Two Scalable Syntheses of (S)-2-Methylazetidine

Article abstract of DOI:10.1021/acs.joc.6b00149

Two orthogonal routes for preparing (S)-2-methylazetidine as a bench stable, crystalline (R)-(-)-CSA salt are presented. One route features the in situ generation and cyclization of a 1,3-bis-triflate to form the azetidine ring, while the second route inv

Full text of DOI:10.1021/acs.joc.6b00149

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Two Scalable Syntheses of (S)-2-methylazetidine
Matthew S. Dowling, Diline P. Fernando, Jie Hou, Bo Liu, and Aaron C Smith
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00149 • Publication Date (Web): 19 Feb 2016
Downloaded from http://pubs.acs.org on February 24, 2016
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Two Scalable Syntheses of (S)ꢀ2ꢀmethylazetidine
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Matthew S. Dowling,*† Dilinie P. Fernando,† Jie Hou,‡ Bo Liu,‡ and Aaron C. Smith*†
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†Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United
States
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‡WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China
Corresponding Authors:
*Eꢀmail: matthew.s.dowling@pfizer.com
*Eꢀmail: aaron.smith2@pfizer.com
Abstract:
Two orthogonal routes for preparing (S)ꢀ2ꢀmethylazetidine as a bench stable, crystalline (R)ꢀ(–)ꢀ
CSA salt are presented. One route features the in situ generation and cyclization of a 1,3ꢀbisꢀtriflate to
form the azetidine ring, while the second route involves chemoselective reduction of NꢀBoc azetidineꢀ2ꢀ
carboxylic acid. Both sequences afford the desired product in good overall yields (61% and 49%) and
high enantiomeric excess (>99% ee), avoid column chromatography, and are suitable for the largeꢀscale
production of this material.
There is a growing recognition that substituted azetidines are a privileged class of compounds in
medicinal chemistry. This fourꢀmembered azaheterocycle tends to exhibit defined, rigid conformations
and often displays superior metabolic stability, ligand efficiency and physicochemical profiles relative to
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its higher homologues.1 Several recently approved drugs (Melagatran, Exanta, Azelnidipine)2 and phase 3
clinical assets (Baricitinib, Cobimetinib, Delafloxacin)3 that incorporate substituted azetidines have been
disclosed. Substituted azetidines have also found applications in the field of chiral ligand design.4
Interestingly, more method development has focused on preparing piperidines and pyrrolidines than
azetidines, likely due to the challenge associated with forming the strained fourꢀmembered ring5a and the
relative prevalence of piperidines and pyrrolidines in natural products. While a variety of methods to
prepare substituted azetidines have been reported in the last decade,5 general approaches for the
preparation of enantioenriched 2ꢀsubstituted azetidines are relatively rare.6
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Scheme 1. Representative precedent for the synthesis of enantioenriched 2ꢀmethylazetidines.
An efficient method to prepare (S)ꢀ2ꢀmethylazetidine (1) on multiꢀhundred gram scale with >98%
ee was desired. Despite the simplicity of this compound, there is limited commercial availability of this
material,7 and few procedures for preparing it in either racemic7,8, 9 or enantioenriched form,6,10,11
(including protected derivatives) have been reported. None of these procedures were deemed suitable for
largeꢀscale application without significant process improvements. For example, Cowart et al. have
described a twoꢀstep synthesis of NꢀBocꢀ2ꢀmethylazetidine (3) from NꢀBocꢀ2ꢀhydroxymethyl azetidine
(2) via mesylation and subsequent SuperꢀHydrideTM reduction on 1 g scale (Scheme 1A).10a Although this
approach is direct, the final step employs column chromatography and only gives a 30% yield. Hodgson,
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et al. have reported a concise approach for preparing enantiomerically enriched 2ꢀsubstituted azetidines
that features alkylation of a C2ꢀlithiated azetidine (Scheme 1B).6c However, this chemistry requires
cryogenic conditions (–98 oC), superꢀstoichiometric amounts of an enantioenriched diamine ligand and
gives the product in 45% yield with 82% ee. Among known routes to 2ꢀmethylazetidine that involve de
novo azetidine ring synthesis, a threeꢀstep synthesis of (R)ꢀ2ꢀmethylazetidine 7 from amine 6 in 14%
yield was reported in 1999 (Scheme 1C);10b yet neither amine 6 nor its antipode are readily available.
Marinetti demonstrated that treatment of the bisꢀmesylate derived from 8 with neat benzyl amine affords
azetidine 9 in 60% yield without erosion of enantiopurity (Scheme 1D).11 However, column
chromatography using basic alumina was required in order to separate the desired azetidine from excess
benzylamine.
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In response to the limitations associated with previous approaches toward enantioenriched 2ꢀ
methylazetidine, the development of a new, scalable route was pursued. Herein we describe our efforts,
which culminated in the development of two orthogonal approaches for preparing this material as a
benchꢀstable, crystalline, (R)ꢀ(–)ꢀCSA salt. Both syntheses avoid the use of column chromatography,
proceed in good yields, provide analytically pure material with >99% ee and utilize readily available
starting materials.
Scheme 2. Synthesis of (S)ꢀ2ꢀmethylazetidine 1 via bisꢀmesylate 11.
Given the wide commercial availability of (R)ꢀ(–)ꢀ1,3ꢀbutanediol 10, initial efforts focused on
applying Marinetti’s chemistry11 to the preparation of Nꢀbenzylꢀ2ꢀmethyl azetidine (Scheme 2).
