Synthesis, structure and reactivity of a macrocyclic imine: Aza-[13]-macrodiolides

Article abstract of DOI:10.1016/j.tetlet.2014.05.081

The in situ synthesis and subsequent reactions of macrocylic imine 2 are reported. The imine was trapped with cyanotrimethylsilane to give α-amino nitrile aza-[13]-macrodiolides in a 1:1 ratio of diastereomers. A crystal structure of the syn α-cyano nitrile diastereomer, 7a, provided insights into the lack of selectivity in reactions of 2 relative to macrocyclic alkene 1. Reactions to functionalize the syn diastereomer 7a are also reported.

Full text of DOI:10.1016/j.tetlet.2014.05.081

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis, structure and reactivity of a macrocyclic
imine: aza-[13]-macrodiolides
⇑
Jun Ma, Raghu Vannam, Daniel W. Terwilliger, Mark W. Peczuh
Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT 06269, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The in situ synthesis and subsequent reactions of macrocylic imine 2 are reported. The imine was trapped
Received 30 April 2014
Revised 15 May 2014
Accepted 16 May 2014
Available online xxxx
with cyanotrimethylsilane to give
a-amino nitrile aza-[13]-macrodiolides in a 1:1 ratio of diastereomers.
A crystal structure of the syn -cyano nitrile diastereomer, 7a, provided insights into the lack of selectiv-
a
ity in reactions of 2 relative to macrocyclic alkene 1. Reactions to functionalize the syn diastereomer 7a
are also reported.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Macrocycle
Imine
Synthesis
Structure
Macrocycles occupy an important niche among organic com-
pounds because they share features with both small molecules
and larger ones.1 The number of atoms in the ring, the presence
and positioning of planar units and the stereogenic centers within
it all contribute to the overall shape or topology of the macrocy-
cle.2,3 We have been focusing recently on how these factors inter-
act in the context of some [13]-macrodiolides such as 1 (Fig. 1).
Planar units such as esters, amides, and alkenes, for example, help
to rigidify macrocyles and thereby reduce the number of low-
energy conformations available to them. In the context of 1, the
ester and alkene units simplified its structure to three planar units
and one ‘hinge’ atom.2b,c Further, the planar units must orient
themselves in a non-coplanar fashion that creates a fold to the ring
much like the twist of E-cyclooctene. Macrocycle 1 exhibits planar
chirality when homochiral starting materials are used; we have
shown that the absolute configuration of key stereogenic centers
govern the planar chirality4 of [13]-macrodiolides.2
Figure 1. [13]-Macrodiolide 1 and aza-[13]-macrodiolide analog 2.
the incorporation of a nitrogen atom into a macrocycle.6–9 Analysis
of products, for example, aza-[13]-macrolide 7 (Scheme 1) that
arise from additions to macrocyclic imine 2 would also provide
information about the structure of 2.10 The structure and reactivity
of imine 2 were of interest because we considered it an aza-analog
of 1. We report the in situ synthesis of macrocyclic imine 2 and its
subsequent functionalization to novel aza-[13]-macrodiolides.
The synthesis of imine 2 followed a strategy similar to the
synthesis of 1.2 Sequential, chemoselective acylations of racemic
1,3-butanediol—first with pentenoic acid then with N-Boc-b-ala-
nine—gave diester 3 in 80% over two steps (Scheme 1). Ozonolyis
of the terminal alkene of 3 then provided aldehyde 4 (86%). It
should be noted that the choice of aldehyde and Boc protected
amine groups for the precursor to the macrocycle was made after
earlier attempts with alternative protecting group schemes (i.e.,
Cbz protected amine with the aldehyde) were unsuccessful. With
compound 4 in hand, the following steps were done sequentially
in one pot in the successful sequence: (i) TFA deprotection of the
Here we evaluate the substitution of an imine for the alkene
unit in 1 (e.g., 2 in Fig. 1).2,5 Specifically, we thought that the imine
functionality, from the
a-carbon through the imine carbon and
nitrogen to the carbon attached to the nitrogen, would act as a
four-atom planar unit (blue atoms in Fig. 1). The investigation
aimed to illustrate the imine as another planar unit that would
rigidify the [13]-macrodiolide structure and also switch the
reactivity from that of a nucleophile to an electrophile. We were
also motivated by the beneficial new properties associated with
⇑
Corresponding author. Tel.: +1 860 486 1605; fax: +1 860 486 2981.
E-mail address: mark.peczuh@uconn.edu (M.W. Peczuh).
http://dx.doi.org/10.1016/j.tetlet.2014.05.081
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ma, J.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.081

