Photochemical Rearrangement of Chiral Oxaziridines in Continuous Flow: Application Toward the Scale-Up of a Chiral Bicyclic Lactam

Article abstract of DOI:10.1021/acs.oprd.6b00213

A method for synthesizing chiral lactams from chiral oxaziridines in continuous flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the oxaziridines using the Booker-Milburn flow system provides conversion to the chiral lactams in good yield and short residence times. Application of this chemistry toward the synthesis of a chiral bicyclic lactam is described.

Full text of DOI:10.1021/acs.oprd.6b00213

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Communication
The Photochemical Rearrangement of Chiral Oxaziridines in Continuous
Flow. Application Toward the Scale-Up of a Chiral Bicyclic Lactam
John E Cochran, and Nathan D. Waal
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00213 • Publication Date (Web): 30 Jun 2016
Downloaded from http://pubs.acs.org on June 30, 2016
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The Photochemical Rearrangement of Chiral
Oxaziridines in Continuous Flow. Application
Toward the ScaleꢀUp of a Chiral Bicyclic Lactam.
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John E. Cochran*, and Nathan Waal
Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, MA 02210, United States
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Table of Contents Graphic:
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ABSTRACT: A method for synthesizing chiral lactams from chiral oxaziridines in continuous
flow is described. The oxaziridines are readily available from cyclic ketones. Photolysis of the
oxaziridines using the BookerꢀMilburn flow system provides conversion to the chiral lactams in
good yield and short residence times. Application of this chemistry toward the synthesis of a
chiral bicyclic lactam is described.
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Keywords: oxaziridine, photolysis, continuous flow, bicyclic
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INTRODUCTION
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The conversion of cyclic ketones to ringꢀexpanded lactams can be readily accomplished using
the Schmidt1, or Beckmann2 rearrangements. On prochiral substrates however, the lack of
directional control over the nitrogen insertion affords both enantiomers of the product (Scheme
1).
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Schmidt Reaction
O
O
O
R
HN3
NH
HN
R
R
Beckmann rearrangement
OH
O
O
O
N
R
H2SO4
H2NOH
NH
HN
R
R
R
Scheme 1. Schmidt & Beckmann rearrangements of prochiral ketones.
An interesting variant originally reported by Lattes3 and studied extensively by Aubé4,
involves a twoꢀstep sequence in which prochiral ketones are converted to chiral oxaziridines that
undergo a stereoselective photolytic rearrangement to produce the lactam as a single
diastereomer (Scheme 2).
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Lattes-Aubé Reaction
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Scheme 2. Photochemical conversion of spiroꢀoxaziridines to lactams.
The drawback to this method is the use of photolysis, a technique not commonly practiced by
most chemists, due in part to scaleꢀlimitations. Light penetration in a UV reactor falls off rapidly
with increasing distance from the lamp leading to nonꢀuniform irradiation of the reaction mixture
on a larger scale. This inefficiency can lead to long reaction times and product decomposition
from overꢀirradiation.5 A solution to this problem, first proposed years ago6, is to pump a
solution of substrate through UVꢀtransparent tubing that is wrapped around the quartz immersion
well of a typical UV reactor. The narrow diameter of the tubing leads to uniform irradiation of
the reaction. The BookerꢀMilburn group demonstrated the utility of this concept for scaleꢀup by
performing 2+2 and 5+2 cycloadditions in flow at a rate that could produce tens of grams of
product per day.7 They improved the efficiency of the original design by tripleꢀwrapping the
tubing around the UV reactor to maximize absorption of the photons generated. The Seeberger
group has used a similar setup to produce the antiꢀmalarial drug, artemisinin, in 200 g quantities
per day.8 Several other groups have also reported good results when performing photochemistry
in continuous flow using wrapped reactors.9
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Recently, we needed to convert a prochiral bicyclic ketone to a chiral bicyclic lactam as part of
our internal medicinal chemistry effort. The oxaziridine chemistry looked like an attractive
method for accomplishing this transformation although bicyclic ring systems are essentially
unknown as substrates for the LattesꢀAubé reaction.10 We were particularly interested in
performing the chemistry in continuous flow as this would allow it to be easily scaled upon
success. To test the feasibility of this approach, our plan was to synthesize several known
oxaziridines derived from prochiral monocyclic ketones and subject them to photolysis in a
wrapped UV reactor.
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SETUP & OPTIMIZATION
Several known oxaziridines4a,4e were synthesized using the conditions in Scheme 3. The
cyclohexanones formed the corresponding imines when refluxed with (S)ꢀαꢀmethylbenzylamine
in toluene with azeotropic removal of water using a DeanꢀStark apparatus. The diastereomeric
imines formed were not isolated but added as a toluene solution to a suspension of mCPBA in
toluene at ꢀ78°C to form the oxaziridines in diastereomeric ratios ranging from 1:1 to 6:1.