Treatment of the bisꢀmesylate 11 with neat benzylamine (5 equiv.) afforded the desired azetidine 12a in
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53% yield with 95% ee; however, this cyclization was plagued by the formation of dimeric and polymeric
sideꢀproducts. Removal of these byproducts and excess benzylamine necessitated tedious column
chromatograpy, which was not suitable for large scale applications. Several attempts were made to render
the cyclization step more scalable by replacing benzylamine with benzhydrylamine, reducing the number
of equivalent of benzylamine, conducting the reaction at elevated temperature, and using solvents (DMF,
CH3CN), and/or bases (Cs2CO3, NaHCO3, Et3N). Unfortunately, none of these changes led to any
significant improvements in the process. During the course of this work, it was discovered that
recrystallization of the (R)ꢀ(–)ꢀCSA salt of azetidine 12a in a solvent mixture of ethyl acetate and
dichloromethane improved the enantiopurity from 95% to >99% ee. Subsequent hydrogenolysis of 12a
proceeded smoothly to give 1 as a crystalline solid.
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Scheme 3: Precedent for the synthesis of 1,3ꢀsubstituted azetidines via oneꢀpot bis triflation/cyclization.
In searching for a more robust method for producing bulk quantities of (S)ꢀ2ꢀmethylazetidine, a
recent report from Hillier et al. describing the oneꢀpot synthesis of 3ꢀsubstituted azetidines from 1,3ꢀdiols
using a bisꢀtriflation/cyclization protocol (Scheme 3) was identified.12 This work demonstrated that 1,3ꢀ
bisꢀtriflates react with primary amines faster and generally in higher yields than 1,3ꢀbisꢀtosylates to give
the corresponding azetidines. However, Hillier et al. only reported the synthesis of 2,4ꢀunsubstituted
azetidines derived from 1,3ꢀunsubstituted primary alcohols; the use of secondary, chiral alcohols was not
reported. While there are literature precedents for the synthesis of 2ꢀsubstituted azetidines through
displacement of secondary alkyl triflates with primary amines without loss of stereochemical integrity,13
these transformations typically employ conformationally preorganized sugarꢀderived substrates that often
lack αꢀhydrogens capable of opening up undesired elimination pathways. Based on these precedents,
several concerns were identified in the potential application of this chemistry to a scalable synthesis of
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enantioenriched 2ꢀmethylazetidine: (1) secondary alkyl triflates may not be viable electrophiles in this
context or may not proceed with clean inversion of stereochemistry;14 (2) excess Hünig’s base (ca. 5
equiv.) must be separated from the tertiary amine product; and (3) alternatives to column chromatography
need to be identified in order to enable practical isolation and purification on a large scale.15
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Table 1. Optimization of the synthesis of 12a, 12b.
Entry
R1
methoda solvent temp. A (°C) temp. B (°C) % yield 12b [%ee]c % yield 16b
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6
CHPh2
CHPh2
CH2Ph
CHPh2
CHPh2
CHPh2
A
A
A
A
B
B
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
–25
–25
–25
–35
–35
–35
70
22
62 [90]
59 [92]
53 [98]
63 [89]
74 [89]
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4
22
22
22
reflux
aGeneration of bisꢀtriflate 15: Method A: Tf2O (2.1 equiv.) is added to a precooled solution of 10 (11.1 mmol). Hünig’s base (5
equiv.) is added followed by the indicated primary amine (1.05 equiv.). Method B: Tf2O (2.2 equiv.) is added to a precooled
solution of diol 10 (11.1 mmol) and Hünig’s base (2.62 equiv.). Additional Hünig’s base (2.62 equiv.) is added followed by the
indicated primary amine (1.05 equiv.). bDetermined by analysis of crude 1H NMR spectra using 2,6ꢀdimethoxytoluene as an
internal standard. cDetermined by chiral GC analysis of a purified sample.
The feasibility of preparing enantioenriched 2ꢀmethylazetidine 12 through the oneꢀpot generation
and cyclization of a bisꢀtriflate was evaluated under several sets of conditions (Table 1). Treatment of a
cold (–25 °C) solution of (R)ꢀ1,3ꢀbutanediol 10 with triflic anhydride followed by Hünig’s base (method
A) cleanly generated the putative bisꢀtriflate 15, as monitored by TLC. Subsequent treatment with
benzhydrylamine followed by warming to 70 °C generated the desired 2ꢀmethylazetidine product 12b in
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62% yield and 90% ee (Table 1, entry 1). Only minor quantities of the elimination byproduct 16 were
observed in the crude 1H NMR.16 Conducting the cyclization step at room temperature afforded a
comparable yield to heating at 70 °C (entry 2). Benzylamine was also viable in this transformation and
afforded the corresponding product in excellent enantiopurity (98% ee) but lower yield compared to
benzhydrylamine (entry 3). The highest yield was obtained by dropwise addition of Tf2O to a premixed
solution of (R)ꢀ1,3ꢀbutanediol and Hünig’s base at –35 °C followed by treatment with benzhydrylamine
and warming to room temperature (Method B, entry 5).
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Scheme 4. Scalable synthesis of (S)ꢀ2ꢀmethylazetidine (1) from diol 10.
