Synthesis of β,β-dimethylated amino acid building blocks utilizing the 9-phenylfluorenyl protecting group

Article abstract of DOI:10.1021/jo982474a

Optically pure β,β-dimethylated amino acid building blocks with functionalized side chains have been prepared from D-aspartic acid. The dimethylation was accomplished by regioselective dialkylation of 9- phenylfluorenyl (PhFl)-protected aspartate diesters. The bulk of the PhFl protecting group also allowed for a variety of functional group manipulations to be carried out on the side chain without affecting the C(α) ester of the aspartate. As a result, the derivatives of the following novel amino acids were synthesized in this study: β,β-dimethyl-D-aspartic acid, β,β- dimethyl-D-homoserine, 3,3-dimethyl-D-2,4-diaminobutyric acid, β,β- dimethyl-D-lysine, β,β-dimethyl-D-homoglutamate, β,β-dimethyl-D- ornithine, and 3,3-dimethylazetidine-2-carboxylic acid. The β,β- dimethylated amino acids were synthesized in high enantiomeric excess as determined by coupling the novel building blocks to chiral reagents.

Full text of DOI:10.1021/jo982474a

4362
J . Org. Chem. 1999, 64, 4362-4369
Syn th esis of â,â-Dim eth yla ted Am in o Acid Bu ild in g Block s
Utilizin g th e 9-P h en ylflu or en yl P r otectin g Gr ou p
Noriyuki Kawahata, Michael Weisberg, and Murray Goodman*
Department of Chemistry and Biochemistry, University of California, San Diego,
La J olla, California 92093-0343
Received December 21, 1998
Optically pure â,â-dimethylated amino acid building blocks with functionalized side chains have
been prepared from D-aspartic acid. The dimethylation was accomplished by regioselective
dialkylation of 9-phenylfluorenyl (PhFl)-protected aspartate diesters. The bulk of the PhFl protecting
group also allowed for a variety of functional group manipulations to be carried out on the side
chain without affecting the CR ester of the aspartate. As a result, the derivatives of the following
novel amino acids were synthesized in this study: â,â-dimethyl-D-aspartic acid, â,â-dimethyl-D-
homoserine, 3,3-dimethyl-D-2,4-diaminobutyric acid, â,â-dimethyl-D-lysine, â,â-dimethyl-D-homo-
glutamate, â,â-dimethyl-D-ornithine, and 3,3-dimethylazetidine-2-carboxylic acid. The â,â-
dimethylated amino acids were synthesized in high enantiomeric excess as determined by coupling
the novel building blocks to chiral reagents.
In tr od u ction
â,â-diMe-D-Dab(Cbz)-OH] (3), NR-Cbz-Nꢀ-Boc-â,â-dimethyl-
D-lysine [Cbz-â,â-diMe-D-Lys(Boc)-OH] (4), NR-Boc-
â,â-dimethyl-D-homoglutamic acid R-methyl ester [Boc-
â,â-diMe-D-Hglu-OMe] (5), NR-Boc-N∆-Cbz-â,â-dimethyl
D-ornithine methyl ester [Boc-â,â-diMe-D-Orn(Cbz)-OMe]
(6), and (2R)-NR-PhFl-3,3-dimethyl-azetidine-2-carboxylic
acid R-methyl ester [PhFl-â,â-diMe-D-Azt-OMe] (7) (Fig-
ure 1).
Numerous methods have been developed for the asym-
metric synthesis of unusual R-amino acids including
stereoselective R-carbon enolate alkylation and hydro-
genation of R,â-conjugated esters.5 However, these meth-
ods cannot be adapted to the synthesis of â,â-dimethyl-
ated amino acids. We have chosen to utilize the unique
properties of the 9-phenylfluorenyl (PhFl) protecting
group originally developed by Rapoport and co-workers.6-10
The steric bulk of the PhFl group attached to the amine
of an aspartate diester prevents abstraction of the CR
proton by strong bases, resulting in enolization exclu-
sively of the side chain ester. Additionally, the PhFl group
shields the R-carbonyl of the aspartate, allowing for
chemistry to be selectively performed on the side chain
ester. These properties allow for the syntheses of a wide
variety of peptidomimetic structures with the chirality
of the R-carbon determined by that of the initial aspar-
tate. Lubell11-16 and Chamberlin, using N-benzyl-N-
Biologically active peptides elicit their effects by bind-
ing to a receptor or enzyme active site. This recognition
process requires the peptides to possess the necessary
constitution or pharmacophoric groups and to present
them in an appropriate three-dimensional array. Al-
though endogenous and naturally occurring peptides are
highly potent, they tend to display a large degree of
conformational mobility. The flexibility of these naturally
occurring ligands may decrease the receptor selectivity
and complicate efforts directed toward the elucidation of
the three-dimensional structures necessary for biological
activity. In addition, the clinical application of peptides
is limited because of unfavorable pharmacological prop-
erties such as poor metabolic stability and low bioavail-
ability. Thus, much work has focused on the development
of analogues of bioactive peptides through the incorpora-
tion of novel amino acid analogues or isosteres designed
to counteract these undesirable pharmacological prop-
erties.1-4 These modified peptides are often subjected to
a series of experimental measurements and calculations.
The results are correlated with biological activity and
receptor selectivity. From these studies, valuable insights
are obtained regarding the conformations required for
activity and selectivity. In this report, we describe the
syntheses of a series of novel building blocks (i.e., highly
functionalized amino acids), â,â-side chain dimethylated
amino acids. Specifically, we developed the synthesis of
optically pure â,â-dimethylated amino acids including NR-
PhFl-â,â-dimethyl-R-tert-butyl-D-aspartate [PhFl-â,â-
diMe-D-Asp-OtBu] (1), NR-Boc-â,â-dimethyl-D-homoserine-
tert-butyl ester [Boc-â,â-diMe-D-Hser-OtBu] (2), (2R)-NR-
Boc-Nγ-Cbz-2,4-diamino-3,3-dimethylbutyric acid [Boc-
(5) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon Press: Oxford, 1989.
(6) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1987, 109, 236-
239.
(7) Wolf, J .-P.; Rapoport, H. J . Org. Chem. 1989, 54, 3164-3173.
(8) Dunn, P. J .; Ha¨ner, R.; Rapoport, H. J . Org. Chem. 1990, 55,
5017-5025.
(9) Gmeiner, P.; Feldman, P. L.; Chu-Moyer, M.; Rapoport, H. J .
Org. Chem. 1990, 55, 3068-3074.
(10) Lubell, W. D.; Rapoport, H. J . Am. Chem. Soc. 1988, 110, 7447-
7455.
(1) Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug
Discovery, 5th ed.; Wolff, M., Ed.; Wiley and Sons: New York, 1995;
pp 803-861.
(2) Sawyer, T. K. In Structure-Based Drug Design; Veerapandian,
P., Ed.; Marcel Dekker: New York, 1997; pp 559-634.
(3) Wiley, R. H.; Rich, D. H. Med. Res. Rev. 1993, 13, 327-384.
(4) Hanessian, S.; McNaughton-Smith, G.; Lombart, H. G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789-12854.
(11) Ibrahim, H. H.; Lubell, W. D. J . Org. Chem. 1993, 58, 6438-
6441.
(12) Lombart, H. G.; Lubell, W. D. J . Org. Chem. 1994, 59, 6147-
6149.
(13) Beausoleil, E.; Archeveˆque, B.; Be´lec, L.; Atfani, M.; Lubell, W.
D. J . Org. Chem. 1996, 61, 9447-9454.
(14) Atfani, M.; Lubell, W. D. J . Org. Chem. 1995, 60, 3184-3188.
(15) Sharma, R.; Lubell, W. D. J . Org. Chem. 1996, 61, 202-209.
