Enantiomerically pure α-amino aldehydes from silylated α-amino acids

Article abstract of DOI:10.1021/ol7028993

(Chemical Equation Presented) The disilylation of α-amino acids 1 to provide 2 (72-87%) was achieved without racemization. An unprecedented borane-mediated semi-reduction strategy was devised to convert 2 to stable, isolable oxazaborolidines 3 (100%) which were hydrolyzed to provide 5 (49-60%) as pure, stable compounds. Analysis of the Mosher amides (8) of the γ-amino esters 7 reveals that ≤2% racemization occurs in the 1 → 8 conversions.

Full text of DOI:10.1021/ol7028993

ORGANIC
LETTERS
2008
Vol. 10, No. 2
333-336
Enantiomerically Pure
r
-Amino
-Amino
Aldehydes from Silylated
r
Acids‡
Buddy Soto-Cairoli, Jorge Justo de Pomar, and John A. Soderquist*
Department of Chemistry, UniVersity of Puerto Rico,
Rio Piedras, Puerto Rico 00931-3346
jas@janice.uprr.pr
Received December 2, 2007
ABSTRACT
The disilylation of
r
-amino acids 1 to provide 2 (72
−
87%) was achieved without racemization. An unprecedented borane-mediated semi-
60%) as
2% racemization occurs in the 1
reduction strategy was devised to convert 2 to stable, isolable oxazaborolidines 3 (100%) which were hydrolyzed to provide 5 (49
pure, stable compounds. Analysis of the Mosher amides (8) of the
conversions.
−
γ
-amino esters 7 reveals that
e
f 8
The synthetically versatile R-amino aldehydes have found
numerous applications in the construction of important
pharmaceuticals, natural products, and modified proteins.1,2
These polyfunctional compounds also can function as transi-
tion state analogue inhibitors for various proteases.3 Because
the free amino aldehydes undergo rapid self-condensation,
numerous N-protected derivatives have been reported with
the most common being N-alkoxycarbonyl (e.g., Boc, Fmoc,
benzyloxycarbonyl (Z)), N-triarylmethyl (e.g., trityl, 9-phen-
ylfluoren-9-yl (PhFl)), or N,N-dibenzyl.1 Semi-reductive
strategies have been devised for the conversion of esters or
amide derivatives of R-amino acids to these aldehydes.1a,4a
However, these procedures can give impure products which
contain both esters and alcohols.4 Thus, they are more
commonly produced from the reduction of R-amino acid
derivatives to the corresponding alcohols followed by their
selective oxidation to the desired aldehydes.1
Racemization is a major issue when electron-withdrawing
groups are employed in the N-substituted amino aldehydes.1,5
Moreover, these intermediates exhibit both thermal and
chromatographic instability. Thus, they are generally isolated
and either used immediately or stored in the cold.4b In fact,
this is a general problem in even N,N-dibenzyl derivatives
‡ Dedicated to the memory of a fine chemist, leader and good friend,
the late Dr. Clinton F. Lane.
(1) (a) Jurczak, J.; Golebiowski, A. Chem. ReV. 1989, 89, 149 and
references cited therein. (b) Reetz, M. T. Chem. ReV. 1999, 99, 1121. (c)
Liang, X.; Andersch, Bols, M. J. Chem. Soc., Perkin Trans. 1 2001, 2136.
(2) (a) Kwon, S.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 16796. (b)
Nicolaou, K. C.; Hummel, C. W.; Pitsinos, E. N.; Nakada, M.; Smith, A.
L.; Shibayama, K.; Saimoto, H. J. Am. Chem. Soc. 1992, 114, 10082. (c)
Corey, E. J.; Reichard, G. A. J. Am. Chem. Soc. 1992, 114, 10677. (d)
Vedejs, E.; Naidu, B. N.; Klapars, A.; Warner, D. L.; Li, V.; Na, Y.; Kohn,
H. J. Am. Chem. Soc. 2003, 125, 15796. (e) Myers, A. G.; Kung, D. W. J.
Am. Chem. Soc. 1999, 121, 10828. (f) Lin, S.; Yang, Z.; Kwok, B. H. B.;
Koldobskiy, Crews, M. C. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004,
126, 6347. (g) Boger, D. L.; Colleti, S. L.; Honda, T.; Menezes, R. F. J.
