Exploring the unique reactivity of diazoesters: An efficient approach to chiral β-amino acids

Article abstract of DOI:10.1021/ol303011f

The development of a highly stereospecific process for the C-O to C-N exchange with retention of configuration is described. This transformation enables access to optically enriched β-amido-α-diazoesters. These products are transformed to β-amino acids not readily accessible using known methods.

Full text of DOI:10.1021/ol303011f

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Exploring the Unique Reactivity of
Diazoesters: An Efficient Approach
to Chiral β‑Amino Acids
Barry M. Trost,* Sushant Malhotra, and Pascal Ellerbrock
Department of Chemistry, Stanford University, Stanford, California 94305-5080,
United States
bmtrost@stanford.edu
Received November 5, 2012
ABSTRACT
The development of a highly stereospecific process for the CÀO to CÀN exchange with retention of configuration is described. This
transformation enables access to optically enriched β-amido-R-diazoesters. These products are transformed to β-amino acids not readily
accessible using known methods.
Optically enriched β-amino acids (β-AA) belong to a
family of privileged structural motifs that are commonly
used in the discovery of small-molecule pharmaceuticals
and are present in several natural products.1 Incorporation
of β-AAs in peptide frameworks has led to novel tertiary
structures possessing greater stability toward proteolysis
thereby elevating our understanding of several biological
mechanisms.2 Taxol3 and sitagliptin,4 both possessing a
β-AA motif, exemplify the importance of these motifs in
cancer chemotherapeutics and as agents for the treatment
of type 2 diabetes mellitus respectively.
The significance of β-AA substructures in advancing
novel therapeutics and natural product analogs led us to
explore alternate ways of accessing these structural motifs,
in particular those that cannot be readily accessed by
current methods. Our work on the asymmetric addition
of ethyl diazoacetate to aldehydes employing a dinuclear
Mg-based chiral catalyst5 prompted us to first investigate
the nucleophilic addition to activated imines; however, in our
hands, low reactivity and enantioselectivity were obtained
although the addition to the N-Boc imine of furfural in
(1) (a) Gelman, M. A.; Gellman, S. H. In Enantioselective Synthesis
of β-Amino Acids; Juaristi, E., Soloshnok, V., Eds.; John Wiley & Sons Inc.:
ꢀ
Hoboken, NJ, 2005. (b) Weiner, B.; Szymanski, W.; Janssen, D. B.; Minnaard,
A.; Feringa, B. L. J. Chem. Soc. Rev. 2010, 39, 1656. (c) Muller, M. M.;
Windsor, M. A.; Pomerantz, W. C.; Gellman, S. H.; Hilvert, D. Angew.
Chem., Int. Ed 2009, 48, 922. (d) Lelais, G.; Seebach, D. Biopolymers 2004,
76, 206.
(2) For representative reviews and articles, see: (a) Cheng, R. P.;
Gellman, S. H.; DeGrado, W. F. Chem. Rev. 2001, 101, 3219. (b) Epand,
R. F.; Raguse, T. L.; Gellman, S. H.; Epand, R. M. Biochemistry 2004,
43, 9527. (c) Horne, W. S.; Gellman, S. H. Acc. Chem. Res. 2008, 41,
1399. (d) Boersma, M. D.; Haasa, H. S.; Peterson-Kaufman, K. J.; Lee,
E. F.; Clarke, O. B.; Colman, P. M.; Smith, B. J.; Horne, W. S.; Fairlie,
W. D.; Gellman, S. H. J. Am. Chem. Soc. 2012, 134, 315. (e) Seebach, D.;
Gardiner, J. Acc. Chem. Res. 2008, 41, 1366. (f) Seebach, D.; Kimmerlin,
(4) Kim, D.; Wang, L.; Beconi, M.; Eiermann, G. J.; Fisher, M. H.;
He, H.; Hickey, G. J.; Kowalchick, J. E.; Leiting, B.; Lyons, K.;
Marsilio, F.; McCann, M. E.; Patel, R. A.; Petrov, A.; Scapin, G.; Patel,
S. B.; Sinha, R.; Wu, J. K.; Wyvratt, M. J.; Zhang, B. B.; Zhu, L.;
Thornberry, N. A.; Weber, A. E. J. Med. Chem. 2005, 48, 141.