10.1021/jo982474a CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/25/1999

Synthesis of â,â-Dimethylated Amino Acid Building Blocks
J . Org. Chem., Vol. 64, No. 12, 1999 4363
Sch em e 1
Sch em e 2
F igu r e 1. The target â,â-dimethylated amino acid analogues
PhFl-â,â-diMe-D-Asp-OtBu (1), Boc-â,â-diMe-D-Hser-OtBu (2),
Boc-â,â-diMe-D-Dab(Cbz)-OH (3), Cbz-â,â-diMe-D-Lys(Boc)-OH
(4), Boc-â,â-diMe-D-Hglu-OMe (5), Boc-â,â-diMe-D-Orn(Cbz)-
OMe (6), and PhFl-â,â-diMe-D-Azt-OMe (7).
phenylfluorenyl,17-19 have recently exploited these prop-
erties in synthesizing constrained â-turn mimetics and
unusual amino acids. Adding to the utility of the PhFl
group are the relatively mild conditions required for its
removal either by treatment with TFA or by catalytic
hydrogenation.
Syn th esis
The synthesis of PhFl-â,â-diMe-D-Asp-OtBu (1) was
initiated with the synthesis of the protected aspartic acid
derivative PhFl-D-Asp(OMe)-OtBu as described by Rapo-
port and co-workers.9 Treatment of PhFl-D-Asp(OMe)-
OtBu with two successive additions of potassium bis-
(trimethylsilyl)amide (KHMDS) (2 equiv each addition)
and methyl iodide (3 equiv each addition) gave the
dimethylated PhFl-â,â-diMe-D-Asp(OMe)-OtBu (8) in good
yield (Scheme 1). Rapoport and co-workers have previ-
ously observed â,â-dimethyl aspartate as a minor side
product during attempts to obtain monoalkylated PhFl-
protected aspartates.8,9 In the current study, the applica-
tion of excess base and electrophile provided the â,â-
dimethylated species as the major product. These findings
are in agreement with those of Sharma and Lubell in
their studies of the dimethylation of proline derivatives.15
Treatment of PhFl-â,â-diMe-D-Asp(OMe)-OtBu (8) with
LiOH gave the desired building block 1. The sterically
congested environment surrounding the methyl ester
necessitated longer reaction times and higher reaction
temperatures (80 °C) than normally required for saponi-
fication of a methyl ester. To assess the retention of
optical purity during the alkylation and saponification
steps, the carboxylic acid of PhFl-â,â-diMe-D-Asp-OtBu
(1) was coupled with (R)- and (S)-R-methylbenzylamine
(separate reactions) to give the diastereomeric adducts
9a and 9b. In each case, only one diastereomer was
1
obtained as the major product. The comparison of the H
NMR spectra of the crude diastereomers indicated that
PhFl-â,â-diMe-D-Asp-OtBu (1) was obtained with a high
degree of optical purity (>95% ee).
With PhFl-â,â-diMe-D-Asp(OMe)-OtBu (8) in hand, the
targeted Boc-â,â-diMe-D-Hser-OtBu derivative (2) was
obtained by treatment of the side chain ester 8 with
DIBAL-H (Scheme 2), followed by the interchanging of
the PhFl for a Boc group. The alteration in protecting
groups decreases the nucleophilicity of the nitrogen, thus
diminishing the possibility of cyclization in the subse-
quent steps. The alcohol 2 was converted to the mesylate
and then to the azide 10. Reduction of the azide by
catalytic hydrogenation followed by treatment with ben-
zyl chloroformate gave the fully protected Boc-â,â-diMe-
Dab(Cbz)-OtBu (11). The Boc and t-Bu groups were
removed by treatment with TFA, and Boc2O was used to
reprotect the amine to yield the desired building block
Boc-â,â-diMe-D-Dab(Cbz)-OH (3). The carboxylic acid of
Boc-â,â-diMe-D-Dab(Cbz)-OH (3) was coupled to (R)- and
(S)-R-methylbenzylamine (in separate reactions) to give
the amides 12a and 12b. In each case, only one diaste-
(16) Lombart, H. G.; Lubell, W. D. J . Org. Chem. 1996, 61, 9437-
9466.
(17) Humphrey, J . M.; Bridges, R. J .; Hart, J . A.; Chamberlin, A.
R. J . Org. Chem. 1994, 59, 2467-2472.
(18) Humphrey, J . M.; Hart, J . A.; Chamberlin, A. R. Bioorg. Med.
Chem. Lett. 1995, 5, 1315-1320.
(19) Humphrey, J . M.; Aggen, J . B.; Chamberlin, A. R. J . Am. Chem.
Soc. 1996, 118, 11759-11770.

4364 J . Org. Chem., Vol. 64, No. 12, 1999
Kawahata et al.
Sch em e 3
side chain ester 13, the reaction was fully regioselective.
In this case, the presence of the trans double bond
precluded any concerns regarding lactone formation. A
one-pot process21 was used to convert the allylic alcohol
to the allylic azide 19 (Scheme 4). Reduction of the azide
to the amine using triphenylphosphine (Ph3P) followed
by treatment with di-tert-butyl dicarbonate (Boc2O) gave
the side chain Boc-protected allylic amine 20. The Ph3P-
mediated reduction of the azide was chosen over catalytic
hydrogenation because of the fear that concurrent reduc-
tion of the olefin and the azide would result in lactam-
ization. Catalytic hydrogenation of the allylic amine 20
resulted in the simultaneous removal of the PhFl group
and reduction of the olefin. The crude amine was allowed
to react with benzyl chloroformate to give the orthogo-
nally protected lysine derivative Cbz-â,â-diMe-D-Lys-
(Boc)-OMe (21).
Saponification of the methyl ester of the protected
building block 21 using LiOH gave the targeted Cbz-â,â-
diMe-D-Lys(Boc)-OH (4) (Scheme 4). To determine the
retention of enantiomeric integrity, the carboxylic acid
of Cbz-â,â-diMe-D-Lys(Boc)-OH (4) was coupled (in sepa-
rate reactions) to (R)- and (S)-R-methylbenzylamine to
give the amides 22a and 22b, respectively. In each case,
only one diastereomer was obtained as the major product.
The comparison of the 1H NMR spectra of the crude
diastereomers indicated that the reactions were carried
out with a high retention of chiral integrity (95% ee). It
is believed that the saponification step could cause a
small amount of epimerization because the steric con-
straints of the â-dimethyl groups required that the
saponification reaction be carried out over longer times
than are routinely used for less sterically encumbered
R-amino acids.
In the effort to synthesize the â,â-dimethylated orni-
thine building block, we were concerned with the pos-
sibility of lactam formation during the functional group
manipulations. Specifically, if the side chain amine was
generated in the presence of the methyl ester, there could
be a distinct possibility of the formation of a six-
membered lactam. Treatment of the R,â-unsaturated
ester 17 with magnesium in methanol (Scheme 5) gave
PhFl-â,â-diMe-D-Hglu(OMe)-OMe (23) without the re-
moval of the PhFl protecting group. Saponification of the
side chain methyl ester was carried out with high
regioselectivity because of the presence of the PhFl
protecting group. Previous studies directed toward the
synthesis of 3-alkyl-2,3-diaminopropionic acid revealed
that a cyclic urea resulted when a PhFl-protected amine
reacted with an isocyanate intermediate of a Curtius
reaction.8 Thus, in our synthesis, the PhFl group was
interchanged with a Boc protecting group to give the
building block Boc-â,â-diMe-D-Hglu-OMe (5) because the
regio-directing properties of the PhFl group were no
longer needed. A Curtius reaction using diphenylphos-
phoryl azide (DPPA) in the presence of benzyl alcohol
provided Boc-â,â-diMe-D-Orn(Cbz)-OMe (6). We believe
that the cyclic urea formation was avoided by use of a
urethane-protected amine.
reomer was obtained as the major product. Comparison
of the 1H NMR spectra of the diastereomers indicated
that Boc-â,â-diMe-D-Dab(Cbz)-OH (3) is obtained with
minimal epimerization of the Dab R-carbon (>95%ee).
