Hetero-Diels-Alder and pyroglutamate approaches to (2S,4R)-2-methylamino-5- hydroxy-4-methylpentanoic acid

Article abstract of DOI:10.1016/j.tet.2004.08.089

The stereoselective syntheses of fully protected (2S,4R)-2-methylamino-5- hydroxy-4-methylpentanoic acid, a non-coded amino acid of cyclomarin A, and its diastereomer are reported. A pyroglutamate template was employed in the key diastereoselective alkylation used for introducing the 4-methyl stereochemistry. In addition, the first diastereoselective intramolecular hetero-Diels-Alder of a 2-cyano-1-azadiene with an electron deficient dienophile is described. Graphical Abstract

Full text of DOI:10.1016/j.tet.2004.08.089

Tetrahedron 60 (2004) 10277–10284
Hetero-Diels–Alder and pyroglutamate approaches to
(2S,4R)-2-methylamino-5-hydroxy-4-methylpentanoic acid
†
James E. Tarver, Jr., Kristen M. Terranova and Madeleine M. Joullie
†
*
´
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104, USA
Received 24 May 2004; revised 16 August 2004; accepted 26 August 2004
Available online 22 September 2004
Abstract—The stereoselective syntheses of fully protected (2S,4R)-2-methylamino-5-hydroxy-4-methylpentanoic acid, a non-coded amino
acid of cyclomarin A, and its diastereomer are reported. A pyroglutamate template was employed in the key diastereoselective alkylation
used for introducing the 4-methyl stereochemistry. In addition, the first diastereoselective intramolecular hetero-Diels–Alder of a 2-cyano-1-
azadiene with an electron deficient dienophile is described.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
azadiene to prepare the fully protected (2S,4R)-2-methyl-
amino-5-hydroxy-4-methylpentanoic acid fragment of
cyclomarin A. We also report the completed synthesis of
this fragment and its diastereomer (2S,4S)-2-methylamino-
5-hydroxy-4-methylpentanoic acid, using a pyroglutamate
framework for the establishment of stereochemistry.
Cyclomarin A (1, Fig. 1) is a potent anti-inflammatory
agent1 that has been a recent target of interest in several
research laboratories,2,3 including our own.4–7 The non-
coded amino acid constituents of cyclomarin A provide a
wealth of structural diversity and challenges which require
extension of the scope of existing methods or development
of new strategies for synthesizing these compounds. In our
continuing efforts to complete both novel and efficient
syntheses of these amino acids, we have investigated the use
of a hetero-Diels–Alder reaction employing a 2-cyano-1-
2. Results
The initial strategy used for making the (2S,4R)-2-
methylamino-5-hydroxy-4-methylpentanoic acid fragment
utilized a hetero-Diels–Alder reaction that allowed for
stereochemical control at both the 2- and 4-positions in one
step. The hydroxyl and N-methyl functionalities would be
introduced by oxidation of the olefin and reduction of the
resultant formyl groups. Azadienes have been used
previously in Diels–Alder (DA) reactions and their
application and scope have been reviewed thoroughly.8,9
Since the nitrogen of 1-azadienes renders the pi system
more electron deficient, its ability to undergo a Type I
Diels–Alder reaction is diminished. Most reported examples
of hetero-DA reactions with 1-azadienes occur via an
inverse electron demand (Type II) mechanism.8,9 If there
are enolizable protons at the 4-position, tautomerization
may occur to generate an enamine which can undergo the
DA reaction more easily with an electron deficient
dienophile8 (Fig. 2). Other factors contributing to the low
yields of hetero-DA reactions using 1-azadienes include
competitive imine [2C2] cycloadditions and the instability
of the enamine products. The low reactivity and product
instability may be reduced by the use of substrates with
N-acyl,10 N,N-sulfonyl8 or N,N-dialkylamino11 substitution
Figure 1. Cyclomarin A.
Keywords: Hetero-Diels–Alder; Pyroglutamate; Cyclomarin A.
* Corresponding author. Tel.: C1-215-898-3158; fax: C1-215-573-9711;
e-mail: mjoullie@sas.upenn.edu
† Lexicon Pharmaceuticals, Medicinal Chemistry, 350 Carter Road,
Princeton, New Jersey 08540, USA.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.089

10278
J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
or methoxy group at the 2-position on the diene (Fig. 4). It
was predicted that the proposed synthon would lead to the
undesired (2S,4S)-diastereomer (Fig. 5); however, there was
reason to believe that the desired compound could be
produced by modification of the chiral auxiliary or
epimerization.
Figure 2. 1-Azadienes can undergo tautomerization to enamides.
The synthesis (Scheme 1) began with S-phenylglycinol,
which is available from Aldrich or from a borohydride
reduction of phenylglycine ethyl ester hydrochloride salt.15,16
The amino alcohol was treated with trans-crotonyl chloride
and 2 N sodium carbonate under biphasic conditions to give
the crotonamide 2 in 97% yield.17 The subsequent
esterification step was achieved by treating the crotonamide
with acryloyl chloride under phase transfer conditions in
93% yield.18 The enamide 3 was then treated with Hunig’s
base and triflic anhydride at K60 8C, followed by displace-
ment of the vinyl triflate by lithium cyanide and 12-crown-4
complex to provide the 2-cyano-1-azadiene 4 in low yield.
This triene was heated to 110 8C in benzene for 48 h,
yielding an unstable bicyclic compound 5 the structure and
stereochemistry of which were determined by spectroscopic
methods to be those of a single diastereomer. Despite the
low yield, this reaction represents the first example of
remote asymmetric induction with either intermolecular or
intramolecular DA reactions of 2-cyano-1-azadienes.4 It is
also the first example of a diastereoselective intramolecular
DA reaction of a 2-cyano-1-azadiene with an electron
deficient dienophile. Unfortunately, treatment of the
unstable cycloadduct with ozone led to decomposition.
on the nitrogen. It is believed that the acyl and sulfonyl
substitution stabilize the enamine products; the dialkyl
group increases the electron density in the system. It has
also been observed that a methoxy or cyano group at the
2-position on the azadiene improves the DA reaction10,12,13
(Fig. 3).