The optimized conditions from Table 1, entry 5 were applied to a 20 gramꢀscale preparation of 1
(Scheme 4). After generation of crude 12b from 10, it was discovered that the desired azetidine could be
separated from excess Hünig’s base by dissolving the crude reaction mixture in toluene and washing the
obtained solution with water.15 This procedure is uniquely effective for separating the desired azetidine
from excess Hünig’s base; employing ethyl acetate or dichloromethane as the extraction solvent led to
contamination of the product with significant quantities of Hünig’s base. Filtration through a short plug of
silica gel17 followed by formation of the (R)ꢀ(–)ꢀCSA salt and two successive recrystallizations from a
mixture of dichloromethane and ethyl acetate afforded 12b in 64% isolated yield as a crystalline white
solid. In addition to removing trace impurities, the recrystallization step improves the enantiopurity from
91% ee to >99.6% ee.18 Hydrogenolysis in the presence of palladium hydroxide afforded (S)ꢀ2ꢀ
methylazetidine (1) as a bench stable, crystalline (R)ꢀ(–)ꢀCSA salt. To date, this general approach has
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been used to produce over 200 g of 1. The absolute stereochemistry of 1 was confirmed through singleꢀ
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crystal Xꢀray diffraction studies, see the supporting information for details.
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Concurrent to the efforts involving azetidine ring synthesis, an orthogonal route beginning from
(R)ꢀazetidineꢀ2ꢀcarboxylic acid (20) to prepare 1 was also developed. Inspired by a process chemistry
route reported to synthesize enantiopure 2ꢀmethylpyrrolidine from Bocꢀproline,19 we sought to improve
upon the disconnection first reported by Cowart, et al.10a using an analogous sequence of (1) reduction,
(2) activation of the hydroxyl, and (3) reduction to the methyl group, followed by a concomitant
deprotection and isolation step.
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Scheme 5: Scalable synthesis of (S)ꢀ2ꢀmethylazetidine (1) from azetidineꢀ2ꢀcarboxylic acid (20).
To this end, (R)ꢀBoc azetidineꢀ2ꢀcarboxylic acid 20 was reduced to 2ꢀhydroxylmethyl azetidine
21 using in situ generated borane; 21 was then converted to the corresponding mesylate (Scheme 5). Due
to the chemical instability of the analogous pyrrolidine intermediate reported in literature,19 the mesylate
was carried forward to the next reaction as a solution. Reduction with SuperꢀHydrideTM then produced the
desired (S)ꢀBocꢀ2ꢀmethylazetidine 22. Due to the volatility of this intermediate, isolation at this stage was
not practical. Bocꢀdeprotection was first attempted using benzenesulfonic acid, which was reported to be
uniquely useful in both effecting Boc deprotection and forming a bench stable crystalline salt with 2ꢀ
methylpyrrolidine.19 When applied to azetidine 22, deꢀprotection with benzenesulfonic acid was
successful, but crystallization and isolation of the salt could not be achieved as the product either stayed
in solution or persisted as an oil. With the knowledge that (R)ꢀ(–)ꢀCSA forms a stable crystalline salt with
(S)ꢀ2ꢀmethylazetidine, direct treatment with (R)ꢀ(–)ꢀCSA was evaluated. Deprotection of 22 in the
presence of (R)ꢀ(–)ꢀCSA was slow in refluxing MTBE/THF. However, by changing solvent from
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MTBE/THF (present from the previous two reactions) to the higherꢀboiling 2ꢀmethyltetrahydrofuran, a
higher reaction temperature (75 oC) could be attained and Bocꢀdeprotection went to completion. Upon
cooling, (S)ꢀ2ꢀmethyl azetidinium (R)ꢀcamphorsulfonate crystallized out of the reaction. Reꢀslurrying,
filtration, and washing led to isolation of the desired material as a white solid in four overall steps (three
of which were telescoped) and 49% overall yield without the need for chromatographic separation.
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Conclusions:
In summary, we have described two scalable routes that are effective in producing hundreds of
grams of (S)ꢀ2ꢀmethylazetidine as a stable, crystalline, nonꢀhygroscopic (R)ꢀ(–)ꢀCSA salt in >99% ee
from readily available starting materials without the need for column chromatography.
Experimental Section
General. Rꢀ(–)ꢀ1,3ꢀbutanediol was purchased from a commercial vendor (>99% ee) and used without
further purification. (R)ꢀ1ꢀ(tertꢀbutoxycarbonyl)azetidineꢀ2ꢀcarboxylic acid was prepared from (R)ꢀ
azetidineꢀ2ꢀcarboxylic acid using a literature procedure.20 All other chemicals and reagents were
purchased from commercial sources and used without further purification. Anhydrous acetonitrile and
tetrahydrofuran were purchased from a commercial vendor and used without further purification. All airꢀ
and/or moistureꢀsensitive reactions were performed under an atmosphere of nitrogen. Reactions were
monitored by thin layer chromatography (TLC) using preꢀcoated 250 ꢁm silica gel plates and visualized
by fluorescence quenching under UV light or staining with iodine, pꢀanisaldehyde or potassium
1
permanganate. Unless otherwise indicated, yields refer to isolated compounds. H NMR spectra were
recorded at 25 °C with a spectrometer equipped with an AutoX ID 600ꢀ5 probe at 600 MHz. 13C NMR
spectra were recorded at 25 °C with a spectrometer equipped with a 5 mm BBO cryoprobe equipped with
a Zꢀaxis gradient at 100 MHz. Chemical shifts are reported in part per million (PPM) using the internal
solvent residual of CD3OD or CDCl3 as an internal standard. Signals are listed as follows: chemical shift
in ppm (multiplicity identified as s = singlet, br = broad, d = doublet, t = triplet, q = quartet, p = pentet, sx
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= sextet, m = multiplet; integration; coupling constants in Hz). The HRMS analysis was conducted on a
TOF mass spectrometer in positive electrospray mode. The sample was separated on a UHPLC system
prior to mass spectrometric analysis. The resulting spectra was automatically lockmass corrected and the
target mass ions and the confirming adduct (Na+) were extracted and combined as a chromatogram. The
mass accuracy was calculated for all observed isotopes against the theoretical mass ions derived from the
chemical formula. Elemental analyses are within 0.4% of theory. Melting points were uncorrected.