H2N
1)
O
R
N
R
O
toluene
major
diastereomer
2) mCPBA
toluene
Scheme 3. Synthesis of oxaziridines.
We assembled the simple flow chemistry setup shown in Figure 1 that was based on the
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BookerꢀMilburn research.7 The photochemical flow system consisted of the following
components11: a Syrris FRX HPLC pump (red module), a mediumꢀpressure 450 watt mercury
vapor lamp, a quartz immersion well, a power source (blue module) and fluorinated ethylene
propylene (FEP) tubing wrapped around the immersion well. The tubing and immersion well for
the lamp were wrapped with aluminum foil (not shown in picture) to avoid UV exposure.
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Figure 1. Flow photochemistry reaction setup.
With the oxaziridines in hand and the photochemical flow system assembled, we initially
explored the oxaziridine derived from 4ꢀtꢀBuꢀcyclohexanone, as this was readily isolated as a
solid. This made it possible to cleanly isolate the major diastereomer by recrystallizing the 5:1
mixture obtained in the oxidation. The relative stereochemistry of this diastereomer was
confirmed through Xꢀray crystallography (Figure 2).
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Figure 2. Oxaziridine diastereomer 3 from 4ꢀtꢀBuꢀcyclohexanone and (S)ꢀαꢀ
methylbenzylamine.
We proceeded to optimize several photolysis parameters such as the solvent choice,
temperature, UV filters, concentration, flow rate, and residence time. Aubé reported the best
results were obtained in cyclohexane and acetonitrile.4a We found that performing the reaction
in cyclohexane led to various levels of decomposition of both the compound and the tubing
depending on the reaction conditions. The decomposition products precipitated in the lines as an
orangeꢀbrown solid that blocked the transmittance of UV light leading to reduced yields of
product. Changing the solvent to acetonitrile minimized the decomposition.
Initially, water was run through the immersion well to cool the reaction but this proved to be
insufficient. The high temperatures that resulted led to substantial decomposition of both the
substrate and eventually the tubing. Since we were not running the system under backpressure
regulation, the higher temperatures led to gas bubbles in the lines caused by solvent vaporizing.
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While a commercial chiller would have sufficed for solving this problem, a simple, inexpensive
solution was to augment the waterꢀcooling with a stream of cooled nitrogen running into a
Dewar flask that surrounded the immersion well. 11 The Dewar flask had the added advantage of
blocking extraneous UV light. The flow of nitrogen was maintained at a rate that easily kept the
outside of the reactor at room temperature.
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When investigating wavelength, a Vycor filter (ca. 220 nm UV cutoff) around the lamp
resulted in a significantly slower reaction than when using the full UV spectrum. After
investigating several concentrations and residence times, the best results were obtained with
more dilute solutions (0.1M) and by tripleꢀwrapping the reactor in FEP tubing to maximize
exposure of the substrate to the UV light.7 It should be noted that during our exploration of the
system, we successfully ran very concentrated solutions and very high flow rates through this
system that in theory equaled 7 kg/day of oxaziridine! However, the yields suffered somewhat
during these runs, partially due to decomposition that precipitated in the tubing, so we elected to
use more dilute solutions of oxaziridine.
RESULTS AND DISCUSSION
At this point, the level of optimization was sufficient to explore the photolytic conversion of
the remaining oxaziridines that we had made to their corresponding lactams. Table 1
summarizes the data and compares the product yields from our flow experiments to the yields
reported in batch by Aubé. As can be seen from the data, the yields for the 3ꢀ and 4ꢀsubstituted
cyclohexyl systems (oxaziridines 1ꢀ8) are comparable if not better than the previously reported
results in batch. Substitution at the 2ꢀposition of the cyclohexyl system led to reduced yields of
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the corresponding lactam although the yield was improved over the reported batch results. What
is most striking is the greatly reduced time required to perform the reaction in continuous flow.
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Batch
Isomer Flow
% yield
Oxaziridine R2
R3
R4
ratio % yielda & time (hr)4a
H
H
H
H
Me
Et
4:1
5:1
pure
5:1
3:1
1:1
pure
5:1
6:1
4:3
83
77
82
81
72
63
74
72
54
76
77 (4)
76 (7)
70 (6)
87 (2)
74 (5)
80 (9.5)
70 (6)
78
1
2
H
H
tꢀBu (S)
Ph
3
H
H
4
H
H
OBn
CO2Et
tꢀBu (R)
H
5
H
H
6
H
H
7
H
Me
H
8
OMe
Me
H
50
9
H
H
57
10
a 0.1M in MeCN @ 5 mL/min flow rate; tubing volume = 130 mL; residence time = 26 min; 1 g scale;
isolated yields are reported.
