A scalable synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3. 1.0]hexane-3-carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2013.09.114

A stereoselective and scalable synthesis of (1R,3S,5R)-2-(tert- butoxycarbonyl)-2-azabicyclo[3.1.0]hexane-3-carboxylic acid (3a) is described. Key to the success of the devised route was the realization that the stereoselectivity of a cyclopropanation ste

Full text of DOI:10.1016/j.tetlet.2013.09.114

Tetrahedron Letters 54 (2013) 6722–6724
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Tetrahedron Letters
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A scalable synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-
2-azabicyclo[3.1.0]hexane-3-carboxylic acid
⇑
Gan Wang , Clint A. James, Nicholas A. Meanwell, Lawrence G. Hamann, Makonen Belema
Department of Discovery Chemistry, Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A stereoselective and scalable synthesis of (1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-
ane-3-carboxylic acid (3a) is described. Key to the success of the devised route was the realization that
the stereoselectivity of a cyclopropanation step could be controlled by the composition of the functional
Received 13 September 2013
Accepted 24 September 2013
Available online 1 October 2013
group at C-a.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropanation
Epimerization
Equilibration
Methanoproline
Oxidative decarboxylation
As part of an effort directed toward developing structure–activ-
ity relationships and addressing sites of potential metabolism asso-
ciated with an HCV NS5A inhibitor class of compounds, a need
arose for an efficient and scalable route to trans-methanoproline
3a.1,2 Two distinct routes to 3a have been reported previously by
Hanessian’s group (Scheme 1), each with its own drawbacks when
considered for the current purpose.3,4 In the first route, involving a
unique stannane-based cyclopropanation methodology, the alkyl-
ation step in going from 1 to 2 exhibited poor stereoselectivity
and the processing of 2a on scale created concern in light of the
documented toxicities of organostannanes.3,5 In the second
approach, a Simmons-Smith–Furukawa (SSF) cyclopropanation of
dihydropyrrole 5a followed by Boc2O treatment, to reinstall the
Boc group which apparently was deprotected during the reaction,
afforded a 1:4 mixture of 6a and 6b, with the desired trans-isomer
6a as the minor component.4,6
reaction temperature was lowered from 0 °C to À23 °C and chloroi-
domethane was used in place of diiodomethane—we observed that
the trans/cis ratio changed from the 1:4 reported by Hanessian to
ꢀ1:11 and that the Boc group survived the reaction conditions.7
The stereoisomers were separated by flash chromatography to
afford trans-6c and cis-6d in 7.7% and 84% yield, respectively.8 Ester
cis-6d was then subjected to epimerization studies, where combi-
nations of base and solvent were surveyed, as summarized in
Table 1. Treatment with lithium bis(trimethylsilyl)amide in THF
at À78 °C followed by allowing the reaction mixture to warm to
room temperature over 4 h resulted in the formation of trans-6a
in only trace quantities. The use of sodium ethoxide in ethanol at
room temperature for 24 h also had a similar outcome. However,
after additional experimentation, it was discovered that treatment
with potassium tert-butoxide in t-BuOH/THF at room temperature
for 7 h effected the desired epimerization where trans-6a was
isolated in 27% yield, along with the recovery of the starting mate-
rial (cis-6d) in 43% yield. Extending the reaction time from 7 h to
14 h had no noticeable effect on isomer ratio or isolated yields.
Clearly, the efficiency of the epimerization step was less than desir-
able and it was not clear at this juncture if the observed ratio favor-
ing the starting cis isomer was reflective of the attainment of a
complete equilibration. In order to probe this question, trans-6a
was ubjected to the same epimerization conditions and, interest-
ingly, here again cis-6d was isolated as the dominant isomer with
similar yield, which indicated that the result obtained when 6d
was used as a substrate is likely an equilibrium ratio. It should
be noted that LC/MS analysis of the reaction mixture indicated
the presence of 610% of t-Bu transesterified derivatives of
unknown stereochemical composition, and this side reaction along
In light of the cis-stereoselectivity reported by Hanessian in
applying SSF-cyclopropanation to dihydropyrrole 5a, we consid-
ered the feasibility of conducting a similar cyclopropanation on
the enantiomer of 5a (i.e., 5b) instead—this would preferentially
set first the desired cyclopropyl stereoconfiguration—and then epi-
merizing the C-
a center of the expected dominant isomer (6d) to
afford the desired ester 6a (see Scheme 2). Initially, it was reasoned
that under equilibrated conditions the epimerization of 6d may
favor the trans isomer 6a.
When applying to 5b
a slightly modified version of the
SSF-cyclopropanation protocol utilized by Hanessian—where the
⇑
Corresponding author.
E-mail address: gan.wang@bms.com (G. Wang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.09.114

