A practical and scaleable synthesis of 1r,5s-bicyclo[3.1.0]hexan-2-one: The development of a catalytic lithium 2,2,6,6-tetramethylpiperidide (LTMP) mediated intramolecular cyclopropanation of (R)-1,2-epoxyhex-5-ene

Article abstract of DOI:10.1021/op700042w

An efficient synthesis of 1R,5S-bicyclo[3.1.0]hexan-2-one from (R)-1,2-epoxyhex-5-ene is described. Development of a catalytic intramolecular cyclopropanation of (R)-1,2-epoxyhex-5-ene gives the key homochiral bicycle[3.1.0]hexan-1-ol, which is then oxidized to the desired ketone. This process has been successfully demonstrated on a multi-kilogram scale.

Full text of DOI:10.1021/op700042w

Organic Process Research & Development 2007, 11, 637−641
A Practical and Scaleable Synthesis of 1R,5S-Bicyclo[3.1.0]hexan-2-one: The
Development of a Catalytic Lithium 2,2,6,6-Tetramethylpiperidide (LTMP)
Mediated Intramolecular Cyclopropanation of (R)-1,2-Epoxyhex-5-ene
Anthony D. Alorati, Matthew M. Bio, Karel M. J. Brands, Ed Cleator,* Antony J. Davies, Robert D. Wilson, and
Chris S. Wise
Department of Process Research, Merck Sharp & Dohme, Hertford Road, Hoddesdon, EN11 9BU, UK
Abstract:
An efficient synthesis of 1R,5S-bicyclo[3.1.0]hexan-2-one from
(R)-1,2-epoxyhex-5-ene is described. Development of a catalytic
intramolecular cyclopropanation of (R)-1,2-epoxyhex-5-ene gives
the key homochiral bicycle[3.1.0]hexan-1-ol, which is then
oxidized to the desired ketone. This process has been success-
Figure 1. 1R,5S-Bicyclo[3.1.0]hexan-2-one 1.
fully demonstrated on a multi-kilogram scale.
approach to generate 1 from cyclopent-2-en-1-one.6,7 This
approach, however, requires extended reaction times for
Introduction
formation of the acetal substrate and affords modest yields
for the key cyclopropanation event, even though the dias-
tereoselectivty is generally quite good (dr up to 13:1). There
has also been considerable effort in the synthetic community
evaluating metal-catalyzed cyclopropanations of suitably
functionalized R-diazoketones. Rhodium8 and copper9 based
chiral catalysts have been employed, with the rhodium
systems giving marginally higher enantioselectivities (87 vs
77% ee, respectively) and much better yields (96 vs 54%,
respectively). However, these methods are not economically
viable on a larger scale due to the high costs for the catalysts,
and these were thus not considered.
The cyclopropyl group is a common moiety which appears
in a number of natural products and pharmaceutically active
compounds.1 In many cases this function appears in the form
of a fused bicycle, and there is often the requirement for
such bicycles to be enantiopure. A short and scalable method
to generate these intermediates, in an enantiopure fashion
and containing functionality for further elaboration, would
therefore be desirable. Whilst there are a number of methods
for generating 1,1′,5-trisubstituted bicyclic-2-ketones,2 there
are far fewer examples for obtaining the enantiopure 1,5-
disubstituted fused systems.3 During the course of an ongoing
project we required multi-kilogram quantities of 1R,5S-
bicyclo[3.1.0]hexan-1-one 1 (Figure 1). This compound is
not available from commercial sources in either racemic or
enantiopure form.