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(2R)-4-[(Methylsulfonyl)oxy]butan-2-yl methanesulfonate (11).21 A solution of Rꢀ(–)ꢀ1,3ꢀbutanediol (3
g, 30 mmol) and triethylamine (10.1 g, 99.9 mmol) in dichloromethane (60 mL) was cooled to 0 °C in an
ice water bath and treated with methanesulfonyl chloride (11.4 g, 99.9 mmol) in a dropwise manner at 0
°C. After 15 min the ice water bath was removed and the mixture was stirred at rt for 2 h. The mixture
was diluted with aqueous saturated ammonium chloride (80 mL) and extracted with dichloromethane (3 x
50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and
concentrated to give a residue. The residue was purified using column chromatography eluting with ethyl
1
acetate/petroleum ether (1:4 to 3:2) to give 11 (7.3 g, 89%) as a colorless oil. H NMR (600 MHz,
CD3OD) δ 4.98 (sx, 1H, J = 6.0 Hz), 4.40 (t, 2H, J = 5.8 Hz), 3.16 (s, 3H), 3.15 (s, 3H), 2.15 (q, 2H, J =
6.0 Hz), 1.52 (d, 3H, J = 6.5 Hz); 13C NMR (100 MHz, CD3OD) δ 77.5, 67.6, 38.6, 37.3, 37.1, 21.7;
[α]D24 = –47.5° (c = 1, CH3OH).
(2S)-1-Benzyl-2-methylazetidine (12a).22 (2R)ꢀ4ꢀ[(methylsulfonyl)oxy]butanꢀ2ꢀyl methanesulfonate (11)
(7.20 g, 29.2 mmol) was dissolved in benzylamine (19.2 mL, 175 mmol) and stirred at 45 °C for 16 h.
The reaction mixture was cooled to rt and a mixture of cyclohexane/methyl tertꢀbutyl ether (1:1, 200 mL)
was added, resulting in the precipitation of white solids. The precipitates were removed by filtration and
the filtrate was evaporated under reduced pressure and purified using column chromatography eluting
with dichloromethane (with 1% ammonium hydroxide)/methanol (100:0 to 99.5:0.5) to give 12a (2.5 g,
1
53%, ee = 94.8% by chiral GC) as a pale yellow oil. H NMR (600 MHz, CD3OD) δ 7.21–7.34 (m, 5H),
3.65 (d, 1H, J = 12.5 Hz), 3.56 (d, 1H, J = 12.5 Hz), 3.33–3.42 (m, 1H), 3.25–3.32 (m, 1H), 2.98 (q, 1H, J
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= 8.5 Hz), 2.07–2.14 (m, 1H), 1.79 (p, 1H, J = 9.4 Hz), 1.02 (d, 3H, J = 6.2 Hz); 13C NMR (100 MHz,
CD3OD) δ 138.4, 130.6, 129.5, 128.6, 64.1, 63.4, 52.5, 26.7, 21.3; [α]D24 = +32.4° (c = 0.5, CH3OH).
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(2S)-1-Benzyl-2-methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-
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yl]methanesulfonate (12a-CSA salt). To a solution of R-(–)-CSA (3.60 g, 15.4 mmol) in EtOH (15 mL)
was added a solution of (2S)ꢀ1ꢀbenzylꢀ2ꢀmethylazetidine 12a (2.50 g, 15.5 mmol) in EtOH (10 mL). The
mixture was stirred at rt for 15 h. The resulting solution was evaporated to remove EtOH. The residue was
suspended in MTBE (60 mL) and evaporated to remove MTBE. The residue was suspended in MTBE (60
mL) and the solids were collected by filtration. The filter cake was dried under reduced pressure to give a
light yellow solid (3.5 g, 95.6%), which was dissolved in dichloromethane (5 mL) and then ethyl acetate
(8 mL) was added. The mixture was stirred at rt for 30 min, during which time substantial solids
precipitated from solution. The solids were collected by filtration and the filter cake was suspended in
dichloromethane (3 mL), stirred at rt for 10 min, and then diluted with ethyl acetate (5 mL). The mixture
was stirred at rt for 30 min and the solids were then collected by filtration. The solids were dried under
reduced pressure to give 12a-CSA salt (2.5 g, 68%, ee = >99% by chiral GC) as a white crystalline solid.
mp = 158ꢀ160 °C; 1H NMR (600 MHz, CD3OD) δ 7.44–7.55 (m, 5H), 4.56–4.66 (m, 1H), 4.37 (s, 2H),
4.07 (q, 1H, J = 9.7 Hz), 3.99 (td, 1H, J = 9.4, 3.5 Hz), 3.33 (d, 1H, J = 15.0 Hz), 2.79 (d, 1H, J = 15 Hz),
2.64–2.73 (m, 1H), 2.52–2.62 (m, 1H), 2.36 (dt, 1H, J = 17, 4 Hz), 2.23–2.33 (m, 1H), 2.00–2.10 (m, 2H),
1.90 (d, 1H, J = 18.3 Hz), 1.58–1.68 (m, 1H), 1.39–1.47 (m, 1H), 1.29 (d, 3H, J = 6.6 Hz), 1.14 (s, 3H),
0.87 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 218.3, 131.5, 131.4, 131.1, 130.6, 67.6, 59.7, 58.9, 52.2,
48.9, 48.3, 44.2, 43.8, 27.9, 25.9, 25.5, 20.6, 20.3,19.0; [α]D24 = –10.0° (c = 1, CH3OH); Elemental
analysis: Anal. Calcd for C21H31NO4S: C = 64.09%, H = 7.94%, N = 3.56%; Found: C = 64.07%, H =
8.01%, N = 3.45%.