(5) (a) Trost, B. M.; Malhotra, S.; Fried, B. A. J. Am. Chem. Soc. 2009,
131, 1674. (b) Trost, B. M.; Malhotra, S.; Koschker, P.; Ellerbrock, P.
J. Am. Chem. Soc. 2012, 134, 2075.
ꢁ
T.; Sebesta, R.; Campo, M. A.; Beck, A. K. Tetrahedron 2004, 60, 7455.
(3) (a) Wani, M. C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail,
A. T. J. Am. Chem. Soc. 1971, 93, 2325. (b) Rowinski, E. K.; Donehower,
R. C. Pharmacol. Ther. 1991, 52, 35.
(6) Kumaraswamy, G.; Jayaprakash, N. Tetrahedron Lett. 2010, 51,
6500.
r
10.1021/ol303011f
XXXX American Chemical Society

62% yield and 84% ee has recently been reported.6 In con-
trast, the use of a Brønsted acid catalyzed process developed
by Terada7 and Maruoka8a,b proved to be more successful
in accessing enantiomerically enriched β-AA precursors,
although this method was limited to aryl imines (Figure 1,
eq 1). Maruoka et al. have recently reported a method to
address this limitation via the use of azomethine imines.8c
Initial evaluation of the CÀO to CÀN exchange on
benzylic alcohol 1a initially investigated by Wang et al.
led to the finding that solvents such as dioxane and
dimethoxyethane led to the greatest erosion of optical
purity. Conversely, less polar solvents such as toluene,
benzene, and hexanes gave enantiomeric ratios up to 93:7 er
(entry 5, Table 1). Furthermore, a dramatic temperature
dependence was observed where conducting the reaction at
rt instead of 4 °C afforded amide 2a as a racemate (entries 5
and 6, Table 1).
Table 1. Initial Solvent and Temperature Screen
Figure 1. Synthesis of β-amido-R-diazoesters.
a Starting material er = 95:5. b Room temperature.
Our interest in exploring the synthetic utility of both
aromatic and aliphatic β-amido-R-diazoesters as β-AA
precursors led to the exploration of an alternate strategy.
Given that the synthesis and purification of imines can be
problematic, having a route that does not require such
substrates would be beneficial. Wang et al. initially re-
ported that the treatment of β-hydroxy-R-diazoesters in
the presence of sodium hydride and trichloroacetonitrile
(TCA) proceeds with an in situ CÀO to CÀN exchange
(Figure 1, eq 2).9 In one example employing a benzylic
alcohol (Figure 1, R = Ph, eq 2), they showed that an
enantioenriched substrate (84:16 er) gave the product of
77:23 er although the stereochemical course of the reaction
remained undefined.9a Our ability to access a broad array
of enantiomerically enriched β-hydroxy-R-diazoesters, an
interest in determining the stereochemical outcome of this
CÀO to CÀN exchange which proved to be quite surpris-
ing, and evaluation of the range of substrates permitting
this transformation inspired the further exploration of this
process. Herein we report that both aliphatic and aromatic
β-hydroxy-R-diazoesters undergo CÀO to CÀN exchange
remarkably with retention in absolute configuration and
with high stereospecificity. The resulting products enabled
the asymmetric synthesis of the enantiomer of the natural
product cytoxazone and cyclopropanated β-AA via a
unique 1,3-CÀH insertion reaction.10,11
Conditions optimized for the CÀO to CÀN exchange
using alcohol 1a enable the direct exchange of both aromatic
and heteroaromatic R-hydroxy-β-diazoesters (Table 2). Sig-
nificant variations on the electronic properties of the aromatic
group are well tolerated. Inductively withdrawing m-meth-
oxyphenyl and electron-donating p-methoxyphenyl furn-
ished trichloroamides 2b and 2c in 93:7 er and 91:9 er.
Electron-withdrawing m- and p-fluorobenzenes afford
amides 2d and 2e in 94:6 er and 94:6 er respectively.
