An asymmetric synthesis of (2S,5S)-5-substituted azepane-2-carboxylate derivatives

Article abstract of DOI:10.1021/jo102475s

To facilitate a drug discovery project, we needed to develop a robust asymmetric synthesis of (2S,5S)-5-substitutedazepane- 2-carboxylate derivatives. Two key requirements for the synthesis were flexibility for elaboration at C5 and suitability for large

Full text of DOI:10.1021/jo102475s

NOTE
pubs.acs.org/joc
An Asymmetric Synthesis of (2S,5S)-5-Substituted
Azepane-2-Carboxylate Derivatives
Donn G. Wishka,*,† Marion Bꢀedard, Katherine E. Brighty, Richard A. Buzon, Kathleen A. Farley,
Michael W. Fichtner, Goss S. Kauffman, Jaap Kooistra,‡ Jason G. Lewis,§ Hardwin O’Dowd,§
Ivan J. Samardjiev, Brian Samas, Geeta Yalamanchi, and Mark C. Noe
†Pfizer Worldwide Research and Development, Eastern Point Rd., Groton, Connecticut 06340, United States
‡Syncom BV, Groningen, The Netherlands
§Vicuron Pharmaceuticals, Fremont, California 94555, United States
S Supporting Information
b
ABSTRACT: To facilitate a drug discovery project, we needed to
develop a robust asymmetric synthesis of (2S,5S)-5-substituted-
azepane-2-carboxylate derivatives. Two key requirements for the
synthesis were flexibility for elaboration at C5 and suitability for
large scale preparation. To this end we have successfully developed a
scalable asymmetric synthesis of these derivatives that starts with
known hydroxy-ketone 8. The key step features an oxidative cleavage of aza-bicyclo[3.2.2]nonene 14, which simultaneously
generates the C2 and C5 substituents in a stereoselective manner.
yclic amino acid derivatives are important components of
biologically active substances, including proteins, because of
C
their conformational rigidity and specific orientation of sub-
stituents.1 For these exact reasons cyclic amino acid derivatives
are ideally suited to serve as chiral building blocks in organic
synthesis and as core structures in effective catalysts for asym-
metric bond forming reactions.2 Additionally, the rich function-
ality of substituted cyclic amino acids makes them attractive
intermediates for natural product synthesis.3 Therefore, strate-
gies for the efficient asymmetric synthesis of substituted cyclic
amino acid derivatives are of intense interest to the pharmaceu-
tical industry. While many good methods exist for the prepara-
tion of substituted proline and pipecolic acid derivatives,
relatively few approaches to the stereospecific preparation of
substituted azepine carboxylic acids have been presented in the
literature.4
Figure 1. Target compounds.
Scheme 1. Initial Approacha
To facilitate a drug discovery project, we needed to develop a
robust asymmetric synthesis of (2S,5S)-5-substituted-azepane-2-
carboxylate derivatives 1 (Figure 1). Two key requirements for
the proposed synthesis were flexibility for elaboration at C-5 and
suitability for large scale preparation.
Our initial approach for the preparation of C5 substituted
azepine 2-carboxylic acids started from (S)-allylglycine (2),
which is an article of commerce or can be readily prepared5,6
(Scheme 1). Subsequent amine protection, followed by N-
alkylation with the appropriately substituted homoallyl group
and ring closing metathesis provides the C-5 substituted dehy-
droazepine-2-carboxylate 5 in good overall yield.7 However,
attempts to reduce the olefin stereoselectively resulted predo-
minantly in the trans-disubstituted amino ester 6. Conversion of
methyl ester 5 to the corresponding bulky ester (R = adamantyl)
a Reagents and conditions: (a) MeOH, SOCl2, 60 °C; (b) NOS-Cl,
NaHCO3, Et2O, water; (c) Ph3P, DIAD, THF, rt, 77% yield; (d) 4%
Hoveyda-Grubbs second generation (301224-40-8), CH2Cl2, re-
flux; (e) PhSH, K2CO3, DMF; (f) MeOH, 5% Rh/Al2O3/H2, 30 bar,
30 °C; (g) PhSH, K2CO3, DMF, BOC2O; (h) LiOH, THF, water; (i)
1-adamantyl bromide, Ag2O, Et2O; (j) 2 M HCl/Et2O.
