A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid

Article abstract of DOI:10.1016/j.tet.2017.05.080

An efficient multi-gram synthesis of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, a key chiral bicyclic proline fragment employed in the construction of the potent anti-HCV drug boceprevir, has been presented. The synthetic route commences with the readily available cis-cypermethric acid, a cheap source of the cyclopropane ring required in the targeted compound, and utilizes the cis-orientation of the 2,2-dichlorovinyl and carboxylic acid side arms, already present in the starting material, to effect a diastereoselective construction of the proline moiety.

Full text of DOI:10.1016/j.tet.2017.05.080

Accepted Manuscript
A diastereoselective synthesis of boceprevir's gem-dimethyl bicyclic [3.1.0] proline
intermediate from an insecticide ingredient cis-cypermethric acid
Srinivasa Reddy Kallam, Vishnuvardhan Reddy Eda, Saikat Sen, Rajender Datrika,
Rajesh Kumar Rapolu, Sandip Khobare, Vikas Gajare, Malavika Banda, Rashid Abdul
Rehman Khan, Manpreet Singh, Michael Lloyd, Bhaskar Kandagatla, Moses Babu
Janagili, Veerabhadra Pratap Tadikonda, Siddaiah Vidavalur, Javed Iqbal, Martin E.
Fox, Vilas H. Dahanukar, Srinivas Oruganti
PII:
S0040-4020(17)30589-6
10.1016/j.tet.2017.05.080
TET 28746
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 February 2017
Revised Date: 18 May 2017
Accepted Date: 26 May 2017
Please cite this article as: Kallam SR, Eda VR, Sen S, Datrika R, Rapolu RK, Khobare S, Gajare V,
Banda M, Rehman Khan RA, Singh M, Lloyd M, Kandagatla B, Janagili MB, Tadikonda VP, Vidavalur
S, Iqbal J, Fox ME, Dahanukar VH, Oruganti S, A diastereoselective synthesis of boceprevir's gem-
dimethyl bicyclic [3.1.0] proline intermediate from an insecticide ingredient cis-cypermethric acid,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.080.
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A diastereoselective synthesis of boceprevir’s
gem-dimethyl bicyclic [3.1.0] proline
intermediate from an insecticide ingredient
cis-cypermethric acid
Leave this area blank for abstract info.
Srinivasa Reddy Kallam, Vishnuvardhan Reddy Eda, Saikat Sen,
Rajender Datrika, Rajesh Kumar Rapolu, Sandip Khobare, Vikas Gajare,
Malavika Banda, Rashid Abdul Rehman Khan, Manpreet Singh, Michael Lloyd,
Bhaskar Kandagatla, Moses Babu Janagili, Veerabhadra Pratap Tadikonda,
Siddaiah Vidavalur, Javed Iqbal, Martin E. Fox, Vilas H. Dahanukar, Srinivas Oruganti

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A diastereoselective synthesis of boceprevir’s gem-dimethyl bicyclic [3.1.0] proline
intermediate from an insecticide ingredient cis-cypermethric acid
Srinivasa Reddy Kallama,d, Vishnuvardhan Reddy Edaa, Saikat Senb, Rajender Datrikaa, Rajesh Kumar
Rapolub, Sandip Khobarea, Vikas Gajarea, Malavika Bandaa, Rashid Abdul Rehman Khana, Manpreet
Singhc, Michael Lloyde, Bhaskar Kandagatlab, Moses Babu Janagilia, Veerabhadra Pratap Tadikondaa,
Siddaiah Vidavalurd, Javed Iqbalb, Martin E. Foxe, Vilas H. Dahanukarc,*, Srinivas Orugantib,
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Hyderabad 500 049, Telangana, India
b Dr. Reddy’s Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Telangana, India
c Integrated Product Development Organization, Dr. Reddy’s Laboratories, Bachupally, Qutbullapur, Hyderabad 500 090, Telangana, India
d Department of Organic Chemistry & FDW, Andhra University, Visakhapatnam 530 003, Andhra Pradesh, India
e Chirotech Technology Centre, Dr Reddy’s Laboratories (EU) Limited, 410 Cambridge Science Park, Cambridge, CB4 0PE, United Kingdom
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient multi-gram synthesis of (1R,2S,5S)-methyl 6,6-dimethyl-3-azabicyclo[3.1.0]
hexane-2-carboxylate, a key chiral bicyclic proline fragment employed in the construction of the
potent anti-HCV drug boceprevir, has been presented. The synthetic route commences with the
readily available cis-cypermethric acid, a cheap source of the cyclopropane ring required in the
targeted compound, and utilizes the cis-orientation of the 2,2-dichlorovinyl and carboxylic acid
side arms, already present in the starting material, to effect a diastereoselective construction of
the proline moiety.
Available online
Keywords:
Boceprevir
Cypermethric acid
2009 Elsevier Ltd. All rights reserved
.
Dimethylcyclopropylproline
Hydroboration of vinyl chlorides
Oxidative esterification
1. Introduction
USFDA approval of the hepatitis C virus (HCV) NS3 protease
inhibitor boceprevir (1, Victrelis®) in 2011 and its introduction as
a direct-acting antiviral (DAA) component in hepatitis C
treatment regimen was one of the key breakthroughs in
combatting chronic HCV infection.1,3b Chronic HCV infection
affects 130-150 million people worldwide, and eventually leads
to liver cirrhosis or liver cancer in a significant number of
cases.2,3 Indeed, in 2012, it was estimated that almost 700000
people die each year from liver diseases resulting from HCV
infection.2 NS3 protease plays a critical role in HCV RNA
replication and virion assembly so that the discovery and
development of 1, a peptidomimetic drug, represented a major
landmark in the quest towards exploiting NS3 protease as a
druggable target for hepatitis C treatment.1b,4
Fig. 1. Boceprevir and its key starting materials
Our interest in 1 was piqued not only by its standing as one of
the first DAAs approved for the treatment of hepatitis C, but also
by the structurally appealing bicyclic [3.1.0] proline moiety that
———
forms the core of 1 and is derived from the methyl ester 3, one of
the three key starting materials 2-4 employed for the synthesis of
1 (Fig. 1).5 The bicyclic framework of 3 bears a 1,1-dimethyl
Corresponding authors. Tel.: +91-40-66571500; fax: +91-40-66571581; e-mail: soruganti@drils.org (Srinivas Oruganti); Tel.: +91-40-
44346127; fax: +91-40-44346285; e-mail: vilasd@drreddys.com (Vilas H. Dahanukar); DRL- Communication No.: IPDO-IPM-00505.

2
Tetrahedron
ACCEPTED MANUSCRIPT
cyclopropane cis-fused onto a proline ring and its construction,
followed by hydrogenolytic opening of the aminal ring, afforded
though well precedented in literature, is evidently more involved
when compared to the L-tert-leucine derived urea 2 or the
racemic cyclobutylalanine derived α-amino amide 4.5 Broadly
speaking, most of the known syntheses of 3 involve either a
cyclopropyl ring formation on an existing proline scaffold
(general approach A) or an elaboration of a pre-existent
cyclopropyl framework to 3 (general approach B) (Fig. 2).
8, which was then transformed to the desired bicyclic [3.1.0]
proline intermediate 3•HCl via sequential Jones oxidation,
methyl ester formation and HCl mediated N–Boc deprotection
(Scheme 1). Though initially followed for small scale generation
of
1
and structurally related library molecules, this
cyclopropanation strategy was later completely abandoned in
favor of increasingly streamlined and efficient variants of the
second approach (general approach B) as means to obtain 3 for
large-scale synthesis of 1.7-9
The practical convenience that approach B offered stemmed
from the built-in framework of 1,1-dimethylcyclopropane ring
present in ethyl chrysanthemate 9, an inexpensive pyrethroid,
which offered a facile access to the bicyclic [3.1.0] proline
moiety, present in 3. All synthetic routes, described under the
ambit of this second approach, involved transformation of the
non-symmetric 9 to the symmetrical caronic anhydride 10 that
served as a template for the synthesis of 3. Typically, elaboration
of 9 to 3 necessarily required: (a) an oxidative degradation of the
isobutylene side arm in 9 to obtain 10, and (b) late-stage use of
cyanide to introduce the carbomethoxy group present in 3
(Schemes 2a-c). Indeed, all known improvements for bulk
production of 3 have largely centered on reducing of the number
of synthetic stages from 10 to the cyanation step, and more
importantly, streamlining the process for introduction of chirality
in 3. For example, the first demonstration7 of approach B, as
Fig. 2. Schematic representation of the two general approaches to 3.
