Completely stereocontrolled aldol reaction of chiral ?2-amino acids

Article abstract of DOI:10.1021/ol503523h

A general protocol to independently access stereoisomerically pure ?2 a?2-hydroxy-?2-amino acid derivatives that is based on dibutylboron triflate-mediated aldol reaction of suitably protected ?2-amino acids bearing chiral oxazolidinone auxiliary is reported. The method smoothly afforded syn-aldol (?±,?2 a?2-syn) products in pure form and excellent isolated yield. Both ?±,?2-syn and ?±,?2-anti isomers are readily accessible solely through the choice of the oxazolidinone chirality. This method allows for the preparation of stereoisomeric ?2 a?2-hydroxy-?2-amino acid derivatives that were previously unreported.

Full text of DOI:10.1021/ol503523h

Letter
pubs.acs.org/OrgLett
Completely Stereocontrolled Aldol Reaction of Chiral β‑Amino Acids
†
‡
‡
‡
†
Martin Gazvoda, Kathrin Hoferl-Prantz, Roland Barth, Wolfgang Felzmann, Andrej Pevec,
̈
,
†
and Janez Kosm
̌
rlj*
†
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecn
̌
a pot 113, SI-1000 Ljubljana, Slovenia
‡
Sandoz Development Centre Austria, Chemical Development, Sandoz Austria GmbH, Biochemiestraße 10, A-6250 Kundl, Tirol,
Austria
*
S Supporting Information
ABSTRACT: A general protocol to independently access
stereoisomerically pure β′-hydroxy-β-amino acid derivatives
that is based on dibutylboron triflate-mediated aldol reaction
of suitably protected β-amino acids bearing chiral oxazolidi-
none auxiliary is reported. The method smoothly afforded syn-
aldol (α,β′-syn) products in pure form and excellent isolated
yield. Both α,β-syn and α,β-anti isomers are readily accessible solely through the choice of the oxazolidinone chirality. This
method allows for the preparation of stereoisomeric β′-hydroxy-β-amino acid derivatives that were previously unreported.
he requirement of the pharmaceutical industry for chiral
chemical entities has been one of the major driving forces in
Scheme 2. Previous Results on Boron-Mediated Aldol
Reaction of Achiral β-Amino Acids
a
T
the development of asymmetric synthetic methods. The aldol
reaction is a powerful means of carbon−carbon bond
construction, allowing the formation of up to two stereocenters
1
,2
in a single step with remarkable stereoselectivity. Because of
work of Evans and others, it allows access to all stereoisomers,
even with β-hydroxy carboxylic acid substrates. In stark contrast,
aldol reactions of chiral β-amino acid nucleophiles with good
diastereo- and enantioselectivity remain largely unexplored
(
Scheme 1).
Scheme 1. Anticipated Stereoisomeric Aldol Products of β-
Amino Acid Nucleophiles
a
For details, see text.
9
formation. The interference of the β-nitrogen atom on the
course of the reaction is greatly illustrated by a report of Kurz et
al. In this case, dibutylboron triflate-mediated addition of a 2-(2-
pyridyl)acetyloxazolidinone derivative to benzaldehyde failed
completely, yielding stable boryl enolate intermediate I, instead
A substrate-controlled version has been realized using N-alkyl-
N-α-alkylbenzyl-functionalized β-amino esters and lactones
3
,4
5−7
10
(
Scheme 2).
Until now, no general method has existed that allows the
by employing lithium diisopropylamide (LDA) for enolate
formation. It results in α,β-anti isomers with rather unpredictable
although in some cases acceptable diastereoselectivity. Surpris-
ingly, only a few reports of boron-mediated reactions are
precedented. Davies et al. reported the reaction of N-benzyl-N-α-
methylbenzyl β-amino acid derivatives with SuperQuat auxiliary
and 9-borabicyclo[3.3.1]nonyl trifluoromethanesulfonate (9-
intrinsic diastereocontrol exhibited by the substrate to be
overridden and provides access to α,β-anti or α,β-syn aldol
products with comparable selectivity. This is surprising as these
scaffolds are of prime importance in the chemistry of β-amino
1
1
12
5
acids, the corresponding peptides, β-aminolactones, and β-
13
8
lactams, to name just a few. Noteworthy, in the context of β-
lactams, is that a unified access to β′-hydroxy-β-amino acid
derivatives would be beneficial for SAR studies in a search for
BBNOTf) to produce α,β′-syn aldols (Scheme 2). Despite the
relative simplicity of the substrates lacking the chirality at the β-
carbon atom, a decrease in both the stereoselectivity and the yield
was noted and was attributed to the choice of the nitrogen
protecting groups. Similar observations were made by Seebach et
al. using N-Boc protection and dibutylboron triflate for enolate
Received: December 6, 2014
Published: January 23, 2015
©
2015 American Chemical Society
512
DOI: 10.1021/ol503523h
Org. Lett. 2015, 17, 512−515

Organic Letters
Letter
Scheme 3. Model β-Amino Acid Substrates 3 Selected to Probe the Dibutylboron Triflate Mediated Aldol Reaction into 4
new lead antibiotics, superior to thienamycin and other potent
carbapenams, carbapenems, and carbacephems.