The synthesis of the â,â-dimethyl-D-lysine building
block was initiated by dimethylation of PhFl-D-Asp(OMe)-
OMe using conditions similar to those used for the
synthesis of PhFl-â,â-diMe-D-Asp(OMe)-OtBu (8). PhFl-
â,â-diMe-D-Asp(OMe)-OMe (13) (Scheme 3) was obtained
in higher yields than PhFl-â,â-diMe-D-Asp(OMe)-OtBu
(8). This is likely because of the decreased steric crowding
of the R-methyl ester versus the R-tert-butyl ester. Initial
attempts to obtain the PhFl-â,â-diMe-D-Hser-OMe (14)
regioselectively using DIBAL-H resulted in a large
amount of the lactone 15. Thus, the bulk of the PhFl
protecting group is sufficient to protect the R-ester from
reduction, but the R-carbonyl is still prone to intramo-
lecular attack as previously observed by Rapoport and
co-workers.7 The X-ray crystallographic analysis of lac-
tone 15 (P. Gantzel, UC San Diego X-ray Crystallography
Facility) confirms that the two methyl groups are placed
at the â-position of the side chain with no alkylation of
the nitrogen. The structure also points to the fact that
the methyl ester reduction occurs regioselectively on the
side chain.
Previous reports indicated that formation of lactone
(15) could be avoided by carrying out the reduction in
THF.7 In our hands, we found that after treatment of
PhFl-â,â-diMe-D-Asp(OMe)-OMe (13) with DIBAL-H in
DCM, the acylic hydroxyester remained intact. Appar-
ently, the formation of lactone 15 occurred during
purification by silica gel column chromatography. Thus,
crude PhFl-â,â-diMe-D-Hser-OMe (14) was oxidized to the
aldehyde 16 using the Dess Martin periodinane20 (Scheme
4) and was purified in good yield. The additional carbons
necessary for the lysine side chain were provided via a
Horner-Wadsworth-Emmons reaction using dieth-
ylphosphononacetate to give the R,â-unsaturated ester
17. The E-olefin was obtained as the major product.
The R,â-unsaturated ester 17 was reduced to the allylic
alcohol 18 using DIBAL-H. As with the reduction of the
To confirm that the transformations were carried out
without loss of chiral integrity, the Boc group of the Boc-
â,â-diMe-D-Orn(Cbz)-OMe (6) was removed and the amine
was coupled to Boc-Tyr(tBu)-OH to give the dipeptide 24
(21) Hojo, K.; Kobayashi, S.; Soai, K.; Ikeda, S.; Mukaiyama, T.
Chem. Lett. 1977, 635-636.
(20) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.

Synthesis of â,â-Dimethylated Amino Acid Building Blocks
Sch em e 4
J . Org. Chem., Vol. 64, No. 12, 1999 4365
Sch em e 5
Sch em e 6
dimethylation of the Câ of PhFl-protected aspartates was
successfully accomplished without methylation of the
nitrogen or the CR. The PhFl protecting group was also
effective at preventing CR epimerization under the highly
basic conditions necessary for dimethylation. In addition,
we have demonstrated that the Horner-Wadsworth-
Emmons and Mg-mediated olefin reduction reactions are
tolerated by the PhFl protecting group and do not
epimerize the CR of PhFl-protected aspartates or react
with the R-ester. Additionally, we have shown that these
building blocks can be coupled with chiral amines or
amino acid derivatives.
The flexibility of the methods outlined above leads to
the synthesis of a variety of side chain functionalized â,â-
dialkylated amino acids. Similar strategies utilizing
glutamic acid can result in a family of γ,γ-dialkylated
amino acids by starting with PhFl-protected glutamic
acid. We will continue to take advantage of the unique
properties of this valuable protecting group in order to
develop other novel peptidomimetic building blocks. The
incorporation of these peptidomimetics into families of
bioactive peptides is currently underway in our labora-
tories. These modified molecules are key to the elucida-
tion of bioactive conformations of peptide-based hor-
mones, opioids, and other bioactive molecules. We will
report these results in future publications.
as the major product. This dipeptide was identified as a
single diastereomer by 1H NMR, thus indicating that the
reactions were carried out without effect on the chirality
of the R-carbon of the ornithine derivative.
Reports of intramolecular cyclization8 prompted us to
examine the synthesis of the proline derivative azetidine-
2-carboxylate. PhFl-â,â-diMe-D-Hser-OMe (14) (Scheme
6) was converted to the mesylate and then heated to give
the novel â,â-dimethyl azetidine-2-carboxylic acid build-
ing block PhFl-â,â-diMe-D-Azt-OMe (7).
Exp er im en ta l Section
Con clu sion s
Gen er a l. Proton nuclear magnetic resonance spectra were
recorded at either 360 or 500 MHz. Chemical shifts are given
in ppm (δ scale) downfield from internal TMS, and coupling
We have synthesized a unique set of modified enan-
tiopure amino acid building blocks. The regioselective

4366 J . Org. Chem., Vol. 64, No. 12, 1999
Kawahata et al.
constants (J ) are given in Hz. Fast atom bombardment and
electrospray mass spectrometry were obtained from the Uni-
versity of California, Riverside (Dr. Richard Kondrat) and The
Scripps Research Institute (Dr. Gary Siuzdak). Infrared
spectroscopy was carried out using either CaF2 plates or KBr
pellets. Optical rotation was measured using a 1.00 dm path
length cell.
Melting points were determined on a Thomas-Hoover capil-
lary melting point apparatus and are uncorrected. Silica gel
plates from E. Merck, Darmstadt (60F-254) were used for thin-
layer chromatography. Visualization of the compounds was
carried out by UV light, ninhydrin, vanillin, o-tolidine, KMnO4,
bromocresol, or phosphomolibdic acid. Column chromatogra-
phy was performed using the indicated solvent mixture on
Kieselgel 60 (60-200 mesh) from E. Merck.
Nr-ter t-Bu tyloxyca r bon yl-â,â-d im eth yl-D-h om oser in e-
Cr-ter t-bu tyl ester [Boc-â,â-d iMe-D-Hser -OtBu ] (2). A
solution of 8 (400 mg, 0.848 mmol) in dry dichloromethane
(DCM) (10 mL) was cooled (-78 °C) under N2, and a solution
of DIBAL-H (2.7 mL, 1 N in hexane) was added over 4 min.
After 10 min, MeOH (0.5 mL) was added, and the reaction
was allowed to warm to ambient temperature. Ethyl acetate
(50 mL) and saturated aqueous Rochelle’s salt (10 mL) were
added, and the reaction was allowed to stir for 15 min. The
organic layer was collected, and the aqueous layer was
extracted with EtOAc. The organic extracts were pooled,
washed with brine, and dried over anhydrous Na2SO4. The
solution was concentrated under reduced pressure to give the
crude alcohol as an oil.
The crude alcohol was dissolved in EtOAc (10 mL) and
MeOH (5 mL), and 10% Pd/C (5 mg) and Boc2O (278 mg, 1.27
mmol) were added. The solution was degassed under reduced
pressure and placed under H2 (2 atm). After 18 h, the mixture
was filtered through Celite, and the filtrate was concentrated.
The crude mixture was chromatographed through silica gel
using EtOAc/hex (10%) as eluent to give the product 2 as a
colorless solid (222 mg, 86%): Rf EtOAc/hex (20%) 0.33; mp
100-101 °C; 1H NMR (360 MHz/CDCl3) δ 5.38 (d, J ) 7.9 Hz,
1H); 4.18 (d, J ) 8.3 Hz, 1H); 3.31 (A of AB, J ) 12 Hz, 1H);
3.05 (B of AB, J ) 12 Hz, 1H); 1.50 (s, 9H); 1.45 (s, 9H); 1.11
Nr-(9-P h en ylflu or en -9-yl)-3,3-dim eth yl-Câ-m eth yl ester -
D-a sp a r tic a cid -Cr-ter t-bu tyl ester [P h F -â,â-d iMe-D-Asp -
(OMe)-OtBu ] (8). A solution of PhFl-D-Asp(OMe)-OtBu9 (600
mg, 1.35 mmol) in dry THF (15 mL) was cooled (-78 °C) under
N2, and a solution of KHMDS (3.3 mL, 0.91 M in THF) was
added over 5 min. After 15 min, the reaction was allowed to
warm to -40 °C, and MeI (0.25 mL, 4.02 mmol) was added.