The best known example of the first approach can be found in
the original medicinal chemistry route to 3 delineated by the
innovator (Schering-Plough).6 The synthesis commenced with
selenoxide elimination in the pyroglutamyl alcohol derivative 5
to obtain the unsaturated γ-lactam 6 that was subjected to
diastereoselective cyclopropanation with i-propylphosphonium
ylide to furnish the key intermediate 7. Lactam reduction in 7,
Scheme 1. An example of a synthetic route to 3, based on the general approach A
(a) NH4HCO3,
Boc2O
(a) KMnO4
(b) Ac2O
(a) Allyl alcohol
O
O
O
O
O
O
(b) (R)-(+)- -Me-
(b) LiAlH4
(c) CbzCl
O-Allyl
HO
EtO
benzylamine
9
10
11
(a) NaOMe,
MeOH
(a) TEMPO,
NaOCl
TMSCN
O
OEt
CN
(b) HCl;
(c) H2/Pd/C
N
N
BF3•Et2O
N
(b) Na2S2O3,
EtOH
CbzHN
OH
OMe
H
Cbz
Cbz
14
12
13
3
(a)
MAON, catalase
O2, NaHSO3
SO3Na
N
H
N
N
H
15
16
18
NaCN
O
CN
N
N
Cl
OMe
H
H
H
17
3•HCl
(b)
Scheme 2. Salient examples of synthetic routes to 3, based on the general approach B
(c)

3
reported by Schering-Plough, involved desymmetrization of
achiral 10 with allyl alcohol and subsequent chiral resolution of
rac-11 with (R)-(+)-α-methylbenzylamine. The (1S,3R) allyl
ester 11 was converted via the intermediacy of 12 into the
protected aminal 13, which was then subjected to Lewis acid
mediated cyanation with TMSCN to afford 14. Sodium
methoxide mediated methanolysis of 14, followed by hydrolysis
of the imido methyl ether intermediate and subsequent N–Cbz
deprotection in the methyl ester obtained, afforded 3 (Scheme
2a).
A considerably shortened second-generation synthesis8 of 3
from 10 employed the achiral bicyclic pyrrolidine 15, which was
desymmetrized to the racemic imine rac-16 in presence of
K2S2O8 and AgNO3. Cyanation of rac-16 and subsequent
methanolysis of the nitrile rac-17 under acidic conditions
afforded rac-3, from which the desired (1R,2S,5S) enantiomer 3
was isolated by diastereomeric salt formation with D-DTTA
(Scheme 2b). Constraints imposed on material generation by this
late stage chiral resolution was later ameliorated through
application of biocatalysis in securing an enantioselective
transformation of 15 to 17 (Scheme 2c).9 The key step in this
route, i.e. 15→16, stands out till date as one of the finest
As illustrated in Scheme 3, the pyrethroid 19 was particularly
ACCEPTED MANUSCRIPT
appealing as a starting material since, unlike the structurally
related 9, it presented us with an opportunity to utilize its entire
carbon framework and delineate an enantiospecific ‘carbon
conservative approach’ to accessing the bicyclic [3.1.0] proline
moiety of 3. More specifically, we desired to employ the built-in
cis-orientation of the 2,2-dichlorovinyl and carboxylic acid side
arms in 19 to construct a bicyclic pyrrolidone, such as 20, and
subsequently capitalize on the topological bias, inherent in 20, to
diastereoselectively transform the vinyl chloride moiety into the
β-oriented carbomethoxy group present in 3. In order to assess
the feasibility of this proposed synthesis of 3 from 19, we
decided to be prudent and establish the proof-of-concept for
chemistry viability with the inexpensive rac-cypermethric acid
chloride (rac-21) first.
Scheme 3. Retrosynthetic analysis of 3 from (1S)-cis-cypermethric acid 19
examples
of
monoamine
oxidase
mediated
chiral
desymmetrization of a pyrrolidine and owes its success to the
extensive enzyme optimization studies that were carried out to
custom-make a monoamine oxidase for the specific substrate in
question. Despite its highlights, the downstream chemistry in this
chemoenzymatic process is definitely undesirable from industrial
safety perspective, since it still depended on a late stage
cyanation with an inorganic cyanide, followed by nitrile
hydrolysis under strongly acidic conditions, to convert 16 to 3.
Against this background, we decided to devise a new synthetic
route to 3, based on the general approach B, which will not only
be bereft of any exotic reagents and customized biocatalytic
transformations, but also address the safety concerns associated
with the use of cyanide for introduction of the carbomethoxy
group present in 3.10
2. Results and discussion
Thus, the commercially available cis-cypermethric acid
chloride rac-21 was treated with ammonia gas at low temperature
to furnish the amide rac-22 in 82% yield (Scheme 4). Cyclization
of the 2,2-dichlorovinyl and amide side arms in rac-22 with NaH
in DMAc afforded the cis-fused bicyclic pyrrolidone rac-20,
presumably via
a
base mediated 5-exo-dig cyclization,12
involving a Z-selective nucleophilic addition of the amide side
arm to a chloroalkyne13 derived from the 2,2-dichlorovinyl
moiety14 present in rac-22. We then decided to explore whether
an epoxidation of the vinyl chloride moiety in rac-20 would
afford an oxirane that would hydrolyze under acidic conditions to
afford an aldehyde (rac-29 or rac-30). However, attempted
epoxidation of rac-20, employing in-situ generated peracids
(such as acetic acid/30% aq. H2O2 or trifluoroacetic acid/30% aq.
In keeping with this intent, (1S)-cis-cypermethric acid 19 was
chosen as a readily available chiral pool for the synthesis of 3.11
Scheme 4. Reagents and conditions: (a) NH3, CH2Cl2, –10 °C, 2-3 h, 82%; (b) NaH, DMAc, 0 ꢀ 35 °C, 6 h, 62%; (c) H2O2, Amberlite® IR120, rt, 5 h; (d) TES,
TFA, CH2Cl2, 5°C ꢀ rt, 16 h, 60%; (e) CH3COONa, TBAB, toluene, 110 – 115 °C, 18 h, 64%; (f) K2CO3, MeOH, rt, 2 h, 86%; (g) LAH, THF, 65 °C, 16 h; (h)
(Boc)2O, CH2Cl2, rt, 2 h, 55% (from rac-26); (i) (COCl)2, DMSO, Et3N ,CH2Cl2, –78 °C ꢀ rt, 45 min, 94%; (j) DBU, CH2Cl2, rt, 3 h; (k) CrO3-H2SO4 (1:1.6),
acetone, –30 ꢀ 0 °C, 3 h, 58% (from rac-28); (l) K2CO3, MeI, acetone, rt, 16 h, 84%; (m) 1M HCl in EtOAc, 1,4-Dioxane, 25 °C, 2 h, 94%.

4
Tetrahedron
ACCEPTED MANUSCRIPT
H2O2), failed to show any product formation. Surprisingly,
amenable for scale-up. We contemplated a one-pot reduction of
when rac-20 was reacted with hydrogen peroxide in presence of
Amberlite® IR120, a product, exhibiting key NMR spectral
signatures of the hydroperoxide15 (or alcohol) 23, could be
isolated in its crude form as a pale yellow solid.
the amide and vinyl chloride present in the intermediate (rac-20)
using borane to directly access the alkyl chloride in order to
avoid a peroxy intermediate due to safety considerations. Based
on the aforementioned thoughts, a scale-up amenable route was
developed as shown in Scheme 6.
Without attempting any further purification, this solid was
subjected to classical silyl hydride reduction, using triethylsilane
and trifluoroacetic acid in dichloromethane. To our pleasant
surprise, the chloromethyl derivative rac-24 was obtained as a
single diastereomer. Displacement of chloride in rac-24 with
acetate was carried out in a facile manner using NaOAc under
phase transfer conditions to obtain rac-25. Hydrolysis of the
acetyl group using K2CO3 gave the alcohol rac-26, which was
further reduced using LAH to access the desired bicyclic [3.1.0]
pyrrolidine (rac-27) followed by protection with (Boc)2O to
furnish rac-28. The stereochemistry of hydroxy-methyl group in
rac-28 syn to the gem-dimethyl cyclopropyl ring was needed to
be inverted. We decided to perform an oxidation of the hydroxy-
methyl moiety to an acid or an aldehdye, thereby creating a
handle for an epimerization to the thermodynamically favored
and desired product.
a
b
O
O
OH
N
N
N
OH
OMe
Boc
Boc
Boc
rac-33
rac-34
rac-28
c
d
O
O
N
N
OH
OMe
Boc
Boc
rac-31
rac-32
Scheme 5. Reagents and Conditions: (a) CrO3:H2SO4 (1: 1.6), Acetone, –5
°Cꢀrt, 16 h, 47%; (b) Cs2CO3, MeI, DMF, rt, 4 h, 33%; (c) NaOMe, MeOH,
rt, 16 h, 84%; (d) K2CO3, MeI, Acetone, rt, 16 h, 85%.