(2S)-2-Methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate (1
from 12a-CSA salt). A solution of 12a-CSA salt (2.5 g, 6.4 mmol) in methanol (25 mL) and THF (25
mL) was treated with 10% palladium hydroxide on carbon (450 mg). The suspension was heated to 60
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°C, filled with H2 (30 psi) and stirred for 20 h. The cooled reaction mixture was filtered and the filtrate
was concentrated under reduced pressure to give 1 (1.9 g, 99%) as a white crystalline solid. Spectral data
match those reported below.
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(2S)-1-(Diphenylmethyl)-2-methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-
yl]methanesulfonate (12b-CSA salt). Method B, 20 g scale. A solution of Rꢀ(–)ꢀ1,3ꢀbutanediol (20.0 g,
222 mmol, > 99% ee by chiral GC) and N,Nꢀdiisopropylethylamine (101.5 mL, 583 mmol) in acetonitrile
(444 mL) was cooled to –30 °C and treated with neat trifluoromethanesulfonic anhydride (81.2 mL, 480
mmol, 2.18 equiv.) dropwise via addition funnel over 90 min, maintaining the internal reaction
temperature between –30 and –35 °C. After the addition was complete, the reaction mixture was stirred
for 10 min at –30 °C and then treated with additional trifluoromethanesulfonic anhydride (1.5 mL)
dropwise and then stirred at –30 °C for an additional 15 min. The reaction mixture was treated with
additional Hünig’s base (101.5 mL, 583 mmol) over the course of 15 min while maintaining the internal
temperature below –30 °C. After an additional 10 min at –30 °C the reaction mixture was treated with a
solution of benzhydrylamine (38.4 mL, 222 mmol) in acetonitrile (40 mL) dropwise over 30 min via an
addition funnel, maintaining the internal reaction temperature below –30 °C. The reaction mixture was
stirred at –30 °C for 20 min then placed in an ice water bath for 30 min. The reaction was then stirred at
rt for 30 min, followed by heating at 45 °C for 30 minutes. The reaction mixture was cooled to rt, poured
into deionized water (900 mL) and extracted with toluene (1 L). The aqueous phase was backꢀextracted
with toluene (300 mL) and the combined organic layers were washed with water (2 x 250 mL), dried over
sodium sulfate, filtered and evaporated. The crude product was dissolved in dichloromethane (300 mL)
and loaded onto a plug of silica gel (300 mL, preflushed with 1:1 heptane/ethyl acetate). The plug was
flushed with 1:1 heptane/ethyl acetate (1.2 L) and the filtrate was evaporated to give a red oil (50.2 g).
The crude product was dissolved in methanol (200 mL), placed in a water bath at 10 °C, and treated with
Rꢀ(–)ꢀcamphorsulfonic acid (49 g) in batches over 5 min. The solution was stirred at rt for 2 h, and the
solvent was evaporated and the solids were dried under high vacuum for 15 h to give crude product (99.2
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g, ee = 91.8% by chiral SFC analysis). The salt was dissolved in dichloromethane (100 mL) and stirred at
rt for 10 min to give a dark solution. Ethyl acetate (850 mL) was added slowly with stirring and solids
precipitated from solution after ~5 min. The suspension was stirred at rt for 2 h, and the solids were
collected by filtration and washed with ethyl acetate (50 mL) to give white solids (72.1 g). These solids
were dissolved in dichloromethane (100 mL) and treated with ethyl acetate (700 mL). The mixture was
stirred at rt and solids immediately precipitated from solution. The suspension was stirred at rt for 15 h,
then the solids were collected by filtration, washed with ethyl acetate (50 mL) and dried under reduced
pressure to give 12b-CSA salt (66.7 g, 64% yield, ee = 99.6% by chiral SFC) as a white crystalline solid.
mp = 199ꢀ201 °C; 1H NMR (600 MHz, CD3OD) δ 7.54–7.59 (m, 4H), 7.43–7.53 (m, 6H), 5.67 (s, 1H),
4.69–4.76 (m, 1H), 3.92–4.06 (m, 2H), 3.36 (d, 1H, J = 14.6 Hz), 2.81 (d, 1H, J = 15.2 Hz), 2.70–2.75
(m, 1H), 2.58–2.64 (m, 1H), 2.31–2.39 (m, 2H), 2.03–2.09 (m, 2H), 1.91 (d, 1H, J = 18.9 Hz), 1.62–1.66
(m, 1H), 1.41–1.47 (m, 1H), 1.16 (s, 3H), 1.11 (d, 3H, J = 6.4 Hz), 0.88 (s, 3H); 13C NMR (100 MHz,
CD3OD) δ 218.2, 136.1, 136.0, 131.1, 130.74, 130.71, 130.4, 129.7, 128.6, 74.8, 69.0, 59.7, 52.4, 48.9,
48.5, 44.2, 43.8, 27.9, 26.0, 24.9, 20.6, 20.3, 19.4; [α]D24 = –42.6° (c = 1, CH3OH); Elemental analysis:
Anal. Calcd for C27H35NO4S: C = 69.05%, H = 7.51%, N = 2.98%; Found: C = 68.90%, H = 7.59%, N =
2.91%.