Electron-rich furan possessing a differential steric disposi-
tion compared to the carbocyclic rings previously studied
resulted in the formation of amide 2f in 90:10 er.
Table 2. Reaction Scope with Aromatic and Heteroaromatic
Alcohols
entrya
R
product
% yield
erb
1
2
3
4
5
6
Ph(1a)
2a
2b
2c
2d
2e
2f
92
85
77
66
78
69
93:7
93:7
91:9
94:6
94:6
90:10
m-CH3OC6H4(1b)
p-CH3OC6H4(1c)
m-FC6H4(1d)
p-FC6H4(1e)
(7) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc. 2005,
127, 9360.
(8) (a) Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2007, 129,
10054. (b) Hashimoto, T.; Kimura, H.; Nakatsu, K.; Maruoka, K.
J. Org. Chem. 2011, 76, 6030. (c) Hashimoto, T.; Kimura, H.; Kawamata,
Y.; Maruoka, K. Nat. Chem. 2011, 3, 642.
2-Furyl(1f)
a Reactions using 1.0 equiv of substrate, 2.0 equiv of NaH, and
3.0 equiv of trichloroacetonitrile. b Enantimeric ratio of resulting product.
(9) (a) Shi, W.; Jiang, N.; Zhang, S.; Wu, W.; Du, D.; Wang, J. Org.
Lett. 2003, 5, 2243. (b) Zhang, Z.; Shi, W.; Zhang, J.; Zhang, B.; Liu, B.;
Liu, Y.; Fan, B.; Xiao, F.; Xu, F.; Wang, J. Chem.;Asian J. 2010, 5,
1112.
(10) Shi, W.; Zhang, B.; Zhang, J.; Liu, B.; Zhang, S.; Wang, J. Org.
Lett. 2005, 7, 3103.
(11) Xu, F.; Zhang, S.; Wu, X.; Liu, Y.; Shi, W.; Wang, J. Org. Lett.
To probe whether the aromatic group was essential for
the highly stereospecific CÀO to CÀN exchange, alcohols
1gÀk were employed (Table 3). Treatment of alcohol 1g
with sodium hydride and TCA in hexanes afforded amide
2g in 39% yield (59% brsm) where the desired product was
2006, 8, 3207.
B
Org. Lett., Vol. XX, No. XX, XXXX

isolated in 92:8 er. Further optimization revealed that
higher enantiomeric ratios can be obtained by switching
the counterion to potassium and the yield can be enhanced
to 53% using 6.0 equiv of TCA. Switching the solvent to
toluene afforded amide 2g in a higher 74% yield afford-
ing the desired product in 89:11 er. With two sets of
conditions in hand, one where products with higher stereo-
specificities can be accessed, and the other where higher
yields can be obtained, we explored the scope using the
latter set of conditions. As presented in Table 3, branched
cyclic and acyclic and unbranched aliphatic substrates
afforded the desired products in respectable yields and
enantiomeric ratios.
of both β2,3‑ and β2,2,3-AA analogs and revealed the
stereochemical course of the CÀO to CÀN transfer. Oxida-
tion of diazoester S-2a using oxone in acetone followed by re-
duction with sodium borohydride furnished protected amino
alcohol (2S,3S)-3a (Scheme 2).12 The relative configuration
of the product was assigned via comparison of the cou-
pling constants with a closely related analog 3b and its
corresponding diastereoisomer.13 The relative configura-
tion observed in this reduction is consistent with the diaster-
eocontrol observed by Maruoka et al. for a related β-amido-
R-diazoester.8 The mandelate ester derived from this alcohol
revealed the absolute configuration at the R-center. Col-
lectively, these results suggested that the CÀO to CÀN
exchange proceeds via net retention.
To reinforce this assignment, oxidation of diazoester
S-2c followed by reduction afforded an intermediary alcohol.
Sodium borohydride reduction of the resulting R-hydroxy
ester followed by treatment with sodium methoxide af-
forded the enantiomer of the natural product cytoxazone
4, thereby reinforcing the assignment of both the relative
and absolute configuration of 3a. Based on this finding, we
propose that the CÀO toCÀN transfer proceeds via a tight
ion pair to afford the product from the net retention of
stereochemistry in the exchange reaction. The initial for-
mation of the trichloroacetimidate is followed by rapid
recombination to the trichloroamide. The hypothesis of a
tight ion pair is supported by the observation that non-
polar solvents (which minimize the separation of charge)
furnish the desired product in high enantiomeric ratios.
