Ugi and Passerini reactions of biocatalytically derived chiral aldehydes: Application to the synthesis of bicyclic pyrrolidines and of antiviral agent telaprevir

Article abstract of DOI:10.1021/jo502829j

Lipase mediated desymmetrization of a meso-diol (1,2-cyclopentanedimethanol) allows the synthesis of both enantiomers of some chiral aldehydes, whose behavior in Passerini and Ugi reactions has been explored. Exploiting these two complementary multicomponent reactions and coupling them with a subsequent cyclization process, we observed that 6 out of all 8 possible stereoisomers of peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been proved by the development of a new efficient synthesis of antiviral drug telaprevir.

Full text of DOI:10.1021/jo502829j

Subscriber access provided by DALHOUSIE UNIV
Article
UGI AND PASSERINI REACTIONS OF BIOCATALYTICALLY DERIVED
CHIRAL ALDEHYDES: APPLICATION TO THE SYNTHESIS OF
BICYCLIC PYRROLIDINES AND OF ANTIVIRAL AGENT TELAPREVIR
Lisa Moni, Luca Banfi, Andrea Basso, Luca Carcone, Marcello Rasparini, and Renata Riva
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502829j • Publication Date (Web): 11 Mar 2015
Downloaded from http://pubs.acs.org on March 12, 2015
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 62
The Journal of Organic Chemistry
1
2
3
4
5
UGI AND PASSERINI REACTIONS OF BIOCATALYTICALLY DERIVED CHIRAL
ALDEHYDES: APPLICATION TO THE SYNTHESIS OF BICYCLIC PYRROLIDINES AND
OF ANTIVIRAL AGENT TELAPREVIR
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
a
a
b
b
a*
Lisa Moni, Luca Banfi, Andrea Basso, Luca Carcone, Marcello Rasparini, and Renata Riva
a
Department of Chemistry and Industrial Chemistry, University of Genova, via Dodecaneso 31 ꢀ
6146 Genova, Italy. Eꢀmail: riva@chimica.unige.it
1
b
Chemessentia Srl, via Bovio 6, 28100 Novara, Italy
Table of contents
1
) Desymmetrization
H
Telaprevir
2) Passerini or
N
R1
HO
OH
Ugi reaction
N
3) Cyclization
O
all possible
O
R2
stereoisomers
Abstract
Lipase mediated desymmetrization of a meso diol (1,2ꢀcyclopentanedimethanol) allows the
synthesis of both enantiomers of some chiral aldehydes, whose behaviour in Passerini and Ugi
reactions has been explored. Exploiting these two complementary multicomponent reactions, and
coupling them with a subsequent cyclization process, 6 out of all 8 possible stereoisomers of
peptidomimetic pyrrolidines can be obtained in good yields. The potential of these protocols has been
proved by the development of a new efficient synthesis of antiviral drug Telaprevir.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Introduction
Isocyanideꢀbased multicomponent reactions (IMCRs) have become very popular in recent years
1
2
especially in the diversityꢀoriented synthesis of libraries of drug candidates. Although the advantages
of high stepꢀ and atomꢀeconomy associated with these methodologies should make them also well
suited to targetꢀoriented synthesis, their exploitation in the total synthesis of Active Pharmaceutical
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3ꢀ6
Ingredients (APIs) has been much less explored, probably because the literature reports typically deal
with the synthesis of racemic substances from simple commercially available building blocks. The
"real" drugs often call for chiral, enantiomerically pure, components, (wrongly) perceived too complex
7
,8
to be used in multicomponent chemistries. Biocatalysis is a "green" and efficient methodology to
prepare chiral building blocks. Our group has been active for nearly 30 years in this field and recently
reported on the utilization of biocatalytically derived building blocks in diastereoselective isocyanideꢀ
9
ꢀ11
based multicomponent reactions.
7,8
In particular, monoesters 2 derived from desymmetrization of meso or prochiral diols 1 are
quite interesting, being convertible into aldehydes 3 and 5 (through the azide 4) or into cyclic imines 6
1
2
(through intramolecular StaudingerꢀAzaꢀWittig
reaction) (Scheme 1). In addition, the
complementarity of enzymatic monoacylation / monohydrolysis and the intrinsic stereodivergency of
these building blocks gives access to both enantiomeric series. Cyclic imines 6 have been subjected to
UgiꢀJoullié tricomponent reactions, which are often stereoconservative (proceeding with no
1
1,13
epimerization) and diastereoselective.
On the other hand, the use of aldehydes 3 or 5 as starting
component in IMCRs is unprecedented. We will therefore describe herein our latest results in this field,
culminated in a new synthesis of important antiꢀviral drug Telaprevir.
ACS Paragon Plus Environment

Page 3 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME
1.
Enzymatically
derived
chiral
building
blocks
for
IMCRs
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
*
*
*
*
*
*
HO
OH
O
OH
O
N3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R
R
1
2
4
O
O
*
*
*
*
*
*
O
O
N
O
N3
R
3
6
5
O
Results and Discussion
1
4,15
We chose as the meso diol for our studies the known cyclopentane derivative 7 (Scheme 2),
1
6ꢀ18
which was best prepared by reduction of cisꢀ1,2ꢀcyclopentanedicarboxylic anhydride.
From this
diol we obtained in high e.e. both enantiomers of monoacetate 8 by using either an enzymatic
acetylation or the complementary enzymatic monohydrolysis of the diacetate of 7. After optimization,
both enantiomers could be obtained in high enantiomeric excess (e.e.) (97% for 8 and 95% for entꢀ8). It
19ꢀ21
20
is worth noting that, although both monohydrolysis
and monoacetylation have been already
reported with other enzymes, in our hands the e.e.s were not fully satisfactory and we had to test
various enzymes and conditions before obtaining the best results. In particular, monoacetylation of 7
® 22
was best carried out by Amano PS lipase supported on Celite .
The following studies were carried out on the (1R,2S) isomer entꢀ8. Oxidation to the aldehyde
entꢀ9 was carried out under Swern conditions. This aldehyde was found to be rather sensitive to
epimerization and afforded the more stable trans isomer. However, by using N,Nꢀ
diisopropylethylamine as the base and performing a rapid workꢀup at pH 4 (in order to remove all the
base before evaporation) we were able to obtain diastereomerically pure entꢀ9. The stereochemical
integrity was checked by BH reduction followed by GC analysis. Due to this lability, the crude
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
23,24
aldehyde was directly submitted to a model Ugi reaction
with nꢀbutyl isocyanide, propionic acid
and pꢀmethoxybenzylamine (PMBꢀNH ). The reaction proceeded in good yield, but with poor
2
diastereoselectivity, affording a 1:1 mixture of the two diastereomers 10a,b. We later demonstrated
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
after conversion into 12a,b) that they were not the expected cis compounds, but the trans ones instead
(
a thorough discussion on the relative configuration is reported after discussion of the Passerini
approach).
SCHEME 2. Ugi approach to transꢀfused bicyclic pyrrolidines
vinyl acetate,
supported Amano PS
lipase, 0 °C, 17 h
9
7%
HO
OH
AcO
OH
7
8
a) Ac O, Et N, CH Cl , rt, 1 h
2
3
2
2
b) phosphate buffer (pH 7)/THF,
Amano PS lipase, 20 °C, 21 h
78%
n-BuNC, EtCO H,
p-MeOC H CH NH ,
2
(
COCl) DMSO, Et(iPr) N,
2
,
2
6 4 2 2
CH Cl , –70 °C
trifluoroethanol, rt, 48 h
3% from ent-8
2
2
PMB
Et
7
AcO
OH
AcO
O
AcO
HN
nBu
N
ent-8
ent-9
O
O
10a,b
a:b = 1:1
a) CAN, CH CN/H O, rt, 1 h
3
2
b) KOH, MeOH, rt, 1 h
3%
8
5
4
3
6
Imd SO , NaH, DMF, 0 °C, 2 h
2
2
a
6a
N 1
H
+
H
N
N
81%
nBu
nBu
HO
HN
nBu
NH
Et
3
N
O
O
a:
b:
=
=
O
O
Et
O
Et
O
12a
12b
11a,b
Since only two diastereomers were detected, epimerization on carbon 6a (12a,b) was complete.
We can rule out that the epimerization occurred during the oxidation, because the stereochemical
integrity of entꢀ9 was demonstrated by GCꢀMS analysis on the crude Swern product (after reduction to
the corresponding alcohol by means of BH ) before submitting it to the Ugi reaction. In addition it
3
ACS Paragon Plus Environment