Figure 3. Electronic stabilizing groups for 1-azadienes.
Motorina and Grierson have extensively investigated the
use of 2-cyano-1-azadienes in DA or intramolecular DA
(IMDA) reactions.14 The authors observed that 2-cyano-1-
azadienes may undergo DA type reactions in a regio-
controlled fashion with moderate stereocontrol. We
expected that existing chirality in the diene or dienophile
in our system would induce asymmetry to the remote methyl
center. It was believed that this effect could be enhanced if
the reaction was run in an intramolecular fashion. In
addition, the regiochemistry of the DA reaction could be
controlled by the tether restriction. The most accessible
location for the chiral auxiliary would be attached to the
nitrogen at the 1-position, though it would reduce the
reactivity of the diene itself. It was hoped that this
deficiency could be overcome by the addition of a cyano
Given the difficulties encountered in formation of the
cyanoazadiene and its low reactivity, other methods were
investigated (Scheme 2). The effect of an electron donating
substituent in the diene system was probed by the addition
of a 2-alkoxy group, employing imidoesters and an oxazo-
line. The methyl imido ester was formed by treatment of the
enamide 3 with methyl triflate, but heating this unstable
compound (7) in a sealed tube yielded only decomposition
products. Use of a microwave reactor gave the same results.
Figure 4. Hetero-Diels–Alder disconnections.
Figure 5. 2-Methylamino-5-hydroxy-4-methylpentanoic acid stereochemistry for both possible Diels–Alder adducts.

J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
10279
conditions having previously used TMSCl, ZnCl2 and TEA
in toluene at high temperature20 to effect the DA reaction of
enamides with a,b-unsaturated esters.21 Using TBSOTf or
TMSCl/ZnCl2 and TEA, attempts were made to form the
azadiene in situ at both ambient and elevated temperature.
Both reactions resulted either in recovery of starting
material or decomposition. In an effort to improve the
electronic alignment, an electron-withdrawing group was
installed on the terminus of the acrylate functionality. The
expectation was that even if the DA reaction did not occur,
maybe a degenerate mechanism, such as a base-mediated
tandem conjugate addition would allow generation of the
desired product. However, after many variations of the
hetero-Diels–Alder route were attempted with no significant
improvement, this approach was eventually abandoned for a
more favorable one.5
3. Discussion
Scheme 1. Reagents and conditions: (a) trans-crotonyl chloride, aq
Na2CO3, CH2Cl2, 97%; (b) 30% aq KOH, CH2Cl2, acryloyl chloride,
TBAI, 0 8C, 93%; (c) DIEA, Tf2O, CH2Cl2, K60 8C; (d) 12-crown-4,
LiCN, THF, K60 8C, 24% over 2 steps; (e) toluene, 120 8C, 48 h, 9%; (f)
ozone, CH2Cl2, K78 8C; NaBH4, MeOH.
The pyroglutamate moiety is a powerful synthetic building
block that has been previously used to prepare glutamic acid
and leucine derivatives.22,23 Its versatility and high func-
tional group density allows it to be used for a variety of
Scheme 2. Reagents and conditions: (a) MeOTf, CH2Cl2; (b) 150 8C, 12 h, neat; (c) benzene, 110 8C, 4d; (d) 5 M ether–LiClO4, 5 days.
Treatment of alcohol 2 with tosyl chloride and triethylamine
produced oxazoline 8 in 63% yield (Scheme 3).17 This
compound was then treated with several conditions includ-
ing various dienophiles, but no reaction was observed
except decomposition in certain instances. The lack of
reactivity was attributed to the preferred s-trans confor-
mation of the pi system when the diene’s 4-position is
substituted.
targets.24 It was envisioned that using a stereoselective
alkylation at the a-position of the amide followed by
inversion would afford the product with the desired
stereochemistry (Fig. 6). Investigations by several
groups24–28 had validated the feasibility of this approach,
but conflicting results were obtained with regard to the
cis:trans selectivity of the alkylation depending on the
substrate, base and electrophile.25,27–30 Young and co-
workers found that the major product of alkylation mixtures
was the cis product.29,30 Furthermore, they were able to
improve both the yield and stereoselectivity of the reaction
to 70% and a 17:1 cis:trans ratio29 if lithium hexamethyl-
disilazide was used as the base and methyl triflate as the
electrophile.
Huang and co-workers reported intramolecular DA reac-
tions with 1-azadiene substrates that were formed in situ for
Figure 6. Pyroglutamic acid disconnection.
Scheme 3. Reagents and conditions: (a) TsCl, TEA, CH2Cl2, 2d, 63%; (b)
maleic anhydride, 110–115 8C; (c) diethyl acetylene dicarboxylate.
In our system, the original protecting group was a benzyl
ester, with the hope that upon lithium hydroxide opening of
the lactam ring little or no hydrolysis of the ester would
occur. The synthesis (Scheme 4) proceeded in good yield
following the procedure of Young and co-workers to afford
the fully protected pyroglutamate 11.22 The stereoselective
alkylation using LiHMDS and methyl triflate followed by
the construction of heterocyclic ring systems.19 The
advantages of these reactions were the mild conditions
(trialkylsilyl chlorides and triethylamine) under which they
proceeded. Fukomoto and co-workers used the milder
trialkylsilyl trifluoromethanesulfonates and triethylamine

10280
J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
DMAP) did not increase the yield. Eventually, changing the
solvent to DMF and using TBSCl with the TEA/DMAP
system successfully provided TBS ether 18 in 91% yield.
N-Boc protected nitrogens have been previously methylated
using NaH or KH32 though in this particular case both
reagents met with limited success. Using NaHMDS as the
base33 provided methylated product 19 in 36% yield. In an
effort to improve the methylation, carbamate 18 was treated
with Ag2O and MeI,34 which led to a clean product in 50%
yield. The nitrogen was methylated in 70% yield using
optimized conditions of NaHMDS (2.5 equiv) and MeI
(10 equiv), to provide the fully protected unnatural
diastereomer of (2S,4S)-2-methylamino-5-hydroxy-4-
methylpentanoic acid 19 with the same stereochemistry as
the product obtained in the hetero-DA reaction.
