Positioning and configuration of key atoms influence the topology of [13]-macrodiolides

Article abstract of DOI:10.1021/jo400383g

Key atoms at specific positions along the ring govern the shape, or topology of a group of [13]-macrodiolides. Here we report the synthesis of these macrocycles and their characterization by functional and structural methods. The [13]-macrodiolides are organized by three four-atom planar units that help to rigidify them and one hinge atom that enables the planar units to orient themselves. The driving force for the organization of the structures is the minimization of steric strain on groups attached to the key atoms. When the key atom is a stereocenter, a macrocycle with planar chirality is observed. An alternative cup-like topology arises when the key atom bears two alkyl groups. Additionally, the key atoms can work in a coordinated fashion to guide one topology over another. The synthesis relied on an acylation-ring closing metathesis sequence. Rigidity was demonstrated by variable-temperature NMR experiments and diastereoselective epoxidation reactions. X-ray crystal structures of representative [13]-macrodiolides served as the basis of the structural observations made. The results provide a framework for the design of new macrocycles with well-defined structures as well as for understanding some general principles that influence the topology of natural product macrocycles.

Full text of DOI:10.1021/jo400383g

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Article
The positioning and configuration of key atoms
influence the topology of [13]-macrodiolides
Jun Ma, and Mark Wayne Peczuh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo400383g • Publication Date (Web): 26 Jun 2013
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The positioning and configuration of key atoms influence the topology of [13]-macrodiolides
Jun Ma, Mark W. Peczuh*
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Department of Chemistry, University of Connecticut, 55 North Eagleville Road U3060, Storrs, CT 06269, USA
mark.peczuh@uconn.edu
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ABSTRACT: Key atoms at specific positions along the ring
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govern the shape, or “topology” of a group of [13]-
macrodiolides. Here we report the synthesis of these
macrocycles and their characterization by functional and
structural methods. The [13]-macrodiolides are organized by
three four-atom planar units that help to rigidify them and one
hinge atom that enables the planar units to orient themselves.
The driving force for the organization of the structures is the
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minimization of steric strain on groups attached to the key atoms. When the key atom is a stereocenter, a
macrocycle with planar chirality is observed. An alternative cup-like topology arises when the key atom
bears two alkyl groups. Additionally, the key atoms can work in a coordinated fashion to guide one
topology over another. The synthesis relied on an acylation-ring closing metathesis sequence. Rigidity
was demonstrated by variable temperature NMR experiments and diastereoselective epoxidation
reactions. X-ray crystal structures of representative [13]-macrodiolides served as the basis of the
structural observations made. The results provide a framework for the design of new macrocycles with
well-defined structures as well as for understanding some general principles that influence the topology
of natural product macrocycles.
Introduction
Macrocycles are a versatile class of compounds with applications in medicinal chemistry,
chemical biology, and materials science. Nature has identified many macrocylic compounds with potent
biological activity, for example. A short list of natural product macrocycles with diverse activities
includes erythromycin (antibacterial), amphotericin (antifungal), rapamycin (immunomodulatory),
epothilone (anti-cancer) and bryostatin (memory-anti-Alzheimers).1 These compounds are either used in
the clinic presently or are undergoing clinical trials for the activities listed. Their effectiveness as
therapeutics has certainly motivated the development of analogs. In fact, over 100 marketed macrocylic
drugs are or are derived from natural products.2 Azithromycin is an excellent example of how
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derivatization of a natural product, in this case erythromycin, expanded the scope of its therapeutic
potential.3 Peptide sequences where natural or un-natural amino acid sidechains are covalently linked to
form a macrocyle also fit into this category. The formation of a macrocycle in these instances helps to
restrict the conformational space adopted by the peptide and enables the sequence to bind a target
protein and inhibit important protein-protein interactions.4
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Due to their novel mechanisms of action and their success as therapeutics, natural product and
natural product analog macrocycles have kindled broad interest in the synthesis5 and characterization of
natural product-like macrocycles.6 This class of compounds is different because it is not directly related
to a specific natural product but is merely motivated by similar (perceived) design principles. Common
ring sizes observed for these macrocycles are 12-14 atoms. They are attractive for investigation as
potential drug candidates because they occupy a molecular space somewhere between traditional small
molecules and biologics. Their size allows them to bind to extended sections of a target protein with the
promise of higher selectivity and potency. They have reduced flexibility relative to acyclic molecules of
similar molecular weight; the rigidification contributes to the selectivity in binding of macrocycles.
A related question is how certain factors such as planar units (e.g., esters, amides, etc.) and the
location of stereocenters along the ring govern the overall shape of a macrocycle.7 The absolute
configuration of atoms at specific places along the ring (key atoms) determines how a molecule folds in
its acyclic form en route to the macrocycle. Such centers have been termed sigma elements.8,9 They are
critical to linking local stereochemistry to the overall topology of a macrocycle. The function of a
macrocycle is intimately associated with its structure, so having a clear understanding of how shape
propagates in macrocycles will aid in the design of ligands for specific protein targets, it will provide
guidance in the design of diversity oriented synthesis campaigns, and it will also provide a context for
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predicting the shapes of natural product macrocycles in the absence of crystallographic or extensive
spectroscopic data.10
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We recently reported on a group of [13]-macrodilactones that possess a planar chirality by virtue
of the interplay between three planar units, a hinge atom and the absolute stereochemistry of a single
asymmetric carbon.11, 12 In the initial investigation, where the macrodilactone ring was fused to a
pyranose ring through C4 and C6 hydroxyl groups, we demonstrated highly stereofacial epoxidation
reactions. Switching the absolute configuration at C4 (D-glucose to D-galactose) resulted in the
presentation of the opposite diastereoface of an embedded alkene unit. Separate X-ray crystal structures
of the D-galactose fused macrocycle as both the alkene 1 and epoxide 2 (Fig. 1) showed that the
selectivity arose from the fact that the [13]-macrodilactone backbone was twisted and the π-bond of the
alkene was perpendicular to the twist axis. This meant that there was an inside and an outside face of the
alkene. Only the outside diastereoface13 reacted with the epoxidation reagent, DMDO. Subsequent
work12 pared down the features of the pyranose that were responsible for the planar chirality.14 Synthesis
of minimalist, chiral hydroxymethyl cyclohexanol “pseudo-enantiomers” of the D-glucose and D-
galactose fused [13]-macrodilactones led to the conclusion that just one key stereocenter contributed to
the planar chirality of the [13]-macrodilactones. An X-ray structure of the racemic [13]-macrodilactone
3 confirmed that one asymmetric carbon governed the planar chirality - the topology - of the
macrocycle.