Received: December 14, 2010
Published: January 28, 2011
r
2011 American Chemical Society
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The Journal of Organic Chemistry
NOTE
Scheme 2. New Approach, Retrosynthesis
Scheme 3. Conversion to Oximea
a Reagents and conditions: (a) baker’s yeast;9d (b) BzCl, DMAP,
CH2Cl2; (c) ethylene glycol, cat. pTsOH, PhCH3, reflux; (d) LiOH,
water, THF; (e) TPAP, NMO, 4 Å sieves, MeCN; (f) hydroxylamine
HCl, NaOAc, MeOH.
greatly improved the stereoselectivity of the olefin reduction
(H2/Rh/Al2O3, MeOH, 30 bar, 30 °C) to give a preponderance
of the cis-disubstituted amino ester 6a. However, this approach
suffered from other limitations. Most notably, the C5 substituent
had to be introduced relatively early in the synthesis, greatly
reducing flexibility for producing alternative substituents at this
position.
Scheme 4. Beckmann Rearrangementa
In considering an alternate strategy, we envisioned solving the
stereoselectivity problem by liberating the C2 and C5 substitu-
ents simultaneously from the oxidative cleavage of an aza-
bicyclo[3.2.2]nonene derivative 14 (Scheme 2). In addition, this
approach enabled oxidative differentiation of the C2 and C5
substituents, leaving a versatile aldehyde substituent at C5 for
further elaboration. Finally, the required azabicyclononene was
envisioned to be derived from Beckmann rearrangement of
bicyclo[2.2.2]oxime 11. This compound is ultimately derived
from the known 6-keto-bicyclo[2.2.2]octanol 8. Compound 8 is
obtained from baker’s yeast reduction of bicyclo[2.2.2]-
octanedione 7.8d,9
The principal advantage to starting the synthesis with bicyclo-
[2.2.2]octanedione (7) was its known desymmetrization, which
sets all of the stereocenters of the final compound9d (Scheme 3).
Since this is a reductive desymmetrization, theoretically either
enantiomer of 1 could be produced by manipulating the oxida-
tion state of the alcohol or ketone functionality of 8. Because
baker’s yeast selectively reduces the pro-R carbonyl group, which
ultimately must participate in the Beckmann rearrangement to
produce the desired enantiomer of 1, our synthesis required
protection of the remaining ketone and reoxidation of the
secondary alcohol. Attempts to directly ketalize 8 with ethylene
glycol and catalytic p-toluenesulfonic acid (PhCH3, reflux)
resulted in extensive retro-aldol reaction with subsequent ketal/
acetal formation and very little formation of the desired ketal.
This side reaction was circumvented by benzoylating the alcohol
before ketalization under these conditions. Removal of the
benzoyl group provided 9 in good overall yield from 8. Oxidation
to the ketone with NMO and catalytic TPAP10 produced 10 in
quantitative yield.
a Reagents and conditions: (a) TsCl, Pyr, 0-55 °C, 9 M H2SO4; (b)
TsCl, Et3N, CH2Cl2, -10 to 0 °C, SiO2, MeOH, Pyr. Condition (a)
produces both lactam 12 and lactam 12a (12/12a = 8/1 to 2/1,
62-78% yield). Condition (b) produces exclusively lactam 12, in
62% yield.
Initially the Beckmann rearrangement was effected with TsCl
in pyridine at 0 °C followed by warming to 55 °C for 1 h
(Scheme 4). Acid-catalyzed hydrolysis (9 M H2SO4, water) of
the intermediate pyridinium imine gave rise to lactam 12
(62-78%). On scales of up to 1 g of oxime 11, this method
produced a favorable 8:1 ratio of the desired 3-oxo-lactam 12 to
the undesired 2-oxo-lactam 12a. However, scaling this procedure
to 3-5 g resulted in severe erosion of this ratio to 2:1. We
hypothesized that the longer heating times necessitated by larger
reaction volumes enabled the intermediate anti tosyloxime to
undergo an acid-catalyzed, nucleophilic oxime isomerization,
producing the undesired lactam isomer 12a.11 Consistent with
this hypothesis, conducting the Beckmann rearrangement at
room temperature over extended periods of time (48 h) pro-
duced the desired lactam 12 as the sole product.