Page 5 of 62
The Journal of Organic Chemistry
1
2
3
should be noted that incubation of aldehyde entꢀ9 in the same solvent with a tertiary amine
triethylamine) for 48 h led to only partial epimerization. Therefore we think that this complete
epimerization is due to imineꢀenamine equilibrium and not to simple base mediated deprotonation of
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
25
26
the aldehyde. This result is in agreement with the pioneering work by Kelly, who noticed partial
epimerization of αꢀchiral aldehydes during Ugi reactions. In our case complete conversion into trans
isomers indicates that they should be much more stable.
Anyway, adducts 10a,b could be useful intermediates for preparing heterocycles through SN2
27
cyclizations.
By removing the pꢀmethoxybenzyl group and the acetate we obtained
chromatographically separable alcohols 11a,b. Then, substitution of the OH group by one of the two
secondary amides to give either a sixꢀmembered or a fiveꢀmembered ring was attempted both on the
diastereomeric mixture or on the isolated isomers. Initial experiments, involving formation of a
mesylate followed by base treatment, were unsuccessful. We eventually found that 1,1'ꢀsulfonyl
2
8ꢀ30
diimidazole in combination with NaH
only pyrrolidines were formed in good yields and no loss of stereochemical integrity was observed
each isomer afforded a single product). Separation of the diastereomers was easier at this level and
was able to promote the desired cyclization. Interestingly,
(
therefore, under a synthetic point of view, it was more convenient to carry out the whole synthesis on
the mixture. Even though the trans bicyclic derivatives 12a,b are quite strained and therefore less
thermodinamically stable than the corresponding cis ones (12c,d, Scheme 3), we did not observe any
epimerization: this is due to the lack of an electron withdrawing group bound to the stereogenic center,
which makes the deprotonation, responsible for the epimerization, unlikely.
In conclusion this synthetic protocol was able to afford the final adducts 12a,b in good overall
yields and is complementary to the synthesis of pyrrolidines through the UgiꢀJoullié reaction of
11,13
bicyclic imines, which affords cisꢀfused products instead.
all four transꢀfused pyrrolidines can be prepared.
Since monoacetate 8 is available as well,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
In order to gain access to the cisꢀfused series as well, we turned our attention to the Passerini
2
3,24
31
reaction,
which was expected to be less troublesome in terms of epimerization.
In this case we chose to start from azidoaldehyde 14 instead of acetoxyaldehyde 9. Passerini
reactions of aldehyde 9 would afford doubly acylated diols, where the two ester moieties were expected
to be difficult to differentiate, on the basis of preliminary experiments carried out by us on similar
adducts. An alternative strategy would involve the hydrolysis of both esters to give a diol, followed by
double substitution of the corresponding dimesylate by ammonia or a synthetic equivalent of it, to give
a pyrrolidine. However, in our hands this approach was found to be inefficient, due to the easy
formation of a tetrahydrofuran. Therefore, we decided to differentiate the two arms before the Passerini
step, converting monoacetate 8 into azidoaldehyde 14 (Scheme 3) through a straightforward procedure,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
already applied by us in similar cases.
Pleasingly, azidoaldehyde 14 underwent a model Passerini reaction with nꢀbutyl isocyanide and
propionic acid in high yield and, most importantly, with no epimerization at all. The whole sequence
from monoacetate 8 to compounds 15a,b can be carried out without any intermediate purification and
with an excellent overall yield (88%). Unfortunately, adducts 15 were obtained as a nearly 1:1
separable diastereomeric mixture. In order to obtain pyrrolidines 12 from these adducts, we carried out
a twoꢀstep protocol involving: a) azide reduction with concomitant acyl migration; b) S 2 cyclization
N
of the resulting secondary amide onto the secondary alcohol. Starting from 15a, both steps worked out
in excellent yields to give pyrrolidine 12c as a single isomer.
ACS Paragon Plus Environment

Page 7 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME 3. Passerini approach to cisꢀfused bicyclic pyrrolidines
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a) MsCl, Et N, 0 °C, 1 h
3
b) NaN , DMF, 90 °C, 17 h
(COCl) , DMSO,
3
2
c) KOH, MeOH, rt, 1 h
Et N, CH Cl , −78 °C
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
AcO
OH
N3
OH
N3
O
8
13
14
n-BuNC, EtCO H,
2
CH Cl , rt, 16 h
2
2
88% (from 8)
a) MsCl, Et N,
CH Cl , –10 °C, 1h
b) NaH, DMF, 0 °C, 1 h
3
PPh , THF/H O,
3 2
2
2
60 °C, 6 h
see text
O
85% (16a),
91% (16b)
O
HN
N3
HO
O
HN
HN
O
nBu
nBu
Et
O
Et
1
6a,b
15a,b
a:b = 1:1
n-BuNC, EtCO H,
2
a:
b:
c:
d:
=
=
=
=
CH Cl , rt
2
2
H
N
nBu
N
N
O
6a
Et
O
1
2c,d
The first stage resembles the PADAM (Passerini – amine deprotection – acyl migration) protocol,
where the acyl group introduced onto the aldehyde oxygen during the Passerini reaction, undergoes a
subsequent O to N acyl migration to give peptidomimetic structure. This protocol was first introduced
3
2
33
by us starting from αꢀaminoaldehydes, and was recently extended to βꢀaminoaldehydes. Now
aldehyde 14 is equivalent to a γꢀaminoaldehyde and therefore the results reported here further extend
the scope of the strategy. As far as the cyclization step is concerned, in this instance 1,1'ꢀsulfonyl
diimidazole worked poorly and the best cyclization yields were obtained by mesylation of the alcohol
followed by baseꢀmediated cyclization. Under these conditions the yield of 12c from 16a was 91%.
However, when we repeated the cyclization on epimer 16b, we surprisingly obtained a 2.7:1
mixture of 12c (major) and 12d (minor). Clearly, while 16a reacts in a stereospecific manner (most
likely with complete inversion of configuration), 16b gives a non stereospecific transformation. The
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
reaction of 16b is also slower and some unreacted mesylate of 16b is recovered. Therefore a possible
explanation is that, being cyclization of the mesylate of 16b sluggish, there is enough time for it to
equilibrate to 16a, which, by contrast, reacts faster. The equilibration may take place through baseꢀ
mediated enolization. Thus a mixture of 16a and 16b could be cyclized to give mostly 12c, which was
isolated in pure diastereomeric form in 73% yield! Also a small amount (10%) of 12d was obtained.
This means that 12c can be produced in a stereoconvergent way with an overall yield of 55% from
monoacetate 8.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The relative and absolute configuration of adduct 12c, obtained through the Passerini route
described in Scheme 3, was unambiguously established by comparison with the major product obtained
3
4
through UgiꢀJoullié reaction of cyclic imine 6a, prepared as previously described, with propionic acid
and nꢀbutyl isocyanide. This reaction afforded, as major product, compound 12c, that was identical
(
NMR, TLC, [α] ) with the one obtained from 16a. The UgiꢀJoullié reaction also gave a small amount
D
of allꢀcis compound 12d (d.r. = 92:8). This was identical (NMR, TLC) with the minor adduct obtained
from 16b (as above described, 16b afforded a mixture of 12c and 12d). The UgiꢀJoullié reactions on 6a
13
were already demonstrated to afford preferentially, with high d.r., the trans adducts. Since isomers
1
2a and 12b, obtained through the Ugi route described in Scheme 2, were clearly different from 12c
and 12d (NMR, TLC), although having spectroscopic and MS data consistent with the same
constitutional formula, the 3aꢀ6a relative configuration must necessarily be trans.
1
The 1ꢀ6a relative configuration of 12a and 12b was established by the values of J1ꢀ6a at H NMR.
This value is larger (9.9 Hz) for allꢀtrans isomer 12a than for 1ꢀ6a cis epimer 12b (7.8 Hz.). Moreover,
in 12b there is a large nOe between Hꢀ1 and Hꢀ6a, which is not possible in 12a. To further corroborate
these assumptions, we carried out a minimization using ChemBio3D Ultra (CambridgeSoft)(PM3).
These bicyclic systems were found to be quite rigid: apart from conformations deriving from rotation
of the single bonds outside the ring, only one significant conformation of the bicyclic system was
ACS Paragon Plus Environment