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O
O
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O
O
OCH3
OBn
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OCH3
OBn
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OBn
OBn
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Figure 1. X-ray crystal structures of 1 and 2 depicting the planar chirality of the [13]-macrodiolides.
90°
3a
Figure 2. Crystal structure of the S-enantiomer [13]-macrodiolide 3a. The R-enantiomer (not shown) is
also present unit cell of the crystal.
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[13]-macrodilactone 3a (Fig. 2 and Fig. 3) contains two ester units, C12-C13-O1-C2 (dihedral
angle = 178.5°) and C4-O5-C6-C7 (175.1°) and one alkene (C8-C11, 174.8°). A scheme that defines
atom numbering for the [13]-macrodiolides is provided in Figure 4. The esters of 3a are in a typical s-
trans conformation and the E-alkene is in a relatively similar orientation. These three planar units, each
containing four atoms, account for 12 of the 13 atoms of the macrocycle. As has been pointed out for
12-membered macrocycles, planar units are effective means for rigidifying the ring.7 The remaining
atom in 3a, C3, is not part of any planar array. Rather, the planar units organize around this center to
minimize steric interactions between the group attached to the chiral center, C2, and the rest of the ring.
We referred to this carbon (C3) as the hinge atom to emphasize how the planar units flex around it with
a specific screw-sense. A substituent as small as a methyl group on C2 was sufficient to direct the fold
of the [13]-macrodilactones.11 Here we follow up on that observation and evaluate how both the planar
units and key atoms in the backbone affect the fold of the novel [13]-macrodiolides through a two-
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pronged approach. First, we evaluated the dynamics of the [13]-macrodiolides by inspecting select H
NMR spectra and evaluating the selectivity of epoxidation of the alkene unit embedded in their
structure. Second, we inspected the structures of several [13]-macrodiolides that were collected by X-ray
crystallography. The data show that the interplay of these features work together to govern macrocycle
topology and have implications for drug design and natural product chemistry.
Results and Discussion
The [13]-macrodiolides 3a-i were synthesized by an acylation – ring closing metathesis (RCM)
route (Scheme 1). Diversity amongst the product [13]-macrodiolides originated from the bis-
functionalized starting materials 4a-i that were used. They consisted of simple diols (4a, 4b, 4d, and
4h/4i),15 amino alcohols (4e, 4f) and diamines (4c, 4g). Each starting material was commercially
available, although we chose to synthesize 4g from 3-aminobutanoic acid via a modified procedure (See
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Experimental Section for details on the synthesis of 4g.).16 Both ends of the diols, amino alcohols and
diamines were acylated with 4-pentenoic acid using DCC as a coupling reagent and DMAP as catalyst.
Yields for the bis-acylation ranged from 46-99%. Using conditions previously established for the RCM
of [13]-macrodiolides,12 the dienes 5a-i were converted to macrocycles 3a-i (61-80-%) in Figure 2.
Macrocycles 3a-i were also hydrogenated to provide completely saturated [13]-macrodiolides 6a-i
(Scheme 2). Yields for the acylation, RCM and hydrogenation reaction for each series are collected in
Table 1. The hydrogenation reaction aided in confirming the structure of the parent compounds and also
demonstrated that the embedded alkenes could be reactive under standard conditions. Hydrogenation of
the alkene destroyed one of the planar units in the macrocycle. We suspected that the saturation of the
alkene unit may have observable physical ramifications for the ring dynamics.
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Scheme 1
O
O
OH
X
X
X
O
DCC, DMAP
Grubbs' II
R
R
R
PhCH3 110 °C
DCM
0 °C to rt
Y
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Y
O
O
46-99%
61-80%
4a-i
5a-i
3a-i
O
O
O
O
O
NH
HN
O
O
O
O
O
O
O
O
O
3a
3c
3d
3b
O
O
O
O
O
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O
NH
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NH
HN
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HN
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3g
3h
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3f
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Figure 3. [13]-macrodiolides 3a-i. Table 1 reports the yields for synthesis and reaction of each
compound.
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To gather information about the ring dynamics of the alkene-containing [13]-macrolides (3) and
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the reduced analogs 6, we collected variable temperature (VT) H NMR data17 on compounds 3h and
6h.18 The spectra of 3h were very similar at rt and 50 °C. There were minor chemical shift changes and
the signals that correspond to the C2, C4 and methyl hydrogens showed some broadening at 50 °C.
Signals for the other protons were essentially unchanged which suggested a relatively rigid structure.
For 6h, there were slight chemical shift changes and also some minor changes in coupling constants. A
significant indicator, however, was the observation that signals corresponding to the alkane region (e.g.,
C9, C10) apparently coalesced between 50 and 75 °C. The interpretation of the data for 6h was that the
structure was relatively rigid at room temperature but that multiple conformations were accessed,
particularly in the C8-C11 region at the higher temperatures. Overall, the VT experiments lent support to
the notion that the parent [13]-macrodiolide structures were rigid due primarily to the planar units
present in their backbone.