2
J. Ma et al. / Tetrahedron Letters xxx (2014) xxx–xxx
O
O
O
HO
O
1)
2)
O
1) TFA, DCM
0 °C to rt
DCC, DMAP
0 °C to rt
HO
OH
2) MgSO4
3) TEA
Boc-β-Ala, DCC, DMAP
X
N
O
O
0 °C to rt
O
BocHN
O
(80%, 2 steps)
X = CH2
X = O
3
4
2
O
3 DCM -78 °C;
PPh3
86%
TMSCN
0 °C to rt
NaBH(OAc)3
(51%, 4 steps)
(6%, 4 steps)
O
O
O
O
O
O
N
OCH3
6
NC
NH
O
O
NH
O
O
7
5
Scheme 1. Synthesis aza-[13]-macrodiolides 5 and 7 via macrocyclic imine 2.
Boc carbamate; (ii) 20-fold dilution and dehydration using
MgSO4 and (iii) neutralization by addition of triethylamine. At
2 acts as an electrophile rather than as a p nucleophile as does the
11
alkene in 1. Conversion of 2 to a ꢀ1:1 mixture of diastereomers 7
the outset we had hoped to characterize and potentially isolate
imine 2 because there is literature precedence for the formation
of other macrocyclic imines.8,12 Attempts at isolation of 2 were
unsuccessful, however. We ultimately resorted to trapping the
imine directly with nucleophiles to confirm that it had in fact
formed. Sodium cyanoborohydride reduction in methanol14 did
not result in the expected aza-[13]-macrodiolide product 5;
instead, intramolecular amidation and transesterification led to a
shows that there is an absence of diastereofacial selectivity for reac-
tions of this p-system, however. This result is in contrast to other
compounds where macrocyclic diastereocontrol was operative.2a,13
The dichotomy indicates a further difference in the nature of mac-
rocycles 1 and 2. The lack of stereoselectivity for TMSCN addition to
2 could be explained by at least four different models: (i) Imine 2
could take up a rigid geometry that is different than the configura-
tion of 1 in Fig. 2 that would allow attack of nucleophiles from
either diastereoface. This is unlikely based on the structural
requirements of 1 and 2. Specifically, we have only observed the
formation of E alkenes (e.g., 1) which suggests that the E configura-
ring contracted
c-lactam 6 (Scheme 1, inset). The structure of 6
strongly suggested that 5, and consequently imine 2 itself, were
intermediates in the ring contraction (See Supporting information).
Hydride reduction using NaBH(OAc)3 did provide aza-[13]-macro-
diolide 5, albeit in only 6% yield as a mixture with other unidenti-
fied products.
Addition of cyanotrimethylsilane (TMSCN) after in situ imine
formation, on the other hand, yielded cyano aza-[13]-macrodio-
lides 7 as a ꢀ1:1 mixture of diastereomers, 7a and 7b (Scheme 1
and Fig. 2) in a combined 51% yield. It should be noted that each
diastereomer of product 7 is itself racemic because the 1,3-butane
diol used to start the synthesis was racemic. The yield for the
formation of 7 was calculated based on N-Boc aldehyde 3 as
starting material and formally included four steps.
tion of the
ture of the 13-membered ring macrocycle. (ii) The
products could equilibrate after they are formed and the reaction
is under thermodynamic control. Epimerization of -amino nitriles
p-system is best accommodated based on the architec-
a
-amino nitrile
a
is known but under conditions that are more robust (either acidic or
basic) than those used in the formation of 7a and 7b.14,15 As
reported here, imine 2 arose by TFA deprotection of a Boc group
and then the acid was neutralized by one equivalent of TEA prior
to addition of TMSCN. Moreover, exposure of 7a to di-isopropyleth-
ylamine for 12 h at 70 °C showed no epimerization. (iii) The macro-
cyclic imines could interconvert via an aminal intermediate. Such a
process could interconvert an E imine to Z or it could interconvert
alternate E imines (Fig. 3A). Although we cannot rule it out, the Z
imine is unlikely based on the ring size and the rigidifying units.
The interconversion of E imines, however, is on equal footing as
the proceeding imine rotational model. (iv) The imine unit is freely
rotating within the [13]-macrodiolide. We argue that the lack of
selectivity is due to facile rotation of the imine unit in 2 in contrast
to the stationary alkene unit of 1 (Fig. 3B and C). In this scenario,
rapid rotation of the imine exposes each diastereoface outward
toward solution and therefore makes each available for attack by
nucleophiles. The nearly 1:1 ratio of diasteromeric products is
consistent with the model. Similar bond lengths for both the alkene
and the imine imply that the removal of the hydrogen is sufficient
to allow facile rotation of the planar unit.16 Although somewhat
speculative, the rotational model is consistent with the structures
and reactivity we have observed for this group of macrocycles.
Our next objective was to modify the newly prepared aza-[13]-
macrodiolides using 7a as the example compound. Alkylation of
The syn diastereomer, 7a, was a crystalline solid. Data from
X-ray crystallography revealed the structure depicted in Figure 2.
Compound 7a has features that are reminiscent of the X-ray struc-
ture collected for 1 and provides clues about macrocyclic imine 2.
First, each ester creates a four atom planar unit that reduces the
number of freely rotating bonds in the backbone of the macrocycle.
Second, the stereogenic centers at C2 and C9 both put the groups
attached to them (methyl at C2 and cyano at C9) in pseudo equa-