Scheme 4. Reagents and conditions: (a) TEA, benzyl chloride, acetone,
85%; (b) Boc2O, DMAP, CH3CN, 73%; (c) LiHMDS, MeOTf, Toluene,
K78 8C; (d) LiHMDS, 2,6-di-t-butylphenol, Toluene, K78 8C, 34% over 2
steps; (e) 1 M LiOH, THF, 30 min, 0 8C, 54%.
The stereoselective alkylation of the protected pyrogluta-
mate yielded two diastereomers, the major product being the
undesired cis product 16, but the products were separable by
column chromatography. The cis product had been
isomerized previously by Ezquerra and co-workers, using
1 equiv of KCN in DMF over 4 days to give a final ratio of
33:67 of cis:trans product.27,26 Conditions which would
allow for faster reaction time while maintaining a similar
yield and product ratio were desired.
inversion using LiHMDS and ammonium chloride pro-
ceeded with a cis:trans ratio of 1:4 in 34% yield over two
steps. The lithium hydroxide ring opening did not proceed
as well as planned and generated what was believed to be
the desired benzyl ester 13 as well as the free carboxylic
acid 14, but never in isolable yields. A modification of the
protecting group scheme was required and we investigated
the use of a tert-butyl group instead of a benzyl moiety.
Initial studies with the benzyl ester indicated that use of
LiHMDS and a kinetic quench with ammonium chloride
would give a cis:trans ratio of 1:4; however, this result did
not translate to the tert-butyl ester series. Despite numerous
trials with various conditions, products were obtained which
consisted primarily of the cis isomer. Use of KHMDS and
ammonium chloride led to decomposition, while NaHMDS
with ammonium chloride led to more successful inversion
(1:2 cis:trans), but in reduced yield. Using acetic acid to
quench the isomerization after enolization with NaHMDS23
led to recovery of starting material. The next bases tried
were DABCO and DBU; DABCO produced no reaction and
led only to the isolation of starting material. However, the
use of 4 equiv of DBU in methylene chloride over 2 days
consistently gave primarily inverted product 20 in a 3:1 ratio
and in high yields (Scheme 6). With epimerization
achieved, the lactam ring was hydrolyzed selectively with
The tert-butyl ester allowed for opening of the lactam ring
without hydrolysis of the ester.22 Beginning with fully
protected pyroglutamate 11, the ester was deprotected using
standard hydrogenation conditions and protected as the tert-
butyl ester 15 using Boc2O, TEA, and DMAP in acetonitrile
in an 83% yield over 2 steps (Scheme 5). The stereoselective
alkylation proceeded in 70% yield with a 7:1 ratio of cis
16:trans. The lithium hydroxide opening proceeded in
quantitative yield, and subsequent reduction of the mixed
anhydride produced the alcohol in 69% yield.22,31 The
resulting alcohol was to be protected as its TBS ether.
Standard conditions of TBSCl and imidazole in methylene
chloride led to consistently low yields. Variation of the
base-catalyst system (imidazole, 2,6-lutidine and TEA/
Scheme 5. Reagents and conditions: (a) (i) H2, Pd/C, EtOAc; (ii) Boc2O,
DMAP, TEA, MeCN, 83%; (b) (i) LiHMDS, THF, K78 8C; (ii) MeOTf,
70% 7:1; (c) LiOH, THF, 0 8C to rt, quant; (d) (i) i-BuOCOCl, TEA, THF,
K40 8C; (ii) NaBH4, H2O, 0 8C, 69%; (e) TBSCl, DMAP, TEA, DMF,
91%; (f) (i) NaHMDS, THF, 0 8C to rt; (ii) MeI, 70%.
Scheme 6. Reagents and conditions: (a) 4 equiv DBU, CH2Cl2, 0 8C to rt,
86%, 3.1:1; (b) LiOH, THF, 0 8C to rt, 78%; (c) (i) i-BuOCOCl, TEA, THF,
K40 8C; (ii) NaBH4, H2O, 0 8C, 67%; (d) TBSCl, DMAP, TEA, DMF,
93%; (e) (i) NaHMDS, THF, 0 8C to rt; (ii) MeI, 57%.

J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
10281
lithium hydroxide. Mixed anhydride reduction of the
resulting acid 21 proceeded in 67% yield to afford the
primary alcohol 22. The TBS protection and subsequent
N-methylation proceeded in 93 and 57% yields, respect-
ively, using conditions developed during synthesis of the
unnatural diastereomer to give fully protected (2S,4R)-2-
methylamino-5-hydroxy-4-methylpentanoic acid 24.
calculated for C15H17NO3Na (MCNa)C282.1106, found
282.1093; [a]2D5C56.4 (c 3.63, CHCl3).
5.1.2. (S)-Acrylic acid 2-(1-cyano-but-2-enylidene-
amino)-2-phenylethyl ester 4. A cold (K60 8C) solution
of acrylate 3 (0.500 g, 1.93 mmol) and diisopropylethyl
amine (0.5 mL, 2.89 mmol) in CH2Cl2 (6.5 mL) was stirred
for 1 h. Triflic anhydride (freshly opened bottle) was added
dropwise. The reaction was allowed to stir 2 h during which
time it turned to a brown solution. To this reaction mixture
was added a suspension of (89 mg, 2.72 mmol) LiCN (dried
over P2O5 under vacuum at 80 8C for 4 h) and 12-crown-4
(30 mL, 0.19 mmol) in THF (6 mL) at K73 8C via cannula
syringe and then warmed to K60 8C for 1.5 h. After that
time, the reaction was warmed to K20 8C over 30 min and
water (6 mL) was added. The reaction was diluted with
ether while warming to room temperature. The layers
formed were separated and the aqueous layer was extracted
with ether (2!10 mL). The combined organic layers were
washed with water (10 mL), dried (Na2SO4) and concen-
trated to a brown oil. Column chromatography (5% acetone/
hexanes to 8% acetone/hexanes) afforded a yellow oil
(0.111 g, 21%). (4): Rf 0.65 (30% acetone/hexanes); 1H
NMR (500 MHz, CDCl3) d 7.27–7.52 (m, 5H), 6.71–6.78
(m, 1H), 6.37–6.41 (m, 2H), 6.09 (dd, JZ17.4, 10.4 Hz,
1H), 5.83 (dd, JZ10.5, 1.3 Hz, 1H), 5.08–5.13 (m, 1H),
4.50 (dd, JZ11.1, 3.9 Hz, 1H), 4.40 (dd, JZ11.1, 9.2 Hz,
1H), 1.96 (dd, JZ6.9, 1.6 Hz, 3H); HRMS (CI) m/z
calculated for C16H17N2O2 (MCH)C269.1284, found
269.1284. Product was too unstable for further
characterization.
