
6629.
(16) (a) Coux, O.; Tanaka, K.; Goldberg, A. L. Annu. ReV. Biochem.
1996, 65, 801. (b) Rivett, A. J. Biochem. J. 1993, 291, 1. (c) Hilt, W.;
Wolf, D. H. Trends Biochem. Sci. 1996, 21, 96. (d) Orlowski, M.
Biochemistry 1990, 29, 10289.
(17) Rock, K. L.; Gramm, C.; Rothstein, L.; Clark, K.; Stein, R.; Dick,
L.; Hwang, D.; Goldberg, A. L. Cell 1994, 78, 761.
(18) King, R. W.; Deshaies, R. J.; Peters, J.-M.; Kirschner, M. W. Science
1996, 274, 1652.
(19) Pahl, H. L.; Baeuerle, P. A. Curr. Opin. Cell Biol. 1996, 8, 340.
S0002-7863(97)03444-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/28/1998

Total Synthesis of Lactacystin in Quantity
J. Am. Chem. Soc., Vol. 120, No. 10, 1998 2331
Because of the problems enumerated above with the aldol
step 4 f 5, we turned to the possibility of using metal chelation
between the basic N-benzyl nitrogen and the formyl oxygen of
4 to activate a Mukaiyama-type aldol process and to enhance
formyl face selectivity. To the best of our knowledge, no
efficient double-face selective, Mukaiyama aldol reactions of
an achiral silyl enol ether have previously been reported.22,23
M. T. Reetz et al. have investigated a single case of a
Mukaiyama aldol reaction, that of chiral N,N-dibenzylalanal with
TiCl4 and the trimethylsilyl enol ether of phenyl acetate, and
observed a poor yield of aldol adduct (25%) with 95:5
monodiastereoselectivity.24,25 Nonetheless, we investigated
extensively the reaction of 4 with TiCl4 and other Lewis acids
with the tert-butyldimethylsilyl (TBS) enol ether of ethyl acetate
to ascertain feasibility of a chelate-controlled aldol reaction. The
use of TiCl4 as catalyst in CH2Cl2 at -78 °C resulted in slow
decomposition of the aldehyde 4 without formation of any aldol
product, as determined by thin-layer chromatographic (TLC)
analysis. Interestingly, experiments with the bicoordinate Lewis
acids SnCl4, ZnCl2, and Cu(OTf)2 in CH2Cl2 in the aldol reaction
of 4 with ethyl acetate enol tert-butyldimethylsilyl ether led
neither to substrate decomposition nor to reaction even at 0 and
23 °C. These results, especially with cupric triflate, seemed to
indicate that the benzyl-protected nitrogen of 4 was probably
too sterically hindered to coordinate to the metal. For this reason
(among others), MgI2 was tried as catalyst. It was extremely
gratifying that this experiment produced the desired aldol adduct
6 in 90% yield with complete diastereoselectivity. None of the
isomeric aldol product 7 could be detected by 1H NMR or TLC
analysis of the crude reaction product. The stereochemistry of
the aldol adduct 6 was proved by two-step conversion to the
crystalline dihydroxy γ-lactam 8, the structure of which was
Figure 1.
process for its synthesis. In this paper we describe a type of
metal-catalyzed, stereocontrolled aldol reaction which has been
successfully applied to lactacystin synthesis. This new advance
and other improvements in the originally described synthesis,7
which are detailed herein, greatly simplify the preparation of
multigram or larger amounts of lactacystin.
Our first synthesis of 1 utilized as an early intermediate the
crystalline aldol 3 which is available in quantity from (S)-serine
methyl ester hydrochloride in three steps (without chromatog-
raphy).7 In the next stage of the process 3 was converted as
shown to the aldehyde 4 which serves as a component in a
second critical aldol coupling with a propionate ester enolate
(or equivalent) to produce an anti-aldol product, 5. On a larger
scale (ca. 70 g) the synthesis of 4 from 3 has been improved so
that it can be carried out simply and in excellent overall yield
(for details, see the Experimental Section). In the Swern
oxidation step leading to the aldehyde 4, it was advantageous
to conduct the reaction by the addition of cold, preformed Swern
reagent (from DMSO and oxalyl chloride in CH2Cl2 at -78
°C) to a mixture of the primary alcohol precursor and triethyl-
amine in CH2Cl2 solution at -78 °C. The normal mode of
Swern oxidation produced a number of byproducts. However,
the initially developed7 aldol process to form 5, R ) 2,6-
dimethylphenyl, using the Pirrung-Heathcock procedure,20 was
much less satisfactory because the best formyl face selectivity
that could be obtained was ca. 2:1, and after a cumbersome
chromatographic separation the yield of 5, R ) 2,6-dimeth-
ylphenyl, was at best 50%. Although improved formyl face
selectivity and good anti diastereoselectivity could be realized
using M. Braun’s chiral controller and the Cp2ZrCl enolate,11,21this
aldol process was also not satisfactory for the production of 5
on a larger scale since a 4-fold excess of the chiral enolate
component was required for complete conversion and since the
next reaction with the bulky Braun ester was too slow to be
practical. In addition, a cumbersome silica gel column chro-
matography was required to obtain pure aldol 5.11
shown by X-ray diffraction analysis.26 The use of MgBr2 as
(22) (a) Mukaiyama, T.; Kobayashi, S. Org. React. 1994, 46, 1. (b)
Mukaiyama, T. Org. React. 1982, 28, 203.
(23) For a general review of functional group mediated diastereoselective
reactions, see: Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993,
93, 1307.
(24) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141.
(20) Pirrung, M. C.; Heathcock, C. H. J. Org. Chem. 1980, 45, 1727.
(21) Braun, M.; Sacha, H. Angew. Chem., Int. Ed. Engl. 1991, 10, 1318.
(25) See also: Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105,
4833.

2332 J. Am. Chem. Soc., Vol. 120, No. 10, 1998
Corey et al.
catalyst in the aldol reaction of 4 also produced 6, but at a slower
rate and in lower yield. We had observed earlier the superiority
of MgI2 over MgBr2 in catalytic enantioselective Diels-Alder
reactions with a chiral bisoxazoline as ligand,27 which can
reasonably be attributed to the more facile dissociation of I-
from species such as L2MgI2.28 The preferred stereochemical
course of the transformation 4 f 6 had been predicted from
the expectation that the reaction would occur via a chelate of
IMg+ with the formyl oxygen and the R-tert-amino group (9)28
believe that the preferential formation of 10 can be explained
most simply on the basis of the IMg+ chelate structure 9 which
allows a low-energy pathway via the transition-state assembly
depicted in 13. This arrangement involves a synclinal relation-
ship between the formyl CO and enol ether CdC about the bond
which is being formed in the aldol process. Structure 13
involves considerably less steric repulsion than alternative
geometries for attachment of the silyl enol ether to the IMg+
chelate, such as the antiperiplanar arrangement shown in 14.
by attack of the nucleophilic silyl enol ether on the si face of
the formyl carbon. The re face of the formyl group in 9 is
sufficiently screened by the N-benzyl and OTBS groups to favor
highly selective formation of aldol product 6.
The corresponding aldol reaction of aldehyde 4 with the (E)-
trimethylsilyl enol ether of methyl propionate and MgI2
proceeded with high si/re formyl face selectivity (ca. 40:1) and
also with very good double diastereoselectivity. Thus, with a
10:1 mixture of (E)- and (Z)-trimethylsilyl enol ethers of methyl
propionate the desired major aldol product 10 was obtained in
9:1 predominance over the diastereomer 11. Possibly the ratio
of 10 to 11 would be even higher starting with pure (E)-silyl
enol ether. The aldol products 10 and 11, which were readily
separated by flash chromatography on silica gel, were isolated
in yields of 77% and 8%, respectively. A very small amount
(ca. 2%) of the double diastereomer of 10, the (2S,3R)-aldol
12, was also isolated. The stereochemistry of the major aldol
product 10 was established by subsequent conversion to
lactacystin (as well as to known synthetic intermediates in the
process; see Scheme 1).