Previous syntheses of 1 have generally been performed
in a racemic fashion. One of the most direct transformations
involves the reaction of trimethylsulfoxonium ylide with
cyclopent-2-en-1-one.4 Whilst this reaction was found to
afford an excellent 92% yield when performed in the racemic
sense, a chiral variant of this reaction is unknown. Another
common method of cyclopropanation is the Simmons-Smith
reaction. It has been shown that the alcohol function in
cyclopent-2-en-1-ol is able to direct this reaction such that
syn-products are formed exclusively.5 Unfortunately, the lack
of an efficient route to the chiral starting material rendered
a Simmons-Smith/oxidation route to 1 unpractical. Mash
et al. have used a chiral auxiliary based Simmons-Smith
Results and Discussion
Work by Hodgson et al.10 has outlined an expedient and
highly diastereoselective synthesis of trans-bicyclo[3.1.0]hexan-
2-ols, including the synthesis of 1R,2R,5S-bicyclo[3.1.0]hexan-
2-ol 4, starting from enantiopure epoxy alkenes such as 2.
The proposed mechanism is that deprotonation of 2 with a
strong hindered base such as LTMP results in R-lithiation
of the epoxide. This deprotonation has been shown to occur
exclusively trans to the â-alkyl chain. Subsequent intramo-
lecular cyclization of the carbenoid intermediate occurs Via
the chair transition state 3 to provide 4 (Scheme 1). This
reaction was found to proceed with excellent retention of
enantiopurity.
The Hodgson group also reported on a further refinement
to the synthesis of trans-bicyclo[3.1.0]hexan-2-ols by gen-
erating the precursor epoxides in situ from chlorohydrin 6
(Scheme 2).11 The latter could be prepared by copper
catalysed ring opening of epichlorohydrin 5 with a suitable
* To whom correspondence should be addressed. E-mail: edward_cleator@
merck.com.
(1) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003,
103, 977.
(6) Mash, E. A.; Hempley, S. B.; Nelson, K. A.; Heidt, P. C.; Van Deusen, S.
J. Org. Chem. 1990, 55, 2045.
(7) Mash, E. A.; Hempley, S. B. J. Org. Chem. 1990, 55, 2055.
(8) Barberis, M.; Pe´rez-Prieto, J.; Salah-Eddine, S.; Lahuerta, P. Org. Lett. 2001,
3, 3317.
(2) (a) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S.
C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024. (b) Bremeyer, N.;
Ley. S. V.; Smith, S. C.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43,
2681.
(3) Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
(4) Newman-Evans, R. H.; Simon, R. J.; Carpenter, B. K. J. Org. Chem. 1990,
55, 695.
(9) Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H. P. Tetrahedron
Lett. 1990, 31, 6969.
(10) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. J. Am. Chem. Soc. 2004, 126,
8664.
(5) Friedrich, E. C.; Briesaw, G. J. Org. Chem. 1982, 47, 1615.
10.1021/op700042w CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/18/2007
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637

Scheme 1a
Table 1. Stress test of 4 with acids/buffers
entrya
acid/buffer
ratiob 7:4
1
2
3
4
5
6
7
6 M HCl
100:0
100:0
60:40
5:95
0:100
0:100
0:100
3 M HCl
1 M HCl
a Reagents and conditions: (a) 0.2 M LTMP in MTBE added to a 0.2 M
solution of 2 over 1 h at 0 °C and then warmed to rt over 16 h.
pH 4 buffer
acetic acid
citric acid
pH 7 buffer
Grignard reagent such as allylmagnesium chloride. A one-
pot ring closure and intramolecular cyclopropanation of 6
then proceeds to give 4. Whilst this protocol allows for the
synthesis of compounds such as 4, the yields for this two-
step sequence are lower than those for the direct cyclopro-
panation described in Scheme 1. Moreover, a total of 3.5
equiv of n-BuLi and 2.5 equiv of TMP are required.
a 1 mL of a 0.1 M MTBE solution of 4 aged overnight at room temperature
in the presence of 1 mL of the appropriate acid/buffer. bRatio determined by 1H
NMR.
though the instability of 4 can be modulated by lowering
the concentration of the acid (entry 3). Quenching the
reaction mixture with acetic acid led to the precipitation of
the TMP acetate. Dissolution of this solid required imprac-
tically large volumes of water, and due to the significant
water solubility of 4, numerous back extractions with MTBE
were required to recover the product with an acceptable yield.
An alternative procedure was to quench the reaction mixture
with a stoichiometric charge of acid to keep the effective
concentration of acid low and minimize the amount of water.