Am. Chem. Soc. 1994, 116, 5607. (h) Hagihara, M.; Schreiber, S. L. J. Am.
Chem. Soc. 1992, 114, 6570.
(4) (a) Garner, P.; Park, J. M. Org. Synth. 1992, 70, 18. (b) Roush, W.
R.; Hunt, J. A. J. Org. Chem. 1995, 60, 798.
(5) (a) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman,
B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359. (b) Concello´n, J. M.;
Mejica, C. Eur. J. Org. Chem. 2007, 5250.
(3) (a) Andersson, L.; Isley, T. C.; Wolfenden, R. Biochemistry 1982,
21, 4177. (b) Otto, H.-H.; Schirmeister, T. Chem. ReV. 1997, 97, 133. (c)
Leung, D.; Abbenante, G.; Fairlie, D. P. J. Med. Chem. 2000, 43, 305. (d)
Fu, Y.; Bieschke, J.; Kelly, J. W. J. Am. Chem. Soc. 2005, 127, 15366.
10.1021/ol7028993 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/20/2007

which decompose with chromatographic purification and
storage.1b In this case, the removal of the benzyl groups
through catalytic hydrogenation can also restrict the potential
synthetic applications of these intermediates.1b,6 Rapoport’s
use of the N-PhFl protection largely solved these racemiza-
tion and purification problems.7 However, the installation
of this group employs stoichiometric quantities of the
environmentally unfriendly Pb(NO3)2, and its removal re-
quires harsh conditions (e.g., TFA, 8 h, 80 °C or Li/NH3
(l)). Thus, the appropriate precursors to these aldehydes are
not commercially available, and these groups are rarely used.
For some time, we have had an interest in new chemistry
orchestrated through the triisopropylsilyl (TIPS) substitution.8
The highly compact and effective steric bulk of the triiso-
propyl substitution on silicon retards reactions not only at
the silyl center but also at adjacent centers. We felt that the
TIPS group should combine ease of installation and removal
with effective steric bulk which impedes the racemization
of enolizable amino aldehydes (i.e., 5). Consideration of these
properties and the above limitations for the known R-amino
aldehydes led us to examine the potential of the bulky,
electron-donating TIPS group to provide thermally stable and
isolable N-protected R-amino aldehydes (5) in enantiomeri-
cally and chemically pure form. We envisaged the N,O-bis-
(triisopropylsilyl)-R-amino acids 2 as convenient precursors
to 5 (Scheme 1). While both TIPS amines and esters are
Table 1. N-TIPS-R-Amino Aldehydes 5 from 1
R
series
2 (%)a
3b (%) (c/t)c
5 (%)a
Me
Prd
(CH2)2SMe
i-Bu
Bn
CH2OBn
Ph
a
b
c
d
e
f
74
72
72
82
87
82
85
100 (31/69)
100 (18/82)
100 (13/87)
100 (14/86)
100 (20/80)
100 (20/80)
100 (25/75)
56
56
56
54
52
50
49
g
a Yields of isolated analytically pure material. b The yields for 3 from
this process were quantitative (100 ( 2%). c The cis isomer exhibits J(H4-
H5) ) 5-6 Hz, while the trans isomer has a negligible three-bond H-H
coupling J(H4-H5) ∼ 0 Hz. d The D-amino acid was also silylated to give
D-2b (83%) and reduced to D-3b (100%, c/t ) 15/85) and hydrolyzed to
D-5b (60%).
tocol. More significantly, the inclusion of the bulky Hu¨nig’s
base in the procedure provided the key to avoiding any loss
of optical purity in the product 2 even for challenging
systems such as O-benzylserine (2f) or phenylglycine (2g).