After 1.5 h, the reaction mixture was cooled to -78 °C, and a
second addition of KHMDS and MeI was carried out in the
same manner as the first. After the MeI addition, the reaction
was placed in a freezer (-20 °C). After 16 h, saturated NH4Cl
(5 mL) was added followed by H2O (5 mL). The mixture was
extracted three times with EtOAc, and the pooled organic
extracts were washed with brine. The organic layer was dried
over anhydrous Na2SO4, concentrated onto Florisil, and chro-
matographed through silica gel using EtOAc/hex (3%) as
eluent. The desired product 8 was obtained as a colorless oil
(0.473 g, 74%): Rf EtOAc/hex (20%) 0.46; 1H NMR (360 MHz/
CDCl3) δ 7.67 (dd, J ) 3.2, 7.6 Hz, 2H); 7.40-7.19 (m, 11H);
3.53 (s, 3H); 2.82 (s, 3H); 1.17 (s, 3H); 1.12 (s, 9H); 1.05 (s,
(s, 3H); 0.74 (s, 3H); IR (neat/CaF2) 3436, 2978, 1725 cm-1
;
[R]27 -27.2 (c ) 1.8, CHCl3); HRMS calcd for C15H30NO5
D
304.2124, found m/z 304.2120.
(2R )-4-Azid o-2-t er t -b u t yloxyca r b on yla m in o-3,3-d i-
m eth yl-bu tyr ic a cid ter t-bu tyl ester (10). A solution of 2
(400 mg, 1.32 mmol) and triethylamine (TEA) (368 µL, 2.64
mmol) in DCM (4 mL) was cooled (0 °C), and MsCl (153 µL,
1.98 mmol) was added. After 5 min, the reaction was diluted
with Et2O (30 mL) and washed with H2O (6 mL). The aqueous
layer was extracted twice with Et2O, and the pooled organic
extracts were washed with brine, dried over anhydrous MgSO4,
and concentrated under reduced pressure to give the crude
mesylate as an oil.
3H); IR (neat/CaF2) 2979, 1731 cm-1; HRMS calcd for C30H34
-
NO4 472.2488, found m/z 472.2478.
Nr-(9-P h en ylflu or en -9-yl)-â,â-d im eth yl-D-a sp a r tic a cid -
Cr-bu tyl ester [P h F -â,â-d iMe-D-Asp -OtBu ] (1). Lithium
hydroxide (1.1 mL, 1 N) was added to a solution of 8 (200 mg,
0.424 mmol) in dioxane (5 mL). The reaction was allowed to
warm to 50 °C and was stirred for 3.5 h. The reaction was
heated to 90 °C. After 16 h, another 1.1 mL of LiOH (1 N) was
added to drive the reaction to completion. The reaction was
concentrated to one-third the original volume, and EtOAc (30
mL) was added. The solution was acidified with 1 N HCl, and
the aqueous layer was extracted twice with EtOAc. The pooled
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and chromatographed through silica gel using EtOAc/
petroleum ether (pet ether) (25%) as eluent. The desired
product 1 was obtained as a colorless foam (170 mg, 98%): Rf
EtOAc/pet ether (20%) 0.27; 1H NMR (360 MHz/CDCl3) δ 7.70
(d, J ) 7.2 Hz, 2H); 7.68-7.19 (m, 11H); 2.83 (s, 1H); 1.20 (s,
3H); 1.11 (s, 9H); 1.05 (s, 3H); IR (neat/CaF2) 2979, 1724, 1702
The crude mesylate was dissolved in HMPA (3.5 mL), and
LiN3 (650 mg, 13.2 mmol) was added. The reaction was heated
to 90 °C and allowed to stir for 16 h. The reaction was cooled,
and H2O (10 mL) was added. The aqueous layer was extracted
three times with EtOAc, and the pooled organic extracts were
washed with brine. The organic layer was dried over anhy-
drous Na2SO4, concentrated, and chromatographed through
silica gel using EtOAc/pet ether (10%) as eluent. The desired
product 10 was obtained as a colorless oil (0.278 g, 64%): Rf
EtOAc/pet ether (20%) 0.48; 1H NMR (360 MHz/CDCl3) δ 5.19
(d, J ) 8.3 Hz, 1H); 4.16 (d, J ) 9.4 Hz, 1H); 3.23 (dd, J ) 8.5,
15 Hz, 2H); 1.49 (s, 9H); 1.45 (s, 9H); 0.99 (s, 3H); 0.98 (s, 3H);
IR (neat/CaF2) 2978, 2104, 1717 cm-1; [R]27 -10.0 (c ) 1.8,
D
CHCl3); HRMS calcd for C15H29N4O4 329.2189, found m/z
329.2197.
Nr-ter t-Bu t yloxyca r b on yl-Nγ-b en zyloxyca r b on yl-â,â-
d im eth yl-D-d ia m in obu tyr ic a cid -ter t-bu tyl ester [Boc-
â,â-d iMe-D-Da b(Cbz)-OtBu ] (11). To a solution of 10 (220
mg, 0.670 mmol) in MeOH (5 mL) was added 10% Pd/C (5 mg).
The mixture was degassed under reduced pressure and placed
under H2 (2 atm). After 20 h, the catalyst was removed by
filtration through Celite, and the filtrate was concentrated and
dried under reduced pressure to give the crude amine as a
colorless oil.
cm-1; [R]27 30.2 (c ) 0.87, CHCl3); HRMS calcd for C29H32
-
D
NO4 458.2331, found m/z 458.2346.
Nr-(9-P h en ylflu or en -9-yl)-â,â-d im eth yl-D-a sp a r tic a cid -
Câ-(R)- or (S)-r-m et h ylben zyla m id e Cr-ter t-b u t yl est er
(9a a n d 9b). A solution of the â,â-dimethylated aspartate (1)
(9 mg, 20 µmol) was dissolved in DMF (0.5 mL), and 1-hydroxy-
7-azabenzotriazole (HOAt) (4 mg, 30 µmol) was added. A dilute
solution of (R)-R-methylbenzylamine in DMF was added until
the pH of the solution was neutral. The solution was cooled
(-20 °C), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC) (6 mg, 30 µmol) was added. After 16 h, 1
N HCl (2 mL) was added, and the mixture was extracted twice
with EtOAc. The organic extracts were pooled and washed
with 1 N HCl, brine, saturated NaHCO3, and brine. The
organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to obtain 9a as a colorless oil.
The diastereomer 9b was synthesized using (S)-R-methyl-
benzylamine and the method described above for 9a . The 500
MHz 1H NMR spectra of the crude diastereomers were
obtained, and the chemical shifts of the of the amide protons
were used for comparison.
The crude amine and 4-methylmorpholine (NMM) (0.15 mL,
1.4 mmol) were dissolved in DCM (4 mL), and benzyl chloro-
formate (Cbz-Cl) (125 µL, 0.876 mmol) was added dropwise
by syringe. After 18 h, the reaction was diluted with Et2O (40
mL) and H2O (10 mL). The aqueous layer was extracted twice
with Et2O, and the pooled organic extracts were washed with
brine. The organic layer was dried over anhydrous MgSO4,
concentrated onto Florisil, and chromatographed through silica
gel using EtOAc/pet ether (8%) as eluent. The desired product
11 was obtained as a colorless oil (0.232 g, 79%): Rf EtOAc/
pet ether (20%) 0.46; 1H NMR (360 MHz/CDCl3) δ 7.36 (m,
5H); 6.00 (m, 1H); 5.22 (d, J ) 7.9 Hz, 1H); 5.11 (s, 2H); 4.08
(d, J ) 8.6 Hz, 1H); 3.19 (dd, J ) 8.5, 14 Hz, 1H); 2.87 (dd, J

Synthesis of â,â-Dimethylated Amino Acid Building Blocks
) 4.5, 14 Hz, 1H); 1.48 (s, 9H); 1.44 (s, 9H); 1.01 (s, 3H); 0.86
J . Org. Chem., Vol. 64, No. 12, 1999 4367
crystals suitable for X-ray analysis. (14): Rf EtOAc/hex (40%)
0.27; H NMR (360 MHz/CDCl3) δ 7.71 (dd, J ) 3.8, 7.4 Hz,
1
(s, 3H); IR (neat/CaF2) 3360, 2977, 1723 cm-1; [R]27 14.8 (c )
D
10.8, CHCl3); HRMS calcd for C23H37N2O6 437.2652, found m/z
437.2672.