Capitalizing on these observations, we developed conditions
more amenable to large scale reactions. Treating oxime 11 with
Et3N in CH2Cl2 at -10 to 0 °C to form the intermediate
tosyloxime, followed by treatment with SiO2, MeOH, and finally
1.1 equiv of pyridine at room temperature consistently pro-
duced the desired 3-oxo-lactam 12 in 62% yield, as the exclusive
lactam product. The absolute configuration of lactam 12 was
verified by single crystal X-ray diffraction studies of its thioamide
derivative, produced by treating 12 with Lawesson’s reagent in
dioxane.12
Formation of the oxime and subsequent Beckmann rearrange-
ment required some optimization to ensure reproducibly high
yields and regioselectivity in the production of the bicyclo [3.2.2]
azepinone 12 (Scheme 4). Refluxing a solution of 10, hydro-
xylamine hydrochloride, and sodium acetate in methanol led
exclusively to the desired trans oxime 11 as a viscous oil.
However, it was discovered that this isomer slowly equilibrates
to a 2:1 mixture of the trans and cis oximes over several days at
room temperature. Heating this mixture in refluxing ethanol for
30 min afforded the trans oxime 11 in quantitative yield.
Conversion of lactam 12 to CBZ protected amine 13 was
achieved in 86% overall yield through amide reduction followed
by protection of the intermediate secondary amine (Scheme 5).
Direct manipulation of the spiroketal to produce the methyl enol
ether failed to give the desired product; therefore, a three-step
process was developed. Cleavage of the dioxolane with 80%
formic acid at room temperature afforded the corresponding
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Scheme 5. Formation of Enol Ether and Ozonolysisa
1-Benzyl-2-methyl-(2S,5S)-5-(hydroxymethyl)azepane 1,2-
Dicarboxylate (16). Compound 14 (220 mg, 0.766 mmol) was
dissolved in 5 mL of CH2Cl2 containing 32 μL of MeOH in a round-
bottomed flask. The solution was cooled to -78 °C (reaction becomes
slightly turbid) and ozone was bubbled into the reaction mixture until
a pale blue color was sustained. The mixture was stirred for 15 min
at -78 °C, then the excess ozone was discharged by using a stream of
nitrogen until the blue color was completely dissipated. The mixture was
treated with Ph3P (393 mg, 1.5 mmol), stirred for 5 min at -78 °C, and
warmed to room temperature. After the solution was stirred for 3 h at rt,
the CH2Cl2 was removed under a stream of nitrogen and the residue was
dissolved in 4 mL of MeOH. The mixture was treated with NaBH4 (56.7
mg, 1.96 mmol) in a single portion. The mixture was stirred for 2 h at
room temperature, the volatiles were removed in vacuo, and the residue
was partitioned between saturated NaHCO3 and ethyl acetate. The
organic layer was dried over anhydrous Na2SO4 and concentrated in
vacuo to a colorless oil. The crude material was purified over silica gel
eluting with ethyl acetate/hexane to give 153 mg (60%) of 16 as a
colorless oil: [R]D -30.8 (c 1.22, CHCl3); IR (film) 1740, 1686, 1416,
a Reagents and conditions; (a) LiAlH4, THF, 50 °C, then CbzCl,
K2CO3 in MeOH; (b) 80% HCO2H, water; (c) p-TsOH, HC(OMe)3,
anhyd. MeOH; (d) Ac2O, FeCl3, 0 °C; (e) O3, 1 equiv of MeOH in
CH2Cl2, -78 °C, Ph3P or Me2S.