Table 1. Results for the photolytic conversion of oxaziridines to lactams.
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In our hands, the same scale reaction that reportedly took several hours in batch, took less than
30 minutes in our flow system. This is probably due in part to using the full UV spectrum rather
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than the specific wavelength of 254 nm used by Aubé. To demonstrate the potential of this
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system for scaleꢀup, we ran oxaziridine 3 (R = tꢀBu) through the system on a 20 g scale obtaining
the desired lactam in >80% yield.
The Xꢀray structure of the lactam diastereomer obtained from the photolytic rearrangement of
3 was consistent with the expected structure and with the results previously reported (Figure 3).4a
Figure 3. Lactam diastereomer from the photolysis of the tꢀBu oxaziridine 3.
After successfully demonstrating that the LattesꢀAubé reaction could be run in continuous
flow, we turned our attention to the transformation of interest. The original route to the chiral
amine 11 (Scheme 4) suffered from low yields including the classical resolution that was
required in the end. Also, the generation of hydrazoic acid in the first step was a potential safety
hazard that we wanted to avoid. The lack of a strong chromophore in each step presented an
additional challenge.
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NaN3
H2SO4
DCM
O
O
O
O
H
H
H
H
N
N
N
N
LAH
55%
O
O
O
O
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45%
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Classical
resolution
25%
NH
O
11
Scheme 4. Original route for the preparation of chiral bicyclic lactam 11.
We proposed a short, fourꢀstep asymmetric route to 11 (Scheme 5) using the LattesꢀAubé
chemistry. The plan was to convert the ketone to a chiral oxaziridine in analogous fashion to the
monocyclic ketones explored earlier. We postulated that (R)ꢀαꢀmethylbenzylamine was needed
to form the oxaziridine that would give lactam 13 after photolysis.12 Reduction of the lactam
followed by removal of the benzyl group would afford 11. This route provided the additional
advantages of having a strong chromophore at each step and it avoided the dangerous hydrazoic
acid used in the original route.
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N
O
Ph
O
Ph
O
O
Ph
O
N
N
hv
O
O
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12
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H
N
O
11
Scheme 5. Proposed synthesis of chiral bicyclic lactam 11.
The commercially available bicyclic ketone 12 was converted to the corresponding oxaziridine
13 (Figure 4) in 51% yield as a single diastereomer. Photolysis of 80 g of 13 as a 0.1M solution
in CH3CN proceeded at a slower rate than the oxaziridines shown in Table 1. After one pass
through the system at the same flow rate of 5 mL/min (tR = 26 min), there was a significant
amount of starting material remaining. However, this material was easily separated from the
product by column chromatography to provide over 40 g of the chiral lactam 14 in 51% yield
(99% yield based on recovered starting material). Borane reduction and debenzylation of 14
proceeded in 82% and 86% respectively to afford the desired chiral amine 11. The
stereochemistry of the amine was confirmed by comparing its optical rotation to an authentic
sample. Due to shifting priorities, all further work toward scaling this compound in flow was
abandoned. However, this method was clearly viable for making the chiral bicyclic amine onꢀ
scale with some additional optimization.
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Figure 4. Oxaziridine diastereomer 13 from 8ꢀoxabicyclo[3.2.1]octanꢀ3ꢀone and (R)ꢀαꢀ
methylbenzylamine
In summary, we have demonstrated the LattesꢀAubé reaction in continuous flow. The yields
are the same or higher than in batch and the reactions are completed in a fraction of the time.
We have demonstrated the rare application of this chemistry to a bicyclic system and have shown
the potential utility for performing this type of photochemical reaction onꢀscale.
EXPERIMENTAL SECTION
All reagents and solvents were purchased from the Aldrich Chemical company and used as
obtained. The 450ꢀwatt mediumꢀpressure UV lamp and the 290 mm immersion well were
obtained from Ace Glass. Analytical thin layer chromatography (TLC) was performed on
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percolated silica gel 60 F254 plates and visualized with UV light (254 nm) or KMnO4 stain. H
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NMR spectra were recorded on a 300 MHz Bruker AVANCE spectrometer. H NMR chemical
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shifts are quoted in parts per million (ppm) referenced to 0.0 ppm for tetramethylsilane. C
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NMR spectra were recorded at 75 MHz and chemical shifts were reported in ppm referenced to
the centerline of a triplet at 77.0 ppm of CDCl3 or a heptet at 39.5 ppm of DMSOꢀd6. LC/MS
data were obtained with a Waters ACQUITY equipped with a QDa mass detector. The UPLC
separations were obtained from a C18 column using an elution gradient of 5ꢀ95% CH3CN/H2O
with 1% TFA. Optical rotations were performed on a Rudolph Autopol III polarimeter. Melting
points were obtained on a MettlerꢀToledo (DSC1) differential scanning calorimeter. Fluorinated
ethylene propylene (FEP) tubing was purchased from E&S Technologies in Chelmsford, MA.