Thus, quenching the reaction mixture at 0 °C with 1 equiv
of 3 M HCl (with respect to the total amount of basic species
present) followed by a second wash with 1 equiv of 3 M
HCl (with respect to the amount of TMP charged) generated
an MTBE stream which was free of TMP and which was
sufficiently pure to be used without any further purification
in the next step. The product yield could be maximized via
a single back extraction with MTBE. This version of the
Hodgson’s procedure containing an optimized workup was
found to reproducibly afford 4 in 86% assay yield.
Our attention then turned to the optimization of the
cyclization reaction itself. The procedure described by
Hodgson et al. is performed at high dilutions, partly due to
the low solubility of LTMP in MTBE (this solvent is critical
for the success of this transformation), making this procedure
unworkable on a larger scale. We envisaged that this problem
could be solved by changing the order of addition of the
reactants. Towards this end, the stability of 2 in the presence
of 2.5 M n-BuLi at 0 °C was assessed. According to GC
analysis compounds 4, 9, and 10 were formed in an area
ratio of 3:67:40, respectively (Scheme 4).
Scheme 2a
a Reagents and conditions: (a) allylmagnesium chloride, CuI (0.1 equiv), THF,
-78 °C f 20 °C, 75%; (b) n-BuLi (3.5 equiv), TMP (2.5 equiv), MTBE, 0 °C
for 2 h then 20 °C for 16 h, 65%.
As (R)-1,2-epoxyhex-5-ene 2 is commercially available,
we decided to investigate the Hodgson methodology as a
potential route to 1. Initially, we repeated the original condi-
tions: namely, addition of a freshly prepared 0.2 M solution
of LTMP in methyl tert-butyl ether (MTBE) to a 0.2 M
solution of 2 in MTBE at 0 °C. After warming to ambient
temperature and aging for an additional 16 h, the reaction
was quenched and worked up as described. 1H NMR analysis
of the crude reaction mixture after workup indicated an
approximate 90% recovery. We were therefore surprised that
in our hands purification by column chromatography, as
described, led only to a modest isolated yield of 38%. The
balance of the material was found to be the ring opened
alcohol 7. The acid sensitivity of 4 was confirmed by treat-
ment of a CDCl3 solution of 4 with methanesulfonic acid
(MSA). After aging overnight, a clean conversion to mesylate
8 was observed (Scheme 3). To overcome this acid instability
initial lab scale samples were therefore purified by distilla-
tion.
Scheme 3a
Scheme 4. Optimization of the cyclization 2 f 4
a Reagents and conditions: (a) SiO2, chromatography, 52% of 7, 38% of 4;
(b) CDCl3, MsOH, rt quantitative.
The acid sensitivity of 4 during the workup caused some
concern, and the stability of a solution of 4 after 20 h was
examined for a series of acids and buffers (Table 1).
The stress test clearly showed that quenching of the
reaction mixture with strong acids should be avoided, even
However, addition of a concentrated solution of 2 (7 mL/
g) to a 0.2 M solution of preformed LTMP in MTBE at 0
°C yielded 4 in practically the same assay yield as that
described above (84%). The same result was also obtained
when a 0.2 M solution of 2 in MTBE containing 2 equiv of
TMP was treated with 2.5 M n-BuLi at 0 °C. Moreover, the
(11) Hodgson, D. M.; Chung, Y. K.; Paris, J.-M. Synthesis 2005, 2264.
