Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters by Lewis Base Catalyzed Dynamic Kinetic Resolution

Article abstract of DOI:10.1021/jacs.6b00207

We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.

Full text of DOI:10.1021/jacs.6b00207

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Article
Regio- and Enantioselective Synthesis of Azole Hemiaminal
Esters by Lewis-Base-Catalyzed Dynamic Kinetic Resolution
David W. Piotrowski, Adam S. Kamlet, Anne-Marie R Dechert-Schmitt,
Jiangli Yan, Thomas A Brandt, Jun Xiao, Liuqing Wei, and Mark T Barrila
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b00207 • Publication Date (Web): 22 Mar 2016
Downloaded from http://pubs.acs.org on March 22, 2016
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Regio- and Enantioselective Synthesis of Azole Hemiaminal Esters
by Lewis-Base-Catalyzed Dynamic Kinetic Resolution
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David W. Piotrowski,*† Adam S. Kamlet,*† Anne-Marie R. Dechert-Schmitt,† Jiangli Yan, †
Thomas A. Brandt,‡ Jun Xiao,† Liuqing Wei,† Mark T. Barrila‡
†Worldwide Medicinal Chemistry, Pfizer, Inc., Eastern Point Road, Groton, Connecticut, 06340, United States
‡Chemical Research and Development, Pfizer, Inc., Eastern Point Road, Groton, Connecticut 06340, United States
ABSTRACT: We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically en-
riched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize
valuable substituted azoles in a regioselective manner by capping (e.g. acylation) of the equilibrating azole-aldehyde ad-
duct. Using a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical
yield and with high enantiomeric excess. The DKR was performed on a multi-kilogram scale to produce a tetrazole pro-
drug fragment for a leading clinical candidate that posed formidable synthesis challenges.
INTRODUCTION
Dynamic kinetic resolutions (DKRs) continue to garner
considerable attention as highly efficient means to intro-
duce new stereogenic centers in active pharmaceutical
ingredients and in the synthesis of natural products.1 En-
zymatic methods offer a partial solution to this problem,
but such transformations remain limited in scope.2
Noyori’s ground-breaking DKR of β-ketoesters by catalyt-
ic asymmetric hydrogenation opened the door to a range
of transition-metal-catalyzed and organocatalyzed dy-
namic processes.
One such conversion, the non-
enzymatic DKR of secondary alcohols, remains a formi-
dable challenge. Recently, Fu developed a dual catalyst
system by combining a Ru-based racemization catalyst
with a planar-chiral DMAP to achieve the first non-
enzymatic DKR of secondary alcohols by acylation.3 We
hypothesized that we could take advantage of the under-
exploited dynamic equilibrium between mildly acidic nu-
cleophiles and aldehydes to enantioselectively acylate
non-isolable hemiaminal species. Outside of the special
cases of aldehydes that form stable hydrates (e.g. formal-
dehyde, chloral), reports of stable hemiaminal adducts are
rare. Non-isolable hemiaminals formed by reversible ad-
dition of triazole to aldehydes followed by capping was
reported by Smith in 1990.4 More recently, Banert dis-
closed the reversible addition of azide to aldehydes fol-
lowed by azide trapping.5 Cyclic hemiaminals derived
from N-unsubstituted azole aldehydes6 or imide alde-
hydes have been reported. Of note, Yamada described the
first DKR of a cyclic hemiaminal derived from an imide
aldehyde by Lewis-base-assisted acylation.7,8 Herein, we
describe a new process that takes advantage of a dynamic
equilibrium to afford substituted tetrazoles and related
azoles in a regio- and enantioselective manner by the use
of a sole Lewis base catalyst.9,10,11,12
Figure 1: Strategies for alkylation of tetrazoles
Substituted tetrazoles are valuable heterocycles to me-
dicinal chemistry. Most notably, tetrazoles appear in the
multi-billion dollar angiotensin II receptor antagonist
class of blood pressure agents (e.g., losartan and valsartan
among others, Figure 1).13 However, the synthesis of te-
trazoles, particularly disubstituted variants, introduces
problems of regio- and enantiocontrol. There are several
ways to synthesize disubstituted tetrazoles in an unselec-
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tive manner, but selective methods to access 2,5-
disubstituted variants typically employ harsh conditions
and are limited in scope.14,15
Hemiaminal-ester-
did not isomerize or decompose in the presence of cata-
lytic DMAP (up to 20 mol%) after long reaction times (>10
d).