Column chromatography was performed using SiliaSep normal phase silica (230ꢀ400 mesh)
cartridges on a Teledyne ISCO Torrent purification system. The oxaziridines 1-8 in Table 1
were synthesized according to the procedures previously reported4a and are further exemplified
in the synthesis of the oxaziridine 3 described below. Oxaziridines 9 & 10 in Table 1 were also
synthesized according to previously reported procedures.4e All characterization data for the
oxaziridines were in agreement with the previously reported values.4a, 4e
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(1R,3r,5S)-2'-((S)-1-phenylethyl)-8-oxaspiro[bicyclo[3.2.1]octane-3,3'-[1,2]oxaziridine] (13).
A solution of 8ꢀoxabicyclo[3.2.1]octanꢀ3ꢀone (12) (10.34 g, 81.96 mmol) and (1R)ꢀ1ꢀ
phenylethanamine (15.6 mL, 123 mmol) in toluene (200 mL) was refluxed for 4 hours in a 500
mL RB flask equipped with a Dean Stark trap and condenser. Approximately 1.5 mL of water
was collected in the trap. The imine solution was cooled to room temperature and added
dropwise under nitrogen to a ꢀ78°C suspension of mCPBA (17.0 g, 99 mmol) in toluene (300
mL). After complete addition (~45 min), the reaction was stirred at ꢀ78°C for an additional 30
minutes. The reaction was quenched at ꢀ78°C by the addition of 1 M Na2S2O3 (~250 mL)
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followed by warm water (250 mL), and the product was extracted using 1L of Et2O. The organic
layer was washed with saturated NaHCO3 solution (250 mL) followed by brine (250 mL), then
concentrated to dryness and purified via silica gel chromatography (220 g ISCO column) eluting
with 0ꢀ30% EtOAc in heptane over 40 minutes. Fractions containing desired product were
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combined and concentrated to afford 11.03 of (13) as a light orange oil. H NMR (300 MHz,
CDCl3) δ 7.48 – 7.40 (m, 2H), 7.39 – 7.27 (m, 3H), 4.44 – 4.35 (m, 1H), 4.33 – 4.24 (m, 1H),
3.48 (q, J = 6.3 Hz, 1H), 2.33 (ddd, J = 12.9, 4.5, 3.5 Hz, 2H), 1.89 (d, J = 14.8 Hz, 1H), 1.71 –
1.60 (m, 1H), 1.55 (t, J = 4.2 Hz, 3H), 1.54 – 1.47 (m, 1H), 1.42 – 1.29 (m, 2H), 0.32 (ddd, J =
11.1, 6.9, 3.4 Hz, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 141.0, 128.8, 128.1, 127.1, 82.0, 73.9,
73.3, 63.3, 43.0, 27.7, 27.6, 24.4 ppm.
General Procedure for Photolysis.
The photochemical flow reactor reported by the BookerꢀMilburn group was assembled by
tripleꢀwrapping 90 ft of 1/8ꢀinch (0.095” I.D.) FEP tubing around a 290 mm quartz immersion
well that housed a 450ꢀwatt mediumꢀpressure UV lamp. The tubing was connected to a Syrris
FRX HPLC pump. A 0.1M solution of the oxaziridine in CH3CN was pumped at 5 mL/min (tR =
26 min) through the photochemistry setup (further described in the supplementary material) and
into a collection flask. The solution was evaporated and the resulting material chromatographed.
(5S)-5-methyl-1- [(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 1, major isomer)
1H NMR (300 MHz, CDCl3) δ 7.33 – 7.20 (m, 5H), 6.05 (q, J = 7.1 Hz, 1H), 3.04 – 2.90 (m,
2H), 2.67 – 2.50 (m, 2H), 1.88 – 1.70 (m, 2H), 1.63 – 1.53 (m, 1H), 1.52 – 1.43 (m, 3H), 1.31 –
1.03 (m, 2H), 0.96 – 0.88 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.20, 141.04, 128.30,
127.03, 50.44, 42.75, 37.84, 36.29, 36.27, 31.51, 22.68, 16.37 ppm. LC/MS m/z 232.17.