4. Conclusions
The synthesis of the fully protected (2S,4R)-2-methyl-
amino-5-hydroxy-4-methylpentanoic acid fragment of
cyclomarin A was accomplished in 8 steps and 14% overall
yield. In addition, we have synthesized (2S,4S)-2-methyl-
amino-5-hydroxy-4-methylpentanoic acid in 7 steps and
26% overall yield. We also have reported the first example
of a diastereoselective intramolecular Diels–Alder reaction
of a 2-cyano-1-azadiene with an electron deficient
dienophile.
5. Experimental
5.1. General
All reactions were performed under argon. THF was
distilled over sodium-benzophenone, while CH2Cl2 and
toluene were distilled over calcium hydride. Flash column
chromatography was carried out on E. Merck silica gel 60
(240–400 mesh) using the solvent systems listed under
individual experiments. Proton and carbon magnetic
resonance spectra were recorded on a Bruker AM-500
Fourier transform spectrometer. Infrared spectra (IR) were
obtained on a Perkin–Elmer Model 1600 FT-IT spectro-
photometer. Optical rotations were recorded on a Perkin–
Elmer Model 341 polarimeter at the sodium D line. Melting
points were obtained on a Thomas Hoover Uni-melt
apparatus and are uncorrected.
5.1.3. (4S,8S,10S)-8-Methyl-1-oxo-4-phenyl-1,3,4,8,9,9a-
hexahydropyrido[2,1-c][1,4]oxazine-6-carbonitrile 5.
Azadiene 4 (164 mg, 0.61 mmol) was dissolved in toluene
(12 mL), placed in a sealed tube and charged with a
magnetic stirrer. The reaction was heated to 130 8C for 50 h.
The compound was concentrated and purified by column
chromatography (2% ethyl acetate/hexanes to 8% ethyl
acetate/hexanes) to afford the product as a brown oil,
(14 mg, 9%) and starting material, as a yellow oil, (39 mg,
1
24%). (5): Rf 0.54 (30% ethyl acetate/hexanes); H NMR
5.1.1. (S)-Acrylic acid 2-but-2-enoylamino-2-phenylethyl
ester 3. To a cold (0 8C) solution of alcohol 2 (2.29 g,
11.0 mol) in CH2Cl2 (20 mL) was added 30:70 KOH
solution (20 mL) and tetrabutylammonium iodide (TBAI,
0.406 g, 1.1 mmol). To the reaction mixture was added
acryloyl chloride (1.3 mL, 15.6 mmol) in CH2Cl2 (3 mL)
via an addition funnel at 0 8C. After 20 min, the organic
layer was separated. The organic layer was then washed
with water (3!10 mL) until the aqueous layer was neutral.
The organic phase was dried (Na2SO4) and concentrated to
yield an orange oil. Column chromatography (20% acetone/
hexanes) afforded a clear white glass (2.65 g, 93%). (3): Rf
0.25 (30% acetone/hexanes, KMnO4 stain); 1H NMR
(500 MHz, CDCl3) d 7.27–7.35 (m, 5H), 6.79–6.89 (m,
1H), 6.55–6.62 (m, 1H), 6.49 (dd, JZ17.4, 1.2 Hz, 1H),
6.10 (dd, JZ17.3, 10.4 Hz, 1H), 5.80–5.89 (m, 2H), 5.36–
5.45 (m, 1H), 4.51 (dd, JZ11.4, 7.5 Hz, 1H), 4.37 (dd, JZ
11.5, 6.7 Hz, 1H), 1.83 (dd, JZ6.9, 1.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 166.2, 165.5, 140.3, 138.4, 131.4,
128.6, 127.8, 127.8, 126.7, 124.8, 66.1, 52.4, 17.6; IR (neat)
3282, 3064, 1726, 1670, 1633, 1541, 1446, 1408, 1294,
1269, 1188, 1060, 968, 810, 700 cmK1; HRMS m/z
(500 MHz, CDCl3) d 7.32–7.45 (m, 5H), 4.93 (t, JZ3.8 Hz,
1H), 5.33 (s, 1H), 4.66–4.76 (m, 2H), 3.86 (dd, JZ11.2,
3.1 Hz, 1H), 2.43–2.51 (m, 2H), 1.65 (quartet of doublets,
JZ12.1, 2.5 Hz, 1H), 1.08 (d, JZ6.7 Hz, 3H); 13C NMR
(125 MHz, CDCl3) d 167.7, 135.4, 128.7, 127.9, 127.3,
123.2, 115.2, 70.6, 56.2, 54.1, 32.7, 29.7, 28.4, 20.3; HRMS
(CI) m/z calculated for C16H17N2O2 (MCH)C269.1284,
found 269.1284. Product was too unstable for further
characterization.