638
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Vol. 11, No. 3, 2007 / Organic Process Research & Development

conveniently by using a TPAP/NMO oxidation.13 However,
these conditions are significantly exothermic, and a safer
alternative was sought. After evaluating a number of alterna-
tives we eventually settled on a TEMPO/bleach oxidation.14
This reaction was performed in a two-phase system consist-
ing of MTBE and buffered aqueous bleach with a catalytic
amount of TEMPO (2.5 mol %) and potassium bromide (15
mol %). The success of the reaction proved critically
dependent on the pH. At lower pH’s (5-8) the oxidation
was incomplete, whilst at high pH (>11) the dibrominated
12 was formed as a significant byproduct (Scheme 5). The
Table 2. Catalytic intramolecular cyclopropanations
entrya
TMP (equiv)
RLi (equiv)
solvent
yieldb
Scheme 5. Oxidation of alcohol 4a
1
2
3
4
5
6c
7
8
1
n-BuLi (2)
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Hexanes
MTBE
95%
97%
95%
85%
63%
91%
80%
90%
0.5
0.5
0.25
0.05
0.25
0.5
0.5
n-BuLi (2)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-BuLi (1.1)
n-HexylLi (1.1)
n-HexylLi (1.1)
a Reagents and conditions: TEMPO (2.5 mol %), NaOCl (11.7 w/w %
available chlorine, 1.6 equiv), MTBE, H2O, K2PO4 (1.5 equiv), KhPO4 (to adjust
pH to ∼8.8 - 8.9), KBr (15 mol %), 95%.
a RLi added to a stirred solution of 2 and TMP in 10 volumes of solvent
(with respect to 2) over 4 h maintaining an internal T e 0 °C, unless otherwise
stated. bQuoted yields are GC assay yields determined with biphenyl as an internal
optimal pH window was found to be 8.5-10.5. Thus,
utilizing 1.5 mol equiv of dibasic potassium phosphate
(∼ pH 9.5), and adjusting the pH to 8.80-8.90 by the
addition of monobasic potassium phosphate, led to a buffer
which maintained the pH in the optimal range 10.0-10.5
during the bleach addition. Even though the reaction works
equally well with conventional dilute bleach (typical 4.7%
w/w available chlorine assay), we preferred to perform the
reaction with commercially available concentrated bleach
solution (typically 11.7% w/w available chlorine assay) in
order to keep the total volume of the aqueous reaction
solution to a minimum. The more dilute conditions required
numerous MTBE extractions of the aqueous layer to recover
the product with an acceptable yield. Using the more
concentrated conditions, only two back extractions of the
aqueous layer with MTBE were typically required to achieve
complete product recovery (92-95% overall yield).
c
standard. 5 volumes of solvent with respect to 2.
concentration of the reaction could also be increased with
no impact on the yield. Thus, when 2 and 2 equiv of TMP
in 10 volumes of MTBE at 0 °C were treated with 2 equiv
of 2.5 M n-BuLi over 1 h, the assay yield was 86%. Most
importantly, it proved possible to reduce the amount of TMP
to substoichiometric (i.e., catalytic) amounts (Table 2). The
rate of n-BuLi addition proved to be the key in making this
concept feasible. Whilst quick additions of n-BuLi led to
poor reaction profiles and relatively low assay yields, a slow
addition rate provided excellent profiles with improved assay
yields (Table 2, entry 1). The best results were achieved when
n-BuLi was added over 4 h. It was demonstrated that both
free n-BuLi and prolonged exposure of 2 to the lithium
alkoxide of 4 results in formation of undesired byproducts.
Entry 2 shows that reducing the amount of TMP from
1.0 to 0.5 equiv does not effect the assay yield. Moreover,
it proved possible to perform this reaction with a near
theoretical amount of n-BuLi without a loss in yield (entry
3). When the amount of TMP is further reduced to 0.25
equiv, the yield becomes lower at the same concentration
(entry 4). However, when the concentration is increased, the
yield returns are >90% (entry 6). A slight drop in the
efficiency of the reaction was observed on lowering the
amount of TMP to 0.05 equiv (entry 5). This is believed to
be a consequence of a slow turnover of LTMP. The presence
of significant amounts of free n-BuLi under these conditions
presumably leads to the side reactions. These reactions can
also be carried out with n-HexylLi rather than n-BuLi (entry
8), the latter also allowing a change to hexane as the solvent
(entry 7). The conditions in entry 3 (0.5 equiv of TMP and
1.1 equiv of n-BuLi) were deemed optimal and reproducibly
yielded 4 in 92-97% assay yield on a 1-200 g scale.12
With a robust method for the production of 4 in hand,
attention turned to the oxidation of 4 to furnish the desired
ketone 1. On a small scale this was accomplished quite
On a lab scale a distillation provided the desired 1 with
>95% recovery from the crude oxidation stream. The
distilled ketone was typically 90-95 wt % pure and was
found to perform well in our subsequent chemistry.