High facial selectivity in reactions involving the embedded alkene unit was observed among the
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[13]-macrodilactones that we previously studied.11 12 Specifically, epoxidations of 1 and related (chiral)
compounds were shown to be highly diastereoselective. The observed selectivity acted as a functional
read-out for the ring dynamics of the macrocycles. Low selectivity in reactions of the double bond
would indicate free rotation around the alkene unit because the rotation would expose both faces to
reaction. Conversely, high facial selectivity would suggest a more rigid structure. We therefore opted to
perform epoxidation reactions on 3a-i as an additional method for assessing their rigidity.
It is important to clarify the relationship between point chirality and planar chirality of 3a-i
before undertaking the analysis of the products of epoxidation. The interrelationship between these
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chiralities defines the topology of the [13]-macrodiolides being studied. We are using planar chirality
here, as others have,19 to connote the nonplanarity or twist of the macrocycle. The point chirality of a
key stereocenter will govern this planar chirality. The starting materials for the synthesis of the [13]-
macrodiolides fall into two groups: i) 1,3-butanediol 4a, 3-amino-1-butanol 4e, 4-amino-2-butanol 4f,
1,3-diaminobutane 4g, and 2,4-pentane diol 4h20,21 were used as their respective racemic mixtures; ii)
2,2-dimethyl-1,3-propanediol 4b, 2,2-dimethyl-1,3-diaminopropane 4c, 1,1-dimethyl-1,3-propanediol
4d and meso-2,4-pentanediol 4i are achiral. We expected that macrocycles synthesized from achiral
starting materials would either adopt a racemic mixture of enantiomeric planar chiralities or they would
potentially adopt some new topology that was symmetric and therefore achiral too. Macrocycles
prepared from racemic starting materials (point chirality) were simply expected to be racemic via the
propagation of enantiomeric planar chiralities. In this case, each enantiomer of the starting material
would directly correspond to one specific planar chirality. The twist of each enantiomeric macrocycle in
the racemate would be determined by the absolute configuration of the key atom. Despite the fact we
were studying these compounds in the optically inactive series, we expected to learn about the structures
and their dynamics. The lessons are directly applicable to either asymmetric series; that is, if the
synthesis began with an optically active starting material, then the topology of the macrocycle could be
predicted based on the starting material’s absolute configuration. Regardless of the exact topology
adopted by [13]-macrodiolides 3a-i, the products of their epoxidation were, by definition, not expected
to be optically active either. Diastereomeric epoxides would arise only if the planar alkene unit was
rotating or oscillating to expose both reactive faces, which was not expected.
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90°
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Figure 4. A general representation of the [13]-macrodiolide structure (with numbering used in the
manuscript) that emphasizes the planar motifs and their organization.
The procedure for epoxidations in this study used in situ generated DMDO as the epoxidizing
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reagent (Scheme 2).7 While we used the same reagent in our previous studies,11 12 it was prepared
separately and added into the epoxidation reaction. We chose the in situ method for its convenience and
because others had shown that this method could selectively, and efficiently epoxidize alkenes
embedded in macrocycles. In all cases but one, a single diastereomeric series of epoxides 7a-i was
obtained. Repeated attempts to epoxidize 3g under the standard conditions, as well as others, 22 were
unsuccessful. Data from chromatography, 1H and 13C NMR experiments supported the conclusion that a
single diastereomer was produced in each epoxidation. These epoxidation results were consistent with a
model where the embedded alkenes reacted via their outside face only and, further, that [13]-
macrodiolides were in fact rigid.
Scheme 2
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O
O
X
X
5
6
7
H2, Pd/C
CH3OH
R
R
Y
Y
8
O
O
88-100%
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6a-i
3a-i
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O
O
X
Oxone, NaHCO3
DCM/H2O
R
Y
O
76-94%
O
7a-f, h, i
Table 1. Yields of cyclization and subsequent reactions of embedded alkene by macrocycle.
Acyl. RCM
(%) 5 (%) 3
Hydr.
(%) 6
85
92
99
99
100
98
Epox.
(%) 7
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Series
a
b
c
d
e
f
g
h
i
87a
90
99
100
65
72a
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97
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-
c
98
88
99
94
91
72b
a Yields for 5a and 3a are from ref 23.
b Synthesized as a mixture of the racemic and meso diasteromers.
c Epoxidation of 3g under the standard conditions was not successful.
Through inspection of the structure obtained from X-ray crystallographic data for [13]-
macrodilactone 3a (Fig. 2), several key characteristics important to the topology of this ring system
became apparent. Because racemic 1,3-butanediol was used in the synthesis, both enantiomers were
present in the unit cell; here only one of the enantiomers is analyzed, but the principles are applicable to
both. Futher, the new compounds we report here, especially the structures derived from X-ray data on
7b and 7d, and 3h and 3i helped to illustrate and refine our understanding of the characteristics. As
outlined above, the planar chirality of 3a can be attributed to its three planar units, the hinge atom and
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the absolute stereochemistry of the chiral center. The stereochemistry at C2 in 3a is the crucial
determinant for the planar chirality of the folded macrocycle. This is because C2 is in an eclipsing
conformation with the carbonyl oxygen of its planar ester unit. Depending on the configuration of that
center, the substituents attached to it will either be pointing into the macrocycle or away from it when it
adopts the twisted conformation. The substituent is too big to occupy a site inside the macrocycle and so
the ring (presumably pre-established in its acyclic form) wraps around to accommodate it on the outside
of the developing ring.
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C2 is not the only atom that is able to dictate the folding of the [13]-macrodiolide structures;
there are other key stereocenters along the chain of the macrocycle (Figure 4). C4 is an ester carbon
analogous to C2, for example, and the chirality of this center could work synergistically with C2 or it
could interfere with it. The α-carbons of both esters (C7 and C12) and the carbons that are adjacent to
the alkene at C8 and C10 are also at positions of the molecule’s backbone that are akin to C2 and C4.