2H); 7.45 (d, J ) 7.6 Hz, 1H); 7.39-7.12 (m, 9H); 7.11 (d, J )
7.9 Hz, 1H); 3.35 (A of AB, J ) 11 Hz, 1H); 3.23 (B of AB, J )
11 Hz, 1H); 3.17 (s, 3H); 2.53 (s, 1H); 1.01 (s, 3H); 0.58 (s, 3H);
IR (neat/CaF2) 3342, 1728, cm-1; MS (FAB) 402 (M + H)+.
(15): Rf EtOAc/hex (40%) 0.66; mp 175-176 °C; 1H NMR (360
MHz/CDCl3) δ 7.69 (d, J ) 7.6 Hz, 1H); 7.63 (d, J ) 7.6 Hz,
1H); 7.53 (d, J ) 7.6 Hz, 1H); 7.46-7.17 (m, 8H); 3.70 (A of
AB, J ) 11 Hz, 1H); 3.44 (B of AB, J ) 11 Hz, 1H); 2.90 (bs,
1H); 2.60 (s, 1H); 1.04 (s, 3H); 0.22 (s, 3H); IR (neat/CaF2) 2958,
Nr-ter t-Bu t yloxyca r b on yl-Nγ-b en zyloxyca r b on yl-â,â-
d im eth yl-D-d ia m in obu tyr ic a cid [Boc-â,â-d iMe-D-Da b-
(Cbz)-OH] (3). A solution of 11 (195 mg, 0.447 mmol) in DCM
(1 mL) was cooled (0 °C), and TFA (1 mL) was added. After 20
min, the reaction was allowed to warm to ambient tempera-
ture, and after 3 h, the solvent was removed under reduced
pressure. Residual TFA was removed by codistillation with
toluene. The crude amino acid was dissolved in dioxane (4 mL),
and saturated NaHCO3 (1 mL) and Boc2O (195 mg, 0.894
mmol) were added. The reaction was allowed to stir at ambient
temperature. After 20 h, the reaction was concentrated, and
the residue was dissolved in Et2O (30 mL) and 0.5 N HCl (8
mL). The aqueous layer was extracted twice with Et2O, and
the pooled organic extracts were washed with brine. The
organic layer was dried over anhydrous MgSO4, concentrated,
and chromatographed through silica gel using CHCl3/MeOH/
AcOH (98:1:1) as eluent. The purified fractions were concen-
trated and codistilled with toluene to remove residual AcOH
to yield the desired product 3 as a colorless oil (138 mg, 84%):
Rf CHCl3/MeOH/AcOH (95:5:3) 0.48; 1H NMR (360 MHz/
CDCl3) δ 7.35 (m, 5H); 5.71 (m, 1H); 5.33 (d, J ) 9.0 Hz, 1H);
5.18 (A of AB, J ) 12 Hz, 1H); 5.00 (B of AB, J ) 12 Hz, 1H);
4.28 (d, J ) 9.4 Hz, 1H); 3.39 (dd, J ) 8.1, 14 Hz, 1H); 2.86
(dd, J ) 4.7, 15 Hz, 1H); 1.44, 0.97 (bd, 6H); IR (neat/CaF2)
3338, 2976, 1705 cm-1; [R]27D 4.9 (c ) 6.1, CHCl3); HRMS calcd
for C19H29N2O6 381.2026, found m/z 381.2019.
1766 cm-1; [R]27D 34.1 (c ) 1.1, CHCl3); HRMS calcd for C25H24
NO2 370.1807, found m/z 370.1797.
-
(2R )-3,3-Dim e t h yl-4-oxo-2-([(9-p h e n ylflu or e n -9-yl)-
a m in o]-bu t yr ic a cid m et h yl est er (16). A solution of 13
(5.47 g, 12.7 mmol) in dry DCM (100 mL) was cooled (-70 °C)
under N2, and a solution of DIBAL-H in hexanes (28 mL, 1 N)
was added over 5 min. After 20 min, saturated Rochelle’s salt
(50 mL) was added followed by Et2O (200 mL). The mixture
was allowed to warm to ambient temperature and stirred for
15 min. The aqueous layer was extracted twice with Et2O, and
the pooled organic extracts were washed with brine. The
organic layer was dried over anhydrous MgSO4 and concen-
trated to give the crude alcohol as (14) as an oil.
The crude alcohol 14 was dissolved in DCM (75 mL) and
cooled (0 °C) under N2. Dess Martin periodinane20 (7.08 g, 16.2
mmol) was added, and the reaction was allowed to warm to
ambient temperature. After 2 h, the reaction was diluted with
EtOAc (100 mL) and an aqueous solution of saturated Na2S2O3/
saturated NaHCO3 (1:3, 30 mL). The mixture was allowed to
stir for 5 min. The aqueous layer was extracted twice with
EtOAc, and the pooled organic extracts were washed with
saturated NaHCO3 and brine. The organic layer was dried over
anhydrous Na2SO4, concentrated onto Florisil, and chromato-
graphed through silica gel using EtOAc/hex (5-10% gradient)
as eluent. The desired product 16 was obtained as a colorless
solid (3.79 g, 75%): Rf EtOAc/hex (25%) 0.48; mp 149-150 °C;
1H NMR (360 MHz/CDCl3) δ 9.19 (s, 1H); 7.70 (dd, J ) 7.2, 14
Hz, 2H); 7.40-7.21 (m, 10H); 7.14 (d, J ) 7.2 Hz, 1H); 3.22 (s,
3H); 2.77 (s, 1H); 1.07 (s, 3H); 0.80 (s, 3H); IR (neat/CaF2) 2975,
Nr-ter t-Bu t yloxyca r b on yl-Nγ-b en zyloxyca r b on yl-â,â-
d im eth yl-D-d ia m in obu tyr ic a cid (R)- or (S)-r-m eth yl-
ben zyla m id e (12a a n d 12b). The title diastereomers were
obtained by coupling 3 to optically active R-methylbenzylamine
as described for 9a . The 360 MHz 1H NMR spectra of the crude
diastereomers were obtained, and the chemical shifts of the
â-methyl groups of the â,â-dimethylated Dab were used for
comparison.
Dim eth yl-Nr-(9-p h en ylflu or en -9-yl)-3,3-d im eth yl-D-a s-
p a r ta te [P h F -â,â-d iMe-D-Asp (OMe)-OMe] (13). A solution
of PhF-D-Asp(OMe)-OMe9 (5.96 g, 14.9 mmol) in dry THF (170
mL) was cooled (-70 °C) under N2, and a solution of KHMDS
in THF (32 mL, 0.91 M) was added over 5 min. After 20 min,
MeI (1.7 mL, 27.3 mmol) was added. The reaction mixture was
allowed to stir for 20 min at -70 °C and then allowed to warm
to 0 °C. After 3.5 h following the MeI addition, the reaction
mixture was cooled (-70 °C), and the addition of KHMDS and
MeI was repeated as before. After 15 h following the second
MeI addition, saturated NH4Cl (50 mL) was added along with
H2O (20 mL). The aqueous layer was extracted twice with
EtOAc, and the pooled organic extracts were washed with 5%
citric acid and brine. The organic layer was dried over
anhydrous Na2SO4 and concentrated. The crude mixture was
chromatographed through silica gel using EtOAc/hex (4-10%
gradient) to give the desired product 13 as a colorless oil (5.79
g, 91%): Rf EtOAc/hex (20%) 0.33; 1H NMR (360 MHz/CDCl3)
δ 7.68 (dd, J ) 7.6, 13 Hz, 2H); 7.42-7.11 (m, 11H); 3.55 (s,
3H); 3.15 (s, 3H); 2.84 (s, 1H); 1.19 (s, 3H); 1.04 (s, 3H); IR
1731 cm-1; [R]27 43.6 (c ) 0.29, CHCl3); HRMS calcd for
D
C
26H26NO3 400.1913, found m/z 400.1926.