Mukaiyama-like aldol reactions via an “open transition state”
(i.e., not six-membered pericyclic processes) have generally been
considered to occur preferentially via antiperiplanar geometry.29
Clearly, the antiperiplanar pathway via 14, which would lead
to a syn-aldol product, is disfavored because of the steric
repulsions which are shown.
The effectiveness of the doubly diastereoselective aldol
reaction was undiminished with increasing scale. In one
experiment conducted in a 1 L flask, 23 g of the aldehyde 4
was converted to 21.8 g of the anti-aldol product 10. The rest
of the sequence for producing synthetic lactacystin could also
be performed readily and efficiently on a larger scale, after
careful experimentation to optimize procedures. Scheme 1
summarizes the conditions and yields for the remaining eight
steps of the synthesis of 1 via the â-lactone precursor 2. In the
conversion of 15 to 16, the modified Swern oxidation procedure
described for the preparation of aldehyde 4 gave much better
results than the conventional Swern procedure. The modified
Swern oxidation was conducted by adding the preformed Swern
reagent to a solution of 15 and Et3N in CH2Cl2, all at -78 °C.
Under these conditions the reaction was both position selective
for the primary alcohol and very clean. It is apparent that the
synthesis of 1 described herein can be used without difficulty
to prepare centigram or kilogram amounts of lactacystin or the
â-lactone 2.
The specific effectiveness of MgI2 for the doubly diastereo-
selective conversion of 5 to the anti-aldol product 10 using an
achiral silyl enol ether is noteworthy and novel. A variety of
other types of anti-selective aldol reactions can be found in the
work of Heathcock,29 Gennari,30 Paterson,31 and Evans.32 We
(26) (a) Crystal structure data for 8: C10H17NO4, orthorhomibic, P212121,
a ) 6.6289(2) Å, b ) 8.5550(2) Å, c ) 19.5992(3) Å; R ) â ) γ ) 90°,
Z ) 4, R1[I > 2σ(I)] ) 0.0449. (b) Detailed X-ray crystallographic data
are available from the Cambridge Crystallographic Data Centre, 12 Union
Rd., Cambridge CB2 1EZ, U.K.
(27) Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807.
(28) The IMg+ chelate 9 can be expected to be much more reactive than
the corresponding MgI2 chelate; see: Hayashi, Y.; Jeffrey, J. R.; Corey, E.
J. J. Am. Chem. Soc. 1996, 118, 5502. However, both chelates would lead
to the observed preference for aldol product 6 over 7.
(29) (a) Danda, H.; Hansen, M. M.; Heathcock, C. H. J. Org. Chem.
1990, 55, 173. (b) Raimundo, B. C.; Heathcock, C. H. Synlett 1995, 1213.
(30) (a) Gennari, C.; Bernardi, A.; Columbo, L.; Scolastico, C. J. Am.
Chem. Soc. 1985, 107, 5812. (b) Palazzi, C.; Colombo, L.; Gennari, C.
Tetrahedron Lett. 1986, 27, 1735.
(31) (a) Paterson, I.; Cumming, J. G.; Smith, J. D.; Ward, R. A.
Tetrahedron Lett. 1994, 35, 441. (b) Paterson, I.; Smith, J. D. Tetrahedron
Lett. 1993, 34, 5351. (c) Paterson, I. Pure Appl. Chem. 1992, 64, 1821. (d)
Paterson, I.; Goodman, J. M.; Lister, M. A.; Schumann, R. C.; McClure,
C. K.; Norcross, R. D. Tetrahedron 1990, 46, 4663. (e) Paterson, I.;
Goodman, J. M. Tetrahedron Lett. 1989, 30, 997. (f) Cowden, C. J.;
Paterson, I. Org. React. 1997, 51, 3.
Doubly diastereoselective MgI2-catalyzed Mukaiyama aldol
reactions were also achievable with the trimethylsilyl enol ethers
of methyl butyrate, methyl valerate, methyl isobutyrate, and
methyl hydrocinnamate to form the anti-aldols 17a-17d in the
indicated yields. These intermediates were then transformed
(32) Evans, D. A.; Yang, M. G.; Dart, M. J.; Duffy, J. L.; Kim, A. S. J.
Am. Chem. Soc. 1995, 117, 9598.

Total Synthesis of Lactacystin in Quantity
J. Am. Chem. Soc., Vol. 120, No. 10, 1998 2333
Scheme 1
reaction mixture was poured into a mixture of half-saturated aqueous
NaHCO3 solution (650 mL) and 20% aqueous K2CO3 solution (50 mL)
carefully and diluted with EtOAc-ether (v/v 2:1, 2000 mL). The
organic layer was washed with water (3 × 500 mL) and brine (500
mL) and dried over MgSO4. Evaporation of the solvent in vacuo
afforded N-benzyl-(S)-R-(hydroxymethyl)-(S)-â-hydroxyleucine methyl
ester as a colorless oil, which was used without further purification
after azeotropic drying with anhydrous benzene (2 × 250 mL). To a
stirred solution of this product in DMF (260 mL) were added imidazole
(21.3 g, 313.2 mmol, 1.5 equiv) and tert-butyldimethylsilyl chloride
(34.5 g, 228.9 mmol, 1.1 equiv). After 25 h of stirring at 23 °C, the
reaction mixture was diluted with ethyl acetate-ether (v/v 2:1, 2000
mL), washed with 0.5 M aqueous citric acid solution (4 × 120 mL),
water (5 × 400 mL), and brine (500 mL), and dried. After evaporation
of the solvent, the resulting oil was dried by azeotropic distillation with
benzene (2 × 500 mL) to give a colorless oil, which without further
purification was taken up into anhydrous benzene (520 mL) and treated
with powdered paraformaldehyde (60.0 g, 2.0 mol, 10 equiv) and
p-TsOH‚H2O (1.90 g, 10.0 mmol, 5 mol %). The resulting suspension
was heated to 80 °C for 0.5 h with efficient stirring, cooled to room
temperature, and filtered through a pad of silica gel. The resulting
filtrate was diluted with ether (2000 mL), washed with 5% aqueous
NaHCO3 solution (250 mL), water (3 × 400 mL), and brine (500 mL),
and dried (MgSO4) overnight. Evaporation of the solvent under reduced
pressure afforded the 1,3-oxazolidine derivative of N-benzyl-(S)-R-
(((tert-butyldimethylsilyl)oxy)methyl)-(S)-â-hydroxyleucine methyl es-
ter as a colorless oil, which was dried by azeotropic distillation with
benzene (2 × 500 mL) and taken up into THF (800 mL). This solution
was treated with a 2 M lithium borohydride solution of THF (Aldrich,
200 mL, 400 mmol, 2.0 equiv) with stirring at 23 °C and then with
methanol (50 mL) (cooling with a water bath to 25 °C). After 15 h of
stirring, more lithium borohydride (2 M in THF, 200 mL, 400 mmol)
was added followed by more methanol (25 mL). After additional
stirring for 5 h, the reaction mixture was treated with water (500 mL)
and diluted with ethyl acetate-ether (v/v 2:1, 3000 mL). The organic
layer was washed with water (3 × 500 mL) and brine (500 mL) and
dried. After evaporation of the solvent in vacuo, the primary alcohol
corresponding to aldehyde 4 was obtained as a colorless oil (ca. 76 g),
which was dried by azeotropic distillation with benzene (3 × 300 mL).