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An alternative procedure for preparing 12b-CSA salt that avoids the use of silica gel plug filtration is as
follows (Method A, 10 g scale):
A solution of Rꢀ(–)ꢀ1,3ꢀbutanediol (10.0 g, 111 mmol) in acetonitrile (222 mL) in a three neck 1L flask
was cooled to –25 °C. The solution was then treated with neat trifluoromethanesulfonic anhydride (37.9
mL, 224 mmol) dropwise over 30 min while maintaining the internal reaction temperature between –25 to
–30 °C. The reaction mixture was stirred for an additional 40 min between –25 to –30 °C, then treated
with Hünig's base (48.3 mL, 266 mmol) dropwise over 30 min while maintaining the internal temperature
between –25 to –30 °C. The resulting slurry was stirred for 60 min at –25 °C, and treated with additional
Hünig's base (48.3 mL, 266 mmol) over 10 min, followed by benzhydrylamine (19.6 g, 107 mmol)
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dropwise over 15 min while maintaining the internal temperature below –20 °C. The reaction is then
warmed to rt and stirred for 30 min, then heated to 45 °C and stirred for 20 min. The cooled reaction
mixture was diluted with toluene (750 mL) and deionized water (500 mL). The layers were separated and
the organic layer was washed with water (500 mL), dried over sodium sulfate, filtered through paper and
evaporated to give an offꢀwhite solid (26.9 g). The solid was dissolved in methanol (25 mL) and treated
with Rꢀ(–)ꢀcamphorsulfonic acid (24.8 g) dissolved in methanol (50 mL) at rt. The solution was
evaporated to dryness and residual methanol was removed by suspending the solids in ethyl acetate (25
mL) and evaporating. The solids were dried under highꢀvacuum for 18 h. The solids were dissolved in
dichloromethane (75 mL) and ethyl acetate (300 mL) was added slowly with stirring. After stirring at rt
for 1h, additional ethyl acetate (200 mL) was added. The suspension was cooled to 0 °C with stirring and
additional ethyl acetate (100 mL) was added. The solids were collected by filtration and dried under
reduced pressure to afford 12b-CSA salt (30.5 g, 58% yield, ee = 99.6% by chiral SFC). Spectral data
were consistent with those obtained using Method B.
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(2S)-2-Methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate (1
from 12b-CSA salt). A 300 mL stainless steel reactor was charged with a solution of 12b-CSA salt (29.4
g, 62.6 mmol) in methanol (125 mL) and 20% palladium hydroxide on carbon (1.78 g). The reactor was
flushed with nitrogen three times and hydrogen three times then pressurized to 60 psi hydrogen and
stirred at rt for 16 h. The hydrogen was released and the reaction mixture was filtered through a pad of
celite, eluting with methanol (100 mL). The filtrate was concentrated in vacuo to give a white solid. The
white solid is suspended in a mixture of ethyl acetate/MTBE (1:1, 200 mL) and stirred for 1 h at 60 °C.
After cooling to rt, the slurry was stirred for an additional 1 h then the solids are collected by filtration.
The solids are suspended in MTBE(100 mL) and stirred at rt for 16 hours. The solids are collected by
filtration, washed with MTBE (25 mL) and dried under reduced pressure to give 1 (18.1 g, 95%, ee >
99%23) as a white crystalline solid. mp = 144ꢀ146 °C; 1H NMR (600 MHz, CD3OD) δ 4.63 (sx, 1H, J =
7.0 Hz), 4.05 (q, 1H, J = 9.4 Hz), 3.92 (td, 1H, J = 10.0, 5.0 Hz), 3.32 (d, 1H, J = 14.8), 2.78 (d, 1H, J =
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14.8 Hz), 2.57–2.67 (m, 2H), 2.36 (dt, 1H, J = 18.1, 4.1 Hz), 2.24–2.32 (m, 1H), 1.99–2.10 (m, 2H), 1.92
(d, 1H, J = 18.7 Hz), 1.62–1.68 (m, 1H), 1.55 (d, 3H, J = 7.0 Hz), 1.41–1.47 (m, 1H), 1.11 (s, 3H), 0.86
(s, 3H); 13C NMR (100 MHz, CD3OD) δ 218.4, 59.7, 59.1, 49.2, 48.5, 44.1, 43.8, 43.7, 27.9, 27.5, 25.9,
20.4, 20.3, 20.0; [α]D24 = –26.5° (c = 1, CH3OH); Elemental analysis: Anal. Calcd for C14H25NO4S: C =
55.42%, H = 8.31%, N = 4.62%; Found: C = 55.59%, H = 8.41%, N = 4.49%.
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Azetidine 1 (25 mg) was dissolved in dichloromethane/toluene (1:1, 1 mL) in an open vial and allowed to
sit for 48 h. Single crystals suitable for Xꢀray diffraction studies were obtained.