Page 9 of 62
The Journal of Organic Chemistry
1
2
3
found. The calculated dihedral angles (Hꢀ1 ꢀ Hꢀ6a) for the four isomers are: −159.3 ° (12a), −36.2 °
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
12b), 122.7 ° (12c), 12.7 ° (12d), which are consistent with the experimental J values.
In conclusion the complementarity of Ugi and Passerini reactions, and the availability of both 8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
and entꢀ8 allowed us to prepare in good yields 6 out of 8 possible stereoisomers of pyrrolidines 12, the
remaining two, namely 12d and entꢀ12d, being accessible only in low yield. The number of steps from
desymmetrized monoacetates 8 or entꢀ8, is comparable, for both routes, to an alternative approach to
pyrrolidines, previously demonstrated by us on similar substrates, where monoacetates are first
1
1
converted into pyrrolines, followed by the UgiꢀJoullié multicomponent reaction. Moreover the here
described approaches are stereochemically more versatile, since 6 stereoisomers (instead of 2) may be
obtained. Finally, the procedure herein avoids the intermediacy of pyrrolines, which are sometimes not
easily manipulated due to their tendency to polymerize.
As a first application of this methodology, we decided to develop a new efficient synthesis of an
important API, Telaprevir 17 (Scheme 4). This compound is one of the most innovative drugs launched
3
5,36
during the last ten years.
It is indeed one of the two first specific drugs directed against Hepatitis C,
a severe and widely distributed disease. Approximately 170 million people worldwide are chronic
carriers of this virus (2% of the world's population). The biological target of Telaprevir is a specific
viral serine protease, and it is effective for genotype 1 of the virus. Although the treatment of HCV
with antiviral drugs is still quite expensive, it is anticipated that the advent of generic drugs will
strongly lower the cost, making this drug available to a larger population, especially in lessꢀdeveloped
countries. For this purpose, costꢀeffective syntheses of this active principle are needed, and
multicomponent reactions can be a good way to achieve this goal, as already demonstrated by Ruijter
5
and others.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SCHEME 4. Initially planned retrosynthesis of Telaprevir 17
O
H
O
N
H
H
N
N
O
N
O
O
N
H
H
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
O
N
N
N
N
N
N
O
N
H
O
H
17
18
O
O
O(P)
CN
O(P)
N3
O
H
N
1
4
O
N
21
H
N
O
N
N
O
OH
N
H
O
H
N
N
N
O
N
H
O
1
9
O
20
The planned retrosynthesis is shown in Scheme 4. Telaprevir can be obtained through a Passerini
reaction on aldehyde 18, which derives from protected alcohol 19. We wanted to prepare intermediate
19 in a very convergent way, employing the same strategy above described for the simple model 12c,
which has the same absolute and relative configuration of our target. 19 Could be in principle obtained
5
in just two linear steps after the Passerini reaction of peptide 20 with azidoaldehyde 14 and a suitably
protected isocyanide 21 derived from Lꢀαꢀaminopentanoic acid. In order to check the feasibility of this
approach, we initially used nꢀbutyl isocyanide as a simplified model for 21.
However, the reaction of peptide 20 with aldehyde 14 and nꢀbutyl isocyanide failed to give the
expected Passerini product. Under the typical Passerini conditions, 20 was nearly completely converted
into the corresponding oxazolone 22 (Scheme 5).
ACS Paragon Plus Environment

Page 11 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME 5. Attempted Passerini reaction employing acid 20
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
H
N
N3
nBu
O
OH
O
O
O
N3
H
N
14
H
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
N
N
N
N
N
H
O
N
H
O
O
n-BuNC
O
20
O
O
H
N
N
N
N
N
N
N
H
N
H
O
O
O
O
O
22
HO
nBu
N
N3
We think that αꢀaddition to the isocyanide takes place normally, to give the usual intermediate.
However, at this level, the activated acyl group is attached by the oxygen of the amide bond between
cyclohexylglycine and tertꢀleucine. This reaction is evidently faster than the usual acyl migration onto
the free hydroxy group. Formation of this type of oxazolones is a well known problem encountered
3
7
during coupling of peptide acids. However, these compounds are not isolated, since they can still
react with amines to give amides, their intermediate formation being deemed responsible of
racemization/epimerization of the obtained coupling product. In this case, the absence of a good
nucleophile like an amine makes this adduct stable enough to be isolated.
It is interesting to note that the behavior of acid 20 is specific for the Passerini reaction, since it
5
can be used as input in UgiꢀJoullié reactions without any problems, as reported by Ruijter et al., and
confirmed by us as well.
Thus we had to redesign our synthesis, employing as the carboxylic component, Boc protected Lꢀ
tertꢀleucine, with the intention to add later the other fragments (Scheme 6). The Passerini reaction of 22
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
with aldehyde 14 (prepared once again by Swern oxidation of alcohol 13) proceeded in good
unoptimized) yield to give 23a,b (a:b 42:58). However, the next Staudingerꢀacyl migration protocol
(
turned out to be troublesome. Probably because of the steric bulk of the acyl residue, migration was
sluggish, required the addition of a base and the yield was unacceptably low.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Thus, we decided to shift to the route depicted on the left (Scheme 6), which involves the same
number of steps and is based on a "truncated" Passerini reaction followed by azide reduction and
31
acylation. Among the various reported methods for performing "truncated" Passerini, the best results
3
8,39
were obtained using boric acid.
The resulting alcohols 24a,b were then straightforwardly converted
into 25a,b in good yield, proving that this second pathway was definitely more efficient. This time the
a:b diastereomeric ratio was 59:41, therefore slightly favoring the correct isomer for Telaprevir
synthesis. Anyway, the final cyclization was carried out on the diastereomeric mixture, being confident
in the stereoconvergent conversion into 26. Actually this isomer was isolated in good yield, whereas
only traces of the epimer could be detected. Finally, the complete peptide chain was smoothly installed
to afford 27. We found out that a stepwise introduction of the remaining two fragments was more
efficient, because of partial epimerization observed when the preꢀassembled dipeptide was directly
used.
ACS Paragon Plus Environment

Page 13 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME 6. Synthesis of model peptide 27
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
L-Boc-tert-Leucine, n-BuNC, CH Cl , rt, 20 h
2
2
59% from 8
O
N3
O
N3
1
4
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
HN
nBu
n-BuNC, CH CN,
H BO , rt, 48 h
a) PPh , THF/H O, 60 °C, 4 h
O
NH
Boc
3a,b
3
3
2
b) Et N, rt, 60 h
3
3
3
67% from 8
29%
2
a:b = 42:58
a) PPh , THF/H O, 70 °C, 3 h
3
2
b) L-Boc-tert-Leucine, NMM, PyBOP, rt, 60 h
O
69%
O
N3
HN
HO
HO
NH
HN
HN
nBu
a) MsCl, Et N, CH Cl , 0 °C, 1 h O
nBu
3
2
2
b) NaH, DMF, 0 °C, 1 h
Boc
24a,b
25a,b
51%
a:b = 59:41
a) TFA, CH Cl , rt, 1 h
2
2
b) L-Boc-cyclohexylglycine,
PyBOP, NMM, CH Cl , rt, 3.5 h
2
2
H
H
N
c) TFA, CH Cl , rt, 1 h
N
nBu
2
2
nBu
d) pyrazinecarboxylic acid, PyBOP,
NMM, CH Cl , rt, 3.5 h
89%
O
N
N
O
2
2
O
N
BocHN
N
O
O
2
7
26
H
O
a:
b:
=
=
N
Having proved on model compounds that the key intermediate could be accessed by the truncated
Passerini protocol, we moved on to apply it to the synthesis of Telaprevir. Towards this goal we needed
chiral, enantiomerically pure, protected isocyanides 33 or 34, that were prepared starting from
commercially available Lꢀαꢀaminopentanol 28 (Scheme 7).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SCHEME 7. Synthesis of αꢀaminopentanol derived isocyanides
HCO Et, reflux,
Bz O, Et(iPr) N, DMAP,
2 2
2
H
N
H
overnight
CH Cl , –10 → 10 °C
H N
2
H
2 2
H
N
OH
OH
OBz
9
9%
90%
O
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28
29
30
a) BnCl, NaH, THF, 70 °C
b) HCl, i-PrOH, acetone
POCl , Et N,
3 3
CH Cl , –30 °C
2
2
53%
quant.
HCO Et, Et N, reflux,
POCl , Et N, CH Cl ,
2
3
3
3
2
2
H
N
overnight
–30 °C
H N
3
H
CN
OBn
OBn
OR
quant.
88%
Cl
O
31
32
33: R = Bz
34: R = Bn
In the case of 33 we introduced first the formyl group and then the benzoyl protection, whereas
for 34 it was better to introduce first the benzyl ether and then to formylate the amine. In both cases
dehydration gave in high yields the required isocyanides.
We first employed isocyanide 33 (Scheme 8). The synthesis proceeded even better than for the
model compound. Actually, not only the truncated Passerini gave a nearly quantitative yield (after
solvent optimization) but it turned out to be more diastereoselective, giving a 2:1 mixture of 35a and
35b. After introduction of protected Lꢀtertꢀleucine, cyclization was also in this case stereoconvergent.
However, while the cyclization of the mesylate of pure 36a gave good results under the usual
conditions (NaH, DMF), in the case of 36a,b we needed to optimize the reaction, finding that the best
conditions involved lithium hexamethyldisilazide (LiHMDS) in THF. Under these conditions, only
isomer 37 was isolated in 63% yield along with 12% of the unreacted mesylate derived from 36b.
Attempts to obtain a complete conversion increasing the reaction times or the amount of base failed,
due to fragility of the benzoate under basic conditions. The pyrrolidine 37 was finally converted into
alcohol 39 by sequential acylations and deprotection.
ACS Paragon Plus Environment