A solution of this product in CH2Cl2 (1000 mL) at -78 °C was treated
with triethylamine (291.3 mL, 2.09 mol, 10 equiv) and then with a
cold (-78 °C) CH2Cl2 solution (850 mL) of Swern reagent prepared
from oxalyl chloride (54.8 mL, 0.63 mol, 3.0 equiv) and DMSO (59.7
mL, 0.84 mol, 4.0 equiv) at -78 °C over 10 min. The resulting reaction
mixture was stirred for 2 h and allowed to warm slowly to 0 °C. The
reaction mixture was diluted with saturated aqueous NaHCO3 (600 mL)
and with ether-EtOAc (v/v 4:1, 2000 mL). The organic phase was
by a sequence analogous to that outlined in Scheme 1 to the
corresponding lactacystin â-lactone analogues 18a-18d, all of
which showed good biological activity. The 7-ethyl analogue
of lactacystin has been found to be even more effective than
lactacystin in blocking the progression of the malaria parasite
Plasmodium berghei to the infective exoerythrocytic and
erythocytic states.33
Experimental Section
General Procedures. All anhydrous solvents (THF, CH2Cl2, Et2O,
CH3CN, benzene) were dried by standard techniques and freshly
distilled before use. All reactions were carried out under N2 and
monitored by thin-layer chromatography (TLC). All organic extracts
were washed with brine before being dried over MgSO4. All oily
products were purified by flash silica gel chromatography (SGC) eluting
with a solvent mixture of hexane and ethyl acetate. Melting points
(mp) were determined using a Fisher-Johns hot stage apparatus and
are uncorrected. Specific optical rotations ([R]) were measured using
a Perkin-Elmer 241 polarimeter at 23 °C with a sodium lamp (D line,
589 nm). FTIR spectra were recorded on a Nicolet 5 ZDX FTIR
spectrometer. 1H and 13C NMR spectra were recorded on a Bruker
AM series instrument. Mass spectral analyses and high-resolution mass
spectral analyses (HRMS) were measured on a JEOL model AX-505
or SX-102 spectrometer by means of EI, CI, or FAB.
Conversion of â-Hydroxy Ester 3 to N-Benzyl Amino Aldehyde
4. To a stirred solution of crystalline â-hydroxy ester 3 (73.0 g, 208.9
mmol) in 95% methanol-water (480 mL) was added dropwise
trifluoromethanesulfonic acid (73.0 mL, 835.6 mmol, 4.0 equiv) at 23
°C (cooling with a water bath). The resulting solution was heated to
80-85 °C in an open flask by an oil bath with efficient stirring, and
the methanol was removed by gradual distillation over 6.5 h. The
(33) Gantt, S. M.; Myung, J. M.; Briones, M. R. S.; Li, W. D.; Corey,
E. J.; Ohmura, S.; Nussenzweig, V.; Sinnis, P. J. Clin. InVest., submitted for
publication.

2334 J. Am. Chem. Soc., Vol. 120, No. 10, 1998
Corey et al.
washed with water and brine and dried. The crude oil was purified by
CHOH), 4.27 (br m, 2 H, NCH2O), 7.18-7.35 (m, 5 H, ArH) ppm.
Data for 12: 1H NMR (500 MHz, CDCl3) δ 0.12 and 0.14 (each s, 3
H, CH3Si), 0.93 (s, 9 H, t-BuSi), 1.03 (t, 6 H, J ) 6.7 Hz, (CH3)2CH),
1.36 (d, 3 H, J ) 7.2 Hz, CH3CH), 2.06 (m, 1 H, CHMe2), 3.03 (m, 1
H, CHCH3), 3.61 (s, 3 H, OCH3), 3.70 (d, 1 H, J ) 7.2 Hz, O-CH),
3.88 and 4.15 (each d, 1 H, J ) 13.7 Hz, CH2Ph), 4.02 (ABq, 2 H, J
) 10.8; 5.4 Hz, CH2OTBS), 3.85 (br d, 1 H, J ) 3.6 Hz, CHOH),
4.30 (br s, OH), 4.26 and 4.33 (each d, 1 H, J ) 2.4 Hz, NCH2O),
7.15-7.35 (m, 5 H, ArH) ppm; 13C NMR (125 MHz, CDCl3) δ -5.8,
-5.7, 17.9, 18.1, 20.1, 21.3, 25.9(3C), 28.4, 39.8, 51.7, 52.3, 61.8,
69.6, 74.7, 85.4, 86.8, 127.0, 127.9, 128.2(2C), 139.9, 177.2 ppm.
flash SGC (eluting with 5% EtOAc in hexane) to give aldehyde 4 (65.5
g, 83%) as a waxy solid, mp 42 °C; Rf 0.60 (Hex-EtOAc 4:1); [R]23
D
-26.4° (c 1.18, CH2Cl2); FTIR (film) νmax 2957, 2929, 2857, 1726,
1472, 1108 cm-1; 1H NMR (500 MHz, CDCl3) δ 0.11 (s, 3 H, CH3Si),
0.13 (s, 3 H, CH3Si), 0.80 (d, 3 H, J ) 6.6 Hz, (CH3)2CH), 1.02 (s, 9
H, C(CH3)3), 1.05 (d, 3 H, J ) 6.6 Hz, (CH3)2CH), 2.07 (m, 1 H,
CH(CH3)2), 3.76 (d, 1 H, J ) 9.6 Hz, OCHCH), 3.84 (d, 1 H, J ) 13.6
Hz, CH2Ph), 3.93 (d, 1 H, J ) 13.6 Hz, CH2Ph), 3.98 (d, 1 H, J )
11.5 Hz, CH2OSi), 4.11 (d, 1 H, J ) 11.5 Hz, CH2OSi), 4.48 (s, 1 H,
NCH2O), 4.50 (s, 1 H, NCH2O), 7.28-7.34 (m, 5 H, Ph-H), 9.42 (s, 1
H, CHO) ppm; 13C NMR (100 MHz, CDCl3) δ -5.9, -5.7, 18.0, 19.3,
20.2, 25.7, 28.7, 50.9, 60.2, 71.8, 86.1, 87.1, 127.3, 128.2, 128.4, 138.6,
200.8 ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C21H35NO3Si]+
378.2464, found for [M + H]+ 378.2455. Data for the primary alcohol
corresponding to aldehyde 4: 1H NMR (500 MHz, CDCl3) δ 0.16 (s,
6 H, CH3Si), 0.99 (s, 9 H, t-BuSi), 1.07 (d, 3 H, J ) 6.6 Hz, (CH3)2-
CH), 1.11 (d, 3 H, J ) 6.6 Hz, (CH3)2CH), 2.06 (br m, 1 H, CH(CH3)2),
3.12 (br s, OH), 3.67 (br d, 1 H, J ) 11.3 Hz, CH2OH), 3.73 (d, 1 H,
J ) 9.1 Hz, OCHCH), 3.76 (d, 1 H, J ) 11.3 Hz, CH2OH), 3.82 (d, 1
H, J ) 13.4 Hz, CH2Ar), 3.87 (ABq, 2 H, J ) 10.8 Hz, CH2OSi), 4.10
(d, 1 H, J ) 13.4 Hz, CH2Ar), 4.40 (s, 1 H, NCH2O), 4.43 (s, 1 H,
NCH2O), 7.20-7.45 (m, 5 H, ArH) ppm; FABMS (NBA + NaI) m/z
402 [M + Na]+ (14%), 380 [M + H]+ (65%), 348 [M - CH2OH]+
(100%); HRMS (CI, NH3) m/z calcd for [C21H38NO3Si]+ 380.2621,
found for [M + H]+ 380.2634.
Conversion of Aldol 10 to Dihydroxy-γ-lactam 15. To a solution
of aldol 10 (20.0 g, 43.0 mmol) and 0.1 mL of i-Pr2NEt in ethanol
(250 mL) was added 10% Pd-C (2.40 g). The resulting mixture was
degassed and hydrogenated under balloon pressure for 22 h at 23 °C.
The reaction mixture was filtered through a pad of Celite, and the
resulting filtrate was concentrated in vacuo. The oily residue was taken
up in methanol (100 mL) and heated to 50 °C for 24 h. After
evaporation of the solvent in vacuo, the resulting crude (((tert-
butyldimethylsilyl)oxy)methyl)hydroxy-γ-lactam intermediate was dis-
solved in CH3CN (300 mL) and treated with a solution of 48% HF
(15.5 mL). After 24 h of stirring at 23 °C, the reaction mixture was
diluted with EtOAc (800 mL), loaded onto a pad of silica gel (1500
g), and eluted with 10% (v/v) methanol in EtOAc (3000 mL). After
evaporation of the solvent under reduced pressure, the resulting solid
residue was recrystallized from 50% EtOAc in hexane to give
dihydroxy-γ-lactam 15 (7.5 g, 76%) as colorless crystals: mp 160 °C
Conversion of Aldehyde 4 to Aldol 10 by MgI2-Mediated
Mukaiyama Aldol. To a stirred suspension of anhydrous MgI2 (from
Aldrich, 97%, 18.6 g, 66.9 mmol, 1.1 equiv) in CH2Cl2 (550 mL) was
added a solution of aldehyde 4 (23.0 g, 60.9 mmol) in CH2Cl2 (50
mL) at 0 °C. The resulting mixture was stirred for 20 min at that
temperature and cooled to -10 °C, whereupon the trimethylsilyl enol
ether of methyl propionate (14.6 g, 91.3 mmol)34 was added dropwise
down the side of the flask over 15 min. The resulting reaction mixture
was allowed to warm gradually to 0 °C over 30 min and stirred at 0
°C for an additional 1.5 h. The reaction mixture was diluted with a
mixture of half-saturated aqueous NaHCO3 (200 mL) in ether (800 mL).