Initial efforts towards epimerization strategy involved direct
oxidation of alcohol rac-28 to the corresponding cis-acid (rac-
33) using Jones oxidation, followed by transformation to the
methyl ester rac-34 (Scheme 5). A one-pot NaOMe mediated
epimerization-ester hydrolysis on rac-34 afforded the epimerized
acid rac-31, which was transformed to the methyl ester using
methyl iodide in the presence of potassium carbonate to access
rac-32. One of the drawbacks in the above route was the
noticeably sluggish epimerization for rac-34, and this prompted
us to look for an alternative epimerization approach.
This time we embarked on the synthesis starting with the
originally envisaged chirally pure (1S)-cis-cypermethric acid 19.
Diastereomeric salt based resolution on rac-19 was studied using
various resolution agents, namely, (S)-1-(1-napthyl)ethylamine,
(R)-2-amino butanol, D-ephedrine, quinine, cinchonidine, S-
prolinol and (R)-phenylethyl amine. Amongst the chiral bases
studied, best results were obtained with (R)-phenylethyl amine
which afford the desired acid 19 with ≥99% ee, albeit with a
moderate yield of 40%. As a complementary approach to the
chiral resolution of rac-19 by diastereomeric salt formation, we
also explored the possibility of accessing the desired enantiomer
19 via enzymatic resolution of the ethyl ester of rac-19. In an
initial screening of reaction conditions with commercially
available enzymes (PLE, CALB-L and BC-esterase), BC-esterase
fared best and catalysed the hydrolysis of rac-cis-cypermethric
acid ethyl ester to furnish the acid 19 with good
enantioselectivity (>98%), albeit at extremely high enzyme
loadings and low substrate concentrations. Esterase V was
subsequently tested on account of our observations that it is able
to promote hydrolysis of substrates deemed refractory with other
enzymes. Exhibiting a substrate selectivity opposite to BC-
esterase, esterase V afforded the desired enantiomer 19 as the
Oxidation to rac-28 under Swern conditions afforded rac-29
with good yield (Scheme 4). Epimerization of rac-29 in the
presence of DBU furnished rac-30, wherein the disposition of the
aldehyde was anti to gem-dimethyl cyclopropyl ring. Further
oxidation of the aldehyde (rac-30) under Jones conditions
afforded the desired acid rac-31, which was then transformed to
the methyl ester rac-32. Treatment of rac-32 with EtOAc-HCl
led to the removal of Boc-group to afford boceprevir intermediate
rac-3 as a hydrochloride salt.
Having established the chemistry proof-of-concept, we
decided to focus on areas of improvement to render the overall
route shorter by using transformations that avoided multiple
functional group manipulations and choosing reaction conditions
Scheme 6. Reagents and conditions: (a) (i) (R)-Phenylethylamine, IPA, Reflux, 30 min; (ii) 2N HCl, water, 40%; (b) SOCl2,toluene, 25 °C, 3 h; (c) aq. NH3,
toluene, 0-10 °C, 2-3 h, (d) t-BuOK, THF, 25 °C, 2-3 h, 80% (from 19); (e,f) (i) BH3•THF or NaBH4, BF3•THF, 50-60 °C, 2-3 h; (ii) 30% H2O2, 10% NaOH
(aq.), 0-10 °C, 2 h; then (Boc)2O, 25 °C, 1-2 h; (g) (i) NaOCl, KBr, TEMPO, DCM , 0 °C, 15 min (ii) NaHSO3, 25-35 °C, then Na2CO3, 7-8 h; 55% (from 20);
(h,i) K2CO3, MeOH, 2-3 h, 25°C, then I2, 25 °C, 2-3 h; (j) 1M HCl in EtOAc, 25 °C, 2 h, 70% (From 29)

5
unreacted ethyl ester with high enantioselectivity (97%) and was
indeed able to bring about excellent conversion (49%) even at
substrate concentrations of 60 g/l.16
formation of 27 from 20 in which the γ-lactam ring in 20 was
ACCEPTED MANUSCRIPT
reduced first, followed by a well-known transformation of the
vinyl chloride intermediate to the primary alcohol 27 under
hydroboration-oxidation conditions.19 In addition, the high degree
of diastereoselection observed in the formation of 27 from 20
indicated that the stereochemistry of the newly generated chiral
center in the postulated second step of this transformation (i.e.
vinyl chloride to primary alcohol) was being controlled by the
topology of the rigid cis-fused bicyclic pyrrolidine framework.
Once the chirally pure 19 was accessed, the corresponding
acid chloride 21 was prepared using thionyl chloride and catalytic
amount of DMF in toluene. The crude product 21 obtained was
treated with aqueous ammonia to afford the amide 22. Owing to
potential hazards associated with the use of sodium hydride in
large-scale processes,17 selected bases (such as NaOMe, t-BuOK,
NaOH and Cs2CO3) were screened to study their suitability as an
alternative to NaH in promoting the cyclization of 22 to 20. We
concluded that this transformation could be effected using either
sodium methoxide or potassium tert-butoxide in THF or DMAc
as the solvent. In the light of our observations, the first two steps,
viz. synthesis of the amide 22 and its subsequent conversion to 20
using t-BuOK in THF, were efficiently telescoped to synthesize
20 from 19 in 80% yield
Given the flammability of borane and obvious risks associated
with handling the material in bulk,20 we decided to examine next
the possibility of obtaining 28 (via 27) from 20 with in situ
generated BH3 using NaBH4 in combination with several Lewis
acids such as I221, TMSCl22 and BF3•THF23. Among all the
reagents studied, NaBH4/BF3•THF was found to be suitable
process amenable replacement for BH3•THF (Scheme 6). Moving
forward, the primary alcohol 28 was oxidized to the aldehyde 29
using TEMPO and sodium hypochlorite. The required product 29
was quite conveniently isolated in pure form from the reaction
mixture by sodium bisulphite adduct formation. For converting
29 to the methyl ester 31, we decided to forgo employing the
earlier developed three step sequence (epimerization of aldehyde,
oxidation to acid and esterification) in favor of a one-pot
epimerization - oxidative esterification24 strategy. Accordingly,
epimerization of 29 in presence of potassium carbonate and
methanol gave 30, which was then treated with iodine at ambient
temperature to furnish the methyl ester 31. Boc-removal in 31
with 1M HCl in EtOAc, followed by recrystallization from 1:4 i-
PrOH-MTBE, afforded 3 as a hydrochloride salt with high
chemical (~99%) and chiral (>99%) purity. Finally,
stereostructure of the chiral 3•HCl thus isolated was
unambiguously secured by single crystal X-ray diffraction
analysis (Fig. 2).25
We subsequently investigated the possibility of reducing the
number of synthetic steps developed in the initial route. In lieu
of the originally developed acidic-resin catalyzed addition of
peroxide and silyl hydride reduction sequence on 20, we decided
to explore a simultaneous borane reduction of the vinyl chloride
as well as the amide moiety in 20 to potentially obtain an
unprotected variant of the aldehyde 29. Quite surprisingly, as
indicated by LC-MS of the crude reaction mixture, treatment of
20 with BH3•THF, followed by oxidative workup gave the
hydroxymethyl pyrrolidine intermediate 27 in place of the
expected aldehyde 29. No attempts were made to isolate 27
owing to the potential risk of aziridine formation. The reaction
mixture, obtained after the hydroboration-oxidation reaction, was
instead treated with (Boc)2O which enabled trapping of the
secondary amine and allowed characterization of the alcohol 28
as the major product. However, a significant amount of a minor
product, presumably the exocyclic methyl chloride 35, was also
detected in the reaction mixture (Scheme 7).18
Scheme 7. Reagents & Conditions: (a) BH3•THF; (b) 30% H2O2, 10% NaOH
(aq.), 0-10 °C, 2 h; (c) (Boc)2O, 25-35 °C, 1-2 h.
In a bid to obtain as clean conversion of 20 to 28 as possible,
we studied the effect of molar equivalents of borane, temperature
and different sources of borane on the preferential formation of
28 over aberrant products, especially 35. When the hydroboration
reaction on 20 was performed at low temperatures (e.g. –40 °C or
0-5 °C), it was observed that the undesired product 35 was
formed in preference to the required 28. On the other hand,
performing the hydroboration at either room temperature or at 55
°C resulted in a cleaner reaction profile and afforded 28 as the
major product. In addition, we found that unless the reaction was
carried out at a very low temperature, employing three
equivalents of BH3 was typically enough in all cases to ensure
complete consumption of the starting material 20. Indeed, when
the reaction were carried out with at 55 °C, adding borane in
excess of 3 equivalents neither resulted in a better reaction profile
nor afforded any further improvement in the ratio of 28 to 35.
Fig. 2. ORTEP diagram of 3•HCl drawn at 30% probability level
3. Conclusion
In short, we have demonstrated herein on a multi-gram scale a
novel telescoped diastereospecific synthesis of a key boceprevir
fragment 3 from cis-cypermethric acid rac-19, an inexpensive
pyrethroid that forms the synthetic precursor of several well-
known insecticides such as cypermethrin. Unlike other known
syntheses of 3, wherein the cyclopropyl ring of 3 is derived from
a
pyrethroid, our synthetic route exemplifies a carbon
conservative approach wherein the entire carbon backbone of the
pyrethroid 19 is retained and simply re-structured into the
bicyclic [3.1.0] proline moiety, present in 3. In addition, the
functional group transformations required for effecting the
construction of the proline ring from 19 are operationally simple,
atom economical and do not require any exotic reagent or a
customized biocatalytic transformation.