Page 15 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME 8. Synthesis of key intermediate 40 through the "benzoate" route
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a) PPh , THF/H O, 70 °C, 3 h
b) L-Boc-tert-Leucine, NMM,
3
2
3
3, CH Cl /CH CN,
2
2
3
H BO , rt, 15 h
PyBOP, rt, 24 h
3
3
92%
O
78%
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N3
O
N3
1
4
HO
HN
35a,b
a:b = 66:34
OBz
a) MsCl, Et N, CH Cl , 0 °C → rt, 2 h
b) LiHDMS, THF, 0 °C, 1 h (for 36a,b) or
NaH, DMF, 0 °C, 1 h (for pure 36a)
3
2
2
OBz
H
N
O
63% (from 36a,b), 78% (from pure 36a)
HN
N
HO
NH
O
O
HN
BocHN
a:
b:
=
=
O
OBz
37
Boc
36a,b
a) TFA, CH Cl , 0 °C → rt, 1 h
b) L-Boc-cyclohexylglycine,
PyBOP, NMM, CH Cl , rt, 2 h
2
2
2
2
OR
H
N
c) TFA, CH Cl , 0 °C → rt, 1 h
d) pyrazinecarboxylic acid,
PyBOP, NMM, CH Cl , rt, 2 h
2
2
O
N
H
O
2
2
N
N
N
75%
N
O
H
O
K CO ,
38 R = Bz
39 R = H
2
3
MeOH, rt, 2 h
0%
9
The incomplete conversion into the cyclization product prompted us to explore an alternative
route to 39, using the more robust benzyl protection, and hence isocyanide 34 (Scheme 9). Moreover,
we thought that the synthesis of azidoaldehyde 14 through Swern oxidation at −78 °C could have not
been ideal for large scale production.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
SCHEME 9. Synthesis of key intermediate 40 through the "benzyl" route
a) TEMPO, PhI(OAc)2,
a) PPh , THF/H O, 70 °C, 2 h
3 2
CH Cl , rt, 2.5 h
b) L-Boc-tert-Leucine, NMM,
2
2
addition of 34, rt, 22 h
PyBOP, rt, 60 h
O
c) KOH, MeOH, rt, 1 h
89% (from 13)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N3
OH
N3
13
HO
HN
40a,b
a:b = 1:1
OBn
a) MsCl, Et N, CH Cl , 0 °C → rt, 1 h
3
2
2
OBn
b) NaH, DMF, 0 °C, 1 h
H
N
65%
O
HN
N
HO
NH
O
O
HN
BocHN
a:
b:
=
=
O
OBn
42
Boc
4
1a,b
a) TFA, CH Cl , 0 °C → rt, 1 h
2
2
b) L-Boc-cyclohexylglycine,
PyBOP, NMM, CH Cl , rt, 2 h
OBn
2
2
H
9
4%
N
N
H
O
N
BocHN
O
O
43
a) H , Pd/C, MeOH/H O/AcOH
2
2
OH
b) TFA, CH Cl , 0 °C → rt, 1 h
2 2
H
N
c) pyrazinecarboxylic acid, PyBOP,
NMM, CH Cl , rt, 2 h
O
N
2
2
H
O
76%
N
N
N
N
H
O
O
39
Recently, various methods for the oneꢀpot conversion of alcohols into Passerini adducts by in situ
4
0ꢀ42
oxidation have been reported. The reagents used are oꢀiodoxybenzoic acid (IBX),
DessꢀMartin
5
43
periodinane, or dioxygen in presence of suitable catalysts. However none of these conditions seemed
4
4
suitable in our case: IBX is poorly soluble and reported to be shock sensitive, DessꢀMartin
ACS Paragon Plus Environment

Page 17 of 62
The Journal of Organic Chemistry
1
2
3
periodinane is quite expensive and its reactions are typically slow, and the catalytic oxidation with
dioxygen requires an excess of isocyanide. Therefore we searched for a stoichiometric oxidant that
would be commercially available, safe, affordable, and compatible with a subsequent oneꢀpot Passerini
reaction. We eventually found out that iodosobenzene diacetate (DIB) in the presence of catalytic
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
5
TEMPO radical ((2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) was ideal for our purposes. This reagent is
4
6
commercially available, not expensive and safe. The oxidation reaction of 13 is fast enough (2.5 h)
and it works very well in the same solvent that is appropriate for the Passerini reaction (CH Cl ),
2
2
allowing an easy oneꢀpot procedure. The presence of acetic acid as an oxidation byꢀproduct does not
allow to perform a truncated Passerini, but the acetyl group can be easily removed, without any
intermediate workꢀup, after the MCR. In this way, crude alcohols 40a,b were obtained in quantitative
yield from alcohol 13.
The crude mixture was pure enough to be used directly for the ensuing step to give 41a,b.
Finally, cyclization afforded pure diastereomer 42 in 65% yield (58% overall yield from azidoalcohol
13!). It is worth noting that the cyclization yield was higher compared to the "benzoate" route, despite
the lower diastereoselectivity of the Passerini reaction. Equilibration of the two mesylates, leading
stereoconvergently to 42 was more efficient in this case, thanks to the higher stability of the benzyl
protecting group under basic conditions. Pyrrolidine 42 was finally converted into alcohol 39. This time
we preferred to remove the benzyl protection before installing the piperazine fragment. The overall
yield of 39 from azido alcohol 13 was 41%, compared to 34% with the "benzoate" route. Both
pathways are efficient, but the "benzyl" route is in our opinion better also because of the higher
operational simplicity.
To complete the synthesis of Telaprevir, alcohol 39 had to be oxidized and subjected to a
Passerini reaction with cyclopropyl isocyanide. We first chose to use the "oneꢀpot" oxidationꢀPasserini
4
7
using DIB and catalytic TEMPO. However, the relative volatility of cyclopropyl isocyanide and its
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
unpleasant smell makes its purification troublesome. This prompted us to explore the possibility to
prepare in situ the isocyanide as well. In the literature we could find very few examples of this
4
8,49
strategy,
but none of them seemed suited for our purposes. After various attempts, we found out
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
50
that the method of choice employed in situ prepared Burgess reagent. The crude isocyanide solution
obtained in this way can be directly used without the need of troublesome purification operations. We
believe that the here reported method for the generation of a crude isocyanide to be directly used
without any purification may find widely application in IMCRs. In this way we were able to obtain
Passerini adduct 44 (Scheme 10) through in situ generation of both the aldehyde (from the alcohol) and
the isocyanide (from the formamide). However, the yield turned out to be only moderate. Therefore we
searched for other oxidation methods, again avoiding those requiring expensive or unsafe reagents. We
eventually found that an excellent overall yield (84%) of the two steps (oxidationꢀPasserini) could be
51
achieved by using the Parikh–Doering method, although in this case a brief extractive workꢀup of the
intermediate aldehyde had to be performed prior to treatment with the in situ generated isocyanide. The
twoꢀstep conversion of Passerini adduct 44 into Telaprevir was finally carried out as previously
5
described.
ACS Paragon Plus Environment

Page 19 of 62
The Journal of Organic Chemistry
1
2
3
SCHEME 10. Completion of Telaprevir synthesis
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a) TEMPO, PhI(OAc) , CH Cl , rt, 2.5 h
b) in situ prepared cy-PrNC, AcOH,
2
2
2
CH Cl , rt, 18 h
2
2
OH
58%
H
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
or
c) SO ⋅pyridine, DMSO, –10 °C
O
N
3
H
O
b) in situ prepared cy-PrNC,
N
N
N
N
O
AcOH, CH
2
Cl
2
, rt, 18 h
H
39
84%
O
a) K CO , MeOH
2
3
OAc H
N
b) Dess-Martin periodinane, CH Cl
2
2
Telaprevir
H
17
8
0%
N
O
N
O
H
O
N
N
N
H
O
44
O
N
In conclusion we were able to set up a convenient synthesis of Telaprevir, also amenable for
upscaling, from desymmetrized monoacetate 8. The overall yield from this biocatalytically derived
chiral building block is a remarkable 26.4%. From the stereochemical point of view, all three
stereogenic centers are fully controlled thanks to the enantioselective enzymatic desymmetrization and
to the stereoconvergent cyclization step that overcomes the low diastereoselectivity of the Passerini
reaction. Although the synthetic pathway is longer and less convergent than the one reported by Ruijter
5
and others, all steps are operationally simple and employ inexpensive reagents. Furthermore, the
biocatalytic step makes use of a cheap and commercially available lipase, avoiding the preparation and
maintenance of a specific bacterial culture to produce the needed proprietary MAOꢀN enzyme
(
MonoAmine Oxidase). Finally, this synthetic approach allowed us to deeply explore the behaviour of
chiral aldehydes derived from enzymatic desymmetrization of meso diols in Passerini and Ugi reactions
and our findings (including the capability to obtain all possible stereoisomers of a given pyrrolidine)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
can be precious for the preparations of other heterocycles and other biologically active
peptidomimetics. Scheme 11 reviews the four alternative strategies based on IMCRs to access chiral
13
pyrrolidines. They are: the desymmetrization of meso pyrrolidines followed by UgiꢀJoullié reaction;
the desymmetrization of meso diols followed by conversion into both enantiomers of pyrrolines and
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
1
again by UgiꢀJoullié reaction; the Ugi and Passerini approaches described in this paper. Studies
directed to the application of IMCRs to aldehydes derived from other desymmetrized meso diols are in
progress.
SCHEME 11. Comparison of the various strategies for the stereocontrolled synthesis of bicyclic
pyrrolidines
lipase
enzymatic
this work
desymmetrization
(Ugi route)
O
HO
OH
HO
OAc
HO
N
HN
H
HN
R1
both enantiomers
accessible
R2
O
MAO-N enzymatic
desymmetrization
1 enantiomer
this work
(Passerini route)
accessible
N3
OH
Ugi-Joullié
H
H
N
R1
O
N
R1
N3
N
N
N
HO
O
HN
R1
O
R2
O
R2
O
1
diastereoisomer
accessible
2 diastereoisomers
accessible
Experimental Section
General Experimental Methods.
1
13
NMR spectra were taken at r.t. in CDCl or in d ꢀDMSO at 300 MHz ( H), and 75 MHz ( C), using, as
3
6
1
1
internal standard, TMS ( H NMR in CDCl ; 0.000 ppm) or the central peak of DMSO ( H NMR in d ꢀ
3
6
1
3
DMSO; 2.506 ppm) or the central peak of CDCl ( C in CDCl ; 77.02 ppm), or the central peak of
3
3
ACS Paragon Plus Environment