That is, they are at the junction of two planar units and may therefore exert an influence on macrocycle
topology in the same way as C2. Each of these centers could either work constructively to reinforce a
given fold or they could work against each other. This could potentially result in alternative ring
topologies. Based on an axis of symmetry, on the other hand, C3 should have no effect on the fold of the
macrocyle. Comparison of the X-ray crystal structures of 7b and 7d helps to illustrate some of these
features.
The structure on the left in Figure 5 corresponds to compound 7b, the epoxidation product of
macrocycle 3b. The fact that it is the macrocyclic epoxide rather than the corresponding alkene requires
some qualification because X-ray structures containing either of these functional groups will be
compared to each other interchangeably. First, the structure illustrates the inside-outside disposition of
faces on the erstwhile alkene. Reaction occurs only on the outside face of the alkene because the interior
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space of the macrocycle is too small to host a reagent molecule.13 Second, the ring topology between
alkene and epoxide is conserved for [13]-macrodiolides. This argument is based on earlier X-ray data
collected in our group for the D-galactose-fused macrocycle as the alkene and epoxide (Fig. 1). The only
difference between structure 1 and 2, aside from the epoxide oxygen atom itself, is the compactness of
the macrocycle. The distance between the ester carbonyl oxygens illustrates this. For 1, the distance is
5.153 Å and for 2 it is 4.289 Å. The correspondence between the shape of structures 1 and 2 means that
analysis of the X-ray structure of the epoxide 7b is essentially the same as for alkene 3b and we can
infer structural information about the alkene through inspection of the epoxide. Substitution on the
macrocyclic ring of 7b is at the C3 position, a position that, in our analysis above, should have little or
no consequence on the specific fold adopted by the macrocyclic ring. Inspection of 7b shows that it
adopts the typical ribbon shape that is reminiscent of the original [13]-macrodiolides. In fact, structures
of both enantiomeric planar chiralities are present in the unit cell. It indicates that the ribbon fold is
likely the lowest energy configuration for the [13]-macrodiolides and also that the C3 position has no
influence on which planar chirality is adopted within that fold.
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Figure 5. X-ray crystal structures of [13]-macrodiolides 7b and 7d.
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Also shown in Figure 5 (on the right) is the X-ray crystal structure of macrocyclic epoxide 7d. It
too contains a geminal dimethyl unit along the macrocyclic backbone but in this case it is at the C2
position. We suspected that if a ribbon topology was to be adopted for 7d, then one of the two methyl
groups would be forced to be inside the macrocyclic ring. Instead, 3d adopts an alternate topology all
together. The topology is more cup-shaped rather than a ribbon fold, although the planar chirality is still
present. The difference in overall topology is best illustrated in lower side-view images of 7b and 7d in
Figure 5. From this perspective, the cup shape is plainly evident. The planar units are maintained, but
their arrangement is changed by a reorganization of the diol unit. For example, the ester carbonyls in the
cup configuration (7d) are parallel to each other whereas they are anti-parallel in the ribbon (7b).
Significantly, the three carbon atoms that are part of the backbone of the macrocycle become nearly co-
planar themselves in 7d, which creates an adventitious fourth planar unit. The O1-C2-C3-C4 and C2-
C3-C4-O5 dihedral angles for this part of the molecule are -62.12° and 66.63°, respectively. For 7a, the
same angles are 50.61° and 50.61°; these angles give rise to the screw-sense of the planar chirality in the
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ribbon configuration. Nonetheless, 7d still contains an attenuated planar chirality. That is, the orientation
of the alkene unit from C8-C11 adopts two configurations, each of which creates a planar chirality.24
The unit cell once again has copies of both enantiomers. It is the absence or presence of the screw-sense
in the diol unit, then, that guides the overall topology of the macrocycle.
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It also became apparent that the key atoms can also work together constructively to reinforce a
given topology based on their absolute configuration. Compounds 3h and 3i were prepared to test this
possibility. A commercially available mixture of racemic and meso-2,4-dimethyl-pentanediol was
acylated under the standard conditions to provide racemic 5h and meso diester 5i. The components of
this mixture could not be separated. Rather, the mixture carried through the RCM reaction, then 3h and
3i were separated by column chromatography. Based on the previous X-ray structures, we reasoned that
[13]-macrodiolide 3h would adopt the ribbon configuration (e.g., 3a, 7b) because the methyl groups at
the C2 and C4 stereocenters, respectively, could sit on the outside the macrocycle. This was because the
absolute configurations of these centers were complementary to the topology. By the same logic, meso
compound 3i would be akin to 3d or 7d. Methyl groups at C2 and C4 on this compound would be best
accommodated by the more elongated or flattened planar chirality as observed for 7d. Structures derived
from X-ray crystallographic data for 3h and 3i are shown in Figure 6.
3h
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Figure 6. X-ray crystal structures of [13]-macrodiolides 3h and 3i.
Conclusion
The structure and reactivity of the compounds investigated support some general trends that
apply to this class of [13]-macrodiolides. Specifically, planar units such as esters, amides and alkenes,
among others, restrict the number of conformations populated in macrocyclic rings. The orientation or
disposition of these planar units one relative to another is mediated by bonds or atoms – referred to as
hinges. The absolute stereochemistry at key centers along the macrocyclic backbone will influence how
the planar units will organize themselves. Moreover, these key atoms work in tandem to drive the
overall molecular topology. The observations made for this simple class of [13]-macrodiolides also have
implications for drug design as macrocycles have become the focus of several research efforts.1 One
area where the new chiral topology may be applied is the development of protein secondary structure
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mimetics. Additionally, the work described here provides a context for rationalizing the shape of natural
product macrocycles.10,25 Our growing appreciation for the interplay between planar units, macrocyclic
ring size, and the identification of key stereocenters has encouraged us to continue investigating these
design principles in the contexts of other macrocyclic rings. Investigation of the biological activity of the
[13]-macrodiolides26 and related structures is also ongoing.