Dim et h yl-Nr-(9-p h en ylflu or en -9-yl)-3,3-d im et h yl-γ,δ-
d eh yd r o-D-h om oglu ta m a te (17). Methyl diethylphospho-
noacetate (2.59 g, 12.3 mmol) in dry DME (15 mL) was added
over 5 min to a cooled (0 °C) mixture of NaH (483 mg, 60% oil
dispersion, 12.1 mmol) in dry DME (15 mL) under N2. After
15 min, a solution of 16 (3.71 g, 9.29 mmol) in DME (40 mL)
was added over 5 min. After 0.5 h, the reaction was allowed
to warm to ambient temperature. After 3 h following addition
of 16, the reaction was concentrated under reduced pressure,
and H2O (20 mL) was added. The aqueous mixture was
extracted three times with EtOAc, and the pooled organic
extracts were washed with brine. The organic layer was dried
over anhydrous Na2SO4, concentrated onto Florisil, and chro-
matographed through silica gel using EtOAc/hex (5%) as
eluent. The product 17 was obtained as a colorless foam (3.36
g, 79%): Rf EtOAc/hex (20%) 0.29; 1H NMR (360 MHz/CDCl3)
δ 7.67 (dd, J ) 7.8, 15 Hz, 2H); 7.42 (dd, J ) 1.8, 7.2 Hz, 2H);
7.37-7.10 (m, 9H); 6.91 (d, J ) 16 Hz, 1H); 5.72 (d, J ) 16
Hz, 1H); 3.75 (s, 3H); 3.13 (s, 3H); 2.37 (s, 1H); 1.00 (s, 3H);
(neat/CaF2) 2993, 1736 cm-1; [R]27 34.3 (c ) 0.46, CHCl3);
D
HRMS calcd for C27H28NO4 430.2018, found m/z 430.2028.
(2R)-3,3-Dim eth yl-4-h yd r oxy-2-[(9-p h en ylflu or en -9-yl)-
a m in o]-bu tyr ic a cid m eth yl ester [Boc-â,â-d iMe-D-Hser -
OMe] (14); (2R)-3,3-Dim eth yl-4-h yd r oxy-2-[(9-p h en ylflu -
or en -9-yl)a m in o]-bu tyr ic a cid -â-la cton e (15). A solution
of 1 (1.04 g, 2.41 mmol) in DCM (20 mL) was cooled (-40 °C)
under N2, and a solution of DIBAL-H in hexanes (7.5 mL, 1
M) was added over 3 min. After 3 h, the reaction was quenched
with acetone (1 mL), and 10 min later, MeOH (3 mL) and H3-
PO4 (10 mL, 1 N) were added. The emulsion was extracted
three times with EtOAc, and the pooled organic extracts were
washed with brine, evaporated onto Florisil, and chromato-
graphed through silica gel using EtOAc/pet ether (15%) as
eluent. The alcohol 14 was obtained as a yellow oil (630 mg,
65%), and the lactone 15 was obtained as a colorless solid (217
mg, 24%). Recrystallization of 15 using EtOAc/hex gave
0.97 (s, 3H); IR (neat/CaF2) 2949, 1727 cm-1; [R]27 152 (c )
D
0.79, CHCl3); HRMS calcd for C29H30NO4 456.2175, found m/z
456.2191.
Meth yl-(2R)-3,3-d im eth yl-6-h yd r oxy-2-[(9-p h en ylflu o-
r en -9-yl)a m in o]-4-h exen oa te (18). A solution of (17) (770
mg, 1.69 mmol) in DCM (15 mL) was cooled (-45 °C) under
N2, and a solution of DIBAL-H in hexanes (3.4 mL, 1 M) was
added over 3 min. After 15 min, MeOH (2 mL) was added
followed by saturated Rochelle’s salt (20 mL) and EtOAc (100
mL). The mixture was allowed to warm to ambient tempera-
ture. After 10 min of stirring, the organic layer was collected,
and the aqueous layer was extracted twice with EtOAc. The
pooled organic extracts were washed with brine and dried over
anhydrous Na2SO4. The solution was evaporated onto Florisil

4368 J . Org. Chem., Vol. 64, No. 12, 1999
Kawahata et al.
and chromatographed using EtOAc/hex (25%) as eluent to give
0.92 (s, 6H); IR (neat/CaF2) 2971, 1713 cm-1; [R]27 -8.0 (c )
D
the desired product 18 as a colorless oil (668 mg, 93%): Rf
3.5, CHCl3); HRMS calcd for C22H35N2O6 423.2495, found m/z
1
EtOAc/hex (25%) 0.37; H NMR (360 MHz/CDCl3) δ 7.68 (dd,
423.2508.
Nr-Ben zyloxyca r b on yl-NE-ter t-b u t yloxyca r b on yl-3,3-
d im eth yl-D-lysin e [Cbz-â,â-d iMe-D-Lys(Boc)-OH] (4). A
solution of LiOH (1.2 mL, 1 N) was added to a cooled (0 °C)
solution of 21 (101 mg, 0.239 mmol) in dioxane (4.8 mL). After
1.5 h, the reaction was allowed to warm to ambient temper-
ature, and after 9 h, the reaction was concentrated to ap-
proximately one-third the original volume. The residue was
diluted with EtOAc (10 mL) and washed with 1 N HCl (4 mL).
The aqueous layer was extracted with fresh EtOAc, and the
pooled organic extracts were washed with brine. The organic
layer was dried over anhydrous Na2SO4, concentrated, and
chromatographed through silica gel using CHCl3/MeOH/AcOH
(98:1:1) as eluent. The desired product 4 was obtained as a
colorless oil (93 mg, 95%): Rf CHCl3/MeOH/AcOH (95:5:3) 0.46;
1H NMR (360 MHz/CDCl3) δ 7.35 (m, 5H); 6.29 (bs, 1H); 5.46
(d, J ) 9.7 Hz, 1H); 5.11 (s, 2H); 4.74 (bs, 1H); 4.28 (d, J ) 8.6
Hz, 1H); 3.05 (bm, 2H); 1.44 (m, 13H); IR (neat/CaF2) 3338,
2973, 1709 cm-1; [R]27D -9.4 (c ) 1.7, CHCl3); HRMS calcd for
J ) 7.8, 12 Hz, 2H); 7.43 (m, 2H); 7.36-7.18 (m, 8H); 7.11 (d,
J ) 7.9 Hz, 1H); 5.58 (m, 2H); 4.08 (d, J ) 4.7 Hz, 2H); 3.12
(s, 3H); 2.31 (s, 1H); 0.98 (s, 3H); 0.94 (s, 3H); IR (neat/CaF2)
3400, 2961, 1728 cm-1; [R]27 32.4 (c ) 1.6, CHCl3); HRMS
D
calcd for C28H30NO3 428.2226, found m/z 428.2228.
