Enantiocontrolled synthesis of α-methyl amino acids via Bn 2N-α-methylserine-β-lactone

Article abstract of DOI:10.1021/ol047761h

(Chemical Equation Presented) Enantiocontrolled synthesis of α-methyl amino acids proceeds via the regioselective organocuprate opening of Bn ₂N-α-methylserine-β-lactone. From this chiral intermediate, a wide variety of α-methyl amino acids and

Full text of DOI:10.1021/ol047761h

ORGANIC
LETTERS
2005
Vol. 7, No. 2
255-258
Enantiocontrolled Synthesis of
Amino Acids via
r-Methyl
Bn2N-r-Methylserine-â
-lactone†
Nicole D. Smith,* Aaron M. Wohlrab, and Murray Goodman‡
Department of Chemistry, UniVersity of California,
San Diego, La Jolla, California 92093
smithn@uchicago.edu
Received November 1, 2004
ABSTRACT
Enantiocontrolled synthesis of
r-methyl amino acids proceeds via the regioselective organocuprate opening of Bn2N-r-methylserine-â-lactone.
From this chiral intermediate, a wide variety of
r
-methyl amino acids and building blocks were synthesized in excellent yields.
Building blocks such as R-methyl amino acids have become
important in bioorganic chemistry. Incorporation of these
constrained building blocks into peptides results in confor-
mational restrictions and increased constraints of the pepti-
domimetic structures.1 These constrained building blocks
have been used to force peptides into their biologically active
conformations, often resulting in peptidomimetics with
remarkable resistance to enzymatic degradation.2 With the
expanding role of R-methyl amino acids in bioorganic
synthesis, a versatile route to optically pure R-methyl amino
acids is desirable and has been the focus of many laborato-
ries. The majority of synthetic routes involve the alkylation
of a chiral alanine derivative. Among these are the bis-lactim
ether of Schollkopf,3 the imidazolidinones and oxazolidinones
of Seebach,4 the diphenyloxazolinones of Williams,5 the
chelation-controlled addition of acyclic alanine enolates of
Ojima,6 and the acyclic chiral alanine-derived dianion of
Berkowitz.7 While these methods are effective, many of them
utilize a chiral auxiliary that is removed and often destroyed
in the process of deprotection.
With the previous success in our laboratory of opening
Boc-R-Me-Ser-â-lactone at the â-carbon with soft sulfur
nucleophiles,8 we were interested in opening this R-Me-Ser-
â-lactone with various carbon nucleophiles to generate a wide
variety of R-methyl amino acids from one common chiral
intermediate. On the basis of previous studies, it was
determined that Grignard-derived organocuprates are the best
source of soft carbon nucleophiles for the opening of
â-lactones. These studies showed that catalytic Cu(I) was
successful in directing the Grignard reagents to 1,4-additions
of enones and â-propiolactones.9
Inherent in the basic nature of the organocopper reagents,
there were concerns about the removal of the acidic proton
† The authors would like to dedicate this paper to the memory of Dr.
Murray Goodman for a lifetime of achievements in bioorganic chemistry.
‡ Deceased June 1, 2004.
(1) Marshall, G. R.; Bosshard, H. E. Circ. Res., Suppl. 1972, 2, 143-
150.
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Almond, H. R.; Manning, D. T.; Niemann, C. Biochemistry 1962, 1, 243-
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Greenstein, J. P. J. Am. Chem. Soc. 1953, 75, 918-920. (e) Baker, C. G.;
Fu, S.-C. J.; Birnbaum, S. M.; Sober, H. A.; Greenstein, J. P. J. Am. Chem.
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Tetrahedron 1989, 45, 403-412.
10.1021/ol047761h CCC: $30.25
© 2005 American Chemical Society
Published on Web 12/23/2004