Table 3. Reaction Scope with Aliphatic Alcohols
a Reactions using 1.0 equiv of alcohol, 2.0 equiv of base, and 3.0
equiv of TCA unless otherwise specified. b Yield based on recovered
starting material at 66% conversion. c 6.0 equiv of TCA used.
Scheme 2. Elucidation of the Relative and Absolute Config-
uration
The high stereospecificity observed in the CÀOtoCÀNex-
change employing alcohol 1l suggests the absence of a rad-
ical fragmentation and recombination pathway (Scheme 1).
Treatment of this alcohol 1l with sodium hydride and TCA in
hexanes at 4 °C afforded amide 2l in 87% yield and 92:8 er
without the formation of any ring opened products.
Scheme 1. Transformation of Alcohol 1l to Amide 2l
The synthesis of highly functionalized amino alcohol 5
was accomplished using a recently described protocol for
the synthesis of 1,2-diols bearing a tertiary center. Here the
oxidation of S-2a using oxone in acetone followed by the
direct treatment of the resulting β-amido-R-ketoester with
allyl iodide in the presence of indium metal afforded amino
alcohol 5 in 79% yield, 93:7 er, and 5:1 diastereoselectivity.
The resulting aromatic and aliphatic β-amido-R-diazo-
esters presented the enantio- and diastereoselective synthesis
(12) The conversion of the diazo group to the carbonyl group can be
accomplished without the preparation of DMDO as described pre-
viously. The two-step protocol involving the oxidation of the diazo
group followed by the reduction to the secondary alcohol has been
described previously (see ref 7).
(13) (a) Patel, R. N.; Banargee, A.; Howell, J. M.; McNamee, C. G.;
Brozozowsk, D.; Mirfakhrae, D.; Mirfakhrae, V.; Thottathil, J. K.;
Szarka, L. J. Tetrahedron: Asymmetry 1993, 4, 2069. (b) Mader, M. M.;
Edel, J. C. J. Org. Chem. 1998, 63, 2761.
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It is noteworthy that under these conditions minimum
racemization of the transient β-amido-R-ketoester is ob-
served (Scheme 3).
Scheme 4. Effect of β-Substituent on Carbenoid Chemistry
Scheme 3. Asymmetric Synthesis of Amino Alcohol 5
Of great significance is the question of the effect of the
β-substituent on the reactivity of a carbenoid derived from
diazo precursors such as compounds 2g, 2i, and 2k.
Rhodium carbenoids derived from β-hydroxy-R-diazoe-
sters undergo a rapid 1,2-shift (Scheme 4).14 Conversely,
treatment of β-amido-R-diazoesters derived from aliphatic
aldehydes15 such as 2g, 2i, and 2k with Rh2(OAc)4 afford
products consistent with traditional carbenoid chemistry
such as intramolecular CÀH insertion and cyclopropa-
nation.16,17 As illustrated in Scheme 4, subjecting the
β-amido-R-diazoester 2k bearing an olefin afforded
cyclopropane 6, a novel bicyclo[3.1.0]hexane β-amino
acid. Wang et al. have previously demonstrated that
treatment of 2g with Rh2(OAc)4 affords the 1,5-CÀH
insertion product affording cyclopentane 7; this work
enables the synthesis of the same compound in enantio-
merically enriched form.9a,18,19 Importantly, the treat-
ment of geometrically constrained β-amido-R-diazoester
2i with Rh catalysts affords cyclopropane 8 via an un-
usual Rh-catalyzed 1,3-CÀH insertion process with high
diastereocontrol.20
the separation of charge, afford products with the greatest
enantiomeric ratios. This stereochemical course is in com-
plete contrast to the normal behavior of trichloroimidates
which invariably proceeds with inversion during substitu-
tion.21 The ability of both aromatic and aliphatic substrates
to participate in this transformation with high stereospeci-
ficity enhances the utility of this method. The ability to
access the β-amido-R-diazoester 2i allowed typical subse-
quent carbenoid chemistry to access cyclic β-amido-esters
including the enantio- and diastereoselective synthesis of the
cyclopropanated product by an unusual 1,3-CÀH insertion
reaction in contrast to the behavior of β-hydroxy-R-diazo-
esters. Further, studies will focus on trapping the putative
carbocation intermediate with other nucleophilic species.