Scheme 4. Reaction of 3a with i-Pr NEt/Bu BOTf To Form
2 2
3a·BBu and Intermediate A Proposed by Seebach et al.
2
We selected compound 1 (Scheme 3) as a model β-amino acid
on the basis of the following considerations: (a) it holds
functionalization that should challenge the chemistry through
the intrinsic conformational restriction and functional group
tolerance, (b) an additional stereochemical challenge may be
posed by the γ-stereocenter, which impacts LDA-mediated aldol
3
reactions, (c) in numerous postaldol manipulations the selected
functionalization gives easy access to compounds of biological
interest through well-established chemistry, and (d) enantiopure
17
14
close B−N interaction. This species was tentatively assigned
1
can be easily prepared from (S)-Roche ester.
It was expected that after the appropriate nitrogen atom
18
the structure of 3a·BBu by NMR spectroscopy (Scheme 4).
2
Alkaline hydrogen peroxide released 3a from 3a·BBu (Scheme
2
protection (1 → 2), followed by ester group saponification and
amidation with (S)-4-isopropyloxazolidin-2-one yielding 3, the
dibutylboron triflate mediated aldol reaction with acetaldehyde
would afford the desired aldol product 4 (Scheme 3). The
oxazolidinone auxiliary was selected vs others on the basis of its
simplicity, availability, and price. By selecting the appropriate
reaction conditions, the formation of 4 should proceed through
the (Z)-boryl enolate intermediate and the six-membered
14
4
). The result is in sharp contrast to the suggestion of Seebach
9
et al. that boron interacts with the carbamate carbonyl oxygen
atom (structure A, Scheme 4).
Phthalimide 3b was expected to provide an effective β-
19
nitrogen atom protection, disabling B−N interactions as
20
observed for 3a·BBu . Thus, compound 3b was combined
2
with i-Pr NEt, Bu BOTf, and acetaldehyde (Scheme 5), leading
2
2
1
5
chairlike Zimmerman−Traxler transition state II. We
hypothesized that in the latter the side chain of the β-amino
acid should have little or no influence on the stereochemical
outcome affording preferentially the α,β-syn-α,β′-syn isomer 4. If
successful, this would provide an entry to β′-hydroxy-β-amino
acid derivatives that were previously inaccessible.
Scheme 5. Synthesis of 4b and 4b′ and a Part of the X-ray
Structure of 4b′
To avoid the potential boron−nitrogen interactions with the
β-amino nitrogen atom as discussed above, it was important to
identify a suitable protecting group NPG. The report of Seebach
9
16
et al. prompted us to initially examine Boc protection. In our
2
case, an attempted aldol reaction under the standard reaction
conditions by premixing 3a with Bu BOTf at −78 °C,
2
subsequent enolate formation by addition of i-Pr NEt, and
2
sequential addition of acetaldehyde returned a complex mixture
of products, but no desired β′-hydroxy-β-amino acid derivative
1
could be detected by H NMR and HRMS analyses. The spectra
indicated that neither Boc nor TBS ether groups were tolerated
by the reaction conditions, presumably due to trace amounts of
triflic acid that accompanied Bu BOTf. Accordingly, the
2
decomposition of 3a was completely suppressed by changing
the order of Bu BOTf and i-Pr NEt addition, with the latter
1
to a single product. On the basis of H NMR spectral analysis, the
2
2
being introduced first to ensure basic reaction conditions
throughout the reaction. Unfortunately, in this case, no traces
of the aldol product could be detected by HRMS analysis of the
reaction mixture, whereas NMR spectroscopy revealed the
crude reaction mixture consisted of the desired aldol product 4b
and unreacted starting material 3b in a 92:8 ratio by integration
with no other diastereomeric aldol products detectable. It is
noteworthy that in contrast to the standard alkaline hydrogen
1
d,2b,e
presence of unreacted 3a and a new species, 3a·BBu (vide infra,
peroxide conditions,
the hydroxyl group of 4b could be
2
Scheme 4).