Meth yl-(2R)-6-a zid o-3,3-d im eth yl-2-[(9-p h en ylflu or en -
9-yl)a m in o]-4-h exen oa te (19). To a solution of 18 (658 mg,
1.54 mmol) and TEA (430 µL, 3.08 mmol) in dry CHCl3 (10
mL) was added 2-fluoro-N-methylpyridinuim tosylate (872 mg,
3.08 mmol). The solution was neutralized with TEA, and after
15 min, the solvent was removed under reduced pressure. The
residue was dissolved in dry HMPA (10 mL), and LiN3 (151
mg, 3.08 mmol) was added. The reaction was heated to 90 °C
under N2. After 15 h following LiN3 addition, the reaction was
allowed to cool to ambient temperature, diluted with H2O (20
mL), and extracted three times with EtOAc. The pooled organic
extracts were washed with brine and dried over anhydrous
Na2SO4. The solution was concentrated under reduced pres-
sure, and the residue was chromatographed through silica gel
using EtOAc/hex (7%) as eluent. The azide 19 was obtained
as a colorless oil (616 mg, 88%): Rf EtOAc/hex (25%) 0.59; 1H
NMR (360 MHz/CDCl3) δ 7.68 (dd, J ) 7.9, 11 Hz, 2H); 7.42
(m, 2H); 7.36-7.16 (m, 8H); 7.11 (d, J ) 7.6 Hz, 1H); 5.68 (d,
J ) 16 Hz, 2H); 5.44 (dt, J ) 6.5, 15 Hz, 1H); 3.71 (d, J ) 6.5
Hz, 2H); 3.11 (s, 3H); 2.93 (bs, 1H); 2.31 (s, 1H); 1.01 (s, 3H);
0.94 (s, 3H); IR (neat/CaF2) 2964, 2100, 1731 cm-1; [R]27D -76.3
(c ) 76.3, CHCl3); HRMS calcd for C28H28N4O2Na 475.2110,
found m/z 475.2089.
C
21H33N2O6 409.2339, found m/z 409.2354.
Nr-Ben zyloxyca r b on yl-NE-ter t-b u t yloxyca r b on yl-3,3-
d im eth yl-D-lysin e (R)- a n d (S)-r-m eth ylben zyla m id e (22a
a n d 22b). The title diastereomers were obtained by coupling
4 to optically active R-methylbenzylamine as described for 9a .
The 360 MHz 1H NMR spectra of the crude diastereomers 22a
and 22b were obtained, and the chemical shifts of the â-methyl
groups were used for comparison.
Dim et h yl-(2R)-3,3-d im et h yl-2-(9-p h en ylflu or en -9-yl)-
h om oglu ta m a te [Boc-â,â-d iMe-D-Hglu (OMe)-OMe] (23).
Magnesium powder (139 mg, 5.70 mmol) was added to a
solution of 17 (0.650 g, 1.43 mmol) in MeOH (15 mL). The
mixture was sonicated for 3 h, and the reaction was monitored
by TLC with KMnO4 stain to monitor the disappearance of
starting material. The reaction was diluted with EtOAc (100
mL), and 1 N HCl (15 mL) was added. The aqueous layer was
extracted twice with EtOAc, and the pooled organic extracts
were washed with brine. The organic layer was dried over
anhydrous Na2SO4, concentrated onto Florisil, and chromato-
graphed through silica gel using EtOAc/hex (15%) as eluent.
The desired product 23 was obtained as a colorless oil (0.594
g, 91%): Rf EtOAc/hex (20%) 0.42; 1H NMR (360 MHz/CDCl3)
δ 7.68 (dd, J ) 7.6, 15 Hz, 2H); 7.45 (d, J ) 6.5 Hz, 2H); 7.37
(m, 7H); 7.13 (dd, J ) 7.4 Hz, 13 Hz, 2H); 3.64 (s, 3H); 3.14 (s,
3H); 2.77 (s, 1H); 2.26 (s, 1H); 2.05 (m, 1H); 1.73 (m, 2H); 1.51
(m, 1H); 0.91 (s, 3H); 0.71 (s, 3H); IR (neat/CaF2) 2950, 1732
Nr-(9-P h en ylflu or en -9-yl)-NE-ter t-b u t yloxyca r b on yl-
3,3-d im eth yl-γ,δ-d eh yd r o-D-lysin e m eth yl ester (20). Tri-
phenylphosphine (163 mg, 0.621 mmol) was added to a solution
of 19 (200 mg, 0.442 mmol) in dry THF (6 mL), and the
reaction was allowed to warm to 65 °C. After 22 h, H2O (0.13
mL) was added, and the reaction was allowed to stir for
another 22 h, at which point the reaction was concentrated
under reduced pressure. The residue was dissolved in dioxane
(5 mL), and saturated NaHCO3 (1 mL) and Boc2O (157 mg,
0.720 mmol) were added. After 6 h, the reaction was concen-
trated, and the residue was taken up in H2O (10 mL). The
aqueous mixture was extracted three times with Et2O and the
pooled organic extracts were washed with brine. The organic
layer was dried over anhydrous MgSO4, concentrated under
reduced pressure, and chromatographed through silica gel
using EtOAc/pet ether (15%) as eluent. The desired product
20 was obtained as a colorless oil (210 mg, 90%): Rf EtOAc/
pet ether (20%) 0.28; 1H NMR (360 MHz/CDCl3) δ 7.68 (dd, J
) 7.9, 11 Hz, 2H); 7.42 (m, 2H); 7.36-7.16 (m, 8H); 7.11 (d, J
) 7.6 Hz, 1H); 5.68 (d, J ) 16 Hz, 1H); 5.44 (dt, J ) 6.5, 15
Hz, 1H); 3.71 (d, J ) 6.5 Hz, 2H); 3.11 (s, 3H); 2.93 (bs, 1H);
2.31 (s, 1H); 1.01 (s, 3H); 0.94 (s, 3H); IR (neat/CaF2) 3371,
cm-1; [R]27 28.3 (c ) 0.15, CHCl3); HRMS calcd for C29H32
-
D
NO4 458.2331, found m/z 458.2329.
Cr-Meth yl-3,3-dim eth yl-2-(ter t-bu tyloxycar bon ylam in o)-
D-h om oglu ta m a te [Boc-â,â-d iMe-D-Hglu -OMe] (5). Sodium
hydroxide (1.0 mL, 1 N) was added to a solution of 23 (153
mg, 0.334 mmol) in MeOH (10 mL). The solution was heated
to reflux, and after 6 h, the reaction was cooled to 0 °C. The
solution was carefully acidified to pH 2-3 by the addition of
1 N HCl. The mixture was extracted three times with EtOAc,
and the pooled organic extracts were washed with brine. The
organic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure to give the carboxylic acid as
an oil.
2973, 1716 cm-1; [R]27 29.0 (c ) 0.40, CHCl3); HRMS calcd
D
for C33H39N2O4 527.2910, found m/z 527.2929.
