Synthesis of C-protected alpha-amino aldehydes of high enantiomeric excess from highly epimerizable N-protected alpha-amino aldehydes.

Article abstract of DOI:10.1021/ol006427s

A new procedure for the preparation of C-protected alpha-amino aldehydes of high enantiomeric excess is illustrated using five differently substituted alpha-(N-Fmoc)amino aldehydes as starting materials. Highly epimerization-prone substrates were converte

Full text of DOI:10.1021/ol006427s

ORGANIC
LETTERS
2000
Vol. 2, No. 21
3337-3340
Synthesis of C-Protected r-Amino
Aldehydes of High Enantiomeric Excess
from Highly Epimerizable N-Protected
r-Amino Aldehydes
Andrew G. Myers,* Boyu Zhong, Daniel W. Kung, Mohammad Movassaghi,
Brian A. Lanman, and Soojin Kwon
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
myers@chemistry.harVard.edu
Received August 7, 2000
ABSTRACT
A new procedure for the preparation of C-protected r-amino aldehydes of high enantiomeric excess is illustrated using five differently substituted
r-(N-Fmoc)amino aldehydes as starting materials. Highly epimerization-prone substrates were converted to the corresponding morpholino
nitrile-protected r-amino aldehydes with minimal racemization (products g 89% ee). Morpholino nitrile derivatives of phenylglycinal were
crystallized and subjected to X-ray structural analysis, allowing for definitive determination of the stereochemistry of amino nitrile formation.
A rationale for the stereoselectivity of amino nitrile formation is presented.
We recently described the preparation of a series of protected
R-amino aldehydes in which the aldehyde carbon was
masked as an amino nitrile function (see, e.g., structures 4).1
These “C-protected” R-amino aldehydes were prepared from
the corresponding R-(N-Fmoc)amino aldehydes in a three-
step sequence (two operations, vide infra), typically in g
92% ee.1,2 Subsequent efforts to extend this methodology
revealed that racemization was a serious problem when
highly epimerizable R-(N-Fmoc)amino aldehydes were used
as substrates. A modified procedure was developed that likely
involves the intermediacy of free R-amino aldehydes.3,4 As
detailed herein, the new method promises to be generally
applicable; highly enantiomerically enriched amino nitrile-
masked R-amino aldehydes have been prepared from all
R-(N-Fmoc)amino aldehydes examined, including those that
are readily epimerized. We have also determined the stere-
ochemistry of amino nitrile formation and have elucidated
conformational features of these products using X-ray
1
crystallography and solution H NMR data. A rationale for
the stereochemistry of amino nitrile formation is presented.
The original procedure for the preparation of amino nitrile-
masked R-amino aldehydes began with cyanohydrin forma-
tion from the corresponding R-(N-Fmoc)amino aldehydes and
hydrogen cyanide in dichloromethane-methanol (Figure 1).
(1) Myers, A. G.; Kung, D. W.; Zhong, B.; Movassaghi, M.; Kwon, S.
J. Am. Chem. Soc. 1999, 121, 8401-8402.
(2) For leading references to prior work describing the preparation of
acetal-, thioacetal-, and aminal-protected R-amino aldehydes, see: (a)
Bringmann, G.; Geisler, J.-P. Synthesis 1989, 608-610. (b) Thiam, M.;
Chastrette, F. Tetrahedron Lett. 1990, 31, 1429-1432. (c) Enders, D.; Funk,
R.; Klatt, M.; Raabe, G.; Hovestreydt, E. R. Angew. Chem., Int. Ed. Engl.
1993, 32, 418-421. (d) Denmark, S. E.; Nicaise, O. Synlett 1993, 359-
361. (e) Muralidharan, K. R.; Mokhallalati, M. K.; Pridgen, L. N.
Tetrahedron Lett. 1994, 35, 7489-7492. (f) Alexakis, A.; Lensen, N.;
Tranchier, J.-P.; Mangeney, P.; Feneau-Dupont, J.; Declercq, J. P. Synthesis
1995, 1038-1049.
(3) Myers, A. G.; Kung, D. W.; Zhong, B. J. Am. Chem. Soc. 2000,
122, 3236-3237.
(4) For other approaches to minimize racemization of R-amino aldehydes,
see: (a) Lubell, W. D.; Rapoport, H. J. Am. Chem. Soc. 1987, 109, 236-
239. (b) Reetz, M. T.; Drewes, M. W.; Schmitz, A. Angew. Chem., Int. Ed.
Engl. 1987, 26, 1141-1143.
10.1021/ol006427s CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/29/2000