G. Wang et al. / Tetrahedron Letters 54 (2013) 6722–6724
6723
Me3Sn
Me3Sn
+
O
O
O
N
Boc
N
Boc
N
Boc
OR
OR
OR
Separate
&
elaborate
1
O
O
2b
2a
(23%)
(63%)
N
Boc
N
Boc
OH
OH
or
3b
3a
CO2Et
CO2Et
CO2Et
CO2Et
O
N
N
Boc
N
Boc
6a
N
Boc
6b
+
Boc
4a
5a
Scheme 1. Highlights of literature synthesis of methanoprolines 3a and 3b.
C-α
because of the unfavorable stereochemical outcome of the equil-
ibration step, which thus stimulated the development of an alter-
nate route. In thinking through the potential reasons behind the
cis selectivity of the SSF-cyclopropanation of dihydropyrrole 5a
or 5b, it was reasoned that the ester group may play a role by
chelating the putative ‘IZnCH2Cl’ species to promote delivery to
the alkene moiety on the same-face as the ester. Thus a question
arose as to what would happen if the ester moiety of 5a was re-
placed by a bulkier silylether (as in 9 in Scheme 3), which would
be less likely to chelate the putative zinc species while its in-
creased steric bulk should impart greater trans-facial selectivity.9
The investigation that resulted from this line of reasoning indeed
proved fruitful.10
CO2Et
CO2Et
CO2Et
CO2Et
N
Boc
N
Boc
6d
N
Boc
6c
?
N
Boc
5b
6a
(R)
Isolate 6d & epimerize
Scheme 2. First generation route to ester 6a.
Table 1
Results from equilibration studies
CO2Et
N
CO2Et
Silyl ether 8, which was readily prepared from the commercially
available alcohol 7 under a combination of standard protection
protocols, was first partially reduced by LiEt3BH and the aminal
dehydrated with the assistance of trifluoroacetic acid anhydride
to afford dihydropyrrole 9 in 82–89% yield.7,11 Treatment of 9 with
iodochloromethane and diethylzinc in toluene at À17 °C for 18 h
provided a mixture of trans 10a and cis 10b in P25 to 1 ratio.
The desired trans-isomer 10a was isolated by flash chromatogra-
phy in a gratifying 83% yield, along with <2% of impure cis-isomer
10b.7 For expediency, however, we found it more convenient to ad-
vance the mixture of isomers resulting from the SSF-cyclopropana-
tion step through the next two reactions and then remove the
minor isomer through recrystallization at the final stage. Thus,
the silyl group of 10a/10b was deprotected using TBAF and the
resultant alcohol 11a/11b was oxidized with ruthenium(III) chlo-
ride and sodium periodate to afford a 1.00:0.04:0.18 mol ratio
(1H NMR) of trans acid 3a: cis acid 3b: pyrrolidinone 12, an oxida-
tive-decarboxylation side product whose structural assignment
was supported by 1H/13C NMR and mass spectral analyses. The
desired acid 3a was isolated in 59% yield from alcohol 11a/11b
after recrystallization.12 This route was readily scaled up to afford
>100 g of acid 3a with high stereochemical purity.
N
Boc
6a
Boc
6d
Conditions surveyed
Starting isomer
Result
LiHMDS (1.0 equiv), THF,
À78 °C to rt in 4 h
cis-6d
Trace trans-6a observeda
NaOEt (1.0 equiv), EtOH,
rt, 24 h
cis-6d
Trace trans-6a observeda
t-BuOK (0.13–0.17 equiv),
t-BuOH/THF, rt, ꢀ7 h
cis-6d
46% cis-6d; 27% trans-6ab
48% cis-6d; 31% trans-6ab
trans-6ac
a
The remaining component is mainly the starting cis-isomer.
Isolated yields.
This study was done on the enantiomer of 6a, which should be inconsequential
b
c
for the current purpose.
with some saponification that likely occurs as the result of adven-
titious water would account for the remaining mass balance of the
reaction.
Although the epimerization route afforded sufficient quanti-
ties of trans-6a that could be elaborated to acid 3a to meet the
initial demand for material, it was not a scalable process, in part
OTBDPS
OTBDPS
OH
OTBDPS
(i)
Ref. 11
(ii)
N
O
N
H
O
N
Boc
8
N
Boc
Boc
10a (trans, 83%)
9
7
10b
(cis, <2%)
(iii)
O
OH
(iv)
O
+
O
N
Boc
N
Boc
+
N
N
Boc
OH
OH
Boc
12
in crude material: 1.00/0.04/0.18
3a
3b
11a/b (trans/cis)
1
3a/3b/12
H NMR ratio of
Scheme 3. Reagents and conditions: (i) LiEt3BH, DIEA, DMAP, TFAA, À55 to À50 °C, 82–89%; (ii) Et2Zn, ICH2Cl, Toluene, À17 °C, 84%; (iii) TBAF/THF, rt, 94%; (iv) RuCl3, NaIO4,
CCl4/ACN/H2O, rt, 59%.