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substituted tetrazoles have been synthesized by alkylation
to afford mixtures of the 1,5- and 2,5-disubstituted prod-
ucts.16 The use of hemiaminal esters such as methyl sub-
stituted pivaloyloxymethyl (MePOM)11a results in further
complexity by introduction of a new stereogenic center.
Methodology to synthesize hemiaminal esters of te-
trazoles with the ability to alter the acyl and alkyl groups
in a regioselective and enantioselective manner could
prove extremely valuable to the development of new bio-
logically active tetrazoles. Furthermore, the ability to
control the regiochemistry and stereochemistry of 2,5-
disubstituted tetrazoles under mild conditions can ex-
pand access to other valuable tetrazole derivatives. Mild
methods to address both of these issues do not exist.
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Figure 2: Proposed mechanistic scenario
The regioselective synthesis of 2,5-disubstituted te-
trazoles was found to be highly modular with respect to
RESULTS AND DISCUSSION
Regioselective Synthesis of 2,5-Disubstituted Te-
trazoles. Direct alkylation of 5-phenyl tetrazole (1) with
excess 1-choroethyl ethyl carbonate afforded a mixture of
regioisomers 2a and 2b favoring the 2,5-disubstituted
tetrazole (Scheme 1, top arrow). The assigned structures
were confirmed by NOE and X-ray crystallographic stud-
ies (see Supporting Information). On the other hand
treatment of 5-phenyl tetrazole with acetaldehyde and
ethyl chloroformate in the presence of catalytic DMAP
showed striking regioselectivily for the 2,5-disubstituted
tetrazoles (Scheme 1, bottom arrow). NMR analysis of
crude reaction material did not show any evidence of 1,5-
disubstituted tetrazole formation.
the three reacting components.
A number of 5-
substituted tetrazoles underwent the reaction with ali-
phatic and aromatic aldehydes and could be capped by
various acylating reagents including chloroformates and
anhydrides (Table 1). Most ketones were not competent
reaction partners presumably because of an unfavorable
equilibrium leading to a tetrazole-ketone hemiaminal.
However, a hemiaminal ester 8 derived from a strained
cyclobutanone could be isolated in good yield.
Table 1: Lewis-base-catalyzed regioselective syn-
thesis 2,5-disubstituted tetrazoles.a
Scheme 1: Synthesis of 1,5- and 2,5-Disubstituted
Tetrazoles
Our observations are consistent with previous literature
descriptions of DMAP-catalyzed acylations of alcohols17
and are summarized below.
Uncatalyzed reactions
formed product in the absence of catalyst after 64–96 h,
while DMAP-catalyzed reactions proceed to completion
in just 14–16 h. When acetaldehyde-d4 was employed, full
incorporation of deuterium was noted with no evidence
of scrambling, lending support to the proposed mechanis-
tic scenario depicted in Figure 2.18 For reactions conduct-
ed for >48 h, no evidence of regioisomeric scrambling of
2,5-isomer 2a was detected. Furthermore, 1,5-isomer 2b
aReactions conducted at [0.3–0.4M] tetrazole. Isolated
yield and ratio of 2,5- to 1,5-tetrazole regioisomers. bReaction
was also conducted with 20 mol% PBu3 and ethyl pyrocar-
bonate to provide 70% of the 2,5-isomer as the sole product.