5.1.4. (S)-Acrylic acid 2-(1-methoxy-but-2-enylidene-
amino)-2-phenylethyl ester 7. To a solution of amide 3
(1.67 g, 7.45 mmol) in CH2Cl2 (25 mL) was added methyl
triflate (1.5 mL, 12.88 mmol) dropwise at room tempera-
ture. The reaction was allowed to stir for 96 h then diluted
with CH2Cl2 (40 mL), washed with saturated sodium
bicarbonate (30 mL) and dried (Na2SO4). The solution
was concentrated in vacuo to a yellow oil. Column
chromatography (10% acetone/hexanes to 20% acetone/
hexanes) afforded the product as a yellow oil (0.844 g, 48%)
as well as starting material (40%). (7): Rf 0.61 (30%

10282
J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
1
acetone/hexanes); H NMR (500 MHz, CDCl3) d 7.45 (m,
2H), 7.32 (m, 2H), 7.25 (m, 1H), 6.54 (m, 1H), 6.35 (m, 1H),
6.08 (m, 2H), 5.78 (m, 1H), 4.90 (dd, JZ8.1, 5.0 Hz, 1H),
4.35 (ddd, JZ10.7, 5.1, 2.8 Hz, 1H), 4.25 (m, 1H), 3.75
(d, JZ2.2 Hz, 3H), 1.80 (m, 3H); 13C NMR (125 MHz,
CDCl3) d 166.0, 158.5, 141.5, 137.7, 130.6, 128.5, 128.3,
127.3, 117.9, 117.8, 69.7, 69.5, 59.8, 52.4, 18.2; IR (neat)
3060, 3028, 2944, 2348, 2096, 17,225, 1673, 1621, 1492,
1437, 1406, 1377, 1287, 1265, 1182, 1098, 1044, 986, 963,
839 cmK1; HRMS (CI) m/z calcd for C16H19NO2 (MCH)C:
274.1440, found 274.1435; [a]2D5C5.98 (c 1.05, CHCl3).
The reaction stirred at 0 8C for 10 min and at room
temperature for 30 min before iodomethane (0.07 mL,
1.07 mmol) was added dropwise. After 2 h, the reaction
was quenched with the addition of saturated NH4Cl and
ether. The aqueous portion was extracted 3 times with ether
and the combined organic portions were washed with water
and brine, dried over MgSO4, filtered and concentrated. The
crude product was purified by flash chromatography using
1% acetone in petroleum ether, which yielded 19 as a yellow
oil (0.0326 g, 70%). (19): Rf 0.64 (5% acetone/petroleum
1
ether); H NMR (500 MHz, CDCl3) d 4.75 (dd, JZ11.8,
2.9 Hz, 0.5H), 4.51 (dd, JZ11.7, 3.7 Hz, 0.5H), 3.43 (dd,
JZ9.7, 5.1 Hz, 1H), 3.35 (m, 1H), 2.73 (d, JZ15.7, 3H),
1.90 (m, 1H), 1.51 (m, 1H), 1.47 (m, 1H), 1.43 (s, 9H), 1.42
5.1.5. (2S,4R)-4-Methyl-5-oxo-pyrrolidine-1,2-dicar-
boxylic acid 2-benzyl ester 1-tert-butyl ester, trans-12,
and (2S,4S)-4-Methyl-5-oxo-pyrrolidine-1,2-dicar-
boxylic acid 2-benzyl ester 1-tert-butyl ester, cis-12. To
a cooled (K78 8C) solution of lactam 11 (1.00 g,
3.13 mmol) in anhydrous toluene (6 mL) was added 1 M
LiHMDS solution in THF (3.6 mL, 3.60 mmol). After
stirring for 1 h at the same temperature, methyl triflate
(0.39 mL, 3.44 mmol) was added via syringe. After stirring
for another 2 h at K78 8C, 1 M LiHMDS in THF (4.1 mL,
4.07 mmol) was added to the reaction mixture. Following
another 2 h of stirring at K78 8C, the reaction was quenched
with saturated ammonium chloride and allowed to warm to
room temperature for 10 min before diluting it with ethyl
acetate. The reaction was extracted into ethyl acetate (3!
25 mL), dried with sodium sulfate and concentrated to a
yellow-tan foam. The crude residue was purified by column
chromatography (5% ethyl acetate/hexanes to 30% ethyl
acetate/hexanes) to afford 0.280 g (27%) of yellow oil trans-
12 and 0.070 g (7%) of yellow oil cis-12. (trans-12): Rf 0.70
1
(s, 9H), 0.87 (m, 3H), 0.86 (s, 9H), 0.01 (s, 6H); H NMR
(500 MHz, d8-toluene, 363 K) d 4.82 (m, 1H), 3.43 (m, 2H),
2.85 (s, 3H), 1.98 (m, 1H), 1.69 (m, 2H), 1.44 (s, 9H), 1.35
(s, 9H), 0.96 (d, JZ2.9 Hz, 3H), 0.93 (s, 9H), 0.05 (s, 6H);
13C NMR (125 MHz, CDCl3) d 171.7, 171.4, 156.4, 155.9,
81.1, 81.0, 79.9, 79.6, 68.3, 68.3, 57.2, 56.1, 32.2, 31.9,
30.1, 28.4, 28.0, 25.9, 18.3, 15.6, 15.5, K5.4; 13C NMR
(125 MHz, d8-toluene, 363 K) d 171.6, 156.5, 80.9, 79.7,
69.1, 58.1, 33.8, 33.4, 31.0, 30.8, 28.9, 28.5, 26.5, 18.9,
16.5, K5.0; IR (neat) 2956, 2930, 2857, 1737, 1700, 1472,
1391, 1367, 1324, 1254, 1154, 1093, 1034, 1007, 950, 912,
838, 776, 666 cmK1; HRMS (ESI) m/z calcd for
C22H45NO5Si (MCNa)C: 454.3051, found 454.2944;
[a]2D5K16.8o (c 1.15, CHCl3).