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[α]23.2D = ꢀ133.102 (c = 2.811, 281.1 mg in 10 mL MeOH).
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(5R)-5-methyl-1- [(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 1, minor isomer)
1H NMR (300 MHz, CDCl3) δ 7.38 ꢀ 7.23 (m, 5H), 6.05 (q, J = 7.0 Hz, 1H), 3.20 ꢀ 3.05 (m, 2H),
2.70 ꢀ 2.57 (m, 1H), 2.57 ꢀ 2.42 (m, 1H), 1.85 ꢀ 1.74 (m, 1H), 1.62 ꢀ 1.21 (m, 6H), 0.82 (t, J = 7.7
Hz, 3H), 0.62 ꢀ 0.41 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.37, 140.63, 128.28,
127.82, 127.32, 50.59, 42.00, 36.56, 36.37, 35.84, 31.28, 22.36, 15.64 ppm.
LC/MS m/z 232.17. [α]19.8D = ꢀ152.574 (c = 0.68, 68 mg in 10 mL MeOH).
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(5S)-5-ethyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 2, major isomer)
1H NMR (300 MHz, CDCl3) δ 7.37 ꢀ 7.21 (m, 5H), 6.03 (q, J = 7.1 Hz, 1H), 3.09 ꢀ 2.90 (m, 2H),
2.70 ꢀ 2.46 (m, 2H), 1.94 ꢀ 1.75 (m, 2H), 1.47 (d, J = 7.3 Hz, 3H), 1.36 ꢀ 1.17 (m, 4H), 1.10 ꢀ
0.97 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.45, 141.16,
128.37, 127.16, 127.10, 50.54, 42.99, 42.86, 36.29, 35.58, 29.66, 29.27, 16.44, 11.35 ppm.
LC/MS m/z 246.16. [α] 20.1D = ꢀ110.371 (c = 3.58, 358 mg in 10 mL MeOH).
(5R)-5-ethyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 2, minor isomer)
1H NMR (300 MHz, CDCl3) δ 7.41 ꢀ 7.22 (m, 5H), 6.04 (q, J = 7.0 Hz, 1H), 3.24 ꢀ 2.99 (m, 2H),
2.72 ꢀ 2.57 (m, 1H), 2.57 ꢀ 2.40 (m, 1H), 1.92 ꢀ 1.76 (m, 1H), 1.53 ꢀ 1.37 (m, 4H), 1.33 ꢀ 1.07 (m,
4H), 0.83 ꢀ 0.70 (m, 3H), 0.61 ꢀ 0.40 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.44,
140.66, 128.27, 127.81, 127.31, 50.56, 42.46, 42.03, 36.31, 34.23, 29.22, 28.93, 15.62, 11.28
ppm. LC/MS m/z 246.16. [α]20.4D = ꢀ106.931 (c=0.88, 88 mg in 10 mL MeOH).
(5S)-5-t-butyl-1- [(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 3)
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1H NMR (300 MHz, CDCl3) δ 7.38 ꢀ 7.24 (m, 5H), 6.05 (q, J = 7.1 Hz, 1H), 3.20 ꢀ 2.90 (m, 2H),
2.76 ꢀ 2.62 (m, 1H), 2.60 ꢀ 2.42 (m, 1H), 2.10 ꢀ 1.85 (m, 2H), 1.58 ꢀ 1.45 (m, 3H), 1.32 ꢀ 1.05 (m,
3H), 0.91 ꢀ 0.82 (m, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.50, 141.16, 128.38, 127.16,
127.12, 51.60, 50.50, 43.25, 36.57, 33.01, 30.61, 27.55, 24.26, 16.50 ppm. LC/MS m/z 274.2
[α] 22.9 D = ꢀ106.809 (c = 1.028, 102.8 mg in 10 mL MeOH). mp 96°C.
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(5S)-5-phenyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 4, major isomer)
1H NMR (300 MHz, CDCl3) δ 7.36 ꢀ 7.17 (m, 10H), 6.15 (q, J = 7.1 Hz, 1H), 3.12 (dd, J = 12.2,
8.4 Hz, 2H), 2.80 ꢀ 2.65 (m, 3H), 2.16 ꢀ 1.72 (m, 4H), 1.61 ꢀ 1.54 (m, 3H) ppm. 13C NMR (75
MHz, CDCl3) δ 175.07, 146.13, 141.07, 128.66, 128.53, 127.28, 127.19, 126.73, 126.58, 50.74,
48.22, 43.16, 37.55, 36.79, 30.84, 16.63 ppm. LC/MS m/z 294.13. [α]19.9D = ꢀ49.673 (c = 1.069,
106.9 mg in 10 mL MeOH).