on the carbamate-protected nitrogen of Boc-R-Me-Ser-â-
lactone. Vederas et al. showed that diprotected Ser-â-lactones
could be opened in higher yields than monoprotected Ser-
â-lactones due to the elimination of a base-catalyzed in-
tramolecular rearrangement that produces an oxazoline and/
or oxazolone, both of which are readily hydrolyzed to serine
upon aqueous workup.9a An additional side reaction that was
observed in their studies was the abstraction of the R-proton
in an elimination reaction resulting in the formation of
dehydroalanine.9a
Therefore, we studied the formation of Bn2N-R-Me-Ser-
â-lactone via activation of the carboxylic acid with various
coupling reagents. Previously, it was reported that BOP was
an efficient reagent for lactonization.15 In our study we chose,
PyBroP, DEPBT, HBTU, DCC/DMAP, PyBoP, and BOP.
The results are listed in Table 1.
Table 1. Lactonization Study of Bn2N-R-Me-Ser
Because of the absence of an R-proton in our R-methyl-
Ser-â-lactone, we were only concerned with the formation
of the oxazoline and/or oxazolone. We therefore sought an
alternative protecting group for the amine that would
eliminate the acidic proton and be stable to Grignard-derived
organocuprates. There are only a few protecting groups that
fit these requirements, including the stabase,10 benzostabase,11
pyrrole,12 2,5-dimethylpyrrole,13 and dibenzyl.14 Dibenzyla-
tion was chosen on the basis of the yield of protection
compared to the others and because of its stability under
aqueous workup conditions.
The starting material for the synthesis of Bn2N-R-Me-Ser-
â-lactone was H2N-R-Me-Ser-OMe, which was enantio-
selectively synthesized as previously described.8 The H2N-
R-Me-Ser-OMe (1) was dibenzylated with BnBr in THF/
DMSO with NaHCO3 in a 64% yield (2, Scheme 1). The
activating agent
% yield of 4
BOP
DEPBT
HBTU
PyBroP
PyBoP
DCC/DMAP (cat.)
36
0a
82
50
36
36
a DEPBT is known to be unreactive toward alcohols.
Three of the activating agents, BOP, PyBOP, and DCC/
DMAP, produced the â-lactone in 36% yield, while PyBroP
was slightly more effective, producing the â-lactone in 50%
yield. The ineffectiveness of DEPBT as a lactonization
reagent was not surprising since it was previously reported
that DEPBT is unreactive toward alcohols.16 By far, HBTU
was the best activating reagent for the lactonization, resulting
in Bn2N-R-Me-Ser-â-lactone in 82% yield. Not only was
this reagent superior to all other activating reagents, but it
afforded yields over 15% higher than those achieved when
utilizing Mitsunobu conditions for â-lactonization.8,9a,17
In examining the structure of the â-lactone, there are two
possible mechanisms of attack. The first is O-acyl fission in
which nucleophiles attack the lactone at the carbonyl carbon,
leading to the undesired ketone intermediate. This ketone
intermediate is then attacked with a second equivalent of
the nucleophile, leading to the tertiary alcohol (Figure 1).
The second mechanism of attack involves O-alkyl fission in
which the nucleophile attacks at the methylene carbon,
resulting in the desired R-methyl amino acids and building
blocks (Figure 1). It is known that softer nucleophiles will
preferentially attack at the methylene carbon, while harder
nucleophiles attack at the carbonyl carbon.9a
Scheme 1. Synthesis of Bn2N-R-Me-Ser and Attempted
Lactonization to Bn2N-R-Me-Ser-â-Lactone
methyl ester was saponified with KOH in MeOH/H2O to
give the carboxylic acid (3) required for lactonization. As
previously described, we attempted the Mitsunobu lacton-
ization utilizing PPh3, as well as DIAD in THF.8 This
reaction was unsuccessful because of the insolubility of the
starting material. In choosing the di-N-benzyl protecting
group, we created a zwitterion that was completely insoluble
in all solvents that are compatible with the Mitsunobu
reaction, including THF, dioxane, DMF, and acetonitrile.
We employed a variety of Grignard reagents for the ring
opening of Bn2N-R-Me-Ser-â-lactone under Cu(I) catalysis.
The results of our study are listed in Table 2. The Bn2N-R-
Me-Ser-â-lactone was opened with primary alkyl Grignards
in the presence of catalytic CuBr‚SMe2 to afford Bn2N-R-
Me-norleucine (5a) and Bn2N-R-Me-homoleucine (6a) in
(10) (a) Bargar, T. M.; McCowan, J. R.; McCarthy, J. R.; Wagner, E.
R. J. Org. Chem. 1987, 52, 678-681. (b) Basha, F. Z.; DeBernardis, J. F.
Tetrahedron Lett. 1984, 25, 5271-5274. (c) Djuric, S.; Venit, J.; Magnus,
P. Tetrahedron Lett. 1981, 22, 1787-1790.
(11) (a) Bonar-Law, R. P.; Davis, A. P.; Dorgan, B. J. Tetrahedron Lett.
1990, 31, 6725-6728. (b) Bonar-Law, R. P.; Davis, A. P.; Dorgan, B. J.
Tetrahedron Lett. 1990, 31, 6721-6724.
(12) (a) Davis, A. P.; Egan, T. J. Tetrahedron Lett. 1992, 33, 8125-
8126. (b) Kashima, C.; Maruyama, T.; Fujioka, Y.; Harada, K. J. Chem.
Soc., Perkin Trans. 1989, 1, 1041-1046.
(15) Lall, M. S.; Ramtohul, Y. K.; James, M. N. G.; Vederas, J. C. J.
Org. Chem. 2002, 67, 1536-1547.
(13) Bruekelman, S. P.; Leach, S. E.; Meakins, G. D.; Tirel, M. D. J.
Chem. Soc., Perkin Trans. 1984, 1, 2801-2807.
(16) Liu, P.; Sun, B.-Y.; Chen, X.-H.; Tian, G.-L.; Ye, Y.-H. Synth.
Commun. 2002, 32, 473-480.
(14) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141-1143.
(17) Arnold, L. D. K., T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985,
107, 7105-7109.
256
Org. Lett., Vol. 7, No. 2, 2005