torial positions. Finally, the cyano moiety at C9 is exocyclic to the
macrocycle; that is, it points outside the ring. Epoxidations on
chiral [13]-macrodiolides akin to 1 were highly diastereoselec-
tive.2a In those examples, the
p-system of the alkene was shown
to react exclusively through its exterior face. The position of the
cyano group on the periphery of the macrocycle in 7a suggests that
the a-cyano amine arose by nucleophilic attack on a planar imine
also from the exterior face.
The structural data from 7a suggest that imine 2 largely resem-
bles [13]-macrodiolide 1 (Fig. 2). The difference is that the imine of
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J. Ma et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Figure 2. Structures of 1 and 7a from X-ray crystallography data.
the amine nitrogen of 7a under standard conditions gave N-alkyl-
partial reduction of the
a-amino nitrile and was coincident with
ated macrocycles 8–10 in 67–86% yields (Scheme 2). Products 8–10
were isolated as an inseparable mixture of diastereomers despite
the fact that the starting material, 7a was of only one (syn) diaste-
reomeric series. NMR data for 8–10 indicated unique chemical 1H
transesterification to give a mixture of 12 and 13 (68%). At a higher
temperature (70 °C) in ethanol, reduction occurred along with
transesterification to give 13 (59%).17 The NMR data on 8–10 and
the products of reduction of 9 were both consistent with epimer-
and 13C NMR signals for the
a
-amino nitrile methine proton and
ization at the a-amino nitrile carbon. The reduction also under-
carbon, respectively, and implicated epimerization of this center
under the reaction conditions. We reasoned that, after alkylation
scored the lability of the ester units in these 13-membered ring
macrocycles.
of the amine, the
a
-amino nitrile could epimerize via deprotona-
Akin to the reduction of the a-amino nitrile carbon, which pre-
tion-reprotonation15 or by transient iminium formation through
loss of cyanide followed by a rapid recapture.10 While either mech-
anism is formally viable, cyanide loss and recapture seemed more
plausible based on the reaction conditions and the requirement of
a stronger base to deprotonate in other cases. To confirm the site of
sumably went through an iminium intermediate, we attempted a
Bruylants reaction on compound 9.10,18,19 Upon the addition of
AgOTf to 9, an iminium salt is presumably produced; subsequent
addition of allylzincbromide to this species gave an inseparable,
1:1 diastereomeric mixture of C9-allyl aza-[13] macrodiolide 14
in 47% yield. These reactions underscore the variety of structures
that may be derived from the parent aza-[13]-macrodiolides by
standard procedures.
In conclusion, we have identified a synthetic route to aza-[13]-
macrodiolides with a novel macrocyclic imine as a key intermedi-
ate. Compound 2 is the nitrogen analog of macrocyclic alkene 1,
although the high levels of macrocyclic diastereocontrol exhibited
by 1 are absent for 2. We argue that the structures of 1 and 2 are
epimerization, we attempted to reduce the a-amino nitrile moiety
of macrocycle 9. Reduction would remove the stereogenicity of the
C9 carbon and the expected product 11, would then simply return
to being a racemic mixture based on the presence of a single stere-
ogenic center (the original center from 1,3-butane diol) at C2.
Attempted reduction of 9 with sodium cyanoborohydride at room
temperature and at 70 °C did not result in any observable reaction.
Potassium borohydride in ethanol at room temperature affected
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J. Ma et al. / Tetrahedron Letters xxx (2014) xxx–xxx
are focused on replacing the esters with more robust planar units
that will still enable the formation of a macrocyclic imine that
may be more thoroughly characterized in terms of its structure
and reactivity. Results from these investigations will be reported
in due course.
Acknowledgments
The authors thank Vittorio Saggiomo for helpful email corre-
spondence. The NSF supported this work through a grant to
MWP (CHE-0957626) and an NSF-REU Grant (CHE-0754580).
400 MHz/100 MHz NMR spectra were collected on an instrument
that was upgraded by an NSF-CRIF Grant (CHE-0947019). Michael
Takase at the Chemistry Instrumentation Center at Yale University
is acknowledged for collection of X-ray data on 7a.
Supplementary data
Supplementary data (experimental details for the synthesis of
new compounds and corresponding characterization data. Crystal-
lographic Data Centre (CCDC), No. 993642. Copies of this informa-
tion may be obtained free of charge from CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (Fax: +44 1223 336033; web: www.ccdc.
cam.ac.uk/conts/retrieving/html; email: deposit@ccdc.cam.ac.uk))
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2014.05.081.
Figure 3. Mechanisms for interconversion of imines. (A) interconversion via bond
rotation in a hemi-aminal intermediate. (B) Rotation of the alkene unit in [13]-
macrodiolides such as 1 has not been observed. C: Proposed free rotation of the
imine (i.e., 2).
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