The above-described intramolecualar cyclopropanation
and oxidation reactions were successfully demonstrated on
the 7.5 kg scale and provided 1 with ee > 99.5%. It should
be noted that the lower cooling capacity of our chosen vessel
required a much longer n-BuLi addition time. Nevertheless,
the cyclization yield was still found to be 86% under these
conditions. After the workup and a concentration of the
product stream to approximately 5 mL/g, we obtained an
MTBE stream containing 82% of 4 by assay (3 and 1% of
4 were lost to the distillate and aquous layer, respectively).
Oxidation of this stream under the reported conditions yielded
1 in 96% isolated (2% were lost to the aqueous layer).
In summary, a highly practical, efficient, and robust proce-
dure for the intramolecular cyclopropanation of (R)-1,2-
(12) Bio, M. M.; Brands, K. M. J.; Cleator, E. Patent WO2007/015111 A1.
(13) Langer. P. J. Prakt. Chem. 2000, 347, 728.
(14) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem. 1987, 52,
2559.
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639

epoxyhex-5-ene (2) followed by oxidation of the resulting
(1R,2R,5S)-bicyclo[3.1.0]hexan-2-ol (4) to the desired (1R,5S)-
bicyclo[3.1.0]hexan-2-one (1) was developed. Most notably,
the first step of this sequence uses a catalytic amount of base
rather than the superstoichiometric amount reported in the
literature.
Inlet temperature (split mode with a ratio of 4.759:1):
220 °C
Retention times
2-(but-3-enyl)oxirane 2
4.9 min
6.7 min
8.2 min
10.4 min
bicyclo[3.1.0]hexan-2-ol 4
Diene 10
Alcohol 9
Experimental Section
GC Conditions for the Determination of Enantiomeric
Purity of Epoxide 2:
Column: RT-GammaDEXsa, 30 m, 0.32 mm id, 0.25
µm df
(1R,5S)-Bicyclo[3.1.0]hexan-2-one 1. To the MTBE
solution of bicyclo[3.1.0]hexan-2-ol from step 1, 30.5 kg of
water were added followed by dibasic potassium phosphate
(16.24 kg, 93.2 mol, 1.48 equiv). The batch was then held
over the weekend. The mixture was cooled to 0 °C, and then
TEMPO was charged (0.243 kg, 1.56 mol, 2.5 mol %).
Sodium hypochlorite (67.7 mol) was added slowly to the
vigorously stirred mixture over 6 h maintaining the internal
temperature at <5 °C. GC analysis showed approximately
20% of starting material remained and the pH was at 10.4.
An additional 14.1 mol of bleach were added to give 13.7%
of remaining starting material. At this point an additional
charge of TEMPO (0.1 kg) and monobasic potassium
phosphate (0.96 kg) was made, and then an additional 18.8
mol of bleach were added. GC then showed complete
conversion of all starting material. A total of 1.63 mol of
bleach were required to reach full conversion of the alcohol.
The oxidation reaction was then quenched by addition of
Na2SO3 aqueous solution until the reaction was negative for
oxidant by starch iodide indicator paper (2.78 kg, 35 mol
%). The quenched reaction was allowed to sit at room
temperature overnight. The aqueous phase was then cut and
drummed. The organic phase was also drummed out of the
vessel. The aqueous phase was extracted twice with 28 kg
of MTBE and 14 kg of MTBE, respectively. All organic
cuts were combined and assayed for 5.75 kg, 95% yield.
1H NMR (CDCl3, 400 MHz) δ 0.90 (m, 1H), 1.16 (m,
1H), 1.73 (m, 1H), 2.05 (m, 5H); 13C NMR (CDCl3, 100
MHz) δ 13.5, 21.6, 22.6, 27.4, 31.4, 215.1.