In the screening experiments, no intermediate, bearing a
pyrrolidone moiety (such as 24 or 26), could be discerned. This
pointed towards a probable mechanism for the borane induced

6
Tetrahedron
g, 61.8%); Rf (30% ethyl acetate in hexane): 0.6;νmax (CHCl3, cm-
4. Experimental section
ACCEPTED MANUSCRIPT
1): 3226, 1684, 1375; δH (400 MHz, CDCl3): 7.26 (brs, 1H), 5.24
(s, 1H), 2.30 (d, J = 5.8 Hz, 1H), 2.11 (dd, J = 4.4 Hz, J = 1.4 Hz,
1H), 1.16 (s, 3H), 1.14 (s, 3H); δC (100 MHz, DMSO-d6): 173.8,
139.0, 89.8, 33.6, 31.3, 26.1, 25.4, 15.2; HRMS (ESI-MS): MH+,
found 172.0564. C8H11NOCl requires 172.0529.
4.1. General information
All reagents were used as received from commercial sources
without further purification or prepared as described in the
literature. Reactions were monitored by thin layer
chromatography (TLC) performed on Merck TLC silica gel 60
F254 aluminium plates. Visualization of the spots on the TLC
plates was achieved by exposure to UV radiation (254 nm) or by
using an appropriate TLC staining reagent (such as PMA,
anisaldehyde and ninhydrin). Chromatographic purification of
products was carried out by flash column chromatography on
silica gel (60-120 mesh or 100-200 mesh or 230-400 mesh as the
4.2.3. (1S*,4R*,5R*)-4-(chloromethyl)-6,6-
dimethyl-3-azabicyclo[3.1.0]hexan-2-one (rac-
24):
To a solution of rac-20 (110 g, 0.641 mol) in hydrogen
peroxide (2.2 L) was added Amberlite IR120 resin (110 g) at
ambient temperature. The resulting mixture was stirred for 5 h at
the same temperature. Upon the completion of the reaction (as
indicated by TLC), the reaction mixture was added to water (1.0
L) and extracted with ethyl acetate (3ꢀ1 L). The organic layers
were combined and washed with brine solution (1.0 L). The
organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure below 50 °C to afford 23 as
a pale yellow solid (110 g). This material was taken forward to
next step without any further purification. δH (400 MHz, CDCl3):
10.72 (s, 1 H), 7.27(s,1H), 3.88 (d, J = 12.2 Hz, 1H), 3.70 (d, J =
12.4 Hz, 1H), 2.1 (d, J =5.6 Hz, 1H), 1.94 (dd, J = 5.6 Hz, J = 1.2
Hz, 1H), 1.29 (s, 3H), 1.18 (s, 3H); δC (100 MHz, CDCl3):
177.94, 94.86, 42.45, 33.15, 32.56, 27.06, 26.42, 16.06.
case required). Melting points were determined using
a
Differential Scanning Calorimeter (DSC, Q-2000, TA) apparatus.
Infrared spectra were recorded on a Perkin-Elmer 1650 Fourier
1
transform spectrometer. H and 13C NMR spectra were recorded
on a Varian 400 MHz spectrometer. Chemical shifts (δ) in ppm
are reported relative to Me4Si (= 0 ppm) by using residual solvent
signals as internal reference [CDCl3: δ = 7.26 ppm (1H NMR)
and 77.0 ppm (13C NMR); CD3OD: δ = 3.31 ppm (1H NMR) and
49.2 ppm (13C NMR); DMSO-d6: δ = 2.50 ppm (1H NMR) and
39.5 ppm (13C NMR)]. LRMS data were recorded on an Agilent
1200 Series liquid chromatography module hyphenated to a 6430
Triple Quad LC/MS system. HRMS spectra were recorded on
Micromass LCT Premier mass spectrometer equipped with an
ESI lock spray source for accurate mass values. Specific optical
rotation was recorded on an Anton Paar MCP 200 polarimeter.
To a solution of 23 (100 g) in dichloromethane (1.5 L) was
added triethylsilane (101.75 g, 0.8771 mol) at 5-10 °C.
Trifluoroacetic acid (633.3 g, 5.555 mol) was added slowly to
this reaction mixture at 5-10°C and the whole contents were
stirred for 16 h at 25-35°C. After the completion of reaction as
monitored by TLC, Saturated NaHCO3 sol. (3.0 L) was added to
the reaction mixture. Both the layers formed were separated and
the aqueous layer was further extracted with DCM (2ꢀ500 mL).
The organic layer was dried over anhydrous sodium sulfate and
concentrated under reduced pressure below 40 °C to afford the
crude compound which was purified by the silica gel column
chromatography (eluted with 50% ethyl acetate in hexane) to
furnish rac-24 as a colorless liquid (65 g, 65.8%); νmax (CHCl3,
cm-1): 3433, 3216, 3018, 1693, 1216; δH (400 MHz, DMSO-d6):
7.61 (brs, 1H), 3.99-3.94 (m, 1H), 3.72-3.67 (m, 1H), 3.57-3.52
(m, 1H), 1.71-1.70 (m, 1H), 1.65-1.63 (m, 1H), 1.22 (s, 3H), 1.02
(s, 3H); δC (100 MHz, DMSO-d6): 174.1, 56.3, 44.2, 33.6, 28.4,
26.7, 22.2, 17.6; HRMS (ESI-MS): MH+, found 174.0690.
C8H13NOCl requires 174.0686.
4.2. Experimental procedures
4.2.1. (1S*,3S*)-3-(2,2-dichlorovinyl)-2,2-
dimethylcyclopropanecarboxamide (rac-22):
Ammonia gas was passed for 2-3 h into a solution of cis-
cypermethric acid chloride rac-21 (300 g, 1.318 mol) in DCM
(3.0 L) maintained at –10°C. After the completion of reaction as
monitored by TLC, water (2.0 L) was added to the reaction
mixture. Both the layers formed were separated and the aqueous
layer was further extracted with DCM (900 mL). Both the
organic layers were combined, washed with brine solution (1.5
L), dried over anhydrous sodium sulfate and concentrated under
reduced pressure below 45°C. The crude material was purified by
trituration with hexane (600 mL) to afford the title compound
rac-22 as a white solid (226 g, 82.4%); Rf (20% ethyl acetate in
hexane): 0.2; νmax (CHCl3, cm-1): 3489, 3332, 1681, 1658, 1611,
1441, 915; δH (400 MHz, DMSO-d6): 7.54 (s, 1H), 6.81 (s, 1H),
6.50 (d, J = 8.8 Hz, 1H), 1.76-1.85 (m, 2H), 1.16 (s, 3H), 1.15 (s,
3H); δC (100 MHz, DMSO-d6): 171.7, 127.8, 117.1, 32.8, 31.2,
28.5, 26.3, 15.2; HRMS (ESI-MS): MH+, found 208.0287.
C8H12NOCl2 requires 208.0296.
4.2.4. ((1R*,2R*,5S*)-6,6-dimethyl-4-oxo-3-
azabicyclo[3.1.0]hexan-2-yl)methyl acetate(rac-
25):
To a solution of compound rac-24 (80.0 g, 0.462 mol) in toluene
(800 mL) was added sodium acetate (151.6 g, 1.85 mole) and
tetrabutylammonium bromide (149 g, 0.462 mol) at 25-35°C.
The resulting mixture was heated to reflux and stirred
continuously for 16 h. After the completion of reaction as
monitored by TLC, The reaction mixture temperature was cooled
to 35°C and water (1.5 L) was added to the reaction mixture.
Both the layers formed were separated and the aqueous layer was
extracted with ethyl acetate (3ꢀ750 mL). The organic layers
were combined, washed with brine solution (500 mL) and dried
over anhydrous sodium sulfate. The organic layer was
concentrated under reduced pressure below 50 °C. The crude
material obtained was purified by triturating with hexane (100
mL) at RT. The solid obtained was filtered and dried below 40
°C under vacuum to afford the title compound rac-25 as a pale
yellow solid (59 g, 64%); Rf (ethyl acetate) 0.5;νmax (CHCl3, cm-
1): 3211, 2954, 1738, 1694, 1368, 1227; δH (400 MHz,DMSO-
4.2.2. (1S*,5R*)-4-(chloromethylene)-6,6-
dimethyl-3-azabicyclo[3.1.0]hexan-2-one (rac-
20):
To a suspension of sodium hydride (115.2 g, 2.8 mol) in N,N-
dimethylacetamide (1.0 L) was added rac-22 (200 g, 0.961 mol)
at 0°C under nitrogen atmosphere. The reaction mixture
temperature was raised to 25-35°C and stirred for further 5-6 h.