Acylation reagents: cethyl chloroformate, dtrimethylacetic
anhydride, eisobutyric anhydride, fp-toluenesulfonyl chloride,
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the related methanesulfonate was also synthesized, see Sup-
4), 2,5-disubstituted product 26 was obtained as the sole
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porting Information S-1.
product. Given these results, we surmised that it is the
rate of acylation of the products of the dynamic aldehyde-
azole equilibrium that ultimately produces the high regi-
oselectivity.
Synthesis of Sulfonate Esters and Further Synthetic
Elaboration. The transient hemiaminal species can not
only be trapped as esters or carbonates, but also as sul-
fonate esters (Table 1, 10).19 Preliminary results have
demonstrated that these racemic sulfonate esters can be
displaced with a range of nucleophiles (Table 2). For ex-
ample, tosylate 10 can react with LiBEt3H or AlMe3 to af-
ford 2-ethyl-5-phenyl-2H-tetrazole (11) and 2-isopropyl-5-
phenyl-2H-tetrazole (12), respectively. The combination
of the two reactions is formally a completely regioselec-
tive alkylation of a tetrazole with primary and secondary
alkane electrophiles. Additionally, 10 could be trans-
formed into alkyl fluoride 13 with TBAF or a benzylated
tetrazole 14 with AlPh3.
Scheme 2: Kinetic analysis of tetrazole and alde-
hyde.
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Table 2: Reactions of sulfonate esters derived from
tetrazole hemiaminals.
1,5-isomer
2,5-isomer
entry
Reagent
R1
Yield (%)
isomer
∆H0 (kcal/mol)
∆S0 (kcal/mol)
1
LiBEt3H
AlMe3
TBAF
H (11)
Me (12)
F (13)
75
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17
-10.3
-10.1
-0.036
-0.038
AlPh3
Ph (14)
Kinetic Analysis of Hemiaminal Adducts. We were
intrigued by the highly regioselective nature of the reac-
tion and wanted to probe whether or not the 1,5-
disubstituted tetrazole isomer of the tetrazole/aldehyde
adduct was forming under the reaction conditions. Vari-
able temperature NMR spectroscopic studies in acetoni-
trile-d3 in which a 5-phenyltetrazole was treated with an
aldehyde under pseudo-first order conditions (ca. 20
equiv. aldehyde) showed a preponderance of the 2,5-
adduct.20 There was no evidence of formation of any 1,5-
adduct for 5-phenyltetrazole and acetaldehyde (see Sup-
porting Information). However, for the more sterically
demanding 5-(biphenyl-2-yl)tetrazole 15 and isobutyral-
dehyde, the 2,5-adduct 16 was present in an approximate-
ly 4.5:1 ratio along with the 1,5-adduct 17 (Scheme 2). Ki-
netic analysis of the two isomers showed that formation
of the 2,5-adduct is favored by approximately 0.8 kcal/mol
at 25 oC. The reaction showed negligible temperature
dependence within the temperature window (-15 to 35 oC)
of the experiment. In this latter case, the greater steric
demand of the ortho-substituted phenyl may twist it out
of conjugation with the tetrazole making the 1-position
more accessible (see Supporting Information for more
detail). In a separate acylation experiment with 15, isobu-
tyraldehyde, and isobutyric anhydride (vide infra, Table
Enantioselective Synthesis of 2,5-Disubstituted Te-
trazoles via Dynamic Kinetic Resolution. With a good
understanding of the regioselective formation of 2,5-
disubstituted tetrazoles in hand, we turned our attention
toward the formation of the hemiaminal stereogenic cen-
ter in an enantioselective fashion. It is now widely ac-
cepted that the rate-determining step in the kinetic reso-
lution of secondary alcohols with chiral Lewis base cata-
lysts is the addition of the alcohol to acylated catalyst.
The difference in energy between diastereomeric transi-
tion states gives rise to reaction selectivity.21,22 In the case
of a tetrazole hemiaminal, selective acylation has addi-
tional challenges, because it requires fast reaction of only
one of the four possible isomers to ensure a successful
selective outcome (Figure 3).