liberated from the dibutylboron 4b·BBu adduct solely by the
2
To shed light on this, the reaction mixture of 3a with i-Pr NEt/
addition of water. Such mild workup conditions provide a wide
compatibility with various functional groups. Product 4b and
unreacted starting material 3b were isolated after flash
chromatography in 89% and 4% yield, respectively. The absolute
stereochemistry of 4b was established unambiguously by X-ray
2
Bu BOTf was analyzed by multinuclear NMR spectroscopy in
2
1
4
1
15
CD Cl . On the basis of H− N gs-HMBC spectral analysis,
the nitrogen atom of the newly formed species was shielded
2
2
significantly (δ = 38 ppm vs 90 ppm in 3a), clearly indicating
N
5
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DOI: 10.1021/ol503523h
Org. Lett. 2015, 17, 512−515

Organic Letters
Letter
crystallography via TBS protection of the β′-hydroxyl group to
Scheme 8. Conversion of 4b and 5 into Lactones 9 and 12,
Respectively
21
provide the crystalline 4b′ (Scheme 5).
Excellent results with the smallest possible aldehyde prompted
us to test the bulkier aromatic aldehyde, benzaldehyde. The
reaction of 3b also afforded syn-aldol product 5 (Scheme 6). The
Scheme 6. Synthesis of 5 and a Part of its X-ray Structure
1
conversion was quantitative as judged by H NMR analysis, with
no other isomers or byproducts being detected. The product was
isolated in 90% yield. The stereochemistry of 5 was confirmed by
21
single-crystal X-ray analysis.
NH NH ·H O. Surprisingly, this resulted in the removal of (S)-
2
2
2
The fact that the dibutylboron triflate-mediated aldol reaction
of 3b resulted in the formation of 4b and 5 with complete
stereocontrol indicates formation through the transition state II
shown in Scheme 3 and that the configurations at the β- and γ-
stereocenters have indeed no impact. This was additionally
proven by the aldol reaction of acetaldehyde with the epimeric
4
-isopropyloxazolidin-2-one in nearly quantitative yield and the
formation of dihydrazide 8 (Scheme 8). The auxiliary could be
recovered in high purity and reused without loss of stereo-
selectivity in the aldol reaction. Even though numerous methods
are available for the oxazolidinone auxiliary cleavage affording
esters, primary alcohols, Weinreb amides, and carboxylic
(
R)-4-isopropyloxazolidin-2-one derivative epi-3b, which re-
2d,e,23
acids,
to our knowledge, this is the first report on
sulted in α,β-anti-α,β′-syn-6 as the sole isomer (Scheme 7). Its
absolute stereochemistry was determined by X-ray crystallog-
raphy via TBS deprotection of the primary hydroxyl group to
provide crystalline 6′.
hydrazinolysis. In a one-pot procedure from 7, acid-promoted
hydrolysis of 8 resulted in spontaneous formation of δ-lactone 9
in enantiomerically pure form and 71% yield. Lactone 12 was
prepared analogously from 10 through dihydrazide 11 in 79%
isolated yield.
Scheme 7. Synthesis of 6 and 6′ To Confirm the
In conclusion, we have reported the first transformation of
chiral β-amino acids into the corresponding β′-hydroxy-β-amino
acid derivatives by an Evans aldol reaction. These densely
functionalized products are formed in complete stereoselectivity
and in excellent yields. The methodology is mild and robust,
readily affording both the α,β-syn and the α,β-anti isomers
independently and in stereochemically pure form, which were
previously inaccessible without the need of tedious chromato-
graphic separations from complex mixtures of isomers. This is of
the utmost importance for bulk synthesis of advanced non-
crystallizable compounds. Our protocol employs one of the
simplest Evans oxazolidinone auxiliaries, which can be recovered
in pure form and reused. The choice of the nitrogen protecting
group was found to be crucial and was described in detail. Work is
in progress toward the application of this chemistry to access
α,β′-anti-aldols as well as to further explore the substrate and
aldehyde scope.
Stereochemistry through the X-ray Structure
ASSOCIATED CONTENT
Supporting Information
■
*
S
Finally, to prove the applicability of this method, we were
prompted to transform 4b and 5 into the corresponding β-
amino-δ-lactones 9 and 12 (Scheme 8). Briefly, deprotection of
the β-amino nitrogen atom in 4b by a variety of the reaction
Synthetic procedures and spectroscopic and X-ray data. This
material is available free of charge via the Internet at http://pubs.
acs.org.