1
1248, 1198, 1176, 1022, 698 cm-1; H NMR (400 MHz, CDCl3) δ
Scheme 6. In Situ Aldehyde Conversiona
7.42-7.28 (m, 5 H), 5.25-5.03 (m, 2 H), 4.76 (dd, J = 5.4, 8.3 Hz, 1 H),
4.59 (dd, J = 5.0, 8.3 Hz, 1 H), 3.82-3.69 (m, 3 H), 3.65-3.45 (m, 4 H),
2.20-2.03 (m, 1 H), 2.04-1.67 (m, 4 H), 1.59-1.35 (m, 2 H); 13C
NMR (126 MHz, CDCl3) (observed) δ 173.0, 172.9, 156.6, 156.0,
136.8, 136.7, 128.7, 128.6, 128.2, 128.0, 127.9, 67.6, 67.6, 66.4, 66.3, 59.4,
59.0, 52.3, 52.2, 43.0, 42.7, 40.0, 39.7, 30.6, 27.6, 27.2, 26.5; HRMS calcd
for C17H24NO5 [M þ H] 322.1654, found 322.1644.
a Reagents and conditions: (a) O3, 1 equiv of MeOH in CH2Cl2,
-78 °C, Ph3P; (b) NaBH4, MeOH; (c) O3, 1 equiv of MeOH in
CH2Cl2, -78 °C, Me2S; (d) Ph3PCHCO2t-Bu, THF, rt.
1-Benzyl-2-methyl-(2S,5S)-5-[(1E)-3-tert-butoxy-3-oxo-
prop-1-en-1-yl]azepane 1,2-Dicarboxylate (17). Compound
14 (0.400 g, 1.39 mmol) was dissolved in 5 mL of CH2Cl2 containing
56 μL of MeOH in a round-bottomed flask. The mixture was treated
with ozone as described above. Following the ozonolysis, the mixture
was treated with Me2S (0.501 mL, 6.96 mmol). After being stirred for
5 min at -78 °C, the mixture was warmed to room temperature and
stirred for 2 h. The volatiles were removed under a stream of nitrogen.
The residue was placed under high vacuum for 10 min and was dissolved
in 4 mL of dry THF. The mixture was treated with tert-butyl triphenyl-
phosphoranylidene-acetate (576 mg, 1.53 mmol) at room temperature
then stirred for 22 h, and the volatiles were removed in vacuo. The crude
material was purified over silica eluting with ethyl acetate/hexane to give
449 mg (77%) of 17 as a colorless oil: [R]D -12.4 (c 1.43, CHCl3); IR
ketone in 80% yield. Initial attempts to directly convert this
ketone to the enol-ether 14 (p-TsOH, MeOH, or TMSOTf with
trimethyl orthoformate) were unsuccessful, resulting in mixtures
of ketone and dimethyl ketal. However, intentional conversion of
the ketone to its dimethyl ketal could be achieved with methanol,
p-toluene sulfonic acid, and trimethyl orthoformate in 94% yield.
Subsequent treatment of the dimethyl ketal with anhydrous ferric
chloride in acetic anhydride smoothly afforded the desired enol-
ether 14 in 92% isolated yield.13,14
Ozonolysis of 14, followed by reduction of the ozonide with
either triphenylphosphine or dimethyl sulfide afforded (2S,5S)-
carboxaldehyde 15 in >75% crude yield. However, due to
instability upon purification, aldehyde 15 was immediately con-
verted to more stable functionalized derivatives as outlined in
Scheme 6. For example, 15 was immediately reduced (NaBH4,
MeOH) to provide alcohol 16 in 60% overall yield from 14.
Alternatively, aldehyde 15 could be homologated in situ with tert-
butyloxycarbonyl-triphenylphosphorane to give diester 17 in
77% overall yield from 14.
In summary, we have devised a robust asymmetric synthesis of
(2S,5S)-5-substituted-azepane-2-carboxylate derivatives that
proceeds in 12 steps and in 17-22% overall yield from known
hydroxy-ketone 8. This synthesis has been successfully scaled to
prepare multigram quantities of the key intermediate enol-ether
14 and represents a practical alternative to other methods for
preparing these complex cyclic amino acids. Furthermore, access
to aldehyde 15 enabled late stage elaboration at C5 to facilitate
SAR development.