(5R)-5-phenyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 4, minor isomer)
1H NMR (300 MHz, CDCl3) δ 7.43 ꢀ 7.16 (m, 8H), 7.04 (dd, J = 5.2, 3.3 Hz, 2H), 6.15 (q, J = 7.0
Hz, 1H), 3.38 ꢀ 3.18 (m, 2H), 2.85 ꢀ 2.57 (m, 3H), 2.09 ꢀ 1.94 (m, 1H), 1.84 ꢀ 1.56 (m, 2H), 1.53
(dd, J = 9.4, 4.5 Hz, 3H), 1.02 ꢀ 0.86 (m, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.03,
146.10, 140.57, 128.53, 128.42, 127.90, 127.58, 126.62, 126.41, 50.71, 47.93, 42.40, 36.98,
35.99, 30.68, 15.61 ppm. LC/MS m/z 294.13. [α]20.3 = ꢀ141.156 (c = 0.917 , 91.7 mg in 10
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mL MeOH).
(5S)-5-benzyloxy-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 5, major isomer)
1H NMR (300 MHz, CDCl3) δ 7.37 ꢀ 7.23 (m, 10H), 6.08 (q, J = 7.0 Hz, 1H), 4.54 ꢀ 4.41 (m,
2H), 3.66 (d, J = 3.6 Hz, 1H), 3.47 ꢀ 3.34 (m, 1H), 2.97 (dd, J = 19.0, 7.5 Hz, 1H), 2.90 ꢀ 2.78
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(m, 1H), 2.40 (ddd, J = 14.2, 8.4, 2.0 Hz, 1H), 2.05 ꢀ 1.86 (m, 2H), 1.75 ꢀ 1.55 (m, 2H), 1.50 (d, J
= 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.31, 140.76, 138.51, 128.47, 128.41,
127.60, 127.40, 127.36, 127.30, 69.99, 50.64, 37.90, 34.10, 31.16, 28.09, 16.31 ppm.
LC/MS m/z 324.15. [α]22.8D = ꢀ 80.919 (c = 1.132, 113.2 mg in 10 mL MeOH).
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(5R)-5-benzyloxy-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 5, minor isomer)
1H NMR (300 MHz, CDCl3) δ 7.37 ꢀ 7.28 (m, 10H), 6.07 (q, J = 7.1 Hz, 1H), 4.48 (t, J = 8.1 Hz,
2H), 3.60 ꢀ 3.47 (m, 1H), 3.39 (dd, J = 15.3, 9.3 Hz, 1H), 2.99 ꢀ 2.80 (m, 2H), 2.46 ꢀ 2.36 (m,
1H), 2.13 ꢀ 1.87 (m, 3H), 1.54 ꢀ 1.43 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.14,
140.82, 138.53, 128.43, 127.62, 127.54, 127.43, 127.37, 70.01, 50.65, 38.03, 33.94, 31.36, 28.19,
15.87 ppm. LC/MS m/z 324.15. [α]22.8D = ꢀ44.908 (c = 2.82, 282 mg in 10 mL MeOH).
Ethyl (4S)-7-oxo-1-[(1S)-1-phenylethyl]azepane-4-carboxylate (Table 1, entry 6, major
isomer)
1H NMR (300 MHz, CDCl3) δ 7.36 ꢀ 7.25 (m, 5H), 6.05 (q, J = 7.1 Hz, 1H), 4.18 ꢀ 4.10 (m, 2H),
3.17 (ddd, J = 15.7, 7.1, 1.5 Hz, 1H), 3.02 (dd, J = 15.3, 9.6 Hz, 1H), 2.79 ꢀ 2.66 (m, 1H), 2.63 ꢀ
2.44 (m, 2H), 2.12 (ddt, J = 18.2, 11.7, 4.8 Hz, 1H), 1.97 ꢀ 1.76 (m, 2H), 1.68 ꢀ 1.56 (m, 1H),
1.50 (t, J = 6.3 Hz, 3H), 1.29 ꢀ 1.23 (m, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 174.56, 174.34,
140.73, 128.43, 127.28, 127.22, 60.60, 50.69, 45.74, 41.58, 35.32, 31.57, 25.62, 16.22, 14.16
ppm. LC/MS m/z 290.13. [α] 22.5D = ꢀ70.259 (c = 1.043, 104.3 mg in 10 mL MeOH).