2
2
conditions including hydrazinolysis, aminolysis with butyl-
amine or methylamine, and NaBH /CH CO H failed. The
AUTHOR INFORMATION
Corresponding Author
■
4
3
2
removal of the phthalimide group through hydrazinolysis
requires strongly acidic reaction conditions, which turned out
to be incompatible with the OTBS ether in 4b. Hence, 4b was
*
E-mail: janez.kosmrlj@fkkt.uni-lj.si.
Notes
14
first TBS deprotected to afford 7 and then subjected to
The authors declare no competing financial interest.
5
14
DOI: 10.1021/ol503523h
Org. Lett. 2015, 17, 512−515

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Letter
(
c) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173−180. (d) Porter, E. A.;
ACKNOWLEDGMENTS
■
Wang, X.; Lee, H.-S.; Weisblum, B.; Gellman, S. H. Nature 2000, 404,
5
1
Biodiversity 2004, 1, 1111−1239. (g) Johnson, L. M.; Gellman, S. H.
Meth. Enzymol. 2013, 523, 408−429.
This work was financed by Sandoz Austria GmbH and the
Ministry of Education, Science and Sport, Republic of Slovenia,
the Slovenian Research Agency (Grant Nos. P1-0230 and P1-
65. (e) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001,
01, 3219−3232. (f) Seebach, D.; Beck, A. K.; Bierbaum, D. J. Chem.
0
175).
(13) (a) The Organic Chemistry of β-Lactams; Georg, G. I., Ed.; VCH
Publishers: New York, 1993. (b) Alcaide, B.; Almendros, P.; Aragoncillo,
C. Chem. Rev. 2007, 107, 4437−4492. (c) Xu, J. Tetrahedron 2012, 68,
REFERENCES
■
(
3
1) Selected reviews: (a) Mukaiyama, T. Org. React. 1982, 28, 203−
31. (b) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
3, 1−115. (c) Heathcock, C. H. In Comprehensive Organic Synthesis;
1
0696−10747. (d) Wright, P. M.; Seiple, I. B.; Myers, A. G. Angew.
Chem., Int. Ed. 2014, 53, 8840−8869.
(
(
1
14) For details, see the Supporting Information.
15) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
Trost, B. M., Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 2,
pp 133−238. (d) Kim, B. M.; Williams, S. F.; Masamune, S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 2, pp 239−275. (e) Paterson,
I. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: New York, 1991; Vol. 2, pp 301−319. (f) Cowden, C.
J.; Paterson, I. Org. React. 1997, 51, 1−200. (g) Arya, P.; Qin, H.
Tetrahedron 2000, 56, 917−947. (h) Machajewski, T. D.; Wong, C.-H.
Angew. Chem., Int. Ed. 2000, 39, 1352−1374. (i) Palomo, C.; Oiarbide,
M.; García, J. M. Chem. Soc. Rev. 2004, 33, 65−75. (j) Modern Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004. (k) Modern
Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2006.
1
(
920−1923.
16) Attempts to prepare N,N-di-Boc protected derivative 3d (NPG =
N(Boc)2 by using literature proceduresemploying either excess
(
Boc) O/DMAP/ACN or LDA/(Boc) O failed.
2
2
(
17) Wrackmeyer, B.; Kupce
Chem. 1992, 30, 393−397.
18) The results were corroborated by an independent experiment
̌
, E.; Ko
̈
ster, R.; Seidel, G. Magn. Reson.
(
wherein model compound i-PrNHBoc was allowed to react with i-
14
Pr NEt/Bu BOTf.
2
2
2
(
19) Significant deshielding of the sp -nitrogen atom would be
expected in an A-type intermediate, similar to that of dimethyl N-
(
7
2
l) Schetter, B.; Mahrwald, R. Angew. Chem., Int. Ed. 2006, 45, 7506−
525. (m) Kan, S. B. J.; Ng, K. K.-H.; Paterson, I. Angew. Chem., Int. Ed.
013, 52, 9097−9108. (n) Modern Methods in Stereoselective Aldol
Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2013.
14
cyclohexylimidocarbonate (δ = 181 ppm).
N
(20) Azide functionality in 3c was initially considered as an alternative
to Boc and phthalimide, however, treating compound 2c with either
LiOH, i-Pr NEt/Bu BOTf/MeCHO, or LDA/MeCHO resulted in
2
2
(
2
2) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
127−2129. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R. J. Am.