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ylpyrocarbonate with only a slight to moderate drop in er.
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The chemistry could also be applied to other azoles such
as pyrazoles and an imidazole to afford (regioselectively)
the corresponding hemiaminal esters in high yield and
good er. Most interestingly, for product 26, catalyst E was
able to predominantly acylate a single regioisomeric and
enantiomeric hemiaminal from the observed mixture in
the NMR study (vide supra). Finally, we were able to as-
sign the stereochemistry of the products by analogy after
the absolute configuration of enantiopure 25 was ob-
tained by X-ray crystallography. The stereochemistry of
aromatic-aldehyde-derived 21 and 24 were assigned in a
similar manner based on the absolute configuration of S-2
(see Supporting Information).
Figure 3: General dynamic kinetic resolution of tetrazoles
(regio- and enantioselective).
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As DMAP was a competent catalyst in the achiral reac-
tion variant, we surveyed known chiral DMAP catalysts
from Fu (A, B),23 Yamada (C, D)24 and Connon (E, F)25 for
enantioinduction (Table 3).26,27 For the preliminary inves-
tigation, 5-phenyltetrazole, acetaldehyde, and isobutyric
anhydride were chosen as the reaction components. Alt-
hough all chiral DMAP catalysts evaluated yielded prod-
uct, enantioselectivity varied. We found that catalyst E
performed best with our model system, affording product
with an enantiomeric ratio (er) 90:10.
Table 4: Chiral-DMAP-catalyzed DKR of tetrazole-
derived hemiaminal esters and carbonates.
Table 3: Survey of chiral DMAP derivatives.
Br
O
O
N
N
24, 83%c
N
Ph
N
er 86:14
aReactions conducted at [0.1M] azole. bReaction conducted
c
in toluene. Acylation reagents: isobutyric anhydride, dpropi-
onic anhydride, ediethylpyrocarbonate.
We were able to further optimize the reaction condi-
tions using catalyst E. Enantioselectivity increased most
dramatically when the solvent was changed from THF to
less polar solvents such as diethyl ether or toluene. Alter-
ing the base did not improve the reaction. As expected,
lowering the temperature of the reaction did increase the
enantioselectivity, but not significantly. Consequently,
ambient conditions were chosen to explore the scope of
the dynamic kinetic resolution (see Supporting Infor-
mation for additional optimization details).
In contrast to the facile chiral DMAP catalyzed acyla-
tions, sulfonylation reactions using catalytic amounts of a
number of chiral Lewis bases furnished racemic products
in modest yield. A reaction conducted with a stoichio-
metric amount of catalyst E produced sulfonate 10 in low
yield and low but quantifiable enantioenrichment (see
Supporting Information).28
Multi-kilogram Synthesis of a Tetrazole Prodrug
Fragment via Dynamic Kinetic Resolution. As noted
previously, tetrazoles are valuable heterocycles in drug
discovery and can serve as carboxylic acid isosteres.29,30
However, the physical properties of tetrazoles can lead to
molecules with low permeability and consequently low
The three-component modularity of the DKR is shown
in Table 4. Aliphatic aldehydes provided the highest er,
but aromatic aldehydes were also suitable reaction part-
ners. The acylation reagent could be varied away from
isobutyric anhydride to propionic anhydride and dieth-
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oral bioavailability.31 One way to overcome this limitation
is to mask the tetrazole as a prodrug. While prodrugs of
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carboxylic acids are well known,32 tetrazole prodrugs are
significantly less common.16 Although a regio- and enan-
tiomeric mixture of prodrugs will ultimately be cleaved in
vivo to the same parent compound, the relative rates of
enzymatic cleavage of the isomers will differ.33 Dosing a
single isomer is therefore preferred. Furthermore the ina-
bility to control regio- and stereochemistry of the prodrug
can hinder the identification and scalability of a com-
pound with suitable biopharmaceutical properties as well
as the crystalline solid form.34
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We were interested in fine-tuning the properties of a
small molecule tetrazole prodrug for a medicinal chemis-
try program. The prodrug would, by design, be enzymati-
cally cleaved in vivo to provide the parent tetrazole as the
active drug species. The modularity of this DKR allowed
us to probe the substitution pattern and properties of the
Reagents and conditions: (a) CDI 1.05 equiv, CH2Cl2, then
NH4Cl 3 equiv, Et3N 3 equiv, 75 % (b) TFAA 2 equiv, 2,6-
lutidine 3 equiv, CH2Cl2, 0 oC, 95 % (c) NaN3 3 equiv, NH4Cl
enzymatically labile prodrug moiety.