Upon the completion of the reaction (as indicated by TLC), the
reaction mixture was slowly poured into cold water (3.5 L). The
pH of reaction mixture was adjusted to 2 to 2.5 with 2N HCl. The
solid obtained was collected by filtration and the cake was
washed with water (1.6 L). The material was dried below 45°C to
afford the title compound rac-20 as a yellow colored solid (102

7
d6): 7.62 (brs, 1H), 4.16-4.04 (m, 2H), 3.99-3.95 (m, 1H), 2.02 (s,
3H), 1.68-1.62 (m, 2H), 1.20 (s, 3H), 1.03 (s, 3H); δC (100 MHz,
DMSO-d6): 174.3, 170.6, 63.5, 53.4, 33.2, 27.5, 26.7, 21.9, 21.1,
17.7; HRMS (ESI-MS): MH+, found 198.1137. C10H16NO3
requires 198.1130.
CDCl3): 156.7, 80.3, 65.2, 64.5, 48.9, 32.4, 28.3, 26.9, 25.1,
ACCEPTED MANUSCRIPT
19.5, 16.3; HRMS (ESI-MS): MH+, found 242.1754 C13H24NO3
requires 242.1856.
4.2.7. (1R*,2R*,5S*)-tert-butyl 2-formyl-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-3-
carboxylate (rac-29) :
4.2.5. (1S*, 4R*, 5R*)-4-(hydroxymethyl)-6,6-
dimethyl-3-azabicyclo[3.1.0]hexan-2-one (rac-
26):
To a solution of oxalyl chloride (10.27g, 0.08 mol) in
dichloromethane (50 mL) was added DMSO (6.8 g, 0.0871 mol)
at –78°C under nitrogen atmosphere and stirred continuously at
the same temperature for 30 min. The solution of rac-28 (15 g,
0.062 mol) in dichloromethane (200 mL) was added to this
reaction mixture at –78 °C followed by addition of triethylamine
(31.49 g, 0.3112 mol). The reaction mixture temperature was
slowly raised to 30-35 °C and stirred for further 45 min. After
completion of reaction as monitored by TLC, cool water was
added to the reaction mixture (200 ml) and both the layers
formed were separated. Aqueous layer was further extracted with
DCM (100 mL) and all the organic layers were combined and
washed with 1N HCl (200 mL) followed by saturated
NaHCO3solution (200 mL). The organic layer was concentrated
under reduced pressure below 40 °C to afford the title compound
rac-29 as brown color liquid (14.0 g, 94%); [Note: Compound
rac-29 exists as mixture of two conformers, so that every unique
1H or 13C signal appears pair wise] Rf (20% ethyl acetate in
hexane) 0.6; νmax (CHCl3, cm-1): 2819, 1730, 1682, 1413, 1388,
1139; δH (400 MHz, CDCl3): 9.61 (d, J = 3.4 Hz, 1H), 4.27-4.18
(m, 1H ), 3.68-3.44 (m, 2H), 1.68-1.65 (m, 1H), 1.51 (m, 1H),
1.40 (s, 9H), 1.15 (s, 3H), 1.01 (s, 3H); δC (100 MHz, CDCl3):
201.8, 153.8, 81.0, 66.9, 47.0, 32.8, 29.3, 28.1, 27.4, 26.4, 20.5,
17.4; HRMS (ESI-MS): MH+, found 240.1606. C13H22NO3
requires 240.1600.
To a solution of rac-25 (59.0 g, 0.299 mol) in methanol (600
mL) was added potassium carbonate (49.59 g, 0.3593 mol) at 25-
35 °C and stirred for 2 h at the same temperature. Upon
completion of the reaction (as indicated by TLC), the reaction
mixture was filtered through Celite and the cake was washed
with methanol (2ꢀ75 mL). The filtrate was collected and
concentrated under reduced pressure below 55°C to get the crude
residue. The crude compound was dissolved in water (40 mL)
and extracted with ethyl acetate (3ꢀ300 mL). The organic layers
were combined, washed with brine solution (75 mL) and then
dried over anhydrous sodium sulfate. The organic layer was
concentrated under reduced pressure below 50°C to furnish the
title compound rac-26 as a pale yellow color solid (40 g, 86%);
Rf (ethyl acetate) 0.2; νmax (CHCl3, cm-1): 3293, 2935, 2869,
1685, 1446, 1364, 1323; δH (400 MHz, DMSO-d6): 7.30 (brs,
1H), 4.80 (brs, 1H), 3.79-3.74 (m, 1H), 3.52-3.41 (m, 2H), 1.63-
1.55 (m, 2H), 1.16 (s, 3H), 1.02 (s, 3H); δC (100 MHz, DMSO-
d6): 174.2, 61.2, 57.3, 33.2, 28.0, 26.9, 21.8, 17.9; HRMS (ESI-
MS): MH+, found 156.1040. C8H14NO2 requires 156.1025.
4.2.6. (1R*,2R*,5S*)-tert-butyl 2-
(hydroxymethyl)-6,6-dimethyl-3-
azabicyclo[3.1.0]hexane-3-carboxylate (rac-28):
To the suspension of lithium aluminium hydride (69.13 g,
1.8193 mol) in dry THF (500 mL) was added rac-26 (47 g, 0.303
mol) in THF (440 mL) at 25-35°C under nitrogen atmosphere.
The reaction mixture temperature was raised to 65°C and
maintained for additional 16 h. Upon completion of reaction (as
indicated by TLC), the reaction mixture was quenched with
saturated aqueous sodium sulfate solution (200 mL). The reaction
mixture was diluted with ethyl acetate (1 L) and filtered through
celite bed. The cake was washed with ethyl acetate (2ꢀ500 mL).
The resulting filtrate was concentrated under reduced pressure
below 50°C to afford the crude material rac-27 which was taken
directly for N–Boc protection (40 g).
4.2.8. (1R*,2S*,5S*)-tert-butyl 2-formyl-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-3-
carboxylate (rac-30):
To a solution of rac-29 (14 g, 0.058 mol) in dichloromethane
(140 mL) was added DBU (4.45 g, 0.0292 mol) under nitrogen
atmosphere at ambient temperature and stirred for 2-3 h. After
the completion of reaction as monitored by TLC, cold water (200
mL) was added to the reaction and both the layers formed were
separated. The aqueous layer was extracted with DCM (100 mL).
The organic layers were combined, washed with brine solution
(100 mL) and concentrated under reduced pressure below 40 °C
to afford the title compound rac-30 (14 g) as pale yellow liquid;
[Note: Compound rac-30 exist as mixture of two conformers, so
Boc2O (68.1 g, 0.312 mol) was added to a solution of rac-27
(40 g, 0.283 mol) in dichloromethane (400 mL) at 25-35°C under
nitrogen atmosphere and stirred for 2 h at the same temperature.
After the completion of reaction as monitored by TLC, the
solvent was concentrated under reduce pressure below 40°C.
Methanol (300 mL) was added to the residue followed by
addition of potassium carbonate (30 g) and the reaction mixture
was stirred for further 1 h at ambient temperature. The solid
obtained was filtered and the cake was washed with methanol (50
mL). The filtrate was concentrated under reduced pressure. The
crude compound was dissolved in DCM (400 mL) and washed
with water (2ꢀ200 mL). The organic layer was dried over
anhydrous sodium sulfate and concentrated under reduced
pressure to get the crude compound which was purified by the
silica gel column chromatography (10-15% ethyl acetate in
hexane) to afford the title compound rac-28 as yellow solid (40g,
55% from rac-26). νmax (CHCl3, cm-1): 3483, 2975, 1676, 1372,
1135, 1031; δH (400 MHz, CDCl3): 5.62 (d, J = 10.2 Hz, 1H),
4.05 (t, J = 5.9 Hz, 1H), 3.81-3.72 (m, 2H), 3.78-3.72 (m, 1H),
3.36 (d, J = 11.7 Hz, 1H), 1.44 (s, 9H), 1.42 (d, J = 2.0 Hz, 1H),
1.23 (t, J = 5.9 Hz, 1H), 1.06 (s, 3H), 0.98 (s, 3H); δC (100 MHz,
1
that every unique H or 13C signal appears pair wise] Rf (20 %
ethyl acetate in hexane) 0.6; νmax (CHCl3, cm-1): 2819, 1730,
1682, 1413, 1388, 1139; δH (400 MHz, CDCl3): δ 9.71 (d, J = 1.2
Hz, 1H), 4.19-4.01 (m, 1H ), 3.76-3.66 (m, 1H), 3.59-3.48 (m,
1H), 1.55-1.33 (m, 11H), 1.09 (s, 3H), 1.05 (s, 3H); δC (100 MHz,
CDCl3): 201.7, 153.8, 81.0, 66.9, 47.0, 32.8, 31.7, 28.2, 28.1,
27.4, 26.5, 20.5, 17.3; HRMS (ESI-MS): MH+, found 240.1606.