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Experimental Section
Scheme 3
O
1) Boc2O; NaBH4
Cbz
Cbz
N
H
X
N
H
OH
2) MsCl, TEA
84%
8
NaN3
DMF
9 X = OMs
10 X = N3
89%
H2
Pd/C
H2N
NH2
4g
3-(N-benzyloxycarbonyl)-amino-1-butyl methanesulfonate (9). N-Cbz-3-amino butanoic acid 8 was
converted to N-Cbz-3-aminobutanol according to a literature procedure.27 The alcohol (2.04 g, 9.2
mmol) and TEA (1.74 mL, 12.5 mmol) in dry DCM (50 mL) were cooled to 0° C, to which MsCl (0.87
ml, 11.2 mmol) was added and stirred at the same temperature for 30 min. Then the whole reaction
solution was stirred overnight at room temperature. The solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography (hexanes: EtOAc 60:40) to give 9 in 84%
yield (2.33 g) as light yellow oil. Rf 0.43 (hexanes: EtOAc 6:4); 1H NMR (400 MHz, CDCl3) δ 7.32 (s,
5H), 5.05 (s, 2H), 5.01 – 4.90 (m, 1H), 4.22 (d, J = 4.0 Hz, 2H), 3.86 (d, J = 4.0 Hz, 1H), 2.92 (s, 3H),
13
1.85 – 1.82 (m, 2H), 1.18 (d, J = 4.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 155.9, 136.6, 128.6,
128.2, 128.1, 67.4, 66.7, 44.2, 37.2, 36.3, 21.3; TOF HRMS (DART) m/z [M+H]+ calcd for C13H20NO5S
302.1062, found 302.1063.
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3-(N-benzyloxycarbonyl)-amino-1-butyl azide (10). Under N2, to a solution of 9 (1.18 g, 3.9 mmol) in
dry DMF (10 mL) was added NaN3 (1.27 g, 19.6 mmol) and the mixture was stirred at 70 °C overnight.
Then H2O (50 mL) and EtOAc (50 mL) were added, the EtOAc layer was washed with saturated
NaHCO3 (2 x 30 mL) and dried with Na2SO4. The solvent was removed under reduced pressure to give a
residue which was purified by silica gel column chromatography (hexanes: EtOAc 85:15) to give 10 in
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1
89% yield (0.87 g) as colorless oil. Rf 0.45 (hexanes: EtOAc 8:2,); H NMR (400 MHz, CDCl3) δ 7.35
(s, 5H), 5.09 (s, 2H), 4.69 (d, J = 4.0 Hz, 1H), 3.86 – 3.83 (m, 1H), 3. 37 – 3.34 (m, 2H), 1.73 – 1.70 (m,
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2H), 1.20 (d, J = 8.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 155.9, 136.6, 128.7, 128.4, 66.9, 48.6,
45.3, 36.2, 21.4; TOF HRMS (DART) m/z [M+H]+ calcd for C12H17N4O2 249.1352, found 249.1324.
1,3-diamino butane (4g). A mixture of 10 (0.86 g, 3.4 mmol), 10% Pd/C (85 mg) and methanol (10
mL) was stirred under a balloon of hydrogen at ambient pressure at rt overnight. Then the reaction
mixture was filtered through a short plug of Celite and the filtrate was concentrated in vacuo to give
crude 4g (0.29 g) which was directly used in the preparation of 5g. TOF HRMS (DART) m/z [M+H]+
calcd for C4H13N2 89.1078, found 89.1080.
General procedure for the synthesis of dienes. A solution of DCC (2.68 g, 0.013 mol) and DMAP
(0.37 g, 0.0030 mmol) in dry DCM (40 mL) was cooled to 0° C. To the solution, 4-pentenoic acid (1.24
ml, 12 mmol) was added and the mixture was stirred at the same temperature for 30 min. The diol,
amino alcohol or diamine 1 (5 mmol) was then added to the mixture as a solution in dry DCM (10 mL).
The suspension was stirred overnight at room temperature. Then the reaction mixture was filtered and
DCM was removed under reduced pressure. The residue was purified by silica gel column
chromatography to give the diene products as described below.
Compound 5b. Obtained according to the general procedure in 90% yield (1.21 g) as colorless oil. Rf
0.51 (hexanes: EtOAc 8:2);1H NMR (400 MHz, CDCl3) δ 5.74 – 5.68 (m, 2H), 5.45 (dd, J = 17.1, 1.2
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Hz, 2H), 4.99 (dd, J = 10.4, 1.0 Hz, 2H), 3.79 (s, 1H), 2.31 – 2.28 (m, 8H), 0.87 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 172.6, 136.5, 115.4, 68.9, 34.6, 33.4, 28.8, 21.7; TOF HRMS (DART) m/z
[M+H]+ calcd for C15H25O4 269.1753, found 269.1716.
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Compound 5c. Obtained according to the general procedure in 99% yield (1.32 g) as colorless oil. Rf
0.36 (EtOAc);1H NMR (400 MHz, CDCl3) δ 6.64 (s, br, 2H), 5.86 – 5.76 (m, 2H), 5.35 (dd, J = 17.2,
1.2 Hz, 2H), 4.97 (dd, J = 10.0, 1.0 Hz, 2H), 2.97 (d, J = 8.0 Hz, 4H), 2.42 – 2.29 (m, 8H), 0.83 (s, 6H);
13C NMR (100 MHz, CDCl3) δ 173.4, 137.1, 115.8, 45.8, 36.6, 36.2, 29.9, 23.8; TOF HRMS (DART)
m/z [M+H]+ calcd for C15H26N2O2 267.2073, found 267.2071.