This is a major issue for these examples when DBU is used
as the base.
With the highly soluble and stable silyl derivatives 2 in
hand, we chose to examine their semi-reduction with
borane-dimethyl sulfide complex (DMSB). While DIBAL-H
is commonly employed for related processes with amino
esters,1a,4a to our knowledge, the analogous borane-based
process is unprecedented. TIPS esters specifically are fully
reduced to the corresponding alcohol when heated neat with
1 molar equiv of DMSB. In fact, when a 1:1:1 mixture of
2e, PhCH2COOTIPS, and DMSB is heated, only the PhCH2-
COOTIPS is reduced (to PhCH2CH2OH) with 2e being
unaffected. With the bulky 2°-amine present in 2, after the
initial “hydroboration” of the carbonyl, we view the BH2
moiety as reversibly complexing this amine, ultimately
reacting further to produce hydrogen and the oxazaborolidine
3. This reaction diminishes both the Lewis acidity and the
mobility of the boron atom. Thus, 3 is stable, showing no
tendency to undergo â-elimination of a BOTIPS moiety to
generate an aldehydic carbonyl group which would be further
reduced. The oxazaborolidines 3 are produced quantitatiVely
as cis/trans mixtures (Table 1). These isomers exhibit a
Scheme 1
known,8a the only reported N,O-disilylated R-amino acids
are the hydrolytically unstable trimethylsilyl derivatives.9 We
expected this process to be straightforward. However,
considerable effort was required to find conditions which
provide an efficient route to 2 without its partial racemiza-
tion. Fortunately, through the slow addition of TIPSOTf to
1/(i-Pr)2NEt in refluxing THF, the clean 1 f 2 conversion
was achieved (Table 1). The unwanted formation of poly-
tetrahydrofuran was completely avoided through this pro-
number of clearly resolved signals in both the H and 13C
1
NMR spectra which can be used to evaluate this ratio in
each case (see Supporting Information). Interestingly, while
these BH oxazaborolidines evidently exist as monomers
(ν(B-H) ) 2550-2580 cm-1, 11B NMR δ 31-33), we were
1
unable to observe a doublet in the H-coupled 11B NMR
spectra of 3. This phenomenon has been observed by Corey
in related systems.10 Remarkably, despite containing the
mixed acetal moiety, 3 is stable and can be stored under
nitrogen for months without significant decomposition!
Very mild reaction conditions were developed to effect
the clean hydrolysis of 3 through 4 to provide the pure
R-amino aldehydes 5. This was accomplished through the
(6) Hyun, S. I.; Kim, Y. G. Tetrahedron Lett. 1998, 39, 4299.
(7) (a) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236.
(b) Lubell, W. D.; Rapoport, H. J. Org. Chem. 1989, 54, 3824. (c) Jamison,
T. F.; Rapoport, H. Org. Synth. 1993, 71, 226.
(8) (a) Ru¨cker, C. Chem. ReV. 1995, 95, 1009 and references cited therein.
(b) Soderquist, J. A.; Vaquer, J.; D´ıaz, M. J.; Bordwell, F. G.; Zhang, S.
Tetrahedron Lett. 1996, 37, 2561. (c) Justo de Pomar, J. C.; Soderquist, J.
A. Tetrahedron Lett. 1998, 39, 4409. (d) Justo de Pomar, J. C.; Soderquist,
J. A. Tetrahedron Lett. 2000, 41, 3285. (e) Soderquist, J. A.; Justo de Pomar,
J. C. Tetrahedron Lett. 2000, 41, 3537.
(9) (a) Gehrke, C. W.; Leimer, K. J. Chromatogr. 1971, 57, 219. (b)
Venkateswaran, P. S.; Bardos, T. J. J. Org. Chem. 1967, 32, 1256.