C13H22NO3 requires 240.1600
4.2.9. (1R*,2S*,5S*)-3-(tert-butoxycarbonyl)-
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
carboxylic acid (rac-31):
To the mixture of rac-30 (14 g, 0.0585 mol) in acetone (280
mL) was added Jones reagent (42 mL) in acetone (30 mL) under
nitrogen atmosphere at –30 °C. The reaction mixture temperature
was warmed to 0-5 °C and stirred for 1 h. After the completion of
reaction as monitored by TLC, isopropyl alcohol (30 mL) was
added to the reaction mixture and stirred for 1 h at room
temperature. Reaction mixture was filtered through Celite bed

8
Tetrahedron
ACCEPTED MANUSCRIPT
and washed with acetone (20 mL). The filtrate was concentrated
To a solution of Jones reagent (60 mL) in acetone (70 mL)
under reduced pressure below 40 °C. Saturated sodium
bicarbonate solution was added to the residue and washed with
ethyl acetate (2ꢀ100 mL). The pH of the aqueous layer was
adjusted to 3.5 to 3.0 with saturated citric acid solution and
extracted with ethyl acetate (2ꢀ100 mL). The organic layers
were combined and concentrated under reduced pressure below
50 °C to afford the title compound rac-31 as a white colored
solid (8.6 g, 58%); Rf (ethyl acetate) 0.1; νmax (CHCl3, cm-1):
3019, 2981, 1721, 1694, 1414, 1174; δH (400 MHz, DMSO-d6):
12.7 (brs, 1H), 3.92-3.88 (m, 1H), 3.50-3.46 (m, 1H), 3.34-3.23
(m, 1H), 1.36-1.23 (m, 11H), 0.95 (s, 3H), 0.90 (s, 3H); δC (100
MHz, DMSO-d6): 173.6, 152.9, 79.3, 59.4, 46.4, 30.7, 28.3, 26.2,
26.1, 19.0, 12.6; Mass: m/z = 254 [M-H]-
was added rac-28 (10 g, 0.0415 mol) in acetone (70 mL) at 0-5°C
under nitrogen atmosphere. The reaction mixture temperature
was warmed to 25-35°C and stirred for 16 h. The progress of the
reaction was monitored by TLC. Isopropyl alcohol (20 mL) was
added to the reaction mixture and stirred for 1 h at the same
temperature. The reaction mixture was filtered through celite bed
and the cake was washed with acetone (20 mL). The resulting
filtrate was concentrated under reduced pressure below 40°C.
Saturated sodium bicarbonate solution (50 mL) was added to the
residue and it was washed with ethyl acetate (2ꢀ50 mL). The
aqueous layer was acidified with saturated citric acid solution
(pH 3 to 3.5) and extracted with ethyl acetate (2ꢀ75 mL) . The
organic layers were combined and concentrated under reduced
pressure to afford the title compound rac-33 as colorless liquid
(5.0 g, 47.3%); Rf (ethyl acetate) 0.1; δH (400 MHz, CDCl3): 8.5
(brs, 1H), 4.60-4.45 (m, 1H), 3.65-3.61 (m, 1H), 3.47-3.35 (m,
1H), 1.76-1.71 (m, 1H), 1.39 (s, 9H), 1.26-1.24 (m, 1H), 1.05 (s,
3H), 1.02 (s, 3H); δC NMR (100 MHz, CDCl3): 176.7, 173.0,
82.1, 61.5, 48.5, 31.4, 30.9, 28.3, 26.8, 26.3, 20.8, 14.4; Mass:
m/z = 254.0 [M-H]-.
4.2.10. (1R*,2S*,5S*)-3-tert-butyl 2-methyl 6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2,3-
dicarboxylate (rac-32):
To a suspension of rac-31 (8.0 g, 0.313 mol), potassium
carbonate (21.65 g, 0.156 mol) in acetone (240 mL) was added
methyl iodide (22.27 g, 0.156 mol) at ambient temperature under
nitrogen atmosphere and stirred for 16 h. Upon the completion of
reaction (as indicated by TLC), the reaction mixture was filtered
through Celite bed and the cake was washed with acetone (2ꢀ50
mL). The filtrates were combined and concentrated under
reduced pressure below 40 °C. Water (100 mL) was added to the
residue and extracted with ethyl acetate (2ꢀ100 mL). The
organic layers were combined and concentrated under reduced
pressure to obtain the crude product which was purified by silica
gel column chromatography (15% ethyl acetate in hexane) to
afford the title compound rac-32 as colorless liquid (7.1 g,
84.2%); [Note: Compound rac-32 exists as mixture of two
4.2.13. (1R*,2R*,5S*)-3-tert-butyl 2-methyl 6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2,3-
dicarboxylate (rac-34):
To a solution of rac-33 (1.0 g, 0.004 mol) in DMF (10 mL) was
added cesium carbonate (1.78 g, 0.005 mol) followed by addition
of methyl iodide (1.0 g, 0.007 mol) at 25-35°C under nitrogen
atmosphere. The resulting reaction mixture was stirred for 4 h at
the same temperature. After the completion of reaction, cold
water (30 mL) was added to the reaction mixture and extracted
with MTBE (3ꢀ20 mL). The combined organic layers were
washed with brine solution and the organic layer was
concentrated under reduced pressure below 50 °C. The crude
compound was purified by silica gel column chromatography
(10% ethyl acetate in hexane) to afford the title compound rac-34
as a pale yellow liquid (0.35 g, 33%); Rf (30% ethyl acetate in
hexane) 0.6; δH (400 MHz, CDCl3): 4.49-4.42 (m, 1H), 3.72-3.71
(m, 3H), 3.71-3.58 (m, 1H), 3.46-3.37 (m, 1H) 1.69-1.62 (m,
1H), 1.44-1.42 (m, 1H) 1.40 (s, 9H), 1.09 (s, 3H), 0.98 (s, 3H);
δC (100 MHz, CDCl3): 171.5, 154.0, 79.9, 60.3, 51.6, 47.4, 31.7,
28.3, 27.2, 26.8, 26.5, 20.8, 20.7, 14.3; Mass: m/z = 170.0 [M-
Boc+H]+
1
conformers, so that every unique H or 13C signal appears pair
wise26]; Rf (30% ethyl acetate in hexane) 0.6; νmax (CHCl3, cm-1):
2975, 2954, 2930, 1753, 1706, 1390, 1175; δH (400 MHz,
CDCl3): 4.21-4.09 (m, 1H), 3.72 (s, 3H), 3.63-3.53 (m, 1H),
3.47-3.38 (m, 1H), 1.67 (t, J = 7.4 Hz, 1H), 1.47 (m, 1H), 1.45 (s,
9H), 1.10 (s, 3H), 0.99 (s, 3H); δC (100 MHz, CDCl3): 173.1,
153.7, 153.1, 79.9, 59.7, 52.1, 46.4, 31.9, 28.3, 27.3, 26.6, 26.2,
19.3, 12.5; HRMS (ESI-MS): MH+, found 270.1692. C14H24NO4
requires 270.1705.