1
(film) 1746, 1699, 1414, 1150, 981, 698 cm-1; H NMR (500 MHz,
CDCl3) δ 7.37-7.27 (m, 5 H), 6.81 (ddd, J = 3.7, 5.8, 15.9 Hz, 1 H), 5.71
(ddd, J = 1.7, 11.0, 15.9 Hz, 1 H), 5.21-5.05 (m, 2 H), 4.70 (dd, J = 5.6, 10.3
Hz, 0.5 H), 4.55 (dd, J = 5.1, 10.0 Hz, 0.5 H), 3.80-3.73 (m, 1 H), 3.72 (s, 2
H), 3.60 (s, 1 H), 3.49 (ddd, J = 3.4, 8.5, 14.9 Hz, 0.5 H), 3.38-3.31 (m, 0.5
H), 2.56-2.49 (m, 1 H), 2.13-2.01 (m, 1 H), 1.97-1.89 (m, 1 H),
1.88-1.70 (m, 4 H), 1.48 (s, 9 H); 13C NMR (126 MHz, CDCl3)
(observed) δ 173.1, 173.0, 166.2, 166.1, 156.6, 156.0, 150.4, 136.8, 136.7,
128.7, 128.6, 128.2, 128.1, 127.9, 127.8, 122.9, 122.8, 80.6, 67.6, 67.6, 59.3,
58.9, 52.4, 52.2, 41.7, 41.4, 38.7, 38.3, 33.1, 33.0, 30.1, 29.7, 28.3, 26.2, 25.9; 1H
NMR (600 MHz, DMSO-d6 at 110 °C) (rotamers resolved) δ 7.41-7.27
(m, 5 H), 6.76 (dd, J = 6.1, 15.9 Hz, 1 H), 5.72 (dd, J = 1.5, 15.9 Hz, 1 H),
5.17-5.04 (m, 2 H), 4.59 (dd, J = 5.1, 8.7 Hz, 1 H), 3.67-3.56 (m, 4 H),
3.55-3.43 (m, 1 H), 2.91 (s, 1 H), 2.08-1.92 (m, 2 H), 1.86-1.77 (m, 1
H), 1.76-1.58 (m, 3 H), 1.46 (s, 9 H); 13C NMR (151 MHz, DMSO-d6 at
110 °C) (rotamers resolved) δ171.4, 164.5, 154.8, 150.2, 136.3, 127.6, 127.1,
126.7, 121.4, 79.1, 66.0, 58.1, 51.0, 41.2, 37.5, 32.0, 28.9, 27.3, 25.3; HRMS
calcd for C23H31NO6Na [M þ Na] 440.2043, found 440.2041.
’ ASSOCIATED CONTENT
’ EXPERIMENTAL SECTION
S
Supporting Information. A Complete description of
The full experimental details and characterization data for the conversion
of compound 8 to compound 14 are found in the Supporting Information.
b
experimental details, product characterization data, copies of
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The Journal of Organic Chemistry
NOTE
proton and carbon NMR spectra, and single crystal X-ray data are
included. This material is available free of charge via the Internet
at http://pubs.acs.org.”
located on N2 was found from the Fourier difference map and refined
freely. All remaining hydrogen atoms were fixed in idealized positions.
The final model refined to a goodness fit of 1.148 with R1 = 0.0778 (I >
2σ) and wR2 = 0.1614. Absolute configuration was assigned based on a
Flack parameter of 0.01(3).
(13) We gratefully acknowledge Professor E .J. Corey for the
extremely useful and timely suggestion of these reaction conditions.
(14) Failure to deactivate the silica gel (0.5-1.0% Et3N) used in the
final purification of 14 results in significant disproportionation on the
column to give mixtures of compound 14, dimethyl ketal, and ketone.
’ AUTHOR INFORMATION
Corresponding Author
donn.g.wishka@pfizer.com
’ ACKNOWLEDGMENT
We would like to gratefully acknowledge Jennifer E. Davoren,
Daniel P. Walker, and Christopher J. O’Donnell for helpful
discussions during the preparation of this manuscript.
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spiro[4-azabicyclo[3.2.2]nonane-6,20-[1,3]dioxolane]-3-thione, X-ray
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