The organic phase was washed successively with 5 wt % aqueous
Na2S2O3, water, and brine (150 mL each) and then dried over MgSO4.
After evaporation of the solvent in vacuo, the resulting residual oil
was taken up into methanol (500 mL) and treated with K2CO3 (3.5 g,
25.4 mmol) at 23 °C with stirring for 20 h (to effect the conversion of
trimethylsilyl ether adduct to the corresponding free aldol). The reaction
mixture was concentrated down to half of the original volume and
poured into a mixture of ether-water (1000 mL/200 mL). The organic
phase was washed with water and brine (200 mL each) and dried.
Evaporation of the solvent under reduced pressure gave crude 10, which
was purified by flash silica gel chromatography (2 kg) eluting with a
solvent mixture of ethyl acetate in hexane (4-8%) to afford anti-aldol
10 (21.8 g, 77%) as a colorless oil along with syn-aldol 11 (8%) and
re facial anti-aldol 12 (2%). Data for 10: Rf 0.4 (Hex-EtOAc 10:1);
dec; Rf 0.38 (EtOAc); [R]23 +44.2° (c 0.95, CH2Cl2); FTIR (film)
D
1
νmax 3367, 1695, 1060, 1045 cm-1; H NMR (500 MHz, CDCl3) δ
1.04 (d, 3 H, J ) 6.7 Hz, (CH3)2CH), 1.06 (d, 3 H, J ) 6.7 Hz, (CH3)2-
CH), 1.32 (d, 3 H, J ) 7.8 Hz, CH3CH), 1.72 (m, 1 H, CH(CH3)2),
2.14 (dd, 1 H, J ) 4.2; 8.5 Hz, HOCH2), 2.96 (dq, 1 H, J ) 9.5; 7.8
Hz, CHCH3), 3.00 (d, 1H, J ) 10.4 Hz, OCHCH), 3.08 (d, 1 H, J )
11.0 Hz, HOCH), 3.75 (dd, 1 H, J ) 4.2; 11.8 Hz, CH2OH), 4.02 (dd,
1 H, J ) 8.5; 11.8 Hz, CH2OH), 4.43 (t, 1 H, J ) 10.2 Hz, CHOH),
4.65 (d, 1 H, J ) 5.0 Hz, NCH2O), 5.18 (d, 1 H, NCH2O) ppm; 13C
NMR (100 MHz, CDCl3) δ 11.0, 18.3, 20.7, 27.8, 45.6, 58.6, 71.8,
73.7, 75.4, 89.5, 179.8 ppm; HRMS (FAB, NBA + NaI) m/z calcd for
[C11H19NO4Na]+ 252.1212, found for [M + Na]+ 252.1228.
Conversion of Dihydroxy-γ-lactam 15 to Dihydroxy Acid 16. A
solution of dihydroxy-γ-lactam 15 (7.5 g, 32.7 mmol) in CH2Cl2 (420
mL) was cooled to -78 °C and treated with Et3N (45.0 mL, 322.8
mmol) and a CH2Cl2 solution of Swern reagent prepared from oxalyl
chloride (5.7 mL, 65.2 mmol, 2 equiv) and DMSO (7.0 mL, 98.0 mmol,
3 equiv) at -78 °C over 10 min. The reaction mixture was stirred for
2 h at -78 °C and poured into a mixture of CH2Cl2 (1200 mL) and
saturated aqueous NaHCO3 (500 mL). The layers were separated, and
the aqueous phase was extracted with CH2Cl2 (800 mL). The combined
organic phases were dried and concentrated in vacuo to give the crude
hydroxy-γ-lactam aldehyde intermediate as a colorless oil, which
without purification was taken up into t-BuOH (350 mL) and 2-methyl-
2-butene (200 mL). The resulting mixture was treated with a freshly
prepared solution of NaClO2 (30.0 g, 331.5 mmol, 10 equiv) in 20%
aqueous NaH2PO4 (200 mL) at 23 °C. After 1 h of vigorous stirring
at 23 °C, the reaction mixture was poured into EtOAc (1500 mL), and
the aqueous phase was extracted with EtOAc (1000 mL). The
combined organic phases were dried and concentrated in vacuo. The
oily residue was taken up into EtOAc (500 mL) and washed with 8%
aqueous NaH2PO4 (50 mL), and the aqueous phase was extracted with
EtOAc (2 × 500 mL). The combined organic phases were dried and
concentrated in vacuo to yield the crude hydroxy carboxylic acid as a
colorless film, which without purification was treated with 1,3-
propanedithiol (11.8 mL, 116.0 mmol, 3.6 equiv) and a saturated
solution of HCl (gas) (ca. 1-2 wt %) in CF3CH2OH (300 mL) at 23
°C. The reaction vessel was sealed with a polypropylene cap and heated
to 50-55 °C for 7.5 h. The reaction mixture was cooled and
concentrated in vacuo. The resulting solid residue was triturated with
20% CH2Cl2 in hexane (5 × 200 mL) and dried under high vacuum to
afford dihydroxy acid 16 (6.0 g, 77%, three steps) as a white powder:
mp 240 °C dec; Rf 0.45 (CHCl3-MeOH-HOAc 10:10:1); [R]23D +44.5
(c 0.90, DMSO); FTIR (film) νmax 3600-2800 (br), 1695, 1687 cm
[R]23D -2.0° (c 1.0, CHCl3); FTIR (film) νmax 3453, 1713, 1737 cm-1
;
1H NMR (500 MHz, CDCl3) δ 0.11 (s, 3 H, CH3Si), 0.12 (s, 3 H,
CH3Si), 0.92 (s, 9 H, t-BuSi), 1.01 (t, 6 H, J ) 6.3 Hz, (CH3)2CH),
1.36 (d, 3 H, J ) 7.1 Hz, CH3CH), 2.13 (m, 1 H, CH(CH3)2), 2.86 (m,
1 H, CHCH3), 3.62 (s, 3 H, CH3OCO), 3.69 (d, 1 H, J ) 4.4 Hz, OCH),
3.90 (d, 1 H, J ) 13.2 Hz, CH2Ph), 4.01 (br m, 1 H, CHOH), 4.07 (s,
2 H, CH2OSi), 4.11 (d, 1 H, J ) 5.6 Hz, HOCH), 4.17 (d, 1 H, J )
13.2 Hz, CH2Ph), 4.26 (d, 1 H, J ) 2.3 Hz, NCH2O), 4.29 (d, 1 H, J
) 2.3 Hz, NCH2O), 7.16-7.30 (m, 5 H, ArH) ppm; 13C NMR (100
MHz, CDCl3) δ -5.8, -5.7, 17.2, 18.1, 19.5, 21.7, 25.9(3C), 28.7,
39.7, 51.7, 52.4, 70.0, 69.6, 75.6, 85.5, 86.5, 127.0, 127.9, 128.3, 128.4,
139.4, 177.1 ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C25H43-
NO5SiNa]+ 488.2808, found for [M + Na]+ 488.2805. Data for 11:
1H NMR (400 MHz, CDCl3) δ 0.13 (s, 6 H, CH3Si), 0.93 (s, 9 H,
t-BuSi), 1.03 (d, 3 H, J ) 6.8 Hz, CH3), 1.06 (d, 3 H, J ) 6.8 Hz,
CH3), 1.33 (d, 3 H, J ) 7.0 Hz, CH3CH), 2.12 (m, 1 H, CHMe2), 2.82
(m, 1 H, CHCH3), 3.65 (s, 3 H, OCH3), 3.75 (d, 1 H, J ) 13.1 Hz,
CH2Ph), 3.91 (m, 2 H), 4.08 (m, 2 H), 4.16 (br d, 1 H, J ) 6.7 Hz,
(34) Prepared according to Kita, Y.; Segowa, J.; Yasuda, H.; Tamura,
Y. J. Chem. Soc., Perkin Trans. 1 1982, 1099.

Total Synthesis of Lactacystin in Quantity
J. Am. Chem. Soc., Vol. 120, No. 10, 1998 2335
-1; 1H NMR (300 MHz, pyridine-d5) δ 1.29 (d, 3 H, J ) 6.8 Hz, (CH3)2-
CH), 1.33 (d, 3 H, J ) 6.6 Hz, (CH3)2CH), 1.57 (d, 3 H, J ) 7.5 Hz,
CH3CH), 2.37 (m, 1 H, CH(CH3)2), 3.73 (m, 1 H, CHCH3), 4.76 (d, 1
H, J ) 6.3 Hz, CHOH), 5.26 (d, 1 H, J ) 5.9 Hz, CHOH), 9.40 (s, 1
H, NHCO) ppm; 1H NMR (500 MHz, DMSO-d6) δ 0.79 (d, 3 H, J )
6.8 Hz, (CH3)2CH), 0.85 (d, 3 H, J ) 6.8 Hz, (CH3)2CH), 0.87 (d, 3
H, J ) 7.8 Hz, CH3CH), 1.57 (m, 1 H, CH(CH3)2), 2.67 (m, 1 H,
CHCH3), 3.72 (d, 1 H, J ) 6.2 Hz, OCHCH), 4.23 (d, 1 H, J ) 5.8
Hz, CHOH), 4.88 (br s, 1 H, OH), 5.28 (br s, 1 H, OH), 7.66 (s, 1 H,
NH) ppm; 13C NMR (100 MHz, DMSO-d6) δ 8.7, 19.0, 20.2, 30.4,
40.4, 74.4, 77.7, 105.4, 172.6, 178.3 ppm; HRMS (FAB, NBA + NaI)
m/z calcd for [C10H18NO5]+ 232.1185, found for [M + H]+ 232.1186.
Conversion of Dihydroxy Acid 16 to â-Lactone 2. A suspension
of dihydroxy acid 16 (800.0 mg, 3.46 mmol) in CH2Cl2 (50 mL) was
treated with Et3N (1.44 mL, 10.3 mmol, 3 equiv) and bis(2-oxo-3-
oxazolidinyl)phosphinic chloride (BOPCl, 1.32 g, 5.2 mmol, 1.5 equiv)
at 23 °C. After 0.5 h of stirring at 23 °C, the resulting reaction mixture
was diluted with water (10 mL) and extracted with EtOAc (3 × 50
mL). The combined organic phases were dried and concentrated in
vacuo. The residue was loaded onto a pad of silica gel (15 g) and
eluted with EtOAc (150 mL). The eluent was concentrated in vacuo,
and the solid residue was recrystallized from EtOAc to give â-lactone
2 (690.0 mg, 93%) as colorless crystals: mp 185 °C dec; Rf 0.10
4.10 (br m, 3 H), 4.16 (d, 1 H, J ) 13.1 Hz, CH2Ph), 4.26 (dd, 2 H,
J ) 2.3; 4.7 Hz, NCH2O), 7.16-7.35 (m, 5 H, ArH) ppm; 13C NMR
(125 MHz, CDCl3) δ -5.8, -5.7, 12.1, 18.1, 19.8, 21.5, 25.2, 25.9,
28.7, 46.7, 51.5, 52.9, 62.1, 69.7, 74.7, 85.8, 86.8, 127.0, 128.3, 139.6,
176.8 ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C25H45NO5-
SiNa]+ 502.2965, found for [M + Na]+ 502.2956.
1
Aldol 17b: 80%; [R]23 -135.5° (c 0.6, EtOAc); H NMR (500
D
MHz, CDCl3) δ 0.11 (s, 3 H, CH3), 0.12 (s, 3 H, CH3), 0.90 (t, 3 H, J
) 7.3 Hz, CH3), 0.91 (s, 9 H, t-BuSi), 0.99 (d, 3 H, J ) 6.6 Hz, CH3),
1.02 (d, 3 H, J ) 6.6 Hz, CH3), 1.16-1.40 (br m, 4 H, CH2), 1.69 (m,
1H), 1.91 (m, 1 H), 2.17 (sept, 1 H, J ) 6.6 Hz, CH), 2.73 (br m, 1 H,
CH-CO2Me), 3.58 (s, 3 H, OCH3), 3.64 (d, 1 H, J ) 6.2 Hz, CHOH),
3.93 (d, 1 H, J ) 13.1 Hz, CH2Ph), 4.16 (d, 1 H, J ) 13.1 Hz, CH2-
Ph), 4.04-4.12 (br m, 3 H), 4.26 (d, 2 H, J ) 2.7 Hz, NCH2O), 7.16-
7.35 (m, 5 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) δ -5.8, -5.7,
14.0, 18.2, 19.7, 21.5, 22.6, 25.9, 28.7, 29.4, 29.8, 31.8, 45.1, 51.5,
52.9, 62.1, 69.7, 74.1, 74.9, 85.8, 86.7, 127.0, 127.8, 128.3, 128.6, 128.6,
139.6, 176.9 ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C28H49-
NO5SiNa]+ 530.3278, found for [M + Na]+ 530.3275.
Aldol 17c: 84%; [R]23D +25.4° (c 0.40, EtOAc); 1H NMR (500 MHz,
CDCl3) δ 0.11 and 0.12 (2s, 3 H, CH3Si), 0.92 (s, 9 H, t-BuSi), 0.93
(d, 3 H, J ) 6.6 Hz, CH3), 0.98 (d, 3 H, J ) 6.6 Hz, CH3), 1.02 (d, 3
H, J ) 6.5 Hz, CH3), 1.04 (d, 3 H, J ) 6.5 Hz, CH3), 2.23 (br m, 2 H,
CH(CH3)2), 2.40 (dd, 1 H, J ) 1.5; 9.4 Hz, CH(CH3)2), 3.50 (s, 3 H,
OCH3), 3.52 (d, 1 H, J ) 7.5 Hz, OCH), 3.95 (d, 1 H, J ) 12.7 Hz,
CH2Ph), 4.09 (d, 1 H, J ) 10.5 Hz, CH2OSi), 4.15 (d, 1 H, J ) 10.5
Hz, CH2OSi), 4.17 (d, 1 H, J ) 12.7 Hz, CH2Ph), 4.12 (br d, 1 H, J )
9.3 Hz, CHOH), 4.20 (d, 1 H, J ) 2.5 Hz, NCH2O), 4.30 (d, 1 H, J )
2.5 Hz, NCH2O), 4.23 (br d, 1 H, J ) 9.3 Hz, HOCH), 7.16-7.36 (m,
5 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) δ -5.7, -5.7, 18.2,
20.4, 20.7, 21.0, 21.1, 25.9, 28.6, 29.6, 50.8, 51.2, 53.8, 62.0, 69.8,
73.2, 86.1, 87.2, 127.0, 128.2, 129.1, 139.8, 177.0 ppm; HRMS (FAB,
NBA + NaI) m/z calcd for [C27H47NO5SiNa]+ 516.3121, found for [M
+ Na]+ 516.3131.
(EtOAc); [R]23 -93.9° (c 0.53, CH3CN); FTIR (CH2Cl2) νmax 3687,
D
3602, 3410, 1840, 1731, 1640 cm-1; 1H NMR (500 MHz, pyridine-d5)
δ 0.98 (d, 3 H, J ) 6.8 Hz, (CH3)2CH), 1.10 (d, 3 H, J ) 6.8 Hz,
(CH3)2CH), 1.45 (d, 3 H, J ) 7.5 Hz, CH3CH), 2.09 (m, 1 H,
CH(CH3)2), 3.03 (dq, 1 H, J ) 6.1; 7.4 Hz, CHCH3), 4.33 (dd, 1 H, J
) 3.6; 6.7 Hz, OCHCH), 5.68 (d, 1 H, J ) 6.1 Hz, CHOCO), 7.85 (d,
1 H, J ) 6.8 Hz, OH), 10.50 (s, 1 H, NH) ppm; 13C NMR (100 MHz,
pyridine-d5) δ 8.8, 16.5, 20.4, 29.8, 38.9, 70.6, 77.0, 80.5, 172.4, 177.4
ppm; HRMS (CI, NH3) m/z calcd for [C10H19N2O4]+ 231.1344, found
for [M + NH4]+ 231.1354.