Tert-butyl (2R)-2-(hydroxymethyl)azetidine-1-carboxylate (21)24 A round bottomed flask was charged
with (2R)ꢀ1ꢀ(tertꢀbutoxycarbonyl)azetidineꢀ2ꢀcarboxylic acid (42.3 g, 210 mmol) and isopropyl acetate
(100 mL) and stirred at rt for 10 min. The internal reaction temperature was then cooled to 0 °C, and
sodium borohydride (13.0 g, 336 mmol) was added in one portion. The reaction was then stirred for 5
min at 0 °C and boron trifluoride diethyl etherate (51.7 mL, 420 mmol) was added dropwise over 1 h,
maintaining the internal reaction temperature between 0 to 10 °C. The reaction was then continued for 3
h at 0 °C. The reaction was then quenched through dropwise addition of 0.5 M NaOH solution (270 mL)
over 30 min, maintaining the internal temperature between 0 to 10 °C. After the addition was complete,
the reaction mixture was heated to 50 °C for 20 min with vigorous stirring, which caused both layers to
appear clear. The layers were separated and the aqueous layer was backꢀextracted with isopropyl acetate
(40 mL). The combined organic layers were then washed with brine (50 mL), dried over sodium sulfate,
filtered, and concentrated in vacuo overnight to provide 21 (38.2 g, 97%) as a colorless, clear oil. 1H
NMR (400 MHz, CDCl3) δ 4.42–4.49 (m, 1H), 3.88 (q, 1H, J = 8.0 Hz), 3.69–3.81 (m, 3H), 2.13–2.22
(m, 1H), 1.89–1.98 (m, 1H), 1.46 (s, 9H); 13C NMR (400 MHz, CDCl3) δ 157.3, 80.1, 66.7, 63.5, 46.7,
28.2, 17.9; HRMS (m/z): Calcd for C9H17NO3 [M+Na]+ 210.1101; found 210.1095.
(2S)-2-Methylazetidinium-[(1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonate (1). A
solution of 21 (38.2 g, 204 mmol) in MTBE (400 mL) was cooled to 0 °C and treated with triethylamine
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(26.2 mL, 189 mmol) followed by DMAP (582 mg, 4.72 mmol). Methanesulfonyl chloride (20.7 mL,
265 mmol) was then added dropwise over 15ꢀ30 min while maintaining the reaction temperature between
0 °C and 5 °C. The reaction was then stirred at 0 °C for 3 h. The reaction was then treated with 1M
aqueous phosphoric acid (175 mL) over the course of 10 min with vigorous stirring, maintaining the
reaction temperature between 5 and 15 °C. The layers were separated and the organic layer was washed
with sat. sodium bicarbonate solution (75 mL) followed by brine (75 mL). The combined organic layers
were dried over sodium sulfate then filtered. The filtrate was concentrated in vacuo to a volume of ~300
mL to azetropically remove any residual water and used directly in the next reaction as a solution. This
solution was cooled to 0 °C and treated with a solution of lithium triethylborohydride (400 mL, 400
mmol, 1M in THF) dropwise over 1 h, maintaining the temperature between 0ꢀ7 °C. After the addition
was complete, the ice bath was removed and the reaction was warmed to rt and stirred for 72 h. The
reaction was then cooled to 0 °C and a separate flask was charged with MTBE (150 mL) and water (150
mL) and also cooled to 0 °C with stirring. The reaction was then poured slowly into the water/MTBE
mixture, maintaining the temperature below 10 °C. After the addition was complete, the mixture was
transferred to a separatory funnel and the layers were separated. The organic layer was then washed
sequentially with 1M phosphoric acid solution (300 mL), saturated sodium bicarbonate (100 mL)
solution, and brine (100 mL). The organic layer was dried over sodium sulfate and filtered to provide the
desired stock solution of product. The reaction mixture was concentrated to ca. 1/4th the volume and 2ꢀ
methyltetrahydrofuran (200 mL) was added. The mixture was concentrated to ca. 1/4th the volume again
and additional 2ꢀmethyltetrahydrofuran (300 mL) was added. The mixture was treated with (R)ꢀ(–)ꢀ
camphorsulfonic acid (49.7 g, 214 mmol) and heated to 75 °C for 15 h. The reaction mixture was cooled
to rt and crystalline material formed. The mixture was heated at 55 °C for 2 h, cooled to 45 °C for 1 h,
then rt for 6 h. The solids were collected by filtration, washed with 2ꢀmethyltetrahydrofuran (100 mL),
then dried in a vacuum oven for 15 h to give 1 as a crystalline white solid (30.8 g, 50%, ee = >99%23).
Spectral data matched those for 1 above. [α]D24 = –23.0° (c = 1, CH3OH).
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Associated Content
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The supporting information is available free of charge on the ACS publication website. DOI:XXX
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CIF file of 1
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1H and 13C NMR spectra for all new compounds.
SFC traces establishing the enantiopurity of 12b and 1.
Author Information
Corresponding Authors:
*Eꢀmail: matthew.s.dowling@pfizer.com
*Eꢀmail: aaron.smith2@pfizer.com
Notes
The authors declare no competing financial interests.
Acknowledgments
We thank Brian Samas for Xꢀray crystallography determination. We thank Jim Bradow, Jason Smith,
Laurence Philippe and Chao Li for performing chiral SFC and chiral GC analyses. We thank Andre
Shavnya and Ping Han for experimental assistance. We thank Vincent Mascitti for helpful discussions.
References
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2 (a) Ericksson, B. I.; Carlsson, S.; Halvarsson, M.; Risberg, B.; Mattsson, C. Thromb. Haemostasis 1997,
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3 (a) Lemaire, S.; Tulkens, P. M.; Van Bambeke F. Antimicrob. Agents Chemother. 2011, 55, 649–658.
(b) Larkin, J.; Ascierto. P. A.; Dréno, B.; Atkinson, V.; Liszkay, G.; Maio, M.; Mandalá, M.; Demidov,
L.; Stroyakovskiy, D.; Thomas, L.; de la CruzꢀMerino, L.; Dutriaux, C.; Garbe, C.; Sovak, M. A.; Chang,
I.; Choong, N.; Hack, S. P.; McArthur, G. A.; Ribas, A. N. Engl. J. Med. 2014, 371, 1867–1876. (c)
Fridman, J. S.; Scherle, P. A.; Collins, R.; Burn, T. C.; Li, Y.; Li, J.; Covington, M. B.; Thomas, B.;
Collier, P.; Favata, M. F.; Wen, X.; Shi, J.; McGee, R.; Haley, P. J.; Shepard, S.; Rodgers, J. D.;
Yeleswaram, S.; Hollis, G.; Newton, R. C.; Metcalf, B.; Friedman, S. M.; Vaddi, K. J. Immunol. 2010,
184, 5298–5307.