Compound 5d. Obtained according to the general procedure in 100% yield (1.43 g) as colorless oil. Rf
0.58 (hexanes: EtOAc 8:2); 1H NMR (400 MHz, CDCl3) δ 5.82 – 5.80 (m, 2H), 5.05 (m, 2H), 4.99 (m,
2H), 4.18 (t, J = 6.0 Hz, 1H), 2.38 – 2.32 (m, 8H), 2.13 (t, J = 8.0 Hz, 2H),1.47 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 173.2, 172.4, 136.9, 136.8, 115.6, 80.9, 60.8, 39.4, 34.8, 33.7, 29.2, 28.9, 26.6; TOF
HRMS (DART) m/z [M+NH3]+ calcd for C15H25O4NH3 286.2018, obs. 286.1973.
Compound 5e. Obtained according to the general procedure in 65% yield (0.82 g) as colorless oil. Rf
0.11 (hexanes: EtOAc 8:2); 1H NMR (400 MHz, CDCl3) δ 5.80 – 5.73 (m, 2H), 4.98 (m, 2H), 4.89 (m,
2H), 4.08 – 4.07 (m, 3H), 2.35 – 2.20 (m, 8H), 1.74 – 1.73 (m, 2H),1.13 (d, J = 8.0 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 173.2, 171.8, 137.2, 136.8, 115.7, 61.7, 42.8, 36.1, 35.6, 33.7, 29.9, 28.9, 21.1;
TOF HRMS (DART) m/z [M+H]+ calcd for C14H24NO3 254.1756, found 254.1744.
Compound 5f. Obtained according to the general procedure in 97% yield (1.23 g) as colorless oil. Rf
0.63 (hexanes: EtOAc 85:15); 1H NMR (400 MHz, CDCl3) δ 6.04 (s, br, 1H), 5.80 – 5.74 (m, 2H), 5.10
(dd, J = 17.3, 1.6 Hz, 2H), 4.95 (m, 3H), 3.46 (t, J = 8.0 Hz, 1H), 2.97 – 2.92 (m, 1H), 2.36 – 2.21 (m,
13
8H), 1.72 – 1.63 (m, 2H),1.20 (d, J = 4.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 173.1, 172.6, 137.2,
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136.7, 115.8, 68.7, 36.0, 35.8, 33.9, 29.8, 29.1, 20.4; TOF HRMS (DART) m/z [M+H]+ calcd for
C14H24NO3 254.1756, found 254.1735.
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Compound 5g. Obtained according to the general procedure in 46% yield (0.58 g) as pale yellow oil. Rf
0.1 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.86 (s, br, 1H), 6.04 (d, J = 8.0 Hz,, 1H), 5.80 – 5.70 (m,
2H), 5.02 (m, 1H), 4.98 (m, 1H), 4.93 (m, 2H), 3.99 (m, 1H), 3.59 – 3.58 (m, 1H), 2.73 – 2.67 (m, 1H),
2.34 – 2.22 (m, 8H), 1.65 – 1.63 (m, 1H), 1.32 – 1.26 (m, 1H),1.19 (d, J = 4.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 172.9, 172.5, 137.2, 136.9, 115.8, 115.4, 42.6, 37.2, 36.1, 35.9, 35.8, 29.8, 29.1, 21.3;
TOF HRMS (DART) m/z [M+H]+ calcd for C14H25N2O2 253.1916, found 253.1928.
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Compounds 5h/5i. The mixture of isomeric diesters was obtained according to the general procedure in
72% yield (0.96 g) as colorless oil. Rf 0.78 (hexanes: EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 5.77 –
5.70 (m, 2H), 4.99 – 4.88 (m, 6H), 2.30 (d, J = 8.0 Hz, 8H), 1.94 – 1.53 (m, 2H), 1.15 (t, J = 4.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 172.4, 136.7, 136.6, 115.5, 115.4, 67.8, 67.1, 42.4, 41.9, 33.8, 33.7,
28.9, 28.9, 20.5, 20.1; TOF HRMS (DART) m/z [M+H]+ calcd for C15H25O4 269.1753, found 269.1750.
General RCM procedure. Under an atmosphere of dry N2, to a solution of diene 5 (1 mmol) in dry
toluene (100 mL) was added Grubbs’ second generation catalyst (0.05 – 0.08 mmol) and the resulting
mixture was refluxed at 110 °C for 18 h. The toluene was removed under reduced pressure to give a
residue, which was purified by silica gel column chromatography.
Compound 3b. Obtained according to the general procedure in 61% yield (0.146 g) as a white solid.
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m.p. 81-82 °C; Rf 0.65 (hexanes: EtOAc 8:2); H NMR (400 MHz, CDCl3) δ 5.39 (d, J = 4.0 Hz, 2H),
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3.79 (s, 4H), 2.31 (d, J = 8.0 Hz, 8H), 0.97 (s, 6H); C NMR (100 MHz, CDCl3) δ 173.9, 130.0, 69.2,
34.4, 33.5, 29.1, 22.9; TOF HRMS (DART) m/z [M+H]+ calcd for C13H21O4 241.1440, found 241.1444.
Compound 3c. Obtained according to the general procedure in 46% yield (0.110 g) as white solid. m.p.
91-93 °C; Rf 0.21 (EtOAc, 0.3% TEA); 1H NMR (400 MHz, CDCl3) δ 6.12 (s, br, 2H), 5.56 (d, J = 4.0
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Hz, 2H), 3.14 (d, J = 8.0 Hz, 4H), 2.31 (s, 8H), 0.93 (d, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
173.3, 131.0, 49.3, 37.4, 35.5, 28.7, 24.8; TOF HRMS (DART) m/z [M+H]+ calcd for C13H23N2O2
239.1759, found 239.1757.
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Compound 3d. Obtained according to the general procedure in 67% yield (0.161 g) as white solid. m.p.
43-44 °C; Rf 0.63 (hexanes: EtOAc 8:2); 1H NMR (400 MHz, CDCl3) δ 5.39 – 5.35 (m, 2H), 4.07 (t, J
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= 6.0 Hz, 2H), 2.29 – 2.16 (m, 10H), 1.36 (s, 6H); C NMR (100 MHz, CDCl3) δ 173.9, 172.2, 129.8,
129.5, 80.5, 60.5, 37.3, 34.9, 28.9, 27.6; TOF HRMS (DART) m/z [M+H]+ calcd for C13H21O4 241.1440,
found 241.1410.