5.1.7. (2S,4R)-4-Methyl-5-oxopyrrolidine-1,2-dicar-
boxylic acid di-tert-butyl ester 20.30 cis-Methylpyrogluta-
mate 16 (0.1571 g, 0.525 mmol) was taken up in 4.1 mL
CH2Cl2 and cooled to 0 8C. DBU (0.31 mL, 2.10 mmol) was
added dropwise and the reaction stirred at 0 8C for 15 min
and then at room temperature for 48 h. The reaction was
diluted with CH2Cl2, washed twice with 10% HCl, and once
each with water and brine. The organic portion was dried
over Na2SO4, filtered and concentrated to give the crude
product which was purified by flash chromatography using
5–10% ethyl acetate in petroleum ether yielding 20 as a
clear colorless oil (0.1351 g, 86% in a 3.1:1 ratio of trans/
1
(40% ethyl acetate/petroleum ether); H NMR (500 MHz,
CDCl3) d 7.26–7.41 (m, 5H), 5.25 (d, JZ12.2 Hz, 1H), 5.20
(d, JZ12.2 Hz, 1H), 4.62 (dd, JZ9.6, 1.3 Hz, 1H), 2.55–
2.73 (m, 1H), 2.14–2.35 (m, 1H), 1.80–2.00 (m, 1H), 1.46
(s, 9H), 1.23 (d, JZ7.1 Hz, 3H); 13C NMR (125 MHz,
CDCl3) d 175.5, 171.1, 149.5, 135.1, 128.7, 128.6, 128.4,
83.5, 67.3, 57.0, 36.5, 30.5, 27.8, 15.1; IR (neat) 3033, 2977,
2934, 2879, 2359, 1792, 1752, 1716, 1498, 1456, 1391,
1368, 1316, 11,284, 1251, 1185, 1153, 1120, 1100, 1061,
973, 014, 854, 776, 750, 699 cmK1; HRMS (ESI) m/z calcd
for C18H23NO5 (MCNa)C: 356.1576, found 356.1484;
[a]2D5K18.08 (c 1.42, CHCl3).
1
cis). (20): Rf 0.65 (30% ethyl acetate/petroleum ether); H
NMR (500 MHz, CDCl3) d 4.35 (dd, JZ9.5, 1.1 Hz, 1H),
2.58 (m, 1H), 2.17 (ddd, JZ13.2, 8.7, 1 Hz, 1H), 1.83 (m,
1H), 1.48 (s, 9H), 1.47 (s, 9H), 1.14 (d, JZ7 Hz, 3H); 13C
NMR (125 MHz, CDCl3) d 175.7, 170.2, 149.4, 89.9, 82.1,
57.6, 36.4, 30.6, 27.8, 22.5, 15.1; IR (neat) 2977, 2934,
2359, 23,341, 1792, 1739, 1717, 1457, 1368, 1315, 1284,
1
(cis-12): Rf 0.57 (40% ethyl acetate/petroleum ether); H
NMR (500 MHz, CDCl3) d 7.26–7.41 (m, 5H), 5.20 (d, JZ
12.1 Hz, 1H), 5.14 (d, JZ12.1 Hz, 1H), 4.47–4.54 (m, 1H),
2.46–2.64 (m, 2H), 1.51–1.64 (m, 1H), 1.47 (s, 9H), 1.19 (d,
JZ6.6 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 175.5,
171.2, 149.3, 134.9, 128.5, 128.5, 128.4, 83.4, 67.1, 57.3,
37.3, 29.5, 27.7, 16.1, 14.1; IR (neat) 3033, 2978, 2934,
2878, 2360, 1790, 1751, 1716, 1498, 1456, 1392, 1369,
1318, 1292, 1259, 1176, 1154, 1124, 969, 913, 850, 784,
749, 699 cmK1; HRMS (CI) m/z calcd for C18H23NO5 (MC
H)C: 334.1654, found 334, 1656; [a]2D5K43.98 (c 1.38,
CHCl3).
1249, 1225, 1154, 1099, 973, 917, 884, 846, 813, 775 cmK1
;
HRMS (ESI) m/z calcd for C15H25NO5 (MH)C: 300.1811,
found 300.1805; [a]2D5K12.68 (c 1.11, CHCl3).
5.1.8. (2S,4R)-2-tert-Butoxycarbonylamino-4-methyl-
pentanedioic acid 1-tert-butyl ester 21. trans-Methyl-
pyroglutamate 20 (0.1039 g, 0.347 mmol) was taken up in
1.8 mL THF and cooled to 0 8C. 0.42 mL 1 M LiOH
(aqueous, 0.416 mmol) was added dropwise over 15 min,
the reaction was stirred for 15 min and was the quenched by
addition of a mixture of ethyl acetate (1 mL) and saturated
sodium bicarbonate (1 mL). The layers were separated and
the organic portion was extracted with saturated sodium
bicarbonate. The aqueous portions were combined, cooled
to 0 8C and acidified to pH 4 using 10% citric acid and
5.1.6. (2S,4S)-2-(tert-Butoxycarbonylmethylamino)-5-
(tert-butyldimethylsilanyloxy)-4-methylpentanoic acid
tert-butyl ester 19. To a solution of TBS ether 18
(0.0448 g, 0.107 mmol) in THF (0.8 mL) at 0 8C, NaHMDS
(1.0 M in THF, 0.27 mL, 0.268 mmol) was added dropwise.

J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
10283
extracted 5 times with ethyl acetate. The combined organic
layers were dried over Na2SO4, filtered and concentrated
yielding 21 as a white solid (0.0862 g, 78%). (21): mp 72–
74 8C; Rf 0.54 (50% ethyl acetate/petroleum ether); 1H
NMR (500 MHz, CDCl3) d 10.42 (bs, 1H), 5.21 (d, JZ
6.6 Hz, 1H), 5.01 (d, JZ8.3 Hz, 1H), 2.56 (m, 1H), 2.17 (m,
1H), 1.64 (m, 1H), 1.43 (s, 9H), 1.40 (s, 9H), 1.20 (d, JZ
6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) d 180.3, 171.4,
155.8, 82.4, 80.2, 52.5, 36.8, 36.2, 28.2, 27.9, 17.4; IR (neat)
3330, 2978, 2931, 2359, 2340, 1714, 1508, 1455, 1396,
1368, 1255, 1154, 1061, 847, 669 cmK1; HRMS (ESI) m/z
calcd for C15H27NO6 (MCNa)C: 340.1838, found
340.1731; [a]2D5K23.48 (c 1.4, MeOH).