also produced utilizing isopropylmagnesium chloride in 43%
yield. The lower yield of this reaction was a result of an
elimination reaction in which dibenzylamine acts as a leaving
group, not from O-acyl fission.
Functionalized alkyl Grignard reagents were also utilized
for the ring opening of Bn2N-R-Me-Ser-â-lactone. To
incorporate an oxygen functional group, (1,3-dioxan-2-
ylethyl)magnesium bromide was utilized to give the protected
aldehyde (8a, Table 2) in 94% yield with no formation of
the O-acyl fission product. To demonstrate the versatility of
this masked aldehyde intermediate, the carboxylic acid was
esterified with CH3I and K2CO3 in DMF to form the methyl
ester in 92% yield and the side chain acetal was cleaved in
83% yield under aqueous acidic conditions to unmask the
aldehyde (8c, Scheme 2). This aldehyde was then reduced
Figure 1. Two mechanistic pathways for â-lactone ring opening
with nucleophiles.
excellent yields (98 and 94%, respectively). These reactions
exhibited complete regioselectivity for O-alkyl fission over
O-acyl fission. The compound Bn2N-R-Me-leucine (7a) was
Scheme 2. Synthesis of an R-Methylhomoserine Derivative
(8d) and an R-Methylglutamic Acid Derivative (8e) from the
Masked Aldehyde (8a)
Table 2. Ring Opening of Bn2N-R-Me-Ser-â-Lactone with
Various Grignard-Derived Organocuprates
with sodium borohydride to the alcohol in 95% yield,
representing an R-methylhomoserine derivative (8d). In
addition, the aldehyde was oxidized with the Jones reagent
to the carboxylic acid in 96% yield to give an R-methyl-
glutamic acid derivative (8e, Scheme 2).
To incorporate a nitrogen functional group, the Grignard
reagent of 1-(3-bromopropyl)pyrrole was synthesized and the
corresponding cuprate reacted with Bn2N-R-Me-Ser-â-lac-
tone to yield the pyrrole-protected R-methyllysine derivative
(9a, Table 2) in 91% yield with no formation of the O-acyl
fission product.
The Bn2N-R-Me-Ser-â-lactone was allowed to react with
allyl and vinylmagnesium chloride in order to install an
alkene group onto the side chain of the R-methyl amino acid.
The reaction with allylmagnesium chloride in the presence
of catalytic CuBr‚SMe2 resulted in exclusively O-acyl fission,
affording the tertiary alcohol (10b) in 87% yield. This
reaction was repeated with stoichiometric CuBr‚SMe2, and
the same result was observed. The preference of allylmag-
nesium chloride to react at the carbonyl carbon of â-
propiolactones was also reported by Kawashima et al.18
Vinylmagnesium chloride provided a mixture of the desired
O-alkyl fission product and O-acyl fission product. The
a Catalytic CuBr‚SMe2 is used for in situ cuprate generation. b Ketone
product (Scheme 3). c Addition of 1.6 equiv of TMSCl. d Tetrabutyl-
ammonium cyanide, Cs2CO3 in DMF.
(18) Kawashima, M.; Sato, T.; Fujisawa, T. Tetrahedron 1989, 45, 403-
412.
Org. Lett., Vol. 7, No. 2, 2005
257