presumed to have occurred during formation of the amino
nitrile (2 f 3).
Among possible solutions to the problem of racemization
during amino nitrile formation, we were led to consider
changing the order of the last two steps, that is, conducting
cleavage of the N-Fmoc group prior to amino nitrile
formation (Figure 2). The proposed alternative sequence was
Figure 1. The original procedure for R-amino morpholino nitrile
synthesis, leading to racemic products 4 in the case of N-Fmoc
phenylglycine (1).
The resulting cyanohydrins were then coupled to an amine
such as morpholine (5.0 equiv) in 2,2,2-trifluoroethanol
(TFE) at 23 °C, followed by cleavage of the N-Fmoc
protective group with DBU or piperidine in dichloro-
methane.1 Although this procedure was highly effective with
the range of R-(N-Fmoc)amino aldehydes originally exam-
ined, when N-Fmoc phenylglycinal (1) was later investigated
as a substrate, racemic products were obtained. Efforts to
develop an alternative procedure therefore focused on the
epimerization-free transformation of this substrate. We began
by identifying those steps in the sequence that were
responsible for racemization. The substrate (1) was prepared
by the oxidation of N-Fmoc phenylglycinol (>99% ee) with
the Dess-Martin periodinane, a reagent found to be optimal
for this purpose in terms of the chemical yield and enan-
tiopurity of the product (>95% yield, unpurified, 99% ee).5
The crude product, a white solid, was used directly in
cyanohydrin formation, for it decomposed upon attempted
chromatography on silica gel. Treatment of a freshly prepared
solution of N-Fmoc phenylglycinal (1) of 99% ee in
dichloromethane with methanolic hydrogen cyanide (pre-
pared in situ by combination of acetic acid and potassium
cyanide, 2.7 and 2.5 equiv, respectively) at 0 °C for 2 h
afforded the corresponding cyanohydrins 2 in 99% yield after
extractive isolation. Reduction of the latter products with
sodium borohydride in methanol afforded N-Fmoc phenyl-
glycinol in 99% yield and 98% ee (chiral HPLC analysis),
establishing that the transformation of 1 to 2 had proceeded
with <1% epimerization. Racemization in the synthesis of
the R-amino morpholino nitrile derivatives 4 must therefore
have occurred after cyanohydrin formation, during mor-
pholino nitrile formation (2 f 3) or later, upon cleavage of
the N-Fmoc group (3 f 4). Given the stability of the
morpholino nitrile group under basic reaction conditions, the
latter possibility seemed unlikely; racemization was thus
Figure 2. Modified procedure for R-amino morpholino nitrile
synthesis, involving “free” R-amino aldehyde 6 as an intermediate.
not viewed optimistically initially because it invoked the
intermediacy of a free R-amino aldehyde. Several lines of
evidence suggested that the idea was not without merit,
however, and we were eventually led to explore the prepara-
tion of R-amino aldehydes without protective groups. We
found that “free” R-amino aldehydes were indefinitely stable,
configurationally as well as constitutionally, in mildly acidic,
protic media, where they were shown to exist as their
ammonium salt carbonyl solvates (hydrate or methanol
adduct).3 Further studies showed that these species could be
intercepted by nucleophilic addition under basic conditions,
for example, with sodium borohydride in methanol, and that
this addition proceeded without detectable epimerization.3
For the present purpose it was necessary to generate the
“free” phenylglycinal intermediate (6) under carefully defined
conditions in order to trap it by Strecker reaction (amino
nitrile formation with morpholine and cyanide) without
epimerization. This entailed the development of a protocol
for cleavage of the N-Fmoc group of 2 under conditions that
did not promote premature breakdown of the cyanohydrin-
masked aldehyde. Morpholine was a particularly attractive
candidate in this regard because of its mild basicity and, more
importantly, because it was incorporated into the product in
the following step, potentially allowing the sequence to be
streamlined. Empirically, the course of reaction of R-(N-
Fmoc)amino cyanohydrins such as 2 with morpholine is
(5) Myers, A. G.; Zhong, B.; Movassaghi, M.; Kung, D. W.; Lanman,
B. A.; Kwon, S. Tetrahedron Lett. 2000, 41, 1359-1362.
3338
Org. Lett., Vol. 2, No. 21, 2000