Conversion of â-Lactone 2 to Lactacystin (1) by Coupling with
N-Acetyl-L-cysteine. A suspension of â-lactone 2 (500.0 mg, 2.35
mmol) in CH2Cl2 was treated with N-acetyl-L-cysteine (383.0 mg, 2.33
mmol, 1.0 equiv) and Et3N (0.98 mL, 7.05 mmol, 3.0 equiv) at 23 °C
under N2. The resulting reaction mixture was stirred for 4 h at 23 °C
and concentrated in vacuo. The solid residue was dissolved in dry
pyridine (10 mL) and evaporated under reduced pressure. The
azeotropic distillation with pyridine was repeated again (to effect the
complete removal of Et3N). Regeneration of the free acid by azeotropic
distillation with a mixture of THF-HOAc (v/v 5:1, 2 × 10 mL) was
followed by trituration with a mixture of EtOAc-HOAc (v/v 20:1, 2
× 20 mL) to afford lactacystin (880.0 mg, >99%) as a colorless
powder: mp 233-235 °C dec; Rf 0.33 (THF-EtOAc-HOAc 4:2:1);
[R]23D +78.6 (c 0.49, MeOH); FTIR (neat) νmax 3584, 3484, 3317, 3216,
1
Aldol 17d: 83%; H NMR (400 MHz, CDCl3) δ 0.084 and 0.10
(each s, 3 H, CH3Si), 0.62 (d, 3 H, J ) 6.7 Hz, CH3), 0.90 (s, 9 H,
t-BuSi), 0.95 (d, 3 H, J ) 6.7 Hz, CH3), 2.12 (m, 1 H, CH), 2.96-
3.14 (m, 2 H), 3.38 (d, 1 H, J ) 7.4 Hz, CH-O), 3.46 (s, 3 H, OCH3),
3.92 (d, 1 H, J ) 13.0 Hz, CH2Ph), 4.19 (d, 1 H, J ) 13.0 Hz, CH2-
Ph), 4.03 (d, 1 H, J ) 10.7 Hz, CH2OTBS), 4.14 (d, 1 H, J ) 10.7 Hz,
CH2OTBS), 4.25 (dd, 2 H, J ) 2.5; 6.1 Hz, NCH2O), 3.97 (br d, 1 H,
J ) 7.1 Hz, HOCH), 4.33 (br d, 1 H, J ) 8.0 Hz, CHOH), 7.15-7.30
(m, 10 H, ArH) ppm; 13C NMR (100 MHz, CDCl3) δ -5.8, -5.7,
18.1, 20.2, 20.5, 25.9(3C), 28.5, 37.5, 46.3, 51.6, 53.3, 61.8, 69.7, 74.0,
86.0, 87.2, 126.7, 126.9, 128.2, 128.3, 128.6, 128.7, 129.2, 138.5, 139.6,
176.5 ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C31H47NO5-
SiNa]+ 564.3121, found for [M + Na]+ 564.3107.
1698, 1674, 1647, 1623, 1617, 1560 cm-1 1H NMR (500 MHz,
;
γ-Lactam 15, Ethyl Analogue: 78%; [R]23D +60° (c 0.01, EtOAc);
1H NMR (500 MHz, CDCl3) δ 1.04 (t, 6 H, J ) 6.7 Hz, (CH3)2CH),
1.12 (t, 3 H, J ) 7.3 Hz, CH3CH2), 1.74 (m, 2 H, CH2), 1.84 (m, 1 H,
CH2CH3), 2.44 (dd, 1 H, J ) 4.0; 8.5 Hz, HOCH2), 2.68 (br q, 1 H, J
) 7.6 Hz, CH), 2.96 (d, 1 H, J ) 10.3 Hz, CHOH), 3.34 (d, 1 H, J )
10.5 Hz, CHOH), 3.76 (dd, 1 H, J ) 4.0; 11.8 Hz, CH2OH), 4.01 (dd,
1 H, J ) 8.5; 11.8 Hz, CH2OH), 4.48 (t, 1 H, J ) 9.8 Hz, CHOH),
4.62 (d, 1 H, J ) 5.0 Hz, NCH2O), 5.17 (d, 1 H, J ) 5.0 Hz, NCH2O)
ppm; 13C NMR (125 MHz, CDCl3) δ 12.8, 18.5, 20.0, 20.8, 27.9, 52.0,
57.5, 59.1, 71.9, 73.3, 76.0, 89.3, 179.8 ppm; HRMS (CI, NH3) m/z
calcd for [C12H22NO4]+ 244.1549, found for [M + H]+ 244.1552.
pyridine-d5) δ 1.18 (d, 3 H, J ) 6.7 Hz, (CH3)2CH), 1.25 (d, 3 H, J )
6.7 Hz, (CH3)2CH), 1.57 (d, 3 H, J ) 7.5 Hz, CH3CH), 2.04 (s, 3 H,
CH3CON), 2.25 (m, 1 H, CH(CH3)2), 3.48 (dq, 1 H, J ) 7.4; 7.4 Hz,
CHCH3), 3.84 (dd, 1 H, J ) 6.7; 13.6 Hz, CH2S), 4.05 (dd, 1 H, J )
4.8; 13.6 Hz, CH2S), 4.60 (d, 1 H, J ) 7.0 Hz, CHOH), 5.34 (d, 1 H,
J ) 7.0 Hz, CHOH), 5.42 (br q, 1 H, J ) 7.0 Hz, CHCH2S), 8.80 (d,
1 H, J ) 8.2 Hz, NH), 9.90 (s, 1 H, NH) ppm; 13C NMR (100 MHz,
pyridine-d5) δ 10.2, 19.9, 21.5, 23.0, 31.4, 32.1, 41.9, 53.0, 75.9, 80.0,
81.4, 170.2, 173.7, 181.3, 203.0 ppm; HRMS (FAB, NBA + NaI) m/z
calcd for [C15H24N2O7SNa]+ 399.1202, found for [M + Na]+ 3399.1198.
Mukaiyama aldol products 17a-17d were prepared by applying the
procedure described above with aldehyde 4 and the trimethylsilyl enol
ethers of methyl butyrate, methyl valerate, methyl isobutyrate, and
methyl hydrocinnamate, respectively. The corresponding â-lactone
analogues 18a-18d were prepared by a sequence analogous to that
described above. The chemical yields and spectral data of the various
intermediates are summarized below.
γ-Lactam 15, n-Butyl Analogue: 80%; [R]23 +14.0° (c 0.02,
D
EtOAc); 1H NMR (500 MHz, CDCl3) δ 0.89 (t, 3 H, J ) 7.3 Hz, CH3-
CH2), 1.00 (d, 3 H, J ) 6.5 Hz, CH3CH), 1.01 (d, 3 H, J ) 6.5 Hz,
CH3), 1.32 (m, 2 H, CH2), 1.48 (m, 2 H), 1.60-1.82 (br m, 3H), 2.71
(q, 1 H, J ) 8.8 Hz, CH), 2.93 (d, 1 H, J ) 10.3 Hz, CHOH), 3.32 (br
s, 1 H, OH), 3.72 (dd, 1 H, J ) 4.5; 11.8 Hz, CH2OH), 3.96 (dd, 1 H,
J ) 7.6; 11.8 Hz, CH2OH), 3.84 (d, 1 H, J ) 9.6 Hz, HOCH2), 4.44
(t, 1 H, J ) 9.6 Hz, CHOH), 4.59 (d, 1 H, J ) 5.0 Hz, NCH2O), 5.09
(d, 1 H, J ) 5.0 Hz, NCH2O) ppm; 13C NMR (125 MHz, CDCl3) δ
13.9, 18.5, 20.8, 22.8, 26.2, 27.9, 30.3, 50.4, 58.9, 71.7, 73.2, 75.6,
89.2, 179.9 ppm; HRMS (CI, NH3) m/z calcd for [C14H26NO4]+
272.1862, found for [M + H]+ 272.1870.