Ethyl (4R)-7-oxo-1-[(1S)-1-phenylethyl]azepane-4-carboxylate (Table 1, entry 6, minor
isomer)
1H NMR (300 MHz, CDCl3) δ 7.33 ꢀ 7.20 (m, 5H), 5.99 (q, J = 7.0 Hz, 1H), 4.09 ꢀ 3.98 (m, 2H),
3.17 (ddd, J = 15.5, 7.6, 1.8 Hz, 1H), 3.05 (ddd, J = 23.7, 13.2, 5.3 Hz, 1H), 2.69 (ddd, J = 14.4,
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9.1, 1.6 Hz, 1H), 2.56 ꢀ 2.39 (m, 2H), 2.07 ꢀ 1.94 (m, 1H), 1.89 ꢀ 1.75 (m, 1H), 1.69 ꢀ 1.57 (m,
1H), 1.43 (d, J = 7.1 Hz, 3H), 1.32 ꢀ 1.21 (m, 1H), 1.16 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75
MHz, CDCl3) δ 174.65, 174.22, 140.32, 128.42, 127.56, 127.41, 60.50, 50.75, 45.04, 41.13,
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35.27, 30.88, 25.28, 15.82, 14.11 ppm. LC/MS m/z 290.08. [α]22.7 = ꢀ81.243 (c = 3.041,
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304.1mg in 10 mL MeOH).
(5R)-5-t-butyl-1-[(1R)-1-phenylethyl]azepan-2-one (Table 1, entry 7)
1H NMR (300 MHz, CDCl3) δ 7.17 ꢀ 7.04 (m, 5H), 5.86 (q, J = 7.1 Hz, 1H), 2.97 ꢀ 2.71 (m, 2H),
2.48 (ddd, J = 7.7, 6.4, 3.9 Hz, 1H), 2.40 ꢀ 2.21 (m, 1H), 1.88 ꢀ 1.65 (m, 2H), 1.37 ꢀ 1.29 (m,
3H), 1.15 ꢀ 0.89 (m, 3H), 0.67 (d, J = 5.8 Hz, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 175.36,
141.10, 128.34, 127.09, 51.48, 50.44, 43.16, 36.50, 32.95, 30.57, 27.52, 27.44, 24.22, 16.47
ppm. LC/MS m/z 274.2. [α]22.6D = 102.739 (c = 1.132 , 113.2 mg in 10 mL MeOH).
(4R)-4-methyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 8, major isomer)
1H NMR (300 MHz, CDCl3) δ 7.38 ꢀ 7.23 (m, 5H), 6.08 (q, J = 7.1 Hz, 1H), 3.15 ꢀ 3.02 (m, 2H),
2.62 ꢀ 2.42 (m, 2H), 1.85 (tdd, J = 9.6, 7.4, 2.3 Hz, 1H), 1.76 ꢀ 1.63 (m, 1H), 1.55 ꢀ 1.36 (m, 4H),
1.26 (ddd, J = 9.6, 6.4, 2.7 Hz, 1H), 1.09 ꢀ 0.90 (m, 4H) ppm. 13C NMR (75 MHz, CDCl3) δ
175.55, 141.18, 128.39, 127.11, 50.57, 50.45, 38.76, 37.31, 35.25, 23.38, 20.51, 16.59 ppm.
LC/MS m/z 232.17. [α]23.0D = ꢀ 184.170 (c = 1.012, 101.2 mg in 10 mL MeOH).
(6R)-6-methyl-1-[(1S)-1-phenylethyl]azepan-2-one (Table 1, entry 15)
1H NMR (300 MHz, CDCl3) δ 7.39 ꢀ 7.22 (m, 5H), 6.06 (q, J = 7.1 Hz, 1H), 2.93 ꢀ 2.69 (m, 2H),
2.67 ꢀ 2.46 (m, 2H), 1.88 (ddd, J = 19.4, 14.2, 7.4 Hz, 2H), 1.68 ꢀ 1.45 (m, 5H), 1.20 ꢀ 1.09 (m,
1H), 0.84 (d, J = 6.9 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 174.27, 140.83, 128.30,
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127.70, 127.27, 50.55, 44.98, 43.24, 38.12, 29.09, 27.29, 22.38, 15.77 ppm.
LC/MS m/z 232.17. [α]23.2D = ꢀ 156.957 (c = 0.999, 99.9 mg in 10 mL MeOH).