(10) For a similar system, see: Corey, E. J.; Bakshi, R. K.; Shibata, S.
J. Am. Chem. Soc. 1987, 109, 5551.
334
Org. Lett., Vol. 10, No. 2, 2008

rate-controlled addition of a solution of water (3 equiv, 1.5
M in THF) to 3 (0.50 M in THF) with its mixed acetal, B-N
and B-H functional groups. Dilution with ethyl acetate and
rapid filtration through activated (I) dry neutral alumina
removes the B(OH)3, giving a mixture of 5, TIPSOH, and
an intermediate hemiacetal 4 which we identified through
NMR experiments.11 After 4-5 h, 4 collapses cleanly to 5
and TIPSOH. Subsequent concentration and rapid distillation
gives a mixture of TIPSOH and the aldehyde.12 Careful
distillation to remove the TIPSOH (bp 40-42 °C, 0.4
mmHg) gives pure 5 in good yields (49-60%). Notably, the
N-TIPS protection faithfully serves its function to preserve
the chemical and optical purity of 5 even when it is filtered
through alumina at ambient temperatures. Moreover, these
aldehydes can be stored in the cold (-20 °C) under a nitrogen
atmosphere for weeks without significant decomposition.
Skeletal rearrangements have not been observed in 5 even
during filtrations through alumina, distillations, or the other
manipulations employed in their isolation and storage. It must
be emphasized that 5 is the only known R-amino aldehyde
which can be distilled without decomposition or racemiza-
tion.13 The bulky, electron-donating N-TIPS group14 provides
particularly effective protection for amino aldehydes.
Computer-generated models reveal the effectiveness of the
N-TIPS group in not only blocking access to the amino nitro-
gen atom but also limiting access to the R-hydrogen and
processes which lead to the racemization of 5 (Figure 1).15
combine this determination with a demonstration of the
synthetic value of 5 through their conversion to the corre-
sponding γ-amino-R,â-unsaturated esters 6 through a simple
Wittig olefination (Scheme 2).1,2,5b
Scheme 2
While rare in nature, unsaturated derivatives of amino acids
provide intriguing building blocks for making significant
structural changes to the backbone of peptides.16 This
conversion also facilitates a new entry to geometrically and
optically pure cysteine and serine protease inhibitors.17 The
removal of the N-TIPS protection takes place rapidly under
very mild conditions (0.16 N HCl, 0 °C). Moreover,
employing a simple basic workup permits 7 to be isolated
in analytically pure form as the free base with preservation
of the trans CdC geometry (Table 2).
Table 2. γ-Amino-R,â-Unsaturated Amino Esters from 5
series
6 (%)a
7 (%)
ee (%)b
a
b
c
d
e
f
73
80
84
85
84
85
90
62
64
64
62
71
66
70
99
99c
98
98
98
98
99
g
a Yields correspond to the product obtained from the pure aldehyde 5.
b Product ee determined by conversion to the Mosher amide of 7 (crude)
1
and analysis by H and 13C NMR. c The D-amino aldehyde D-5b was also
Figure 1. Space-filling MM model of phenylglycinal 5g.
olefinated to give D-6b (81%) and desilylated D-7b (65%, 99% ee).
Traditionally, the optical purities of N-protected R-amino
aldehydes have been obtained through the analysis of the
corresponding amino alcohols.1 However, we chose to
The amines 7 were converted to the corresponding Mosher
1
amides 8. These were rigorously analyzed by 13C and H
NMR. In each case, the racemic amino acids (()-1 were
carried through the reaction sequence 1 f 8 for comparison
and analysis purposes. No kinetic resolution was observed
in the acylation of 7 to provide 8. The limits of detection
for this method were determined to be <0.5%, thereby
clearly revealing that no more than 2% racemization (i.e., 7
g98% ee) had occurred in any of the representative systems
(11) The major (1S,2S)-4d diastereomer was identified through: (1) OH
and NHTIPS 1H NMR signals at δ 3.91 and 0.20, which were exchangeable
with D2O, (2) 13C NMR data showing diastereotopic isopropyl methyl
groups for both the OTIPS (δ 17.78, 17.87) and NHTIPS (δ 18.43, 18.48)
signals at δ 56.28 (C2) and 92.13 (C1), and (3) its clean conversion to 5d
and TIPSOH (see Supporting Information).