4.2.11. (1R*,2S*,5S*)-methyl 6,6-dimethyl-3-
azabicyclo [3.1.0]hexane-2-carboxylate
hydrochloride (rac-3•HCl):
4.2.14. (1R*,2S*,5S*)-3-(tert-butoxycarbonyl)-
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
carboxylic acid (rac-31):
To a solution of rac-3 (7 g, 0.026 mol) in 1,4-dioxane (35 mL)
was added 1M HCl in ethyl acetate solution (105 mL) at 10°C
under nitrogen atmosphere. The reaction mixture temperature
was warmed to 25-35°C and stirred for 4 h. After the completion
of reaction as monitored by TLC, the solvent was evaporated
under reduced pressure below 55°C and co evaporated with
toluene (15 mL). The crude product was triturated with MTBE
(20 mL) and the solid was collected by filtration to afford the title
compound as light brown colored solid (5.0 g, 94%); Rf (30 %
To a solution of rac-34 (0.14 g, 0.5 m.mol) in methanol (5
mL) was added sodium methoxide (0.113g, 0.0070 mol) under
nitrogen atmosphere at ambient temperature. Reaction mixture
temperature was heated to reflux and stirred for 16 h. After the
completion of the reaction as monitored by TLC, the solvent was
evaporated under reduced pressure below 50 °C. Cold water (10
mL) was added to the residue and washed with ethyl acetate (10
mL). Aqueous layer was acidified with saturated citric acid
solution (pH 3.0-3.5) and extracted with ethyl acetate (2ꢀ15
mL). The combined organic layers were washed with brine
solution (5 mL) and concentrated under reduced pressure below
50 °C to afford the title compound rac-31 as a off-white colored
solid (0.11 g, 83%); Rf (ethyl acetate) 0.2; νmax (CHCl3, cm-1):
3019, 2981, 1721, 1694, 1414, 1174; δH (400 MHz, CDCl3):
12.7 (brs, 1H), 3.92-3.88 (m, 1H), 3.50-3.46 (m, 1H), 3.34-3.23
(m, 1H), 1.36-1.23 (m, 11H), 0.95 (s, 3H), 0.90 (s, 3H); δC (100
MHz, CDCl3): 173.6, 153.2, 79.3, 59.7, 46.5, 31.6, 30.7, 28.4,
26.9, 26.2, 26.1, 19.0, 12.8; Mass: m/z = 254.1 [M-H] +
ethyl acetate in hexane) 0.6; νmax (CHCl3, cm-1 ): 2564, 1759,
,
1267, 1214, 1029; δH (400 MHz, DMSO-d6): 9.81 (brs, 1H) 4.13
(d, J = 1.6 Hz, 1H), 3.79 (s, 3H), 3.61-3.57 (m, 1H), 3.03 (dd, J =
10.8 Hz, J = 2 Hz, 1H), 1.90-1.87 (m, 1H), 1.74-1.78 (m, 1H),
1.07 (s, 3H), 1.04 (s, 3H); δC (100 MHz, CD3OD): 170.1, 61.4,
54.3, 47.2, 34.4, 30.7, 26.2, 23.5, 14.0; HRMS (ESI-MS): MH+,
found 170.1188, C9H16NO2 requires 170.1181
4.2.12. (1R*,2R*,5S*)-3-(tert-butoxycarbonyl)-
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-
carboxylic acid (rac-33):

9
4.2.15. (1S,3S)-3-(2,2-dichlorovinyl)-2,2-
dimethylcyclopropanecarboxylic acid (19):
hydroxide (150 mL) solution was added followed by 30%
ACCEPTED MANUSCRIPT
hydrogen peroxide solution at 0°C. The reaction mixture
temperature was raised to 25-35°C and stirred for 2 h. Boc2O
(16.6 mL, 0.0699 mol) was added to the reaction mixture at 25-
35 °C and stirred for 1-2 h. The reaction mixture was filtered
through Celite bed and the product was extracted with MTBE
(2ꢀ50 mL). The organic layers were combined, washed with
20% sodium sulfite solution (2ꢀ50 mL), dried over anhydrous
sodium sulfate and concentrated under reduced pressure to get
intermediate 28. The obtained crude product (10 g) was taken for
next step.
To a stirred solution of (R)-phenylethyl amine (63.75 g, 0.526
mol) in isopropanol (2.5 L) was added cis-cypermethric acid rac-
19 (100 g, 0.478 mol) at 25 °C and stirred for 30 min at the same
temperature. The reaction mixture was heated to reflux for 30
min and then slowly cooled to ambient temperature. The solid
product obtained was filtered and recrystallized from IPA (800
mL) to afford the chirally pure salt. The salt was suspended in
water (1.0 L) and the pH of the reaction mixture was adjusted to
2.0-2.5 using 2N HCl. The solid obtained was collected by
filtration, washed with water (100 mL) and dried at 50 °C under
To the solution of alcohol intermediate 28 (10 g, 0.041 mol) in
DCM (200 mL) was added potassium bromide (0.98 g, 0.008
mol) in water (10 mL) at 0-5 °C. TEMPO (0.129 g, 0.00082 mol)
followed by 9% sodium hypochlorite (pH was adjusted 9.3 by
using sodium bicarbonate) was added to the reaction mixture at
0-10 °C and stirring continuously for 10 min. The both layers
formed were separated and the organic layer was washed with
10% aq. sodium thiosulfate (100 mL). 25% of aq. sodium
bisulphite solution (75 mL) was added to the organic layer and
stirred for 7-8 h at 25-35 °C. Both layers formed were separated
and the aqueous layer was washed with MTBE (2ꢀ50 mL).The
pH of the aqueous layer was adjusted to 9.0 using sodium
carbonate and extracted with MTBE (2ꢀ50 mL). The organic
layers were combined and concentrated under vacuum to afford
aldehyde 29 as a light brown color liquid (7.7 g, 55% yield from
20); [Note: Compound 29 exists as mixture of two conformers,
20
vacuum to afford the chirally pure acid 19 (20 g, 40%); [α]589
–
39.40 (c 1.5, CH2Cl2) [lit.27 [α]589 –38.0 (c 1.5, CH2Cl2)]; δH
(400 MHz, CDCl3): 11.3 (brs, 1H), 6.21 (d, J = 8.7 Hz, 1H), 2.10
(t, J = 8.7 Hz, 1H),1.84 (d, J = 8.3 Hz, 1H), 1.28 (s, 3H), 1.27 (s,
3H). Determination of the chiral purity of the product was carried
out by chiral HPLC analysis [Column: Chiralpak-ADH, 250ꢀ4.6
mm, 5 ꢀm particle size; Eluent: 1% TFA in 95:5 n-hexane-
isopropanol; Flow rate: 0.6 mL/min; UV detection at 210 nm;
retention times for 19 and ent-19 were 7.1 and 7.9 minutes
respectively]. Enantiomeric excess of 19 in the product was
>99%.
20
4.2.16. (1S,5R,)-4-(chloromethylene)-6,6-
dimethyl-3-azabicyclo[3.1.0]hexan-2-one (20):
To a suspension of 19 (30.0 g, 0.143 mol) in toluene (60 mL)
and DMF (0.15 mL), thionyl chloride (20.49 g, 0.172 mol) was
added at 25-35 °C under nitrogen atmosphere and stirred for 3 h
at the same temperature. The reaction mixture was added to aq.
ammonia (300 mL) at 0-10 °C and stirred for further 2-3 h at 25
°C. Toluene (240 mL) was added to the reaction mass mixture
and both the layers formed were separated. The aqueous layer
was further extracted with toluene (150 mL).The organic layers
were combined and washed with brine solution and evaporated
under vacuum to afford 22 (26.9 g).
1
so that every unique H or 13C signal appears pair wise] νmax
(CHCl3, cm-1): 2819, 1730, 1682, 1413, 1388, 1139; δH (400
MHz, CDCl3): 9.61 (d, J = 3.4 Hz, 1H), 4.27-4.18 (m, 1H ), 3.68-
3.44 (m, 2H), 1.68-1.65 (m, 1H), 1.51 (m, 1H), 1.40 (s, 9H),
1.15 (s, 3H), 1.01 (s, 3H); δC (100 MHz, CDCl3): 201.8, 153.8,
81.0, 66.9, 47.0, 32.8, 29.3, 28.2, 27.4, 26.5, 26.0, 20.5, 17.3;
HRMS (ESI-MS): MH+, found 240.1603. C13H22NO3, requires
240.1600.
4.2.18. (1R,2S,5S)-3-tert-butyl 2-methyl 6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-2,3-
dicarboxylate (32):
To a stirred solution of 22 (20.39 g, 0.098 mol) in toluene
(180 mL), was added a solution of potassium tert-butoxide
(40.26 g, 0.358 mol) in THF (150 mL) at 25-35 °C under
nitrogen atmosphere and stirred for 2-3 h at the same
temperature. The reaction mixture was quenched with saturated
ammonium chloride solution at 0-10 °C. The both layers formed
were separated and the aqueous layer was further extracted with
toluene (2ꢀ100 mL). The organic layers were combined and
evaporated under vacuum to afford 20 as off white colored solid
(15.1 g, 80% yield from 19); νmax (CHCl3, cm-1): 3226, 1684,
1375; δH (400 MHz, CDCl3): δ 7.26 (brs, 1H), 5.24 (s, 1H), 2.30
(d, J = 5.8 Hz, 1H), 2.11 (dd, J = 4.4 Hz, J = 1.4 Hz, 1H), 1.16 (s,
3H), 1.14 (s, 3H); δC (100 MHz, DMSO-d6): 173.8, 139.0, 89.8,
33.6, 31.3, 26.1, 25.4, 15.2; HRMS (ESI-MS): MH+, found
172.0554. C8H11NOCl requires 172.0529.
To a solution of aldehyde 29 (15 g, 0.063 mol) in methanol
(150 mL) was added potassium carbonate (21.65 g, 0.156 mol)
and the contents were stirred for 3 h at 25 °C. Upon completion
of reaction as indicated by TLC, iodine (16.07 g, 0.063 mol) was
added to the reaction mixture, which was then stirred for 3 h
under dark conditions. 10% sodium thiosulfate solution (150 mL)
was added to the reaction mixture the methanol present was
evaporated under vacuum. The product was extracted with ethyl
acetate (2ꢀ10 mL) and the organic layers were combined,
washed with brine solution and distilled under vacuum to afford
ester 32 (17.2 g crude); [Note: Compound 32 exists as mixture of
1
two conformers, so that every unique H or 13C signal appears
pair wise26]νmax (CHCl3, cm-1): 2975, 2954, 2930, 1753, 1706,
1390, 1175; ; δH (400 MHz, CDCl3): 4.50-4.43 (m, 1H), 3.72 (s,
3H), 3.63-3.53 (m, 1H), 3.47-3.38 (m, 1H), 1.67 (t, J = 7.4 Hz,
1H), 1.47 (m, 1H), 1.45 (s, 9H), 1.10 (s, 3H), 0.99 (s, 3H); δC
(100 MHz, CDCl3): 173.1, 153.7, 79.9, 59.7, 52.1, 46.4, 31.9,
28.3, 27.3, 26.6, 26.2, 19.3, 12.5; HRMS (ESI-MS): MH+, found
270.1696. C14H24NO4 requires 270.1705.
4.2.17. (1R,2R,5S)-tert-butyl 2-formyl-6,6-
dimethyl-3-azabicyclo[3.1.0]hexane-3-
carboxylate (29):
To a stirred suspension of sodium borohydride (9.91 g, 0.262
mol) in THF (140 mL) was added BF3•THF (45% BF3) (41.5 mL,
0.349 mol) at 0 °C under nitrogen atmosphere. The reaction
mixture temperature was raised to 25-35 °C and stirred for 2 h.