(neat) 3359, 2956, 2930, 2857, 2348, 1718, 1501, 1472,
1392, 1366, 1252, 1154, 1093, 1049, 836, 776 cmK1
;
HRMS (ESI) m/z calcd for C21H43NO5Si (MCNa)C:
440.2910, found 440.2796; [a]2D5K0.58 (c 1.09, CHCl3).
5.1.11. (2S,4R)-2-(tert-Butoxycarbonylmethylamino)-5-
(tert-butyldimethylsilanyloxy)-4-methylpentanoic acid
tert-butyl ester 24. The procedure described above for
compound 19 was followed, using TBS-ether 23 (0.1250 g,
0.299 mmol). Compound 24 was isolated as a pale yellow
oil (0.0739 g, 57%). (24): Rf 0.59 (5% acetone/petroleum
1
ether); H NMR (500 MHz, CDCl3) d 4.67 (dd, JZ10.2,
5.0 Hz, 0.5H), 4.40 (dd, JZ10.1, 5.0 Hz, 0.5H), 3.43 (m,
2H), 2.76 (d, JZ20.6 Hz, 3H), 1.92 (m, 1H), 1.56 (m, 1H),
1.44 (m, 1H), 1.42 (s, 9H), 1.41 (s, 9H), 0.92 (d, JZ6.8 Hz,
3H), 0.86 (s, 9H), 0.01 (d, JZ4.7 Hz, 6H); 1H NMR
(500 MHz, d8-toluene, 363 K) d 4.77 (m, 1H), 3.51 (d, JZ
4.0 Hz, 2H), 2.84 (d, JZ12.8 Hz, 3H), 1.69 (m, 1H), 1.53
(m, 2H), 1.48 (s, 9H), 1.41 (s, 9H), 0.98–0.94 (m, 3H), 0.97
(s, 9H), 0.08 (d, JZ7.3 Hz, 6H); 13C NMR (125 MHz,
CDCl3) d 171.5, 171.3, 156.2, 155.9, 81.1, 79.9, 79.6, 66.5,
57.9, 56.6, 32.3, 32.0, 30.5, 29.7, 28.4, 28.0, 25.9, 18.3,
17.7, 17.5, K5.4; 13C NMR (125 MHz, d8-toluene, 363 K) d
171.5, 156.4, 80.8, 79.7, 67.7, 58.5, 33.7, 33.4, 31.0, 28.9,
28.5, 26.5, 18.9, 17.9, K5.0; IR (neat) 2956, 2930, 2857,
2350, 1737, 1700, 1472, 1391, 1367, 1323, 1254, 1148,
1096, 1045, 1006, 952, 910, 838, 776, 665 cmK1; HRMS
(ESI) m/z calcd for C22H45NO5Si (MCNa)C: 454.3051,
found 454.2977; [a]2D5K18.48 (c 1.06, CHCl3).
5.1.9. (2S,4R)-2-tert-Butoxycarbonylamino-5-hydroxy-4-
methylpentanoic acid tert-butyl ester 22. To a solution of
acid 21 (0.1429 g, 0.450 mmol) in 2.3 mL THF at K40 8C,
Et3N (0.08 mL, 0.585 mmol) was added dropwise. Isobutyl
chloroformate (0.07 mL, 0.540 mmol) was added dropwise
over 10 min, to give a yellow/orange color and the reaction
was stirred at K40 8C for 2 h. The reaction was warmed to
0 8C, NaBH4 (0.102 g, 2.70 mmol) in H2O (2 mL) was
added and the reaction stirred at 0 8C for 1 h and then
warmed to room temperature. After stirring at room
temperature for 3.5 h, the reaction was quenched with the
addition of ethyl acetate and brine at 0 8C. The organic
portion was washed with ice cold 10% citric acid 3 times,
twice with brine, dried over Na2SO4, filtered and concen-
trated. The crude product was purified using flash
chromatography using 25% ethyl acetate/petroleum ether
yielding 22 as a clear colorless oil (0.0913 g, 67%). (22): Rf
0.48 (30% ethyl acetate/petroleum ether); 1H NMR
(500 MHz, CDCl3) d 5.22 (d, JZ6.8 Hz, 1H), 4.24 (d, JZ
4.7 Hz, 1H), 3.48 (dd, JZ10.7, 5.3 Hz, 1H), 3.41 (dd, JZ
10.7, 6.3 Hz, 1H), 2.65 (bs, 1H), 1.75 (m, 2H), 1.44–1.35
(m, 1H), 1.40 (s, 9H), 1.38 (s, 9H), 0.90 (d, JZ6.7, 3H); 13C
NMR (125 MHz, CDCl3) d 172.2, 155.6, 81.8, 79.7, 67.7,
52.6, 37.7, 32.3, 28.2, 27.9, 17.4; IR (neat) 3364, 2976,
Acknowledgements
We would like to thank the UNCF Merck Science Initiative
and NSF (CHE-0130958) for funding this work.
1712, 1511, 1455, 1390, 1367, 1251, 1154, 1046, 848 cmK1
;
HRMS (ESI) m/z calcd for C15H29NO5 (MCNa)C:
326.2045, found 326.1941; [a]2D5C5.168 (c 1.03, CHCl3).
References and notes
1. Renner, M. K.; Shen, Y.-C.; Cheng, X.-C.; Jensen, P. R.;
Frankmoelle, W.; Kauffman, C. A.; Fenical, W.; Lobkovsky,
E.; Clardy, J. J. Am. Chem. Soc. 1999, 121, 11273–11276.
2. Sugiyama, H.; Shioiri, T.; Yokokawa, F. Tetrahedron Lett.
2002, 43, 3489–3492.