(12) For 5f and 5g, the aldehydes are generated through the distillation
process from the crude hydrolysate. Once isolated, as for the other examples
of 5, they are stable (>1 week) when stored in the cold (-20 °C).
(13) Garner’s aldehyde is isolated by distillation, but in neither chemically
nor enantiomerically pure form. Therefore, its thermal stability in the
distillation process has not been established.4a
(16) (a) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber,
S. L. J. Am. Chem. Soc. 1992, 114, 6568. (b) Baldauf, C.; Gunther, R.;
Hofmann, H. J. J. Org. Chem. 2005, 70, 5351.
(17) Powers, J. C.; Asgian, J. L.; Ekici, O. D.; James, K. E. Chem. ReV.
2002, 102, 4639.
1
(14) For example, H NMR δ 0.5-0.7 for NH proton in 2, 5, and 6.
(15) Generated with the Spartan 06 V112 program.
Org. Lett., Vol. 10, No. 2, 2008
335

studied. This includes the particularly challenging examples,
serinal 5g and phenylglycinal 5h. We also prepared the pure
D-amino compounds for the b series (R ) Pr) (see footnotes,
Tables 1 and 2). The Mosher amide 8a (R ) Me) was
purified to obtain a crystalline derivative whose single-crystal
X-ray structure is pictured in Figure 2.
These aldehydes possess high thermal stability, can be fil-
tered through neutral alumina, and resist both racemization
and chemical degradation upon handling and storage! The
Wittig olefination of 5 with Ph3PCHCOOEt provides a sim-
ple entry to N-TIPS-γ-amino-R,â-unsaturated amino esters
6 (73-90%) which are readily deprotected and converted
to provide the free amines 7 (62-71%). Analysis of the
Mosher amide derivatives of these amines 7 reveals them to
be g98% ee in every case, even with the traditionally
difficult serine and phenylglycine examples. Thus, the TIPS
group not only facilitates the preparation and isolation of 5
in pure form without racemization but also permits these
aldehydes to be used for further synthetic conversions without
loss of optical purity. These meritorious features should
dramatically increase the number of applications for these
polyfunctional intermediates in chemical synthesis.
Acknowledgment. The support of the NSF (CHE0517194)
and NIH SCORE (S06GM8102) Program is gratefully
acknowledged. We thank Dr. Hong Zhao (University of
Puerto Rico) for the X-ray structure of the Mosher amide
8a. The help of Dr. Iveliz Kock, Ms. Carmen Garcia, Mr.
Jose Guzman, and Ms. Raquel Nieves (University of Puerto
Rico) with this study is also gratefully acknowledged.
Figure 2. X-ray structure of the Mosher amide 8a.
In summary, a new borane-based route to N-TIPS-R-amino
aldehydes 5 from amino acids 1 was demonstrated for
eight representative examples through a simple three-step
process. First, N,O-bisTIPS-R-amino esters 2 were prepared
(72-87%) through a new silylation protocol which avoids
product racemization. Next, an unprecedented borane-medi-
ated semi-reduction strategy was devised to convert 2 to
stable, isolable oxazaborolidines 3 (100%) containing the
mixed acetal functional group. The controlled hydrolysis of
3 gives 5 (49-60%) through a hemiacetal intermediate 4.
Supporting Information Available: Full experimental
procedures, characterization data, selected spectra for 2, 3,
4-7, and derivatives and X-ray crystallographic data for 8a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL7028993
336
Org. Lett., Vol. 10, No. 2, 2008