The solution of the compound 20 (10 g, 0.058 mol.) in THF (50
mL) was added to reaction at 25 °C and then the reaction mixture
was heated to 50-60 °C and stirred continuously for 2-3 h. The
mixture was cooled to 0-10 °C. The reaction mixture was
quenched with water (100 mL) and then 10% aqueous sodium
4.2.19. (1R,2S,5S)-methyl 6,6-dimethyl-3-
azabicyclo[3.1.0] hexane-2-carboxylate
hydrochloride (3•HCl):
To a solution of ester 32(10.0 g, 0.37 mol) in ethyl acetate (30
mL) was added 1M HCl in ethyl acetate (30 mL) at 0 °C and
stirred for 2 h. Charcoal was added to the reaction mixture and

10
Tetrahedron
ACCEPTED MANUSCRIPT
12. Jacobi, P. A.; Brielmann, H. L.; Hauck, S. I. J. Org. Chem. 1996, 61,
filtered through Celite and then filtrate was concentrated
5013-5023.
under vacuum. The crude product obtained was re-crystallized
from the mixture of IPA-MTBE (1:4) (100 mL) to afford
compound 3 as an off-white colored solid (5.3 g, 70% overall
yield from 29, ee by chiral HPLC analysis >99%). MP: 162-164
°C; νmax (CHCl3, cm-1): 2564, 1759, 1540, 1267, 1214, 1029; δH
(400 MHz, DMSO-d6): δ 9.81 (brs, 1H), 4.13 (d, J = 1.6 Hz, 1H),
3.79 (s, 3H), 3.61-3.57 (m, 1H), 3.03 (dd, J = 10.8 Hz, J = 2 Hz,
1H), 1.90-1.87 (m, 1H), 1.78-1.74 (m, 1H), 1.07 (s, 3H), 1.04 (s,
3H); δC (100 MHz, CD3OD): 170.1, 61.4, 54.3, 47.2, 34.4, 30.7,
26.2, 23.5, 14.0; HRMS (ESI-MS): MH+, found: 170.1182,
C9H16NO2 requires 170.1181. Determination of the chiral purity
of the product was carried out by chiral HPLC analysis [Column:
Chiralpak-IC, 250ꢀ4.6 mm, 5 ꢀm particle size; Eluent: 0.05%
diethylamine in 9:1 n-hexane-ethanol; Flow rate: 0.6 mL/min;
UV detection at 210 nm; retention times for 3 and ent-3 were
18.3 and 13.7 minutes respectively]. Enantiomeric excess of 3 in
the product was >99%.
13. Yamagishi, M.; Nishigai, K.; Hata, T.; Urabe, H. Org. Lett. 2011, 13,
4873–4875.
14. Klemmensen, P. D.; Kolind-Andersen, H.; Madsen, H. B.; Svendsen,
A. J. Org. Chem. 1979, 44, 416–420.
15. (a) Tian, H.; Ermolenko, L.; Gabant, M.; Vergne, C.; Moriou, C.;
Retailleau, P.; Al-Mourabit, A. Adv. Synth. Catal. 2011, 353, 1525–
1533; (b) Gramain, J.-C.; Remuson, R.; Troin, Y. J. Chem. Soc.,
Chem. Commun. 1976, 194-195.
16. Determination of substrate conversion and chiral purity of 19 (either
as a product of hydrolysis or as the unreacted ethyl ester) was
concomitantly carried out by chiral HPLC analysis [Column:
Chiralpak AS-RH, 150ꢀ4.6 mm, 5 ꢀm particle size; Mobile phase
A: 0.1 % trifluoroacetic acid in water; Mobile phase B: 0.1 %
trifluoroacetic acid in acetonitrile; Time/%B: 0/40, 8/60, 8.01/40,
12/40; Flow rate: 1.0 mL/min; UV detection at 210 nm; retention
times for 19 and ent-19 were 5.15 and 5.51 minutes respectively;
retention times for the ethyl esters of 19 and ent-19 were 9.89 and
10.23 minutes respectively].
17. Wallace, D. In The Art of Process Chemistry; Yasuda, N., Ed.;
WILEY-VCH Verlag GmbH & Co. KGaA: Weinheim, 2011; pp.
256-257.
18. While an exact mechanism for the formation of 35 may be difficult
to speculate within the ambit of the present endeavour, instances of
competing enamine reduction during hydroboration-oxidation
reactions are known in the literature; see: (a) Barieux, J.-J.; Gore, J.
Tetrahedron 1972, 28, 1537-1553; (b) Barieux, J.-J.; Gore, J.
Tetrahedron 1972, 28, 1555-1563.
Acknowledgments
We thank Prof. Goverdhan Mehta for his critical comments and
collaboration.
19. (a) Brown, H. C.; Chen, J. J. Org. Chem. 1981, 46, 3978-3988; (b)
Brown, H. C.; Sharp, R. L. J. Am. Chem. Soc. 1968, 90, 2915–2927;
(c) Pasto, D. J.; Hickman, J. J. Am. Chem. Soc. 1967, 89, 5608–
5615.
20. Guercio, G.; Manzo, A. M.; Goodyear, M.; Bacchi, S.; Curti, S.;
Provera, S. Org. Process Res. Dev. 2009, 13, 489–493.
21. McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
Chem. 1993, 58, 3568-3578.
22. Dharanipragada, R.; Alarcon, A.; Hruby, V. J. Org. Prep. Proc. Int.
1991, 23, 396-397.
References and notes
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24. Togo, H.; Iida, S. Synlett. 2006, 2159–2175.
25. X-ray diffraction analysis. X-ray data was collected at 291 K on a
Bruker Kappa APEX II diffractometer with graphite monochromated
MoKα radiation (λ = 0.7107Å). The crystal structure was solved by
direct methods (SIR92) and refined by full-matrix least-squares
method on F2 using SHELXL-97. Crystallographic data have been
deposited with the Cambridge Crystallographic Data Centre. Crystal
data of 3•HCl: C9H16ClNO2, M = 205.68, orthorhombic, P212121, a =
7.3136(11), b = 8.9011(10), c = 16.441(3) Å, V = 1070.3(3) Å3, Z =
4, ρcalcd = 1.276 g/cm3, 4836 reflections measured, 1945 unique (Rint
= 0.0501), R1 = 0.0548 and wR2 = 0.1278 for 1423 observed
reflections, CCDC no. 1526924.
6.
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27. Bicker, W.; Kacprzak, K.; Kwit, M.; Lämmerhofer, M.; Gawronski,
J.; Lindner, W. Tetrahedron: Asymmetry 2009, 20, 1027–1035.
7.
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Tsai, D. J.-S.; Nanfei, Z. PCT Patent Application WO 2007/075790
A1, 2007; Chem. Abstr. 2007, 147:143273.
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Supplementary Material
Experimental details of BC-esterase and Esterase V mediated
hydrolysis of cis-cypermethric acid ethyl ester, selected entries
from the experiments directed towards optimizing the
hydroboration of 20, 1H and 13C NMR spectra of all key
compounds reported herein, and detailed information on the
crystal structure of 3•HCl.
10. Nariyam, S. M.; Bhalerao, D. S.; Dahanukar, V. H.; Oruganti, S.;
Rapolu, R. K.; Kandagatla, B.; Iqbal, J.; Khobare, S. R.; Kallam, S.
R.; Banda, M.; Garare, V. S.; Eda, V. V. R. PCT Patent Application
WO 2013/190509 A2, 2013; Chem. Abstr. 2013, 160:118032.
11. As will be demonstrated ahead, (1S)-cis-cypermethric acid 19 can be
conveniently obtained by chiral resolution of cis-cypermethric acid
rac-19, a widely employed synthetic precursor of many pyrethroid
class of insecticides.