Nr-Ben zyloxyca r b on yl-NE-ter t-b u t yloxyca r b on yl-3,3-
dim eth yl-D-lysin e m eth yl ester [Cbz-â,â-diMe-D-Lys(Boc)-
OMe] (21). A mixture of 20 (172 mg, 0.327 mmol) and 10%
Pd/C (7 mg) in MeOH/EtOAc (10 mL, 2:1) was degassed under
reduced pressure and placed under H2 (2 atm). After 16 h, the
catalyst was removed by filtration through Celite, and the
filtrate was concentrated under reduced pressure. The residue
was dissolved in dry DCM (5 mL) and NMM (71 µL, 0.65
mmol) was added. The solution was cooled (0 °C) under N2,
and Cbz-Cl (70 µL, 0.49 mmol) was added over 3 min. After
18 h, H2O (8 mL) was added, and the mixture was extracted
twice with Et2O. The pooled organic extracts were washed with
0.5 N HCl and brine. The organic layer was dried over
anhydrous MgSO4, concentrated onto Florisil, and chromato-
graphed through silica gel using EtOAc/pet ether (15-25%
gradient) as eluent. The desired product 21 was obtained as a
colorless oil (115 mg, 83%): Rf EtOAc/pet ether (30%) 0.24;
1H NMR (360 MHz/CDCl3) δ 7.36 (m, 5H); 5.37 (d, J ) 9.7 Hz,
1H); 5.11 (s, 2H); 4.69 (bs, 1H); 4.28 (d, J ) 10 Hz, 1H); 3.73
(s, 3H); 3.08 (m, 2H); 1.52 (m, 2H); 1.33 (s, 9H); 1.28 (m, 2H);
The crude carboxylic acid was dissolved in MeOH (2 mL)
and EtOAc (2 mL), and 10% Pd/C (3 mg) and Boc2O (110 mg,
0.505 mmol) were added. The solution was degassed under
reduced pressure and placed under H2 (2 atm). After 40 h, the
mixture was filtered through Celite, and the filter was washed
with EtOAc. The filtrate was concentrated and chromato-
graphed through silica gel using CHCl3/MeOH/AcOH (98:1:1)
as eluent. The purified fractions were concentrated, and
residual AcOH was removed by codistillation with toluene. The
product 5 was obtained as a colorless oil (91.0 mg, 89%): Rf
1
CHCl3/MeOH/AcOH (98:1:1) 0.30; H NMR (360 MHz/CDCl3)
δ 5.18 (d, J ) 9.7 Hz, 1H); 4.21(d, J ) 9.7 Hz, 1H); 3.74 (s,
3H); 2.42 (m, 1H); 1.65 (m, 2H); 1.44 (s, 9H); 0.95 (s, 3H); 0.94

Synthesis of â,â-Dimethylated Amino Acid Building Blocks
J . Org. Chem., Vol. 64, No. 12, 1999 4369
(s, 3H); IR (neat/CaF2) 3284, 2975, 1713 cm-1; [R]27 -23.5 (c
(m, 1H); 4.41 (d, J ) 9.0 Hz, 1H); 4.33 (m, 1H); 3.69 (s, 3H);
3.22 (m, 1H); 3.01 (m, 3H); 1.41 (s, 9H); 1.31 (s, 9H); 1.26 (m,
1H); 1.12 (m, 1H); 0.86 (s, 3H); 0.82 (s, 3H); HRMS calcd for
C34H50N3O8 628.3598, found m/z 628.3607.
D
) 1.7, CHCl3); HRMS calcd for C14H26NO6 304.1760, found m/z
304.1760.
Nr-ter t-Bu t yloxyca r b on yl-Nδ-b en zyloxyca r b on yl-3,3-
d im eth yl-D-or n ith in e-m eth yl ester [Boc-â,â-d iMe-D-Or n -
(Cbz)-OMe] (6). Benzyl alcohol (34 µL, 0.33 mmol), DPPA (71
µL, 0.33 mmol), and TEA (69 µL, 0.50 mmol) were added to a
solution of 5 (50 mg, 0.165 mmol) in toluene (3 mL). The
solution was heated to reflux under N2. After 22 h, the reaction
was diluted with saturated NaHCO3 (5 mL) and extracted
twice with Et2O. The pooled organic extracts were washed with
brine and dried over anhydrous MgSO4. The solution was
concentrated and chromatographed through silica gel using
EtOAc/pet ether (25%) as eluent to give 6 as a colorless oil (38
mg, 56%): Rf EtOAc/pet ether (25%) 0.28; 1H NMR (360 MHz/
CDCl3) δ 7.35 (m, 5H); 5.13 (d, J ) 10 Hz, 1H); 5.09 (s, 2H);
4.86 (m, 1H); 4.20 (d, J ) 9.4 Hz, 1H); 3.73 (s, 3H); 3.27 (m,
2H); 1.51 (t, J ) 8.4 Hz, 2H); 1.43 (s, 9H); IR (neat/CaF2) 2974,
(R)-N-(9-P h en ylflu or en -9-yl)-3,3-d im eth yl-a zetid in e-2-
ca r boxylic a cid m eth yl ester [P h F l-â,â-d iMe-D-Azt-OMe]
(7). Mesyl chloride (58 µL, 0.75 mmol) was added to a solution
of 14 (100 mg, 0.250 mmol) and TEA (105 µL, 0.750 mmol) in
DCM (4 mL), and the mixture was allowed to stir at ambient
temperature. After 0.5 h, the reaction was diluted with DCM
(10 mL) and H2O (4 mL). The aqueous layer was extracted
with DCM, and the pooled organic extracts were washed with
brine. The organic layer was dried over anhydrous Na2SO4 and
concentrated to give a yellow oil. The crude material was
dissolved in HMPA (2 mL), and TEA (0.10 mL, 0.75 mmol)
was added. The reaction was heated (85 °C) and allowed to
stir under N2. After 16 h, the reaction was diluted with H2O
(5 mL) and extracted twice with EtOAc. The pooled organic
layers were washed with brine, dried over anhydrous Na2SO4,
and concentrated. The crude material was chromatographed
through silica gel using EtOAc/pet ether (8%) as eluent to give
the azetidine 7 as a colorless oil (60 mg, 60%): Rf EtOAc/pet
ether (10%) 0.50; 1H NMR (360 MHz/CDCl3) δ 7.76 (d, J ) 7.6
Hz, 1H); 7.59-7.11 (m, 12H); 3.35 (s, 3H); 3.20 (m, 2H); 3.05
(s, 1H); 1.16 (s, 3H); 0.83 (s, 3H); IR (neat/CaF2) 2952, 1752
1712 cm-1; [R]27 -15.7 (c ) 8.7, CHCl3); HRMS calcd for
D
C21H33N2O6 409.2339, found m/z 409.2318.
Nr-ter t-Bu t yloxyca r b on yl-O-ter t-b u t yl-t yr osin yl-Nδ-
ben zyloxyca r bon yl-3,3-d im eth yl-D-or n ith in e-m eth yl es-
ter [Boc-Tyr (tBu )-â,â-d iMe-D-Or n (Cbz)-OMe] (24). A so-
lution of 6 (24 mg, 59 µmol) in DCM (0.5 mL) was cooled (0
°C), and TFA (0.5 mL) was added. After 5 min, the reaction
was allowed to warm to ambient temperature, and after 1 h,
the solvent was removed under reduced pressure. Residual
TFA was removed by codistillation with toluene. The crude
amine was dissolved in DMF (1 mL), and HOAt (12 mg, 88
µmol) and Boc-Tyr(tBu)-OH (30 mg, 89 µmol) were added. The
reaction was cooled (-20 °C) under N2 and neutralized with
NMM, and EDC (17 mg, 89 µmol) was added. The reaction
was allowed to warm to ambient temperature, and after 18 h,
the reaction was concentrated under reduced pressure. The
residue was dissolved in 0.5 N HCl (3 mL), and the solution
was extracted three times with EtOAc. The pooled organic
extracts were washed with 0.5 N HCl, brine, saturated
NaHCO3, and brine. The organic layer was dried over anhy-
drous Na2SO4, concentrated onto Florisil, and chromato-
graphed through silica gel using EtOAc/hex (30%) as eluent.
The desired product 24 was obtained as a colorless foam (31
mg, 84%): Rf EtOAc/hex (50%) 0.48; 1H NMR (360 MHz/CDCl3)
δ 7.36 (m, 5H); 7.11 (d, J ) 7.9 Hz, 2H); 6.92 (d, J ) 7.9 Hz,
2H); 6.35 (bd, J ) 6.5 Hz, 1H); 5.21 (m, 1H); 5.10 (s, 2H); 5.00
cm-1; [R]27 -20.1 (c ) 0.34, CHCl3); HRMS calcd for C26H26
-
D
NO2 384.1966, found m/z 384.1972.
Ack n ow led gm en t. The authors wish to thank J o-
seph Taulane and Dr. Heather Sings for their assistance
and Dr. Peter Gantzel for solving the X-ray crystal-
lographic structure of lactone 15. Thanks also go to Li
1
Zhang for measuring the 500 MHz H NMR of 9a and
9b. The mass spectral analyses were performed by Dr.
Gary Siuzdak at The Scripps Research Institute, La
J olla, CA and Dr. Richard Kondrat at the University of
California, Riverside. This work is funded by the
National Institutes of Health (NIH DA 05539).
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra of
compounds 1-24. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O982474A