Compound 3e. Obtained according to the general procedure in 80% yield (0.181 g) as white solid. m.p.
85-87 °C; Rf 0.32 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 5.88 (s, br, 1H), 5.59 – 5.46 (m, 2H), 4.31 (t,
J = 12.0 Hz, 1H), 4.20 (t, J = 12.0 Hz, 1H), 4.09 – 4.03 (m, 1H), 2.45 – 2.10 (m, 8H), 2.04 – 1.98 (m,
1H), 1.71 – 1.70 (m, 1H), 1.18 (d, , J = 4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.6, 171.9, 130.8,
130.6, 61.6, 43.7, 36.4, 34.7, 33.6, 28.1, 27.8, 20.7; TOF HRMS (DART) m/z [M+H]+ calcd for
C12H20NO3 226.1443, found 226.1453.
Compound 3f. Obtained according to the general procedure in 61% yield (0.137 g) as white solid. m.p.
90-91 °C; Rf 0.30 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.02 (s, br, 1H), 5.53 – 5.49 (m, 2H), 5.03 (t,
J = 12.0 Hz, 1H), 3.52 – 3.48 (m, 1H), 3.18 – 3.12 (m, 1H), 2.39 – 2.10 (m, 8H), 1.80 – 1.77 (m, 2H),
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1.21 (d, J = 4.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ 173.2, 172.9, 131.1, 130.9, 70.7, 37.1, 36.4,
34.9, 34.1, 28.2, 27.6, 20.9; TOF HRMS (DART) m/z [M+H]+ calcd for C12H20NO3 226.1443, found
226.1457.
Compound 3g. Obtained according to the general procedure in 72% yield (0.161 g) as white solid. m.p.
93-95 °C; Rf 0.05 (EtOAc, 0.5% TEA); 1H NMR (400 MHz, CDCl3) δ 6.04 (s, br, 1H), 5.61 (s, br, 1H),
5.54 (d, J = 4.0 Hz, 2H), 4.12 (t, J = 4.0 Hz, 1H), 3.76 (t, J = 12.0 Hz, 1H), 3.04 – 2.97 (m, 1H), 2.38 –
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2.15 (m, 8H), 1.78 – 1.76 (m, 1H), 1.66 – 1.64 (m, 1H),1.19 (d, J = 8.0 Hz, 3H); C NMR (100 MHz,
CDCl3) δ 172.9, 172.1, 130.9, 130.4, 44.9, 37.3, 37.0, 36.9, 35.8, 28.4, 28.2, 22.2; TOF HRMS (DART)
m/z [M+H]+ calcd for C12H21N2O2 225.1603, found 225.1597.
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Compound 3h. (racemate) Obtained according to the general procedure in 50% yield (0.120 g) as white
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solid. m.p. 116-117 °C; Rf 0.82 (hexanes: EtOAc 95:5); H NMR (400 MHz, CDCl3) δ 5.41 (t, J = 4.0
Hz, 2H), 4.94 – 4.92 (m, 2H), 2.39 – 2.14 (m, 8H), 1.78 (t, J = 8.0 Hz, 2H), 1.24 (d, J = 4.0 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 173.1, 130.7, 67.2, 41.6, 34.6, 28.3, 20.5; TOF HRMS (DART) m/z [M+H]+
calcd for C13H21O4 241.1440, found 241.1444.
Compound 3i. (meso) Obtained according to the general procedure in 26% yield (0.062 g) as white
solid. m.p. 83-84 °C; Rf 0.78 (hexanes: EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 5.51 (s, 2H), 5.03 –
4.99 (m, 2H), 2.38 – 2.19 (m, 8H), 2.03 – 1.99 (m, 1H), 1.65 (d, J = 12.0 Hz, 1H), 1.20 (d, J = 4.0 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 173.1, 130.1, 70.6, 41.9, 35.3, 27.4, 21.9; TOF HRMS (DART) m/z
[M+H]+ calcd for C13H21O4 241.1440, found 241.1446.
General hydrogenation procedure. A stirred mixture of macrocycle ring 4 (10 mg), 10% Pd/C (1 mg)
in methanol (1 mL) was hydrogenated at ambient pressure (H2 balloon) and rt for 3 h. Then the reaction
mixture was filtered through Celite and the filtrate was concentrated in vacuo to give each product.
Compound 6a. Obtained according to the general procedure in 85% yield (9.0 mg) as a white solid.
m.p. 37-38°C; Rf 0.81 (hexanes: EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 5.08– 5.04 (m, 1H), 4.29–
4.24 (m, 1H), 4.09– 4.04 (m, 1H), 2.31 (t, J = 6.0 Hz, 4H), 2.02 – 1.90 (m, 2H), 1.84 – 1.73 (m, 2H),
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1.62 – 1.56 (m, 2H), 1.41 – 1.30 (m, 4H), 1.27 (d, J = 6.0 Hz, 3H); C NMR (100 MHz, CDCl3) δ
174.8, 174.0, 69.5, 61.8, 33.9, 33.8, 33.7, 26.6, 26.4, 24.8, 24.4, 20.9; TOF HRMS (DART) m/z [M+H]+
calcd for C12H21O4 229.1440, found 229.1429.
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Compound 6b. Obtained according to the general procedure in 92% yield (9.0 mg) as a white solid.
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m.p. 73-74 °C; Rf 0.68 (hexanes: EtOAc 8:2); H NMR (400 MHz, CDCl3) δ 3.82 (s, 4H), 2.36 – 2.24
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(m, 4H), 1.66 – 1.63 (m, 4H), 1.27 – 1.24 (m, 4H), 0.96 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 174.8,
70.4, 33.2, 28.9, 27.1, 23.1, 21.9; TOF HRMS (DART) m/z [M+H]+ calcd for C13H23O4 243.1596, found
243.1569.