Ultimately, te-
trazole prodrug 35, derived from acetaldehyde and isobu-
tyric anhydride, possessed the desired properties and was
selected for advanced in vivo and toxicology studies. Mul-
ti-gram quantities of the prodrug 35 was required. Con-
version of commercially available acid 30 by a two-step
amidation/dehydration sequence provided nitrile 31 in
71% yield. With due caution, cycloaddition of nitrile 31
with hydrazoic acid, formed in situ, gave tetrazole 32.35
On a 2.5 kg scale, tetrazole 32 was converted into 33 in a
regioselective and enantioselective manner using catalyst
E (189 g, 3 mol%) and slightly modified conditions com-
pared to Table 4. The solvent was changed to methyl
tert-butyl ether, and the equivalents of aldehyde were
increased to drive the reaction to completion. The pro-
drug fragment 33 was obtained in quantitative yield and
er 97:3 before subsequent processing. After removal of
the minor enantiomer by chiral preparative chromatog-
raphy, 33 was treated with iPrMgCl to effect magnesiation
o
3 equiv, 2.3:1 DMF/H2O, 100 C, 16 h, 90 % (d) CH3CHO 2
equiv, 3 mol% catalyst E, Et3N 1.5 equiv, isobutyric anhydride
1.5 equiv, MTBE [0.07M tetrazole], 0 oC. 100% (d) (i) iPrMgCl
1.3 equiv, [2.0M in THF], THF, - 49 oC, 35 min, (ii) ZnCl2, 0.69
equiv [1.9M in 2-MeTHF], - 49oC – RT, (iii) Pd-117 0.66 mol
o
%, THF, 50 C, 78 % (g) HCl 7 equiv [2.0M in Et2O], CH3CN,
1.5 h, 25 oC, 89%.
CONCLUSIONS
A modular, operationally simple and mild method for
the regioselective formation of 2,5-disubstituted tetrazole
hemiaminal esters was developed. The chemistry was ex-
tended to sulfonate esters, which upon reaction with nu-
cleophiles, provided a formal, regioselective alkylation of
a tetrazole with primary and secondary alkane electro-
philes. An azole/aldehyde dynamic equilibrium was ex-
ploited to resolve a transient hemiaminal via a chiral
DMAP-catalyzed enantioselective acylation. This new
methodology was applied on multi-kilogram scale to facil-
itate the synthesis of a compound for a medicinal chemis-
try program. Extension of this DKR to sulfonate and
phosphate esters, additional heterocycles and other clas-
ses of Lewis base catalysts is underway.
o
at -40 C followed by transmetalation with ZnCl2. Negishi
coupling with 4-bromobenzamide 34 and deprotection
provided multi-gram quantities of 35 (Scheme 3).36
Scheme 3: Large-scale application of the tetrazole-
based DKR.
ASSOCIATED CONTENT
SUPPORTING INFORMATION
Experimental details and characterization data. This material
is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
david.w.piotrowski@pfizer.com, adam.kamlet@pfizer.com
Notes
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The authors declare the following competing financial inter-
1
2
est(s): All authors were employed by Pfizer Inc at the time
this work was done.
3
4
(13) (a) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem.