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4 Shi, M.; Jiang, J.ꢀK. Tetrahedron: Asymmetry 1999, 10, 1673–1679.
5 (a) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988–4035. (b) Rousseau, G.; Robin,
S. FourꢀMembered Heterocycles: Structure and Reactivity. In Modern Heterocyclic Chemistry, 1st ed.;
AlzerezꢀBuilla, J., Vaquero, J. J., Barluenga, J., Eds.; WileyꢀVCH; Weinheim, 2011; Vol. 1, pp 163ꢀ268.
(c) Bott, T. M.; West, F. G. Heterocycles 2012, 84, 223–264.
6 (a) Ghorai, M. K.; Das, K.; Kumar, A. Tetrahedron Lett. 2007, 48, 2471–2475. (b) Martínez, R. F.;
Fleet, G. W. J. Tetrahedron: Asymmetry 2014, 25, 373–380. (c) Hodgson, D. M.; Mortimer, C. L.;
McKenna, J. M. Org. Lett. 2015, 17, 330–333. (d) Jensen, K. L.; Nielsen, D .U.; Jamison, T. F. Chem.
Eur. J. 2015, 21, 7379–7383. (e) Kapoor, R.; Chawla, R.; Singh, S.; Yadav. L.D.S. Synlett 2012, 23,
1321–1326. (f) He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012, 134, 3–6.
7 The listed prices for this material are prohibitively expensive. (S)ꢀ2ꢀmethylazetidine HCl: 1 g/$1995
from a single vendor. Prices generally range $300ꢀ$1000 for 1 g of racemic 2ꢀmethylazetidine HCl.
8 (a) Vaughn, W. R.; Klonowski, R. S.; McElhinney, R. S.; Millward, B. B. J. Org. Chem. 1961, 26, 138–
144. (b) Malik, S.; Nadir, U. K. Synlett 2008, 1, 0108–0110. (c) Kenis, S.; D’hooghe, M.; Verniest, G.;
Anh Dang Thi, T.; Pham The, C.; Van Nguyes, T. V.; De Kimpe, N. J. Org. Chem. 2012, 77, 5982–5992.
(d) Drouillat, B.; d’Aboville, E.; Bourdreux, F.; Couty, F. Eur. J. Org. Chem. 2014, 1103–1109. (e)
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51, 7380–7395. (f) Nadir, U. K.; Sharma, R. L.; Koul, V. K. J. Chem. Soc., Perkin Trans. 1 1991, 2015–
2019.
9 The reported methods for accessing racemic 2ꢀmethylazetidine are also generally not suitable for largeꢀ
scale application. Moreover, while the resolution of racemic Nꢀbenzyl 2ꢀmethylazetidine as a CSA or
tartaric acid salt has been reported, no experimental details were provided and the material loss inherent
to this process was undesirable, see: Miyamae, H.; Enomoto, K.; Tsuboyama, S.; Yajima, KI.; Sassa, M.;
Kobayashi, K. X-Ray Structure Analysis Online 2003, 19, 53–54.
10 (a) Cowart, M. D.; Ku, Y.ꢀY; Chang, S.ꢀJ.; Fernando, D. P.; Grieme, T. A.; Altenbach, R. J. Patent
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14 Partial epimerization during the SN2 displacement of a secondary alkyl triflate has been reported, see:
Raghuraman, A.; Xin, D.; Perez, L. M.; Burgess, K. J. Org. Chem. 2013, 78, 4823–4833.
15 A kilogramꢀscale preparation of azetidineꢀ3ꢀcarboxylic acid that uses a protocol similar to that
described by Hillier et al. and avoids column chromatography has been reported, however isolation in this
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B.; Zewge, D.; Song, Z. J.; Karady, S. Synth. Commun. 2003, 33, 3347–3353.
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16 The corresponding internal alkene was not detected in the crude 1H NMR spectrum.
17 This filtration step is necessary to remove impurities that inhibit the subsequent recrystallization. An
alternative procedure based on method A from Table 1 has been developed that obviates the need for plug
filtration, see the Experimental Section for details.
18 Determined by chiral SFC analysis, see supporting information.
19 Zhao, D.; Kuethe, J. T.; Journet, M.; Peng, Z.; Humphrey, G. R. J. Org. Chem. 2006, 71, 4336–4338.
20 Chu, W.; Zhang, J.; Zeng, C.; Rothfuss, J.; Tu, Z.; Chu, Y.; Reichert, D. E.; Welch, M. J.; Mach, R. H.
J. Med. Chem. 2005, 48, 7637–7647.
21 This material has previously been reported as a racemate, see: Paquette, L. E.; Freeman, J. P. J. Org.
Chem. 1970, 35, 2249–2253.
22 This material has previously been reported as a racemate, see: Kenis, S.; D’hooghe, M.; Verniest, G.;
Anh Dang Thi, T.; Pham The, C.; Van Nguyen, T.; De Kimpe, N. J. Org. Chem. 2012, 77, 5982–5992.
23 Determined through SFC analysis of the corresponding 3ꢀnitrophenylamide.
24 The antipode has been reported previously, see: Hodgson, D. M.; Kloesges, J. Angew. Chem. Int. Ed.
2010, 49, 2900–2903.
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