Flow: Helium at 10 psi
Injector temperature: 200 °C
Detector temperature: 200 °C
Oven temperature: 40 °C
Run time: 60 min
Sample dissolved in methanol (e.g., 50 µL in 5 mL)
Split flow: 50:1
Injection volume: 1 µL
Retention times for desired and minor enantiomers 46.5
and 50.7 min, respectively.
(1R,2R,5S)-Bicyclo[3.1.0]hexan-2-ol 4. (R)-1,2-Epoxy-
hex-5-ene (7.5 kg, 1 equiv) was charged to the vessel
containing MTBE (75 L, 10 volumes). To this solution was
added tetramethylpiperidine (5.4 kg, 0.5 equiv), and the
reaction mixture was cooled to between -5 and 0 °C. n-BuLi
(2.5 M in hexanes, 1.1 equiv) was added at such a rate so as
to maintain the temperature between -5 and 0 °C (12 h total
addition time). The resulting pale orange reaction mixture
was maintained at <0 °C overnight, after which all starting
epoxide had been consumed (assay for 86% yield by GC).
The reaction was then quenched by the addition of 3 N HCl
(40.8 L, 122.3 mol, 1.6 equiv). The aqueous phase was cut
and retained. The organic phase was washed again with 3
M HCl (12.7 L, 38.2 mol, 0.5 equiv). The combined aqueous
cuts were then back extracted twice, first with 38 L of MTBE
(5 volumes) and finally with 19 L (2.5 volumes). The organic
phases were combined and concentrated by vacuum distil-
lation at a <30 °C pot temperature to give the alcohol as a
solution in approximately 38 L of total volume. This pale
yellow oil was assayed for 6.2 kg of (1R,2R,5S)-bicyclo-
[3.1.0]hexan-2-ol 4 (82% yield) and was used directly in the
oxidation step. N.B. there was found to be 3% in the distillate
and 1% in the aqueous cut by assay.
GC Conditions as those above.
Retention times
bicyclo[3.1.0]hexan-2-ol 4
bicyclo[3.1.0]hexan-2-one 1
6.70 min
7.71 min
HPLC Conditions
Column: Phenomenex Luna C18, 3 µ (150 mm × 4.6 mm)
1H NMR (CDCl3, 400 MHz) δ -0.07-0.00 (m, 1H),
0.38-0.47 (m, 1H), 1.27-1.37 (m, 2H), 1.38-1.43 (m, 1H),
1.53 (dd, J ) 8.4, 14.4 Hz, 1H), 1.65 (dd, J ) 8.0, 12.4 Hz,
1H), 1.83 (s, 1H, OH), 1.87-1.98 (m, 1H), 4.21 (d, J ) 4.8
Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 6.9, 16.1, 24.2,
24.5, 30.3, 74.3.
Column temperature: 35 °C
Flow rate: 1.0 mL/min
Wavelength: 210 nm
A ) 0.1% aqueous phosphoric acid solution
B ) acetonitrile
HPLC Conditions
GC Conditions
Column: HP 5 (30 m × 0.53 µm × 1.5 µm)
Time
0
20
25
27
A%
90
10
10
90
90
B%
10
90
90
10
10
Oven conditions
Initial temperature: 60 °C
Initial time at 60 °C: 3.0 min
12.0 °C/min ramp to final temperature of 200 °C.
Final time at 200 °C: 4.0 min
35
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Retention Times
bicyclo[3.1.0]hexan-2-one
Run time: 30 min
Sample dissolved in methanol
Retention times of desired and minor enantiomers 22.0
and 24.3 min, respectively.
6.22 min
GC Conditions for the Determination of Enantiomeric
Purity of Ketone 1:
Column: RT-GammaDEXsa, 30 m, 0.32 mm id, 0.25 µm
df
Acknowledgment
We thank Sophie Strickfuss and Andy Kirtley for their
help with GC-MS and Chiral HPLC analyses.
Flow: Helium at 10 psi
Injector temperature: 200 °C
Detector temperature: 200 °C
Oven temperature: 110 °C
Received for review February 16, 2007.
OP700042W
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