Chem. Soc. 1981, 103, 3099−3111. (c) Evans, D. A. Aldrichimica Acta
982, 15, 23−32. (d) Evans, D. A.; Bender, S. L.; Morris, J. J. Am. Chem.
Soc. 1988, 110, 2506−2526. (e) Gage, J. R.; Evans, D. A. Org. Synth.
990, 68, 83−91. Gage, J. R.; Evans, D. A. Organic Synthesis; Wiley: New
York, 1993; Collect. Vol. VIII, pp 339−343.
3) Tsukada, N.; Shimada, T.; Gyoung, Y. S.; Asao, N.; Yamamoto, Y. J.
Org. Chem. 1995, 60, 143−148.
4) (a) Davies, S. G.; Fenwick, D. R. Chem. Commun. 1997, 565−566.
elimination of HN3 and the formation of (R,E)-methyl 5-((tert-
14
butyldimethylsilyl)oxy)-4-methylpent-2-enoate as the sole product.
(
21) Although the X-ray data for 4b′ and 5 were poorly refined due to
1
14
very weakly diffracting crystals, the results can serve as an
unambiguous proof of the absolute configuration at the newly formed
stereocenters in the aldolization steps.
1
(
22) Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in
Organic Synthesis, 4th ed.; John Wiley & Sons: Hoboken, 2007; pp 790−
93.
23) Hintermann, T.; Seebach, D. Helv. Chim. Acta 1998, 81, 2093−
126.
(
7
(
2
(
(
b) Ma, D.; Zhang, J. Tetrahedron Lett. 1998, 39, 9067−9068. (c) Reetz,
M. T. Chem. Rev. 1999, 99, 1121−1162. (d) Ma, D.; Sun, H. Tetrahedron
Lett. 2000, 41, 1947−1950. (e) Davies, S. G.; Smethurst, C. A. P.; Smith,
A. D.; Smyth, G. D. Tetrahedron: Asymmetry 2000, 11, 2437−2441.
(
f) Baldwin, I. C.; Briner, P.; Eastgate, M. D.; Fox, D. J.; Warren, S. Org.
Lett. 2002, 4, 4381−4384. (g) Chernega, A.; Davies, S. G.; Elend, D. L.;
Smethurst, C. A. P.; Roberts, P. M.; Smith, A. D.; Darren Smyth, G.
Tetrahedron 2007, 63, 7036−7046.
(
5) (a) Iimori, T.; Takahashi, Y.; Izawa, T.; Kobayashi, S.; Ohno, M. J.
Am. Chem. Soc. 1983, 105, 1659−1660. (b) Takahashi, Y.; Hasegawa, S.;
Izawa, T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, 34, 3020−
3
2
(
024. (c) Collis, M. P.; Perlmutter, P. Tetrahedron Asymmetry 1996, 7,
117−2134.
6) An example of a stereoselective aldol reaction of chiral tin enolates
is also reported, see: Iwasawa, N.; Mukayama, T. Chem. Lett. 1986, 637−
40.
7) For recent examples of related chemistry on α-amino acids, see:
6
(
Seiple, I. B.; Mercer, J. A. M.; Sussman, R. J.; Zhang, Z.; Myers, A. G.
Angew. Chem., Int. Ed. 2014, 53, 4642−4647.
(
8) Beddow, J. E.; Davies, S. G.; Ling, K. B.; Roberts, P. M.; Russell, A.
J.; Smith, A. D.; Thomson, J. E. Org. Biomol. Chem. 2007, 5, 2812−2825.
9) Gessier, F.; Schaeffer, L.; Kimmerlin, T.; Flogel, O.; Seebach, D.
Helv. Chim. Acta 2005, 88, 2235−2249.
10) Baringhaus, K.-H.; Matter, H.; Kurz, M. J. Org. Chem. 2000, 65,
031−5033.
11) (a) Enantioselective Synthesis of β-Amino Acids; Juraisti, E.,
(
̈
(
5
(
Soloshonok, V. A., Eds.; John Wiley & Sons: Hoboken, 2005. (b) Evans,
D. A.; Song, H.-J.; Fandrick, K. R. Org. Lett. 2006, 8, 3351−3354.
(
1
c) Kudo, F.; Miyanaga, A.; Eguchi, T. Nat. Prod. Rep. 2014, 31, 1056−
073.
12) (a) Seebach, D.; Matthews, J. L. Chem. Commun. 1997, 2015−
022. (b) Koert, U. Angew. Chem., Int. Ed. Engl. 1997, 36, 1836−1837.
(
2
5
15
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