Page 21 of 62
The Journal of Organic Chemistry
1
2
3
13
DMSO ( C in d ꢀDMSO; 39.43 ppm). Chemical shifts are reported in ppm (δ scale). Peak assignments
6
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
were made with the aid of gCOSY and gHSQC experiments. In ABX system, the proton A is
considered upfield and B downfield. NMR spectra of Nꢀacylpyrrolidines and of Ugi adducts have
always been recorded at various temperatures. At temperatures ≤ 40 °C, two sets of signals are often
detected, because of the presence of a mixture of rotamers at the tertiary amide (M = major, m =
minor). At high temperature (120 °C) coalescence is observed, demonstrating that the two sets of
signals are due to conformers (and not to diastereomers or different products). However, since at 120°C
several signals become broad, we preferred to report and describe here the spectra recorded at low
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
52
temperatures.
IR spectra were recorded as solid, oil, or foamy samples, with the ATR (attenuated total reflectance)
technique or as CHCl solutions. TLC analyses were carried out on silica gel plates and viewed at UV
3
(λ=254 nm or 360 nm) and developed with Hanessian stain (dipping into a solution of
(NH ) MoO ·4H O (21 g) and Ce(SO ) ·4H O (1 g) in H SO (31 mL) and H O (469 mL) and
4
4
4
2
4 2
2
2
4
2
warming). R values were measured after an elution of 7–9 cm. HRMS was performed by employing
f
electron
impact
ionization;
the
analyzer
is
a
trisector
magnetic
Sector
(electrostatic/magnetic/electrostatic EBE mass spectrometer). GCꢀMS analyses were performed on
column HPꢀ1, 0.33 ꢁm, 0.201 mm i.d., 12 m. Analysis conditions are as follows: solvent delay 2 min,
mass range 33–600, injector temperature 250 °C, detector temperature 280 °C, MS temperature around
1
70 °C, starting temperature 50 or 70 °C, starting time 2 min, temperature gradient 20 °C/min, final
temperature 260 °C, flux through column 1.0 mL/min, split ratio 100:1, sample concentration 1
mg/mL, amount injected 1 ꢁL. Column chromatography was done with the "flash" methodology by
using 220–400 mesh silica. Petroleum ether (40–60 °C) is abbreviated as PE. All reactions employing
dry solvents were carried out under nitrogen.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
1S,2R)ꢀ2ꢀ(Hydroxymethyl)cyclopentyl)methyl acetate 8. Supportation of Amano PS Lipase. It was
®
supported on Celite following the same procedure already described by us for Pig Pancreatic Lipase
2
2
(SPPLꢀ4). (1 g of this supported enzyme corresponds to 0.23 g of original Lipase). To a solution of
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
mesoꢀdiol 7 (5.00 g, 38.4 mmol, 87% purity by GC) (obtained by LiAlH reduction of cisꢀ
4
1
6ꢀ18
cyclopentaneꢀ1,2ꢀdicarboxylic anhydride)
in vinyl acetate (190 mL) cooled to 0 °C, freshly
activated powered 3 Å molecular sieves (0.50 g) and supported Amano PS (3.25 g) were added. The
reaction mixture was stirred at 0 °C for 17 h, then filtered through a sintered funnel and washed with
CH Cl (100 mL). The filtrate was concentrated and the residue was eluted from a column of silica gel
2
2
with PEꢀEt O (from 2:1 to 1:3) to give 8 (6.39 g, 97%, e.e. = 97%) as an oil. R = 0.56 (PEꢀEt O 1:2).
2
f
2
21 1
[
α] +7.30 (c=2.13, CHCl ). Lit. for (1R,2S) enantiomer: −8.2. H NMR (CDCl , 25 °C): δ = 4.03 and
D
3
3
4
.12 (AB part of an ABX system, J = 11.0, J = 6.9, JBX = 7.4 Hz, 2 H, CH OAc), 3.56 and 3.66
AB AX 2
(AB part of an ABX system, J = 10.9, J = 6.8, J = 7.5 Hz, 2 H, CH OH), 2.35 (hexuplet, 1 H, J =
AB AX BX 2
7.2 Hz, CH), 2.23 (hexuplet, 1 H, J = 7.4 Hz, CH), 2.07 (s, 3 H, CH ), 1.98 (br s, 1H, OH), 1.36ꢀ1.87
3
13
(m, 6 H, 3 CH ). C NMR (CDCl , 25 °C): δ = 171.2 (CO), 65.2 (CH ), 63.2 (CH ), 44.0 (CH), 39.7
2
3
2
2
(CH), 28.8 (CH ), 27.9 (CH ), 23.0 (CH ), 21.0 (CH ). IR (ATR): ν = 3415, 2953, 2873, 1736, 1716,
2
2
2
3
−
1
+
1
4
453, 1392, 1367, 1236, 1029, 971 cm ; GCꢀMS (initial temp: 70 °C): R = 5.77 min; m/z: 129 (M –
t
3, 7.0%), 112 (7.5), 111 (23), 97 (7.3), 94 (22), 93 (14), 91 (6.1), 83 (11), 82 (61), 81 (69), 80 (12), 79
(44), 77 (5.5), 70 (14), 69 (7.0), 68 (25), 67 (79), 66 (5.6), 61 (17), 57 (13), 55 (14), 54 (14), 53 (8.5),
+
4
1
4 (11), 43 (100), 41 (22), 39 (11). HRMS (EI) m/z: [M] Calcd for C H O 172.1099; Found
9
16
3
72.1101.
(1R,2S)ꢀ2ꢀ(Hydroxymethyl)cyclopentyl)methyl acetate entꢀ8. A solution of mesoꢀdiol 7 (1.99 g, 15.4
mmol) in dry CH Cl (30 mL) at room temperature was treated with triethylamine (8.5 mL, 61.5
2
2
mmol), 4ꢀdimethylaminopyridine (0.38 g, 3.1 mmol) and acetic anhydride (3.6 mL, 38.4 mmol). The
ACS Paragon Plus Environment