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(1S,6R)-3-((S)-1-phenylethyl)-9-oxa-3-azabicyclo[4.2.1]nonan-4-one (14)
1H NMR (300 MHz, CDCl3) δ 7.29 (dddd, J = 15.5, 7.3, 5.0, 1.2 Hz, 5H), 6.18 – 6.04 (m, 1H),
4.38 (tt, J = 9.0, 7.7 Hz, 2H), 3.14 (d, J = 15.7 Hz, 1H), 2.92 – 2.75 (m, 3H), 2.11 – 1.82 (m,
4H), 1.50 (d, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ 173.59, 140.25, 128.53,
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127.37, 127.21, 75.61, 72.25, 51.03, 50.50, 50.44, 47.88, 28.75, 26.44, 16.01 ppm. [α]
160.2° (c = 1, 100 mg / 10 mL MeOH).
=
D
(1S,6R)-3-((S)-1-phenylethyl)-9-oxa-3-azabicyclo[4.2.1]nonane (15)
To a solution of (1R,6S)ꢀ4ꢀ[(1R)ꢀ1ꢀphenylethyl]ꢀ9ꢀoxaꢀ4ꢀazabicyclo[4.2.1]nonanꢀ3ꢀone 4 (29.6 g,
120.7 mmol) in THF (300 mL) under nitrogen was added dropwise BH3ꢀTHF (240 mL of 1 M,
240 mmol) in THF. The reaction was refluxed for 5.5 hours. The reaction was cooled to room
temperature and the mixture was brought to pH 1 by carefully adding 20 mL of 6N aqueous HCl
over 5 minutes. The solution was stirred for 1 hour, diluted with 200 mL water, and stirred for an
additional hour. The solution was brought to pH 8 with saturated aqueous NaHCO3 and then
extracted thrice with EtOAc. The combined organics were dried (MgSO4), filtered, and
evaporated in vacuo to afford 27.6 g of a light yellow oil. The material was chromatographed on
a 120 g ISCO silica gel column (0ꢀ25% EtOAc/heptane) to afford 23.0 g (82%) of 5 as a
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colorless oil. H NMR (300 MHz, CDCl3) δ 7.44 – 7.24 (m, 5H), 4.45 (t, J = 8.4 Hz, 1H), 4.38 –
4.28 (m, 1H), 3.85 – 3.74 (m, 1H), 2.77 (ddd, J = 19.5, 8.8, 4.1 Hz, 1H), 2.58 (dd, J = 10.6, 3.4
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Hz, 2H), 2.43 – 2.28 (m, 1H), 2.23 – 2.06 (m, 1H), 2.02 – 1.84 (m, 4H), 1.44 – 1.29 (m, 4H)
ppm. [α] 19.2 D = 25.683 (c = 0.989, 98.9 mg in 10 mL MeOH).
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(1S,6R)-9-oxa-3-azabicyclo[4.2.1]nonane (11)
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To a suspension of (1R,6S)ꢀ4ꢀ[(1R)ꢀ1ꢀphenylethyl]ꢀ9ꢀoxaꢀ4ꢀazabicyclo[4.2.1]nonane (6 g,
25.9 mmol) and 10% Pd/C (wet, Degussaꢀtype, 2.1 g, 2.01 mmol) in EtOH (90 mL) was added
HCl (7.1 mL of 4 M, 28.4 mmol) in dioxane . The reaction was shaken for three hours under 50
psi hydrogen on a Parr shaker. LCMS shows some remaining benzylamine. The reaction was
shaken under 50 psi of H2 overnight. The mixture was filtered over Celite, washed with EtOH
then EtOAc, and the filtrate was concentrated to give a white solid. The product was taken up in
minimal MeOH and dropped into diethyl ether while stirring vigorously. The resulting white
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solid was filtered and dried to give 3.86 g (86%) of 11 as a white solid. H NMR (300 MHz,
CDCl3) δ 9.88 (s, 1H), 9.34 (s, 1H), 4.71 ꢀ 4.31 (m, 2H), 3.56 ꢀ 2.88 (m, 4H), 2.49 ꢀ 1.70 (m, 6H)
ppm. ESIꢀMS found 128.0 (M+1) +. [α] 22.0 D = ꢀ10.88 (c = 0.92, 92 mg in 10 mL MeOH).
SUPPORTING INFORMATION
Continuous flow photochemical reactor setup and Xꢀray crystallographic information for
oxaziridines 3 & 13, and the lactam derived from 3. This information is available free of charge
via the internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: john_cochran@vrtx.com
Present address
50 Northern Avenue, Boston, MA 02210
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We would like to thank Dr. Curtis Moore at the UCSD Crystallography Lab for his assistance in
solving the Xꢀray structures of the oxaziridines and lactam. We would also like to thank Ron
Grey for supplying analytical standards for this work.
REFERENCES
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(11) See supplementary material for more information.
(12) The expected stereochemical outcomes for oxaziridine formation and rearrangement
upon photolysis are discussed in references 3 and 4.
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