Aldol 17a: 79%; 1H NMR (500 MHz, CDCl3) δ 0.11 and 0.12 (each
s, 3 H, CH3Si), 0.92 (s, 9 H, t-BuSi), 0.94 (t, 3 H, J ) 7.3 Hz, CH3-
CH2), 0.99 (d, 3 H, J ) 6.7 Hz, (CH3)2CH), 1.03 (d, 3 H, J ) 6.7 Hz,
(CH3)2CH), 1.74 (m, 1 H, CH2CH3), 1.92 (m, 1 H, CH2CH3), 2.18 (sept,
1 H, J ) 6.7 Hz, CH(CH3)2), 2.68 (m, 1 H, CH), 3.58 (s, 3 H, OCH3),
3.63 (d, 1 H, J ) 6.3 Hz, CHOH), 3.93 (d, 1 H, J ) 13.1 Hz, CH2Ph),

2336 J. Am. Chem. Soc., Vol. 120, No. 10, 1998
Corey et al.
1
tert-Butyldimethylsilyl Ether of the n-Butyl Analogue of 15: H
NMR (500 MHz, CDCl3) δ 0.082 and 0.090 (2s, 3 H, CH3Si), 0.90 (s,
9 H, t-BuSi), 0.89 (t, 3 H, J ) 7.3 Hz, CH3), 1.00 (d, 3 H, J ) 6.4 Hz,
CH3), 1.02 (d, 3 H, J ) 6.4 Hz, CH3), 1.32 (m, 2 H), 1.50 (br m, 2 H),
1.60-1.80 (br m, 3 H), 2.70 (q, 1 H, J ) 9.2 Hz, CH), 2.90 (d, 1 H,
J ) 10.4 Hz, OH), 3.62 (d, 1 H, J ) 10.9 Hz, OCH), 3.70 (d, 1 H, J
) 10.8 Hz, CH2OSi), 3.99 (d, 1 H, J ) 10.8 Hz, CH2OSi), 4.39 (t, 1
H, J ) 10.1 Hz, CHOH), 4.54 (d, 1 H, J ) 5.0 Hz, NCH2O), 5.14 (d,
1 H, J ) 5.0 Hz, NCH2O) ppm; 13C NMR (125 MHz, CDCl3) δ -5.6,
-5.3, 14.0, 18.4, 18.5, 20.8, 22.8, 25.9, 26.4, 27.9, 30.2, 50.4, 60.3,
72.0, 73.0, 75.7, 89.4, 179.2 ppm.
Acid 16, Isopropyl Analogue: 77%; [R]23D +15° (c 0.02, MeOH);
1H NMR (400 MHz, pyridine-d5) δ 1.28 (d, 3 H, J ) 6.8 Hz, CH3),
1.30 (d, 3 H, J ) 6.8 Hz, CH3), 1.33 (d, 3 H, J ) 6.6 Hz, CH3), 1.58
(d, 3 H, J ) 6.6 Hz, CH3), 2.36 (sept, 1 H, J ) 6.6 Hz, CH), 2.66 (m,
1 H, CH), 2.40 (dd, 1 H, J ) 5.2; 9.6 Hz, CH), 4.73 (d, 1 H, J ) 5.7
Hz, CHOH), 5.28 (d, 1 H, J ) 5.3 Hz, HOCH), 9.11 (s, 1 H, NH)
ppm; 13C NMR (125 MHz, pyridine-d5) δ 18.9, 21.2, 21.7, 22.5, 26.1,
32.3, 53.0, 76.0, 76.9, 79.5, 174.8, 179.3 ppm; HRMS (FAB, NBA +
NaI) m/z calcd for [C12H21NO5Na]+ 282.1317; found for [M + Na]+
282.1323.
Acid 16, Benzyl Analogue: 76%; [R]23D -30° (c 0.02, MeOH); 1H
NMR (500 MHz, pyridine-d5) δ 1.27 (d, 3 H, J ) 6.6 Hz, CH3), 1.34
(d, 3 H, J ) 6.6 Hz, CH3), 2.36 (m, 1 H, CH), 3.64 (br d, 2 H, CH2-
Ph), 4.08 (br m, 1 H, CH), 4.65 (d, 1 H, J ) 5.5 Hz, CHOH), 5.13 (d,
1 H, J ) 5.6 Hz, CHOH), 7.15-7.60 (m, 5 H, ArH), 9.50 (s, 1 H, NH)
ppm; 13C NMR (100 MHz, pyridine-d5) δ 19.1, 21.1, 30.8, 32.2, 49.7,
75.5, 76.9, 79.3, 125.9, 128.7, 129.5, 142.8, 174.7, 178.6 ppm; HRMS
(FAB, NBA + NaI) m/z calcd for [C16H22NO5]+ 308.1498; found for
[M + H]+ 308.1487.
γ-Lactam 15, Isopropyl Analogue: 82%; [R]23 +11.4° (c 0.1,
D
1
EtOAc); H NMR (500 MHz, CDCl3) δ 1.00 (d, 6 H, J ) 6.3 Hz,
(CH3)2CH), 1.09 and 1.12 (each d, 3 H, J ) 6.8 Hz, CH3), 1.75 (br m,
1 H, CH), 2.24 (m, 1 H, CH), 2.53 (dd, 1 H, J ) 6.6; 8.8 Hz, CH),
2.86 (d, 1 H, J ) 10.2 Hz, CHOH), 3.30 (br s, OH), 3.77 (d, 1 H, J )
11.8 Hz, CH2OH), 3.99 (d, 1 H, J ) 11.8 Hz, CH2OH), 4.06 (d, 1 H,
J ) 9.1 Hz, CHOH), 4.52 (t, 1 H, J ) 9.1 Hz, CHOH), 4.56 (d, 1 H,
J ) 5.0 Hz, NCH2O), 5.13 (d, 1 H, J ) 5.0 Hz, NCH2O) ppm; 13C
NMR (100 MHz, CDCl3) δ 18.7, 20.3, 20.9, 23.3, 26.1, 28.0, 55.3,
59.2, 71.9, 72.4, 76.0, 88.4, 179.9 ppm; HRMS (CI, NH3) m/z calcd
for [C13H24NO4]+ 258.1705, found for [M + H]+ 258.1709.
â-Lactone 18a: [R]23D -215° (c 0.01, EtOAc); 1H NMR (500 MHz,
CDCl3) δ 0.91 (d, 3 H, J ) 6.8 Hz, CH3), 1.07 (d, 3 H, J ) 6.8 Hz,
CH3), 1.12 (t, 3 H, J ) 7.5 Hz, CH3CH2), 1.73 (m, 1 H, CH2CH3),
1.89 (m, 1 H, CHCH3), 1.96 (m, 1 H, CH2CH3), 2.10 (d, 1 H, J ) 6.5
Hz, CHOH), 2. 59 (m, 1 H, CH), 3.96 (dd, 1 H, J ) 4.60; 6.5 Hz,
tert-Butyldimethylsilyl Ether of the Isopropyl Analogue of 15:
1H NMR (500 MHz, CDCl3) δ 0.066 and 0.076 (each s, 3 H, CH3Si),
0.875 (s, 9 H, t-BuSi), 0.99 and 1.00 (each d, 3 H, J ) 6.5 Hz, CH3),
1.08 and 1.10 (each d, 3 H, J ) 6.7 Hz, CH3), 1.70 (m, 1 H), 2.22
(sept, 1 H, J ) 6.7 Hz, CH), 2.46 (dd, 1 H, J ) 7.4; 8.8 Hz, CH), 2.82
(d, 1 H, J ) 10.3 Hz, CHOH), 3.74 (d, 1 H, J ) 10.7 Hz, CH2OSi),
3.81 (d, 1 H, J ) 9.3 Hz, CHOH), 4.00 (d, 1 H, J ) 10.7 Hz, CH2-
OSi), 4.46 (t, 1 H, J ) 9.2 Hz, HOCH), 4.49 (d, 1 H, J ) 5.0 Hz,
NCH2O), 5.14 (d, 1 H, J ) 5.0 Hz, NCH2O) ppm; 13C NMR (125
MHz, CDCl3) δ -5.7, -5.5, 18.3, 18.8, 20.4, 20.9, 23.3, 25.8, 26.0,
28.0, 55.4, 60.5, 72.0, 72.3, 76.0, 88.5, 179.1 ppm.