6724
G. Wang et al. / Tetrahedron Letters 54 (2013) 6722–6724
Wang, C.; Knipe, J. O.; Chien, C.; Colonno, R. J.; Grasela, D. M.; Meanwell, N. A.;
In summary, we have investigated two approaches to the syn-
Hamann, L. G. Nature 2010, 465, 96.
thesis of trans-methanoproline 3a and uncovered in the process
two noteworthy chemical findings. First, in an attempt to epimer-
ize cis-6d to trans-6a, or vice versa, the equilibrium mixture that is
established actually favors the cis isomer. Second, the trans/cis
selectivity of an SSF-cyclopropanation of a Boc-dihydropyrrole
2. Wilfret, D.; Walker, J.; Adkison, K; Jones, L.; Lou, Y.; Gan, J.; Castellino, S.;
Moseley, C.; Horton, J.; de Serres, M.; Culp, A.; Goljer, I.; Spreen, W. Antimicrob.
Agents Chemother. 2013, doi: http://dx.doi.org/10.1123/AAC.00910-13.
3. Hanessian, S.; Reinhold, U.; Gentile, G. Angew. Chem., Int. Ed. 1997, 36, 1881–
1884.
4. Hanessian, S.; Reinhold, U.; Saulnier, M.; Claridge, S. Bioorg. Med. Chem. Lett.
1998, 8, 2123–2138.
5. (a) Buck, B.; Mascioni, A.; Que, L., Jr.; Veglia, G. J. Am. Chem. Soc. 2003, 125,
13316; (b) Boyer, I. J. Toxicology 1989, 55, 253–298. and references cited
therein.
moiety is dependent on the composition of its C-
a functional
group, where the trans/cis stereochemical outcome changes from
1:11 to P25:1 by replacing an ester group with a silyl ether. The
latter finding has enabled us to devise a highly stereoselective
and scalable synthesis of trans-methanoproline 3a.
6. (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966, 28, 3353–
3354; (b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron 1968, 24, 53–
58.
7. Vu, T. C.; Brzozowski, D. B.; Fox, R.; Godfrey, J. D., Jr.; Hanson, R. L.;
Kolotuchin, S. V.; Mazzullo, J. A., Jr.; Patel, R. N.; Wang, J.; Wong, K.; Yu, J.;
Zhu, J.; Magnin, D. R.; Augeri, D. J.; Hamann, L.G. World Patent Application
WO 2004/052850.
8. Cis-6d elutes ahead of trans-6c from a silica gel column. It is noteworthy
that the 1H NMR signals of trans-6c in DMSO-d6 were relatively broader
than that of cis-6d, which might be suggestive of differential
conformational rigidity.
Acknowledgements
We thank Xiaohua Huang, a member of the Bristol-Myers
Squibb analytical chemistry group, for conducting NMR analyses.
Supplementary data
9. After the conclusion of our work, Komarov and co-workers communicated
that treatment of
a methyl ester variant of dihydropyrrole 5a with
difluorocarbene, generated from CF2ClCO2Na/diglyme at 177 °C, afforded
only the trans-cyclopropanated product in 71% yield: Kubyshkin, V. S.;
Mykhailiuk, P. K.; Afonin, S.; Ulrich, A. S.; Komarov, I. V. Org. Lett. 2012, 14,
5811–5814.
Supplementary data (detailed experimental procedures for the
route illustrated in Scheme 2 along with supporting spectral data
and an epimerization protocol to prepare trans-6a from cis-6d, or
vice versa) associated with this article can be found, in the online
version, at http://dx.doi.org/10.1016/j.tetlet.2013.09.114.
10. Bachand, C.; Belema, M.; Deon, D. H.; Good, A. C.; Goodrich, J.; James, C. A.;
Lavoie, R.; Lopez, O. D.; Martel, A.; Meanwell, N. A.; Nguyen, V. N.; Romine, J. L.;
Ruediger, E. H.; Snyder, L. B.; St. Laurent, D. R.; Yang, F.; Langley, D. R.; Wang,
G.; Hamann, L. G. World Patent Application WO 2009/102325.
11. Bunch, L.; Norryby, P.; Frydenrang, K.; Krogsgaard-Larsen, P.; Madsen, U. Org.
Lett. 2001, 3, 433–435.
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