5
6
Heterocycl. Compd. 2007, 43, 1–9. (b) Muszalska, I.; Sobczak, A.;
Dolhan, A.; Jelinska, A. J. Pharm. Sci. 2014, 103, 2–28.
ACKNOWLEDGMENT
(14) (a) Ostrovskii, V. A.; Trifonov, R. E.; Popova, E. A. Russ.
Chem. Bull., Int. Ed. 2012, 61, 768–780. (b) Huff, L.; Henry, R. A. J.
Med. Chem. 1970, 13, 777–779. (c) Koldobskii, G. I.; Kharbash, R.
B. Russ. J. Org. Chem. 2003, 39, 453–470. (d) Koldobskii, G. I.
Russ. J. Org. Chem. 2006, 42, 469–486. (e) Gaponik, P. N.;
Voitekhovich, S. V.; Klyaus, B. G. Russ. J. Org. Chem. 2004, 40,
598–600. (f) Koren, A. O.; Gaponik, P. N.; Ostrovskii, V. A. Int. J.
Chem. Kinet. 1993, 25, 1043–1051.
(15) For recent regioselective methods to synthesize 2,5-
disubstitutedtetrazoles, see: (a) Wang, L.; Zhu, K.; Chen, Q.; He,
M. J. Org. Chem. 2014, 79, 11780−11786. (b) Rajamanickam, S.;
Majji, G.; Santra, S. K.; Patel, B. K. Org. Lett. 2015, 17, 5586-5589.
(16) (a) Harusawa, S.; Yoneyama, H.; Fujisue, D.; Nishiura, M.;
Fujitake, M.; Usami, Y.; Zhao, Z.-y.; McPhee, S. A.; Wilson, T. J.;
Lilley, D. M. J. Tetrahedron Lett. 2012, 53, 5891–5894. (b) Ryono,
D. E.; Lloyd, J.; Poss, M. A.; Bird, J. E.; Buote, J.; Chong, S.;
Dejneka, T.; Dickinson, K. E. J.; Gu, Z.; Mathers, P.; Moreland, S.;
Morrison, R. A.; Petrillo, E. W.; Powell, J. R.; Schaeffer, T.;
Spitzmiller, E. R.; White, R. E. Bioorg. Med. Chem. Lett. 1994, 4,
201–206. (c) O'Brien, N. J.; Amran, S.; Medan, J.; Cleary, B.;
Deady, L. W.; Jennings, I. G.; Thompson, P. E.; Abbott, B. M.
Chem. Med. Chem. 2013, 8, 914–918. (d) Obermeier, M. T.;
Chong, S.; Dando, S. A.; Marino, A. M.; Ryono, D. E.; Starrett-
Arroyo, A.; Didonato, G. C.; Warrack, B. M.; White, R. E.; Morri-
son, R. A. J. Pharm. Sci. 1996, 85, 828–833. (e) Alexander, J.;
Renyer, M.; Rork, G. S. J. Pharm. Sci. 1994, 83, 893–897.
(17) (a) Fischer, C. B.; Xu, S.; Zipse, H. Chem. Eur. J. 2006, 12,
5779–5784. (b) Wei, Y.; Held, I.; Zipse, H. Org. Biomol. Chem.
2006, 4, 4223–4230.
(18) There is a remote possibility that a vinyl ester could form
under the reaction conditions. Full incorporation of deuterium
rules out the aza-Markovnikov addition of the tetrazole to a
vinyl ester observed by others, see: Lin, S.; Sun, Q.; Li, R.; Cheng,
T.; Ge, Z. Synthesis, 2007, 1933–1938.
(19) Preliminary results with phosphate and carbamate variants
have established feasibility but require additional optimization
before disclosure.
(20) For acetaldehyde and 5-phenyltetrazole, Keq = 2 L/mol at
298K, as determined by 1H NMR spectroscopy.