Inconclusion, we have developed conditionsthat exploit
a reactivity pattern unique to diazo esters to form enan-
tioenriched β-amino acid building blocks. These studies
revealed that the CÀO to CÀN exchange proceeds via net
retention and that nonpolar solvents, those that prevent
(14) For selected examples of a 1,2-hydrogen shift, see: (a) Xiao, F.;
Liu, Y.; Wang, J. Tetrahedron Lett. 2007, 48, 1147. (b) Liao, M.; Wang,
J. Tetrahedron Lett. 2006, 47, 8859. (c) Pellicciari, R.; Fringuelli, R.;
Ceccherelli, P.; Sisani, E. J. Chem. Soc., Chem. Commun. 1979, 21, 959.
(d) Padwa, A.; Kulkarni, Y. S.; Zhang, Z. J. Org. Chem. 1990, 55, 4144.
(15) The treatment of 2a with Rh2(OAc)4 affords the product derived
from the 1,2-phenyl shift. See: (a) Jiang, N.; Qu, Z.; Wang, J. Org. Lett.
2001, 3, 2989. (b) Jiang, N.; Ma, Z.; Qu, Z.; Xing, X.; Xie, L.; Wang, J.
J. Org. Chem. 2003, 68, 893. (c) Shi, W.; Jiang, N.; Zhang, S.; Wu, W.;
Du, D.; Wang, J. Org. Lett. 2003, 5, 2243.
(16) For selected reviews, see: (a) Doyle, M. P. Acc. Chem. Res. 1986,
19, 348. (b) Lebel, H.; Marcoux, J. M.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977. (c) Davies, H. M. L.; Beckwith, R. E. J. Chem.
Rev. 2003, 103, 2861. (d) Doyle, M. P.; Duffy, R.; Ratnikov, M.; Zhou,
L. Chem. Rev. 2010, 110, 704.
Acknowledgment. This work has been supported by the
National Science Foundation (CHE-1145236). S.M. grate-
fully acknowledges Stanford University for a graduate
fellowship. P.E. acknowledges the DAAD and the Bayer
Fellowship Program.
Supporting Information Available. Experimental pro-
1
cedures, product characterization data, and H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Recent reports demonstrate that β-hydride transfer can be
avoided using bulkier rhodium carboxylates; however, these catalysts
were not investigated in the present work. For selected examples, see: (a)
DeAngelis, A.; Shurtleff, V. W.; Dmitrenko, O.; Fox, J. M. J. Am. Chem.
Soc. 2011, 133, 1650. (b) Sambasivan, R.; Ball, Z. T. J. Am. Chem. Soc.
2010, 132, 9289. (c) DeAngelis, A.; Panne, P.; Yap, G. P. A.; Fox, J. M.
J. Org. Chem. 2008, 73, 1435. (d) Panne, P.; Fox, J. M. J. Am. Chem. Soc.
2007, 129, 22.
(19) For a review highlighting the significance of such products, see:
€ €
Fulop, F. Chem. Rev. 2001, 101, 2181.
(20) For a selectd example for this process, see: Shi, W.; Zhang, B.;
Zhang, J.; Liu, B.; Zhang, S.; Wang, J. Org. Lett. 2005, 7, 3103.
ꢀ
(21) van den Bos, L. J.; Codee, J. D. C.; van Boom, J. H.; Overkleeft,
H. S.; van der Marel, G. A. Org. Biomol. Chem. 2003, 1, 4160.
(18) Zhang, Z.; Shi, W.; Zhang, J.; Zhang, B.; Liu, B.; Liu, Y.; Fan,
B.; Xiao, F.; Xu, F.; Wang, J. Chem.;Asian J. 2010, 5, 1112.
The authors declare no competing financial interest.
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