5.1.10. (2S,4R)-2-tert-Butoxycarbonylamino-5-(tert-
butyldimethylsilanyloxy)-4-methyl-pentanoic acid tert-
butyl ester 23. Alcohol 22 (0.0857 g, 0.282 mmol) was
dissolved in 0.7 mL DMF and TBS-Cl (0.128 g,
0.846 mmol) was added. The reaction was stirred for
10 min. DMAP (0.0345 g, 0.282 mmol) and Et3N
(0.24 mL, 1.69 mmol) were added and the solution was
allowed to stir for 18 h. The reaction was quenched with the
addition of brine and was extracted 3 times with ether. The
organic portion was washed sequentially with H2O (3
times), ice cold 10% HCl, brine, dried over MgSO4, filtered
and concentrated. The crude product was purified by flash
chromatography using 10% ethyl acetate in petroleum ether,
yielding 23 as a pale yellow oil (0.1093 g, 93%). (23): Rf
3. Wen, S.-J.; Zhang, H.-W.; Yao, Z.-J. Tetrahedron Lett. 2002,
43, 5291–5294.
4. Tarver, J. E., Jr.; Joullie, M. M. Abstracts of Papers, 224th
ACS National Meeting, Boston, MA 2002, ORGN-499.
5. Tarver, J. E., Jr. PhD, University of Pennsylvania, 2003.
6. Tarver, J. E.; Joullie, M. M. J. Org. Chem. 2004, 69, 815–820.
7. Hansen, D. B.; Joullie, M. M. Abstracts of Papers, 224th ACS
National Meeting, Boston, MA 2002, ORGN-502.
8. Boger, D. L. Tetrahedron 1983, 39, 2869–2939.
9. Behforouz, M.; Ahmadian, M. Tetrahedron 2000, 56,
5259–5288.
1
0.46 (5% acetone/petroleum ether); H NMR (500 MHz,
CDCl3) d 5.20 (d, JZ7.7 Hz, 1H), 4.13 (m, 1H), 3.49 (dd,
JZ9.9, 5.1 Hz, 1H), 3.36 (dd, JZ9.9, 5.8 Hz, 1H), 1.81 (m,
2H), 1.70 (m, 1H), 1.42 (s, 9H), 1.40 (s, 9H), 0.90 (d, JZ6.9,
3H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR
(125 MHz, CDCl3) d 172.3, 155.4, 81.4, 79.3, 67.1, 52.6,
36.2, 32.4, 28.3, 28.0, 25.9, 25.6, 17.3, K3.6, K5.5; IR
10. Trione, C.; Toledo, L. M.; Kuduk, S. D.; Fowler, F. W.;
Grierson, D. S. J. Org. Chem. 1993, 58, 2075–2080.
11. Tamion, R.; Mineur, C.; Ghosez, L. Tetrahedron Lett. 1995,
36, 8977–8980.
12. Sisti, N. J.; Zeller, E.; Grierson, D. S.; Fowler, F. W. J. Org.
Chem. 1997, 62, 2093–2097.

10284
J. E. Tarver, Jr. / Tetrahedron 60 (2004) 10277–10284
13. Sisti, N. J.; Motorina, I. A.; Dau, M.-E. T. H.; Riche, C.;
Fowler, F. W.; Grierson, D. S. J. Org. Chem. 1996, 61,
3715–3728.
25. Baldwin, J. E.; Miranda, T.; Moloney, M.; Hokelek, T.
Tetrahedron 1989, 45, 7459–7468.
26. Coudert, E.; Archer, F.; Azerad, R. Synthesis 1997, 863–865.
27. Ezquerra, J.; Pegregal, C.; Rubio, A.; Yrurtagoyena, B.;
Escribano, A.; Sanchez-Ferrando, F. Tetrahedron 1993, 49,
8665–8678.
14. Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999, 40,
7215–7218.
15. Seki, H.; Koga, K.; Matsuo, H.; Ohki, S.; Matsuo, I.; Yamada,
S.-i. Chem. Pharm. Bull. 1965, 13, 995–1000.
16. Pointdexter, G. S.; Meyers, A. I. Tetrahedron Lett. 1977, 40,
3527–3528.
28. Langlois, N.; Rojas, A. Tetrahedron Lett. 1993, 34,
2477–2480.
29. Charrier, J.-D.; Duffy, J. E. S.; Hitchcock, P. B.; Young,
D. W. Tetrahedron Lett. 1998, 39, 2199–2202.
30. Charrier, J.-D.; Duffy, J. E. S.; Hitchcock, P. B.; Young, D. W.
J. Chem. Soc., Perkin Trans. 1 2001, 2367–2371.
31. Moody, C. M.; Starkmann, B. A.; Young, D. W. Tetrahedron
Lett. 1994, 35, 5485–5488.
17. Elliot, M. C.; Kruiswijk, E. J. Chem. Soc., Perkin Trans. 1
1999, 3157–3166.
18. Szeja, W. Synthesis 1980, 402–403.
19. Li, Z.; Jin, Z.; Huang, R. Synthesis 2001, 2365–2378.
20. Ihara, M.; Kirihara, T.; Fukumoto, K.; Kametani, T. Hetero-
cycles 1985, 23, 1097–1100.
32. Boger, D. L.; Patane, M. A.; Zhou, J. J. Am. Chem. Soc. 1994,
116, 8544–8556.
21. Ihara, M.; Tsuruta, M.; Fukumoto, K.; Kametani, T. J. Chem.
Soc., Chem. Commun. 1985, 1159–1161.
33. Ding, X.; Vera, M. D.; Liang, B.; Zhao, Y.; Leonard,
M. S.; Joullie, M. M. Bioorg. Med. Chem. Lett. 2001, 11,
231–234.
22. August, R. A.; Khan, J. A.; Moody, C. M.; Young, D. W.
J. Chem. Soc., Perkin Trans. 1 1996, 507–514.
23. Acevedo, C. M.; Kogut, E. F.; Lipton, M. A. Tetrahedron
2001, 57, 6353–6359.
34. Olsen, R. K. J. Org. Chem. 1970, 35, 1912–1915.
´
24. Najera, C.; Yus, M. Tetrahedron: Asymmetry 1999, 10,
2245–2303.