found to be exceedingly sensitive to the reaction solvent. In
polar, protic media such as TFE, Strecker reaction of the
cyanohydrin group occurs preferentially, leading to the
formation of the R-(N-Fmoc)amino morpholino nitriles,
which were racemic in the case of products 3, as discussed
above. By contrast, in aprotic media cleavage of the N-Fmoc
group is observed to occur preferentially. Thus, treatment
of R-(N-Fmoc)amino cyanohydrins 2 with a 50% solution
of morpholine in dichloromethane led to complete N-Fmoc
cleavage within 2 h at 23 °C, leaving intact the cyanohydrin
group. Reduction of the resulting R-amino cyanohydrins (5)-
with sodium borohydride in methanol afforded phenylgly-
cinol of 72% ee. That partial racemization had occurred was
interpreted as evidence for reversible breakdown of the
cyanohydrin intermediate during cleavage of the N-Fmoc
group, providing an avenue for R-epimerization via the
aldehyde intermediate. What was not clear was whether
epimerization had occurred prior to N-Fmoc cleavage or
subsequently, via the free R-amino aldehyde. This question
was largely resolved when extended exposure of the products
5 to morpholine-dichloromethane (20 h for complete
reaction, 23 °C) was shown to provide the diastereomeric
R-amino morpholino nitriles 4 with little additional epimer-
ization (46 and 11% yields, 63 and 66% ee, respectively),
despite the 10-fold increase in reaction time. That the
majority of racemization had occurred during cleavage of
the N-Fmoc group, and not during the subsequent amino
nitrile synthesis, showed that the R-(N-Fmoc)amino aldehyde
was much more prone to epimerization than the correspond-
ing R-amino aldehyde, validating the hypothesis that led to
the proposed inverted reaction sequence. However, further
enhancement of the enantiomeric purity of the products was
viewed as necessary for the development of a useful process.
This was achieved by conducting the cleavage reaction in
the dipolar aprotic solvent N,N-dimethylformamide (DMF).6
N-Fmoc cleavage was found to be much faster in DMF than
in dichloromethane,4 whereas further transformation of the
R-amino cyanohydrin products to the corresponding R-amino
morpholino nitriles was negligibly slow in this solvent,
consistent with the idea that the cyanohydrin group was
stabilized against breakdown. By adding the protic solvent
TFE (and additional morpholine), amino nitrile formation
occurred smoothly at ambient temperature (23 °C, 10 h),
and with little racemization. After isolation by flash column
chromatography, the diastereomeric morpholino nitriles were
obtained in 67% and 12% yields (93 and 89% ee, respec-
tively). Recrystallization of each diastereomer afforded
crystals suitable for X-ray analysis; the structures are shown
in Figure 3. The major diastereomer was thus shown to have
the (S,S)-configuration (anti) and, correspondingly, the minor
diastereomer the (R,S)-configuration (syn). In the solid state,
both diastereomeric products adopt the one staggered con-
formation that avoids any syn-pentane like interactions
between the morpholine ring and the non-hydrogen substit-
uents of the R-carbon while maintaining an antiperiplanar
Figure 3. Solid-state structures of anti and syn morpholino nitrile
derivatives of phenylglycinal.
orientation of the morpholine nitrogen lone pair and the
cyano group. This would appear to be energetically more
important than any preference for the vicinal amines or the
bulky phenyl and morpholino groups to adopt trans orienta-
tions. The solid-state structures show no evidence of in-
tramolecular hydrogen-bonding interactions. Both diastere-
omers are believed to adopt solution conformations that are
quite similar to the solid-state conformations on the basis of
1H NMR evidence. For example, the 1H-1H coupling
constants between the R-protons and the vicinal protons of
the amino nitrile groups in solution are large (8-10 Hz) and
nearly identical for the two diastereomers (precluding ster-
eochemical determination on this basis), consistent with the
solid-state structures in which these protons are antiperiplanar
in both cases.
As shown in Table 1, the modifed procedure has provided
superior results in the formation of optically active mor-
pholino nitrile products. Substrates whose amino acid
counterparts were known to be problematic with regard to
racemization in peptide couplings were chosen specifically
for study. Thus, R-(N-Fmoc)amino aldehyde derivatives of
alanine and methionine were transformed into the corre-
sponding morpholino nitrile derivatives, in both cases with
high enantiomeric excesses (entries 7 and 8, Table 1).
Parenthetically, the preparation of C-protected methioninal
required a reliable route to methioninal of high enantiomeric
purity. Oxidation of the corresponding N-Fmoc amino
alcohol with the Dess-Martin periodinane in moist dichlo-
romethane proved to be optimal for this purpose, as it was
for the synthesis of optically active N-Fmoc phenylglycinal.
The compatibility of the thioether group of methioninal to
the conditions of the oxidation is especially noteworthy.7 As
in the case of N-Fmoc phenylglycinal, N-Fmoc methioninal
(6) Atherton, E.; Sheppard, R. C. In The Peptides; Undenfriend, S.,
Meienhofer, J., Eds.; Academic Press: San Diego, 1987; Vol. 9, Chapter
1, pp 16-20.
(7) Swern oxidation is complicated by the oxidation of the thioether
group, see: Wen, J. J.; Crews, C. M. Tetrahedron: Asymmetry 1998, 9,
1855-1858.
Org. Lett., Vol. 2, No. 21, 2000
3339