Page 23 of 62
The Journal of Organic Chemistry
1
2
3
mixture was stirred at room temperature for 1 h, then it was treated with saturated aq NaHCO solution
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
80 mL) and extracted with CH Cl (100 + 50 +50 mL). The combined organic phases were washed
2 2
with brine (50 mL), dried (Na SO ), and concentrated. The residue was eluted from a column of silica
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
19ꢀ21
gel with PEꢀEt O (from 3:1 to 2:1) to give the diacetate
(3.20 g, 97%) as an oil. A suspension of
this diacetate (2.61 g, 12.18 mmol) in THF (8.7 ml) was treated with 1 M pH 7 phosphate buffer
K HPO /KH PO ) (87 ml), at 20 °C, and then with Amano PS lipase (550 mg). The suspension was
2
(
2
4
2
4
stirred at 20 °C for 21 h. The mixture was saturated with NaCl, diluted with AcOEt and filtered through
a celite cake, washing thoroughly with AcOEt. The phases were separated and the organic phase dried
(Na SO ), and concentrated. The residue was eluted from a column of silica gel with PEꢀEt O (1:1 to
2
4
2
2
1
1
:2) to give entꢀ8 (1.68 g, 80%, e.e. 95%) as an oil. [α] –7.20 (c=2.27, CHCl ). Lit.: –8.2. The other
D
3
spectroscopic data were identical to those of enantiomer 8.
Determination of e.e.s of 8 and entꢀ8. A solution of monoacetate 8 (4.0 mg, 23.8 ꢁmol) in dry CH Cl
2
2
(1 mL) was cooled to 0 °C and treated with DMAP (5.8 mg, 47.6 ꢁmol) and (R)ꢀαꢀmethoxyꢀαꢀ
trifluoromethylphenylacetyl chloride (6.7 ꢁL, 35.7 ꢁmol). The mixture was allowed to reach room
temperature for 50 min, then it was concentrated. The crude was purified by preparative TLC (PEꢀEt O
2
1
2
:1) to give the corresponding Mosher ester as an oil (7 mg, 0.025 mmol, 76%). HꢀNMR analysis
allowed determination of e.e.s through integration of CH OCO signals.
2
(2S,1'R,2'R)
and
(2R,1'R,2'R)
2ꢀ(2ꢀ(Acetoxymethyl)cyclopentyl)ꢀNꢀbutylꢀ2ꢀ(Nꢀ(4ꢀ
methoxybenzyl)propionamido)acetamides 10a,b. To a solution of DMSO (0.62 mL, 8.70 mmol) in
dry CH Cl (20 ml), at −70 °C under nitrogen atmosphere, a solution of oxalyl chloride in dry CH Cl
2
2
2
2
(1.43 M, 4.5 mL) was added. The solution was stirred for approx. 10 min, until effervescence ceased. A
solution of entꢀ8 (0.60 g, 3.48 mmol) in dry CH Cl (10 + 4 ml) was added dropwise, and the solution
2
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was stirred for 10 min at –70 °C. N,NꢀDiisopropylethylamine (2.80 mL, 16.35 mmol) was then added
and the solution was stirred for 2 h at –70 °C and 1.5 h at –50 °C. After this time the reaction mixture
was poured into a mixture of 5% aq. (NH )H PO (70 mL) and 1 M HCl (5 mL) (final pH = 4) and
4
2
4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
extracted with CH Cl (100 + 30 ml). The organic layer was washed with saturated aq NaHCO
3
2
2
solution (20 mL), water (2 x 20 mL) and brine (20 mL), dried (Na SO ) and concentrated. The resulting
2
4
crude aldehyde entꢀ9 was at once taken up in trifluoroethanol (7 mL) and treated with freshly activated
Å powdered molecular sieves (87 mg), pꢀmethoxybenzylamine (644 ꢁL, 4.93 mmol), propionic acid
4
(315 ꢁL, 4.22 mmol) and nꢀbutylisocyanide (441 ꢁL, 4.22 mmol). The reaction mixture was stirred at
room temperature for 48 h, then the molecular sieves were filtered away and the solvent evaporated.
The residue was eluted from a column of silica gel with PEꢀAcOEt (4:1 → 1:1) to give 10a,b (1.14 g,
73%) as a 54:46 mixture of diastereoisomers (HPLC analysis; Synergi HydroꢀRP 150x3 mm, 4ꢁm,
temp. 21 °C, flow = 0.4 mL/min, mobile phase H O/CH CN from 90:10 to 0:100 in 30 min. R (a) =
2
3
t
2
0.52 min, (b) = 21.08 min). Note that the relative configuration has not been assigned at this level.
Therefore we do not know if 10a is the precursor of 11a or of 11b. R = 0.18 (PEꢀEt O 1:2) (the two
f
2
1
diastereomers were not separated); H NMR (CDCl , 25 °C): δ = 7.04 (a+b) (dd, J = 8.4 (o), 4.8 (m)
3
Hz, 2 H, ArH), 6.82 (a+b) (dd, J = 8.4 (o), 2.7 (m) Hz, 2 H, ArH), 6.50 (a+b) (broad s, 1 H, NH), 4.68
and 4.53 (a+b) (AB syst., J = 17.1 Hz, 2 H, CH ꢀPMB), 4.61ꢀ4.46 (a+b) (m, 1 H, CHꢀN), 4.04 and
2
4
.90 (a) (AB part of ABX syst., J = 12.9, J = 4.8, J = 7.2 Hz, 1 H, CH ꢀOAc), 3.87 and 3.70 (b)
AB AX BX 2
(AB part of ABX syst., JAB = 10.8, JAX = 4.5, JBX = 8.4 Hz, 1 H, CH ꢀOAc), 3.79 (a) (s, 1.5 H, OMe),
2
3
.78 (b) (s, 1.5 H, OMe), 3.23ꢀ2.97 (a+b) (m, 2 H, CH NH), 2.57 (a+b) (center of m, 1 H, Hꢀ1), 2.47ꢀ
2
2
.19 (a+b) (m, 2 H, COCH CH ), 2.06 (a) (s, 1.5 H, COCH ), 2.02 (b) (s, 1.5 H, COCH ), 1.91 (a+b)
2
3
3
3
(centre of m, 1 H, Hꢀ2), 1.87ꢀ1.45 (a+b) (m, 6 H, Hꢀ3, Hꢀ4, Hꢀ5), 1.50ꢀ1.38 (a+b) (m, 2 H,
CH CH NH), 1.34ꢀ1.25 (a+b) (m, 2 H, CH CH CH NH), 1.10 (a) (t, J = 7.5 Hz, 1.5 H, COCH CH ),
2
2
2
2
2
2
3
3
1
1
.09 (b) (t, J = 7.5 Hz, 1.5 H, COCH CH ), 0.91 (a+b) (t, J = 7.2 Hz, 3 H, CH CH CH CH NH). C
2
3
3
2
2
2
ACS Paragon Plus Environment