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We thank Brian Samas and Ivan Samardjiev for X-ray crystal
structures of 2b (CCDC 1445809), 25 (CCDC 1445810) and S-2
(CCDC 1468821), Dennis Anderson for 13C NMR spectrum of
d4-2a, Jason Smith and Xiaochun Wang for enantiomeric
ratio determinations by HPLC on chiral stationary phase, Jim
Bradow for separation of rac-25 and S-2, and John Brennan
for the kilo-lab reaction to make 33.
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REFERENCES
(1) (a) Pellissier, H. Chirality from Dynamic Kinetic Resolution;
Royal Society of Chemistry: Cambridge, 2011. (b) Pellissier, H.
Tetrahedron 2011, 67, 3769–3802. (c) Pellissier, H. Tetrahedron
2008, 64, 1563–1601. (d) Pellissier, H. Tetrahedron 2003, 59, 8291–
8327.
(2) (a) Ahmed, M.; Kelly, T.; Ghanem, A. Tetrahedron 2012, 68,
6781–6802. (b) Verho, O.; Bäckvall, J.-E. J. Am. Chem. Soc. 2015,
137, 3996−4009.
(3) Lee, S. Y.; Murphy, J. M.; Ukai, A.; Fu, G. C. J. Am. Chem. Soc.
2012, 134, 15149–15153.
(
4
) Smith, K.; Hammond, M. E. W.; James, D. M.; Ellison, I. J.;
Hutchings, M. G. Chem. Lett. 1990, 351–354.
) Banert, K.; Berndt, C.; Firdous, S.; Hagedorn, M.; Joo, Y.-H.;
Rüffer, T.; Lang, H. Angew. Chem., Int. Ed. 2010, 49, 10206–10209.
) Browne, E. J. Aust. J. Chem., 1971, 24, 2389-2397.
(5
(6
(7) (a) Yamada, S.; Noguchi, E. Tetrahedron Lett. 2001, 42, 3621–
3624. (b) Yamada, S.; Yamashita, K. Tetrahedron Lett. 2008, 49,
32–35.
(8) Non-enzymatic DKR of ketone-derived cyanohydrin esters
has been reported, see: (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc.
2001, 123, 6195–6196. (b) Tian, S.-K.; Deng, L. Tetrahedron 2006,
62, 11320–11330. (c) Li, F.; Widyan,K.; Wingstrand, E.; Moberg, C.
Eur. J. Org. Chem. 2009, 3917–3922.
(9) For a recent review on Lewis base catalyzed reactions, see:
Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560–1638.
(10) For recent reviews on organocatalytic acyl transfer, see: (a)
Spivey, A. C.; Arseniyadis, S. Top. Curr. Chem. 2010, 291, 233–280.
(b) Müller, C. E.; Schreiner, P. R. Angew. Chem., Int. Ed. 2011, 50,
6012–6042.
(11) For reviews on catalytic non-enzymatic kinetic resolutions,
see: (a) Vedejs, E.; Jure, M. Angew. Chem., Int. Ed. 2005, 44,
3974–4001. (b) Pellissier, H. Adv. Synth. Catal. 2011, 353, 1613–
1666.
(12) For a recent example of the application of a DYKAT process
for the synthesis of a hemiaminal containing active pharmaceu-
tical ingredient, see: Li, H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde,
A.; Ji, Y.; Oliver, S.; Tudge, M. T.; Campeau, L.-C.; Campos, K. R.
J. Am. Chem. Soc. 2015, 137, 13728–13731.
(21) Larionov, E.; Mahesh, M.; Spivey, A. C.; Wei, Y.; Zipse, H. J.
Am. Chem. Soc. 2012, 134, 9390–9399.
(22) Wagner, A. J.; Rychnovsky, S. D. Org. Lett. 2013, 15, 5504–
5507.
(23) (a) Ruble, J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230–7231.
(b) Ruble, J. C.; Latham, H. A.; Fu, G. C. J. Am. Chem. Soc. 1997,
119, 1492–1493.
(24) Yamada, S.; Misono, T.; Iwai, Y.; Masumizu, A.; Akiyama, Y.