the nitrile carbon resonance (δ 116.1-116.3 major, δ 114.7-
115.6, minor) as a function of stereochemistry.8 In addition,
in every case the major diastereomer produced in the
modified procedure is found to be the less polar compound
(higher Rf value, SiO2, MeOH-CH2Cl2). While no one of
these features is compelling in and of itself, taken together,
the evidence suggests that each reaction follows a similar
stereochemical course.
Table 1. Synthesis of R-Amino Morpholino Nitrilesa
The stereoselectivity of amino nitrile formation is clearly
kinetically determined.9 This was established conclusively
in the case of the products derived from phenylglycine, where
each diastereomer was recovered unchanged when resub-
jected to the conditions of its formation. The selectivity of
amino nitrile formation can be rationalized by invoking
addition of cyanide to a rotamer of the morpholinium ion
intermediate in which the R-CH bond is coplanar, or nearly
so, with the iminium ion. In such a model, the major
diastereomer results from addition of cyanide to the iminium
ion along a trajectory close to the vector defined by the
adjacent R-CN bond, perhaps directed by hydrogen bonding
between hydrogen cyanide and the amino group (possibly
mediated by a bridging solvent molecule).
a Original procedure: HCN, CH2Cl2-MeOH; morpholine, TFE; DBU,
CH2Cl2. Modified procedure: HCN, CH2Cl2-MeOH; morpholine, DMF;
morpholine, TFE. Yields are determined using R-(N-Fmoc)amino alcohols
as starting materials and include oxidation to the R-(N-Fmoc)amino aldehyde
with the Dess-Martin periodinane.3 b Lower yield due to multiple
chromatographic purifications in this experiment. c Cleavage of N-Fmoc
group conducted in morpholine-CH2Cl2 (1:1).
The method elaborated herein provides a simple and, it is
proposed, general route to a useful class of C-protected
R-amino aldehyde intermediates for chemical synthesis.
These have been shown to be fundamental components of
more complex structures, assembled by a variety of basic
condensation reactions.10
did not survive chromatography on silica gel and was
therefore used in crude form.
Acknowledgment. Financial support from the National
Institutes of Health is gratefully acknowledged. D.W.K. and
B.A.L. acknowledge predoctoral fellowships from the Na-
tional Science Foundation. M.M. is supported by a Roche
predoctoral fellowship.
Entries 9 and 10 of Table 1 provide two examples of
morpholino nitrile derivatives of nonnatural R-amino alde-
hydes that we have employed as key intermediates in
complex synthetic problems; in both cases improved enan-
tioselectivities were obtained using the modified procedure
elaborated herein. Although the combined yield of mor-
pholino nitrile diastereomers may be slightly lower in the
modified procedure relative to the original protocol, the
enhanced optical purity of the products makes it by far the
superior method.
Supporting Information Available: Spectroscopic and
analytical data for morpholino nitrile-protected R-amino
aldehydes as well as experimental procedures for 2 and 4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The stereochemistry of amino nitrile formation is interest-
ing and merits comment. In the five cases examined the
diastereoselectivity of morpholino nitrile formation was
substantially higher in the modified procedure than in the
earlier procedure proceeding via R-(N-Fmoc)amino aldehyde
intermediates. The major stereoisomer is proposed to be the
(S,S)-diastereomer in all cases. Although only the products
derived from phenylglycinal have been rigorously deter-
mined, careful analysis of the 13C spectra (CDCl3) of the 10
products of Table 1 has shown small, but consistent,
variations in the chemical shifts of a morpholine N-CH2
resonance (δ 50.7-51.0, major, δ 50.2-50.4, minor) and
OL006427S
(8) Vicinal H-1H coupling constants between the methine hydrogens
1
are not reliable indicators of syn or anti stereochemistry. As noted in the
discussion above, the preferred conformations of both diastereomers place
the R-CH and the amino nitrile CH bonds antiperiplanar. The corresponding
coupling constants are thus quite similar and cannot be used to differentiate
the diastereomers.
(9) (a) Ogata, Y.; Kawasaki, A. J. Chem. Soc. B 1971, 2, 325-329. (b)
Taillades, J.; Commeyras, A. Tetrahedron 1974, 30, 2493-2501. (c) Stout,
D. M.; Black, L. A.; Matier, W. L. J. Org. Chem. 1983, 48, 5369-5373.
(d) Chakraborty, T. K.; Hussain, K. A.; Reddy, G. V. Tetrahedron 1995,
51, 9179-9190.
(10) Myers, A. G.; Kung, D. W. J. Am. Chem. Soc. 1999, 121, 10828-
10829.
3340
Org. Lett., Vol. 2, No. 21, 2000