Page 25 of 62
The Journal of Organic Chemistry
1
2
3
NMR (CDCl , 25 °C): δ = 176.7 and 176.6 (a+b) (CO), 171.2 and 171.1 (a+b) (C =O), 170.1 and
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
1
69.9 (a+b) (C =O), 158.8 (a+b) (Cq), 129.2 and 129.1 (a+b) (Cq), 127.7, 127.4, 114.0 and 113.9
(a+b) (aromatic CH), 67.3 (a+b) (CH ꢀOAc), 62.7 (a+b) (CHꢀN), 55.3 (a+b) (OMe), 48.9 (a+b)
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(
(
(
(
CH ꢀPMB), 41.9 (a) (Cꢀ2), 40.3 (b) (Cꢀ1), 39.8 and 39.7 (a+b) (Cꢀ2), 39.0 (a+b) (CH NH), 31.4
2
2
a+b) (CH CH NH), 29.8, 29.6, 29.4 and 29.3 (a+b) (Cꢀ3 and Cꢀ5), 27.52 and 27.48 (a+b)
2
2
COCH CH ), 24.5 and 24.2 (a+b) (Cꢀ4), 21.1 and 21.0 (a+b) (COCH ), 20.1 (a+b)
2
3
3
CH CH CH NH), 13.8 (a+b) (CH CH CH CH NH), 9.6 and 9.5 (a+b) (COCH CH ). IR (ATR): ν =
2
2
2
3
2
2
2
2
3
3312, 2955, 2872, 1737, 1675, 1625, 1586, 1540, 1513, 1462, 1416, 1364, 1303, 1232, 1175, 1110,
−1
+
1
4
080, 1031, 973, 808, 738, 605 cm . HRMS (EI) m/z: [M] Calcd for C H N O 446.2781; Found
25 38 2 5
46.2780.
(2S,1'R,2'R)
and
(2R,1'R,2'R)
NꢀButylꢀ2ꢀ(2ꢀ(hydroxymethyl)cyclopentyl)ꢀ2ꢀ
(propionamido)acetamides 11a and 11b. To a solution of 10a,b (0.60 g, 1.34 mmol) in CH CNꢀH O
3
2
(3:1, 16 mL) at room temperature, was added CAN (ceric ammonium nitrate) (2.95 g, 5.37 mmol). The
reaction mixture was stirred at room temperature for 1 h, then diluted with H O (25 mL). After
2
evaporation of most CH CN, the aqueous phase was extracted with AcOEt (100 + 40 mL), washed
3
with saturated aq Na CO (25 mL) and with brine (25 mL), dried (Na SO ), and concentrated. This
2
3
2
4
crude was taken up in MeOH (8 mL) and added, at room temperature, with KOH (0.11 g, 2.01 mmol).
The reaction mixture was stirred at room temperature for 1 h, then treated with saturated aq NH Cl
4
solution (30 mL). After evaporation of most MeOH, the pH was adjusted to 5ꢀ6 by addition of 1 M HCl
solution, and the aqueous phase was extracted with AcOEt (100 + 50 mL), washed with brine (10 mL),
dried (Na SO ), and concentrated. The residue was eluted from a column of silica gel with PEꢀAcOEt
2
4
(1:1 → 0:1) containing 1% of MeOH to give 11a,b (315 mg, 83%) as a mixture of diastereoisomers.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Analytical samples of pure diastereomers were obtained by careful chromatography with AcOEtꢀ
MeOH 99:1.
1
1a (white solid): R = 0.26 (AcOEtꢀMeOH 99:1). M.p. = 164.5ꢀ167.0 °C. [α] +19.9 (c=1.22, MeOH).
f
D
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H NMR (DMSOꢀd , 40 °C): δ = 7.84 (t, J = 5.4 Hz, 1 H, NHBu), 7.71 (d, J = 8.4 Hz, 1 H, NHꢀCH),
6
4.58 (t, J = 4.8 Hz, 1 H, OH), 4.07 (t, J = 8.4 Hz, 1 H, NHꢀCH), 3.35ꢀ3.16 (m, 2 H, CH OH), 3.15ꢀ2.92
2
(
m, 2 H, NHCH ), 2.12 (m, 2 H, CH of Et), 1.84 (center of m, 2 H, Hꢀ2, H ꢀ1), 1.64ꢀ1.22 (m, 10 H, Hꢀ
2 2
3
, Hꢀ4, Hꢀ5, 2 CH of Bu), 0.99 (t, J = 7.5 Hz, 3 H, COCH CH ), 0.87 (t, J = 6.9 Hz, 3 H, CH of Bu).
2 2 3 3
1
3
C NMR (DMSOꢀd , 40 °C): δ = 172.4, 170.9 (CO), 64.6 (CH ꢀOH), 55.9 (CHꢀNH), 43.7 and 43.5 (Cꢀ
6
2
1
and Cꢀ2), 37.9 (CH NH), 30.9 (CH CH NH), 29.4 and 29.0 (Cꢀ3 and Cꢀ5), 28.2 (COCH CH ), 24.2
2 2 2 2 3
(Cꢀ4), 19.3 (CH CH CH NH), 13.4 (CH CH CH CH NH), 9.7 (COCH CH ). IR (ATR): ν = 3396,
2
2
2
3
2
2
2
2
3
3
9
281, 3096, 2936, 2869, 1633, 1541, 1462, 1367, 1340, 1275, 1229, 1179, 1152, 1121, 1056, 1023,
−
1
+
47, 892, 783, 711, 636 cm . HRMS (EI) m/z: [M] Calcd for C H N O 284.2100; Found 284.2096.
15
28
2
3
1
1b (white solid): R = 0.33 (AcOEtꢀMeOH 99:1). M.p. = 187.0ꢀ189.9 °C; [α] –29.80 (c=1.00,
f
D
1
MeOH). H NMR (DMSOꢀd , 40 °C): δ = 7.80 (t, J = 5.4 Hz, 1 H, NHBu), 7.69 (d, J = 8.7 Hz, 1 H,
6
NHꢀCH), 4.35 (t, J = 4.9 Hz, 1 H, OH), 4.26 (dd, J = 8.7, 6.9 Hz, 1 H, NHꢀCH), 3.33 (dt, J = 10.2 (d),
4
.9 (t) Hz, 1 H, CH ꢀOH), 3.18 (ddd, J = 10.2, 7.2, 4.9 Hz, 1 H, CH ꢀOH), 3.04 (m center, 2 H, NHꢀ
2 2
CH ), 2.15 (m, 2 H, CH CO), 1.89 (quintuplet, J = 6.9 Hz, 1 H, Hꢀ1), 1.83ꢀ1.74 (m, 1 H, Hꢀ2), 1.66ꢀ
2
2
1
3
.21 (m, 10 H, Hꢀ3, Hꢀ4, Hꢀ5, 2 CH of Bu), 0.99 (t, J = 7.5 Hz, 3 H, COCH CH ), 0.87 (t, J = 7.2 Hz,
2 2 3
1
3
H, CH of Bu). C NMR (DMSOꢀd , 40 °C): δ = 172.6, 170.9 (CO), 63.7 (CH ꢀOH), 54.3 (CHꢀNH),
3
6
2
43.6 (Cꢀ1), 42.8 (Cꢀ2), 37.9 (CH NH), 30.9 (CH CH NH), 29.0 and 28.1 (Cꢀ3 and Cꢀ5), 28.2
2
2
2
(
COCH CH ), 23.8 (Cꢀ4), 19.3 (CH CH CH NH), 13.4 (CH CH CH CH NH), 9.8 (COCH CH ). IR
2 3 2 2 2 3 2 2 2 2 3
(ATR): ν = 3404, 3280, 3096, 2958, 2936, 2863, 1631, 1540, 1461, 1387, 1365, 1314, 1277, 1231,
−
1
+
1
212, 1152, 1118, 1073, 1058, 1025, 950, 917, 897, 864, 788, 721, 633 cm . HRMS (EI) m/z: [M]
Calcd for C H N O 284.2100; Found 284.2097.
1
5
28
2
3
ACS Paragon Plus Environment