CHOH), 5.28 (d, 1 H, J ) 6.0 Hz, CH), 6.26 (br s, 1 H, NH) ppm; 13
C
NMR(125 MHz, CDCl3) δ 12.4, 16.5, 18.0, 19.7, 29.8, 45.2, 72.1, 75.5,
78.5, 162.1, 179.2 ppm; HRMS (CI, NH3) m/z calcd for [C11H21N2O4]+
245.1501, found for [M + NH3]+ 245.1499.
â-Lactone 18b: [R]23D -253° (c 0.015, EtOAc); 1H NMR (400 MHz,
pyridine-d5) δ 0.80 (t, 3 H, J ) 7.3 Hz, CH3CH2), 1.03 (d, 3 H, J )
6.7 Hz, CH3), 1.12 (d, 3 H, J ) 6.7 Hz, CH3), 1.27 (br m, 2 H, CH2),
1.49 (br m, 2 H), 1.89 (br m, 1 H, CH), 2.13 (br m, 2 H), 3.01 (m, 1
H), 4.36 (br s, OH), 5.81 (d, 1 H, J ) 6.0 Hz, CH-O), 7.84 (br s, 1
H, OH), 10.46 (s, 1 H, NH) ppm; 13C NMR (100 MHz, pyridine-d5) δ
14.0, 16.6, 20.4, 23.0, 25.0, 29.9, 30.3, 44.4, 70.7, 76.5, 80.5, 172.3,
177.0 ppm; HRMS (CI, NH3) m/z calcd for [C13H25N2O4]+ 273.1814,
found for [M + NH4]+ 273.1809.
â-Lactone 18c: [R]23D -280° (c 0.015, EtOAc); 1H NMR (400 MHz,
pyridine-d5) δ 1.02 (d, 3 H, J ) 6.7 Hz, CH3), 1.11 (d, 3 H, J ) 6.9
Hz, CH3), 1.18 (d, 3 H, J ) 6.7 Hz, CH3), 1.42 (d, 3 H, J ) 6.9 Hz,
CH3), 2.10 (br m, 1 H, CH), 2.39 (m, 1 H, CH), 2.80 (dd, 1 H, J )
6.1; 8.6 Hz, CH), 4.32 (br s, 1 H, CHOH), 5.82 (d, 1 H, J ) 6.0 Hz,
CH-OCO), 7.84 (br d, 1 H, OH), 10.40 (s, 1 H, NH) ppm; 13C NMR
(125 MHz, pyridine-d5) δ 16.8, 20.4, 20.7, 22.0, 27.0, 29.9, 49.6, 70.8,
77.3, 79.9, 172.1, 176.3 ppm; HRMS (CI, NH3) m/z calcd for
[C12H23N2O4]+ 259.1658, found for [M + NH4]+ 259.1657.
â-Lactone 18d: [R]23D -320° (c 0.01, EtOAc); 1H NMR (400 MHz,
pyridine-d5) δ 0.90 (d, 3 H, J ) 6.4 Hz, CH3), 1.07 (d, 3 H, J ) 6.4
Hz, CH3), 2.07 (br m, 1 H, CH), 3.20 (t, 1 H, J ) 12.8 Hz, CH2Ar),
3.45 (m, 1 H, O-CH), 3.58 (dd, 1 H, J ) 3.6; 12.8 Hz, CH2Ar), 4.33
(br m, 1 H, CHOH), 5.62 (d, 1 H, J ) 5.8 Hz, HCOCO), 7.20-7.45
(m, 5 H, ArH), 7.83 (d, 1 H, J ) 6.7 Hz, OH), 10.69 (s, 1 H, NH)
ppm; 13C NMR (125 MHz, CDCl3) δ 16.5, 19.6, 29.8, 30.1, 46.4, 72.0,
75.1, 78.4, 126.9, 128.9, 128.9, 169.2 ppm; HRMS (FAB, NBA + NaI)
m/z calcd for [C16H19NO4Na]+ 312.1212, found for [M + Na]+
312.1217.
γ-Lactam 15, Benzyl Analogue: 84%; [R]23D +50° (c 0.01, EtOAc);
1H NMR (400 MHz, acetone-d6) δ 0.99 (dd, 6 H, J ) 6.7; 8.1 Hz,
(CH3)2CH), 1.85 (m, 1 H, CH), 2.98 (dd, 1 H, J ) 5.6; 13.9 Hz, CH2-
Ph), 3.04-3.14 (m, 2 H), 3.23 (dd, 1 H, J ) 8.6; 13.9 Hz, CH2Ph),
3.78 (dd, 1 H, J ) 5.6; 11.7 Hz, CH2OH), 4.01 (dd, 1 H, J ) 6.4; 11.7
Hz, CH2OH), 4.24 (t, 1 H, J ) 6.0 Hz, HOCH2), 4.56 (d, 1 H, J ) 4.6
Hz, NCH2O), 4.58 (t, 1 H, J ) 8.1 Hz, CHOH), 4.71 (d, 1 H, J ) 7.8
Hz, HOCH), 5.02 (d, 1 H, J ) 4.6 Hz, NCH2O), 7.10-7.35 (m, 5 H,
ArH) ppm; 13C NMR (100 MHz, acetone-d6) δ 18.9, 21.2, 28.7, 32.5,
52.2, 59.6, 50.7, 71.4, 73.4, 76.4, 88.9, 126.6, 128.9, 129.8, 141.7, 179.4
ppm; HRMS (FAB, NBA + NaI) m/z calcd for [C17H24NO4]+ 306.1705,
found for [M + H]+ 306.1715.
1
Acid 16, Ethyl Analogue: 75%; [R]23 -10° (c 0.01, MeOH); H
D
NMR (300 MHz, pyridine-d5) δ 1.13 (t, 3 H, J ) 7.3 Hz, CH3CH2),
1.29 (d, 3 H, J ) 6.8 Hz, CH3), 1.34 (d, 3 H, J ) 6.8 Hz, CH3), 2.26
(m, 2 H, CH2CH3), 2.37 (m, 1 H, CH(CH3)2), 3.54 (br q, 1 H, J ) 6.0
Hz, CH), 4.76 (d, 1 H, J ) 5.9 Hz, CHOH), 5.28 (d, 1 H, J ) 5.7 Hz,
CHOH), 9.36 (s, 1 H, NH) ppm; 13C NMR (125 MHz, pyridine-d5) δ
13.1, 18.3, 19.0, 21.2, 32.3, 49.2, 75.9, 76.8, 79.7, 174.9, 179.6 ppm;
HRMS (FAB, NBA + NaI) m/z calcd for [C11H20NO5]+ 246.1341,
found for [M + H]+ 246.1344.
Acid 16, n-Butyl Analogue: 78%; [R]23 -21° (c 0.01, MeOH);
D
1H NMR (400 MHz, pyridine-d5) δ 0.78 (t, 3 H, J ) 7.3 Hz, CH3),
1.30 (d, 3 H, J ) 6.6 Hz, CH3), 1.35 (d, 3 H, J ) 6.6 Hz, CH3), 1.21-
1.37 (br m, 2 H, CH2), 1.48 (br m, 1 H), 1.63 (br m, 1 H), 2.23 (br m,
2 H, CH2), 2.38 (sept, 1 H, J ) 6.1 Hz, CHOH), 5.28 (d, 1 H, J ) 5.7
Hz, HOCH), 9.30 (s, 1 H, NH) ppm; 13C NMR (100 MHz, pyridine-
d5) δ 14.3, 19.2, 21.1, 23.3, 24.7, 30.8, 32.3, 47.48, 76.0, 76.8, 79.8,
174.9, 179.7 ppm; HRMS (FAB, glycerol) m/z calcd for [C13H24NO5]+
274.1654, found for [M + H]+ 274.1662.
Acknowledgment. We are grateful for a supporting grant
from the National Institutes of Health.
JA973444C