J. Org. Chem. 2006, 71, 6872–6880.
(25) O’Dálaigh C; Connon, S. J. J. Org. Chem. 2007, 72, 7066–
7069. The catalyst is commercially available (CAS number
951008-65-4, MFCD17015289).
(26) For a review and selected references for other chiral DMAP
catalysts, see: (a) Wurz, R. P. Chem. Rev. 2007, 107, 5570–5595.
(b) Shaw, S. A.; Aleman, P.; Christy, J.; Kampf, J. W.; Va, P.;
Vedejs, E. J. Am. Chem. Soc., 2006, 128, 925–934. (c) Duffey, T. A.;
6
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1
2
3
4
Shaw, S. A.; Vedejs, E., J. Am. Chem. Soc., 2009, 131, 14–15. (d)
(32) Maag, H. Prodrugs of Carboxylic Acids; Springer-AAPS Press,
5
6
7
8
Crittall, M. R.; Rzepa, H. S.; Carbery, D. R. Org. Lett. 2011, 13,
1250–1253. (e) Ma, G.; Deng, J.; Sibi, M. P. Angew. Chem., Int. Ed.
2014, 53, 11818–11821.
2007; Vol. 5.
(33) Udata, C.; Tirucherai, G.; Mitra, A. K. J. Pharm. Sci. 1999, 88,
544–550.
(34) Byrn, S. R.; Henck, J.-O. Drug Discov. Today Technol. 2012,
9, e73–e78.
(35) Hydrazoic acid is highly toxic, explosive and its vapors have
a low detonation threshold, see: (a) Wiss, J.; Fleury, C.; Onken,
U. Org. Process Res. Dev. 2006, 10, 349–353. (b) Bräse, S.; Gil, C.;
Knepper, K.; Zimmermann, V. Angew. Chem. Int. Ed. 2005, 44,
5188-5240.
(36)Darout, E.; Dullea, R.; Hawkins, J. J. L.; Londregan, A. T.;
Loria, P. M.; Maguire, B.; McClure, K. F.; Petersen, D. N.; Pi-
otrowski, D. W. PCT Int. Appl. (2014), WO204170786.
(27) For leading references on non-DMAP Lewis base catalysts,
see: (a) Copeland, G. T.; Miller, S. J. J. Am. Chem. Soc. 2001, 123,
6496–6502. (b) Vedejs, E.; Daugulis, O. J. Am. Chem. Soc. 2003,
125, 4166–4173. (c) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.;
Kibane, C. J. J. Am. Chem. Soc. 2004, 126, 12226–12227. (d) Ishi-
hara, K.; Kosugi, Y.; Akakura, M. J. Am. Chem. Soc. 2004, 126,
12212–12213. (e) Kano, T.; Sasaki, K.; Maruoka, K. Org. Lett. 2005,
7, 1347–1349. (f) Kawamata, Y.; Oriyama, T. Chem. Lett. 2010, 39,
382–384. (g) Zhang, Z.; Xie, F.; Jia, J.; Wanbin Zhang, W. J. Am.
Chem. Soc. 2010, 132, 15939–15941. (h) Harada, S.; Kuwano, S.;
Yamaoka, Y.; Yamada, K.; Takasu, K. Angew. Chem., Int. Ed. 2013,
52, 10227–10230.
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36
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45
46
47
48
49
50
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59
60
(2
using a tetrapeptide Lewis base catalyst, see: Fiori, K. W.;
Puchlopek, A. L. A.; Miller, S. J. Nat Chem. 2009, 1,630-634
8) There is one report of an enantioselective sulfonylation
.
(29) Roh, J.; Katerˇina Vávrová, K.; Hrabálek, A. Eur. J. Org. 2012,
6101–6118.
(30) Herr, R. J. Bioorg. Med. Chem. 2002, 10, 3379–3393.
(31) Maag, H. Drug Discov. Today Technol. 2012, 9, e121–e130.
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