Page 27 of 62
The Journal of Organic Chemistry
1
2
3
(1R,3aR,6aR)
and
(1S,3aR,6aR)
NꢀButylꢀ2ꢀpropionyloctahydrocyclopenta[c]pyrroleꢀ1ꢀ
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
carboxamides 12a and 12b. To a solution of 11a,b (100 mg, 0.35 mmol) in dry DMF (1.5 mL) at 0
°C, 1,1′ꢀsulfonyldiimidazole (0.104 g, 0.53 mmol) and sodium hydride (60%, dispersion in mineral oil,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
1 mg, 0.52 mmol) were added. The mixture is stirred for 2 h at 0 °C, then treated with saturated aq
NH Cl solution (15 mL) and extracted with AcOEt (50 mL x 2). The combined organic phases were
4
washed with brine (10 mL), dried (Na SO ), and concentrated. The residue is eluted from a column of
2
4
silica gel with AcOEt/MeOH 99:1 to give 12a (37 mg) and 12b (39 mg) (81% overall yield).
Cyclization carried out on separated 11a and 11b showed that 11a gives 12a whereas 11b gives 12b.
1
1
2a (oil): R = 0.21 (AcOEtꢀMeOH 99:1). [α] +77.40 (c=1.00, CHCl ). H NMR (CDCl , 25 °C)
f
D
3
3
(82:18 mixture of rotamers M and m): δ = 6.43 (M) (br t, J = 5.1 Hz, 1 H, NHBu), 6.06 (m) (br t, J =
.1 Hz, 1 H, NHBu), 4.18 (m) (dd, J = 10.8, 6.0 Hz, 1 H, Hꢀ3), 3.83 (m) (d, J = 9.9 Hz, Hꢀ1), 3.78 (M)
5
(
d, J = 10.2 Hz, 1 H, Hꢀ1), 3.64 (M) (dd, J = 9.3, 6.3 Hz, Hꢀ3), 3.38ꢀ3.17 (M+m) (m, 2 H, NHCH2),
3
.19 (M) (dd, J = 9.3, 11.1 Hz, 1 H, Hꢀ3), 2.93 (m) (t, J = 10.5 Hz, 1 H, Hꢀ3), 2.30 (M+m) (q, J = 7.5
Hz, 2 H, CH CO), 2.32ꢀ2.20 (M) (m, 1 H, Hꢀ6a), 2.19ꢀ2.06 (M+m) (m, 2 H, Hꢀ4 or Hꢀ6), 1.97ꢀ1.68 (m,
2
3 H, Hꢀ4 or Hꢀ6 (M+m), Hꢀ6a (m), Hꢀ3a (M)), 1.55ꢀ1.23 (M+m) (m, 6 H, 2 CH of Bu, Hꢀ5), 1.13
2
(
M+m) (t, J = 7.5 Hz, 3 H, COCH CH ), 0.93 (m) (t, J = 7.2 Hz, 3 H, CH of Bu), 0.92 (M) (t, J = 7.2
2 3 3
1
3
Hz, 3 H, CH of Bu). C NMR (CDCl , 25 °C) (82:18 mixture of rotamers M and m): δ = 174.8 (m)
3
3
(CO), 173.6 (M) (CO), 171.7 (m) (CO), 171.1 (M) (CO), 64.3 (m) (Cꢀ1), 62.5 (M) (Cꢀ1), 59.0 (m) (Cꢀ
a), 54.6 (M) (Cꢀ6a), 50.3 (M) (Cꢀ3a), 50.1 (M) (Cꢀ3), 49.5 (m) (Cꢀ3a), 48.9 (m) (Cꢀ3), 39.3 (M)
CH NH), 39.1 (m) (CH NH), 31.6 (m) (CH CH NH), 31.5 (M) (CH CH NH), 28.0 (M+m)
6
(
2
2
2
2
2
2
(COCH CH ), 28.3, 24.2 and 23.7 (M) (Cꢀ4, Cꢀ5 and Cꢀ6), 26.8, 24.5 and 23.8 (m) (Cꢀ4, Cꢀ5 and Cꢀ6),
2
3
2
0.0 (M+m) (CH CH CH NH), 13.73 (M) (COCH CH ), 13.67 (m) (COCH CH ), 9.0 (M)
2 2 2 2 3 2 3
(
CH CH CH CH NH), 8.9 (m) (CH CH CH CH NH). GCꢀMS (initial temp: 70 °C): R = 10.03 min;
3 2 2 2 3 2 2 2 t
+
m/z: 266 (M , 1.7%), 167 (24), 166 (50), 111 (9.5), 110 (100), 81 (9.2), 68 (58), 57 (14), 41 (8.6). IR
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 62
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
ATR): ν = 3294, 3096, 2956, 2934, 2871, 1643, 1558, 1460, 1432, 1374, 1310, 1244, 1204, 1181,
−
1
+
1
164, 1150, 1115, 1078, 1021, 985, 945, 915, 811, 745, 691, 616 cm . HRMS (EI) m/z: [M] Calcd
for C H N O 266.1994; Found 266.1988.
1
5
26
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
12b (white solid): R = 0.41 (AcOEtꢀMeOH 99:1). M.p. 113.3ꢀ114.7 °C. [α] +1.44 (c=1.2, CHCl ). H
f
D
3
NMR (CDCl , 25 °C) (68:32 mixture of rotamers M and m): δ = 6.35 (M) (br t, J = 5.1 Hz, 1H, NHBu),
3
6
.11 (m) (br t, J = 5.1 Hz, 1H, NHBu), 4.38 (M) (d, J = 7.8 Hz, 1H, Hꢀ1), 4.27 (m) (d, J = 7.8 Hz, 1 H,
Hꢀ1), 3.82 (m) (dd, J = 11.1, 6.6 Hz, 1 H, Hꢀ3), 3.68 (M) (dd, J = 9.3, 6.9 Hz, 1 H, Hꢀ3), 3.32ꢀ3.12
(M+m) (m, 2 H, NHꢀCH ), 2.97 (M+m) (dd, J = 9.3, 10.5 Hz, 1 H, Hꢀ3), 2.57 (M) (qt, J = 11.8 (q), 5.9
2
(t) Hz, 1 H, Hꢀ3a), 2.31 (M+m) (center of m, 2 H CH CO), 2.20 (m) (center of m, Hꢀ6a), 2.15ꢀ1.65 (m,
2
5
2
H, Hꢀ4 and Hꢀ6 (M+m), Hꢀ6a (M), Hꢀ3a (m)), 1.56ꢀ1.41 (M+m) (m, 2 H, Hꢀ5), 1.38ꢀ1.19 (M+m) (m,
H, CH of Bu), 1.13 (M) (t, J = 7.5 Hz, 3 H, COCH CH ), 1.12 (m) (t, J = 7.5 Hz, 3 H, COCH CH ),
2
2
3
2
3
13
0.93 (m) (t, J = 7.2 Hz, 3 H, CH of Bu), 0.87 (M) (t, J = 7.2 Hz, 3 H, CH of Bu). C NMR (CDCl ,
3
3
3
2
5 °C) (68:32 mixture of rotamers M and m): δ = 174.2 (m) (CO), 173.5 (M) (CO), 169.5 (M) (CO),
69.0 (m) (CO), 61.5 (m) (Cꢀ1), 58.9 (M) (Cꢀ1), 54.7 (m) (Cꢀ6a), 53.1 (M) (Cꢀ6a), 49.2 (M) (Cꢀ3), 48.1
1
(m) (Cꢀ3), 47.7 (M) (Cꢀ3a), 46.2 (m) (Cꢀ3a), 39.1 (m) (CH NH), 39.0 (M) (CH NH), 31.8 (m)
2
2
(CH CH NH), 31.6 (M) (CH CH NH), 27.9 (M) (COCH CH ), 27.6 (m) (COCH CH ), 27.5 and 24.4
2 2 2 2 2 3 2 3
(m) (Cꢀ4 and Cꢀ6), 27.4 and 24.3 (M) (Cꢀ4 and Cꢀ6), 22.9 (m) (CH CH CH NH), 22.0 (M)
2 2 2
(CH CH CH NH), 20.01 (m) (Cꢀ5), 20.00 (M) (Cꢀ5), 13.7 (M) (COCH CH ), 13.6 (m) (COCH CH ),
2 2 2 2 3 2 3
8
.9 (m) (CH CH CH CH NH), 8.7 (M) (CH CH CH CH NH). GCꢀMS (initial temp: 70 °C): R = 9.98
3 2 2 2 3 2 2 2 t
+
min. m/z: 266 (M , 1.8%), 166 (54), 111 (8.9), 110 (100), 81 (8.6), 57 (11), 41 (6.7). IR (ATR): ν =
3
397, 3281, 3096, 2936, 2869, 1633, 1542, 1462, 1371, 1340, 1313, 1276, 1229, 1180, 1152, 1121,
−
1
+
1
057, 1023, 947, 893, 784, 712, 637 cm . HRMS (EI) m/z: [M] Calcd for C H N O 266.1994;
15 26 2 2
Found 266.1982.
ACS Paragon Plus Environment

Page 29 of 62
The Journal of Organic Chemistry
1
2
3
((1S,2R)ꢀ2ꢀ(Azidomethyl)cyclopentyl)methanol 13. A solution of monoacetate 8 (5.75 g, 33.4 mmol)
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in dry CH Cl (80 mL) was cooled to 0 °C and treated with Et N (6.0 mL, 43.4 mmol) and
2
2
3
methanesulfonyl chloride (3.1 mL, 40.1 mmol). The mixture was allowed to reach room temperature,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
kept 1 h at this temperature, then quenched with saturated aq NH Cl solution (60 mL) and extracted
4
with CH Cl (50 + 100 mL). The combined organic phases were washed with water (60 mL), brine (60
2
2
mL), dried (Na SO ), and concentrated to give the crude mesylate (8.35 g) as an oil. R = 0.51
2
4
f
(
PE/CH Cl /Et O 2:2:1). It was taken up in dry DMF (60 mL), treated with NaN (5.42 g, 83.4 mmol),
2
2
2
3
stirred for 17 h at 90 °C, then diluted with H O (100 mL) and extracted with Et O (200 + 100 mL). The
2
2
combined organic phases were washed with brine (30 mL), dried (Na SO ), and concentrated. This
2
4
crude azido acetate (6.42 g) was taken up in MeOH (60 mL) at room temperature, and added with a 1
M solution of KOH in MeOH (48.5 mL, 48.5 mmol). The reaction mixture was stirred at room
temperature for 1 h, then treated with saturated aq NH Cl solution (60 mL). After evaporation of most
4
MeOH, the pH was adjusted to 5ꢀ6 by addition of 1 M HCl solution, and then the remaining aqueous
phase was extracted with AcOEt (2 x 150 mL), washed with brine (40 mL), dried (Na SO ), and
2
4
concentrated to give crude azidoalcohol 13 (4.92 g, 95% from 8). This crude product could be used in
the next step without further purification. An analytical sample was purified by flash chromatography
1
eluting with 3:1 PEꢀEt O to give 13 as an oil. R = 0.20 (PEꢀEt O 3:1). [α] +2.69 (c=1.45, CHCl ). H
2
f
2
D
3
NMR (CDCl , 25 °C): δ = 3.54ꢀ3.67 (m, 2 H, CH OH), 3.29 and 3.45 (AB part of an ABX system, J
AB
3
2
= 12.3, JAX = 6.9; JBX = 7.8 Hz, 2 H, CH N ), 2.28 (hexuplet, J = 7.2 Hz, Hꢀ1 or Hꢀ2), 2.22 (center of
2
3
13
m, 1 H, Hꢀ1 or Hꢀ2), 1.31ꢀ1.90 (m, 7 H). C NMR (CDCl , 25 °C): δ = 63.1 (CH ), 52.6 (CH ), 44.0
3
2
2
(CH), 40.9 (CH), 29.7 (CH ), 27.8 (CH ), 23.1 (CH ). IR (CHCl ): ν = 3673, 3613, 3497, 3040, 2947,
2
2
2
3
−
1
2
871, 2391, 2097, 1601, 1446, 1216, 1011, 926, 658 cm . GCꢀMS (initial temp: 70 °C): R = 5.44 min;
t
+
m/z: 126 (M – 29, 1.8 %), 96 (10), 95 (5.3), 86 (5.1), 82 (19), 81 (41), 80 (10), 79 (29), 77 (5.7), 70
(9.7), 69 (25), 68 (23), 67 (100), 66 (9.0), 65 (7.8), 59 (68), 57 (20), 56 (73), 55 (25), 54 (37), 53 (21),
ACS Paragon Plus Environment