R-methyl amino acid (11a) was isolated in 51% yield.
Interestingly, the tertiary alcohol (11b) was not isolated.
Instead, the ketone (11d, Scheme 3) resulting from a Michael
Table 2) with 9% yield of the O-acyl fission side product.
The effects of TMSCl were limited to the addition of
organocuprates derived from aryl Grignard reagents. There
was no change in regioselectivity for the additions of
organocuprates derived from allyl or vinylmagnesium chlo-
ride.
Scheme 3. Formation of the Ketone Side Product via
In addition to Grignard-derived organocuprates, Bn2N-R-
Me-Ser-â-lactone was opened with tetrabutylammonium
cyanide to install a nitrile on the side chain of the dibenzyl-
protected R-methyl amino acid. This reaction was carried
out in DMF in the presence of Cs2CO3 to give (15a) in 58%
yield (Table 2).21 Once again, despite the reduced yield of
15a, the reaction was regioselective for O-alkyl fission,
resulting in the R-methyl amino acid derivative.
Conjugate Addition of a Presumed Vinylcuprate
To prove the versatility of this synthetic strategy for the
synthesis of R-methyl amino acid derivatives, a representative
example was chosen for deprotection (Scheme 4). The
addition to the R,â-unsaturated ketone intermediate (11c) of
the initial O-acyl opening was the only side product observed
(Scheme 3). This side reaction was also noted by Kawashima
et al. in their studies with â-propiolactones.18
The Bn2N-R-Me-Ser-â-lactone was opened with aryl
Grignard reagents to give Bn2N-R-Me-Phe, Bn2N-R-Me- Tyr,
and Bn2N-R-Me-Trp building blocks. The opening of Bn2N-
R-Me-Ser-â-lactone with phenylmagnesium chloride in the
presence of catalytic CuBr‚SMe2 resulted in 73% yield of
the desired Bn2N-R-Me-Phe (12a) and 19% yield of the
tertiary alcohol (12b). The results were very similar with
4-methoxyphenylmagnesium bromide, producing 70% yield
of Bn2N-R-Me-Tyr (13a) and 30% yield of the tertiary
alcohol (13b). The opening of Bn2N-R-Me-Ser-â-lactone
with indole Grignard was less successful, producing Bn2N-
R-Me-Trp (14a) in 59% yield.
In an attempt to improve the regioselectivity of the phenyl
and 4-methoxyphenyl Grignard-derived organocuprate ad-
ditions, TMSCl was added to the reaction mixture. The
beneficial effects of adding TMSCl to organocopper-medi-
ated addition reactions are well documented,19 and Nelson
et al. have reported an improved regioselectivity for the SN2
addition of methylmagnesium bromide to â-lactones.20 The
exact role of TMSCl in these addition reactions remains
unclear. It is possible that the TMS group coordinates to the
carbonyl oxygen, increasing the steric hindrance about the
carbonyl carbon and therefore directing the nucleophile to
the less hindered methylene carbon, resulting in O-alkyl
fission of the â-lactone.
Scheme 4. Dibenzyl Deprotection of Bn2N-R-Me-Phe-OCH3
carboxylic acid of Bn2N-R-Me-Phe (12a) was esterified
utilizing MeI and K2CO3 in DMF to give methyl ester (12c)
in 90% yield. The dibenzyl group was then removed under
hydrogenation conditions utilizing 5% Pd/C to give the free
amine (12d) in a quantitative yield. The ease of dibenzyl
deprotection makes these amino acid building blocks valuable
tools for peptidomimetic synthesis.
In conclusion, we have developed a novel, versatile,
enantioselective route to R-methyl amino acids and building
blocks utilizing Bn2N-R-Me-Ser-â-lactone. This â-lactone
can be synthesized in high yield from Bn2N-R-Me-Ser
utilizing HBTU and TEA in CH2Cl2. With HBTU, the
lactonization proceeded in 82% yield, which is remarkably
higher than the yields achieved with other activating reagents
and under Mitsunobu conditions. The Bn2N-R-Me-Ser-â-
lactone was regioselectively opened at the methylene carbon
with alkyl, functionalized alkyl, alkene, and aryl Grignard-
derived organocuprates, resulting in R-methyl amino acid
building blocks in excellent yields.
When TMSCl was added to the reaction mixture of
phenylmagnesium chloride, the regioselectivity for O-alkyl
fission was improved, resulting in a 90% yield of Bn2N-R-
Me-Phe as compared to 73% without TMSCl (12, Table 2).
There was still 9% formation of the O-acyl fission side
product. Similar results were observed when TMSCl was
added to the organocuprate derived from 4-methoxyphenyl-
magnesium bromide. The yield of Bn2N-R-Me-Tyr was
improved from 70 to 91% by the addition of TMSCl (13,
Acknowledgment. We thank the NIH (DA05539) for
financial support and fellowship support (N.D.S.) (DA07315)
and Joseph Taulane for helpful discussions on purification
and characterization.
Supporting Information Available: Experimental pro-
cedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(19) (a) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1985, 26, 6019-
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1993, 115, 9283-9284.
(20) Nelson, S. G.; Wan, Z.; Stan, M. A. J. Org. Chem. 2002, 67, 4680-
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OL047761H
(21) Arnold, L. D.; May, R. G.; Vederas, J. C. J. Am. Chem. Soc. 1988,
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