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Compound 6c. The compound was prepared according to the general procedure in 99% yield (10.0 mg)
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as a white solid. m.p. 161 °C (decomp); Rf 0.28 (EtOAc); H NMR (400 MHz, CDCl3) δ 6.37 (s, br,
2H), 3.16 (d, J = 4.0 Hz, 4H), 2.28 (q, J = 4.0 Hz, 4H), 1.73 (t, J = 4.0 Hz, 4H), 1.41 – 1.38 (m, 4H),
0.94 (d, J = 12.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 173.9, 50.1, 36.8, 36.5, 27.4, 24.4, 21.9; TOF
HRMS (DART) m/z [M+H]+ calcd for C13H25N2O2 241.1916, found 241.1902.
Compound 6d. The compound was prepared according to the general procedure in 99% yield (10.0 mg)
as a white solid. m.p. 79-80 °C; Rf 0.52 (hexanes: EtOAc 8:2,);1H NMR (400 MHz, CDCl3) δ 4.17 –
4.13 (m, 2H), 2.28 – 2.07 (m, 6H), 1.61 – 1.54 (m, 4H), 1.51 (s, 6H), 1.47– 1.43 (m, 4H), 0.88 (t, J =
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.8, 173.1, 80.6, 60.6, 39.0, 35.7, 34.4, 28.9, 28.8, 26.7, 25.0,
24.9, 24.8; TOF HRMS (DART) m/z [M+H]+ calcd for C13H23O4 243.1596, found 243.1595.
Compound 6e. The compound was prepared according to the general procedure in 100% yield (10.0
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mg) as a white solid. m.p. 107-108 °C; Rf 0.55 (hexanes: EtOAc 8:2,); H NMR (400 MHz, CDCl3) δ
5.52 (d, J = 4.0 Hz, 1H), 4.33 (td, J = 8.0, 4.0 Hz, 1H), 4.23 – 4.20 (m, 1H), 4.13 (td, J = 8.0, 4.0 Hz,
1H), 2.31 – 2.27 (m, 3H), 2.05 – 2.01 (m, 1H), 1.89 – 1.87 (m, 1H), 1.77 – 1.67 (m, 3H), 1.51 – 1.34 (m,
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5H), 1.26 (d, J = 4 Hz, 3H); C NMR (100 MHz, CDCl3) δ 174.7, 172.4, 62.6, 44.7, 36.2, 34.4, 34.2,
27.4, 26.6, 24.5, 21.4; TOF HRMS (DART) m/z [M+H]+ calcd for C12H22NO3 228.1600, found
228.1596.
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Compound 6f. The compound was prepared according to the general procedure in 98% yield (10.0 mg)
as a white solid. m.p. 112-113 °C; Rf 0.58 (hexanes: EtOAc 7:3,); 1H NMR (400 MHz, CDCl3) δ 5.78 (s,
br, 1H), 5.07 – 5.03 (m, 1H), 3.67 – 3.63 (m, 1H), 3.18 – 3.11 (m, 1H), 2.40 – 2.25 (m, 2H), 2.19 (t, J =
6.0 Hz, 2H), 1.90 – 1.70 (m, 6H), 1.46 – 1.39 (m, 4H), 1.26 (d, J = 8.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.3, 173.2, 71.5, 38.0, 36.2, 34.8, 34.0, 27.0, 26.2, 24.4, 23.7, 21.4; TOF HRMS (DART)
m/z [M+H]+ calcd for C12H22NO3 228.1600, found 228.1588.
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Compound 6g. The compound was prepared according to the general procedure in 98% yield (10.0 mg)
as a white solid. m.p. 203-204 °C; Rf 0.18 (EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.33 (s, br, 1H), 5.75
(d, J = 8.0 Hz, 1H), 4.12 – 4.06 (m, 1H), 3.96 – 3.88 (m, 1H), 2.91 – 2.88 (m, 1H), 2.37 – 2.21 (m, 3H),
2.08 (td, J = 8.0, 4.0 Hz, 1H), 1.91 – 1.81 (m, 1H), 1.71 – 1.36 (m, 9H), 1.18 (d, J = 8.0 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 173.4, 172.6, 45.3, 37.5, 36.9, 36.2, 36.0, 26.9, 26.2, 23.2, 22.5, 22.3; TOF
HRMS (DART) m/z [M+H]+ calcd for C12H23N2O2 227.1760, found 227.1768.
Compound 6h. (racemate) Obtained according to the general procedure in 88% yield (9.0 mg) as a
white solid. m.p. 123-124 °C; Rf 0.79 (hexanes: EtOAc 9:1); 1H NMR (400 MHz, CDCl3) δ 5.11 (dd, J =
16.0, 8.0 Hz, 2H), 2.31 (q, J = 4.0 Hz 4H), 1.92 (t, J = 4.5 Hz, 2H), 1.85 – 1.81 (m, 2H), 1.56 – 1.50 (m,
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3H), 1.42 – 1.36 (m, 3H), 1.28 (d, J = 4.0 Hz, 6H); C NMR (100 MHz, CDCl3) δ 174.1, 67.6, 40.9,
33.4, 25.9, 24.4, 20.8; TOF HRMS (DART) m/z [M+H]+ calcd for C13H23O4 243.1596, found 243.1572.
Compound 6i. (meso) Obtained according to the general procedure in 99% yield (10.0 mg) as a white
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solid. m.p. 117-118 °C; Rf 0.73 (hexanes: EtOAc 9:1); H NMR (400 MHz, CDCl3) δ 5.02 – 4.98 (m,
2H), 2.31 (t, J = 8.0 Hz, 4H), 2.13 – 2.09 (m, 1H), 1.70 – 1.61 (m, 5H), 1.36 (d, J = 4.0 Hz, 4H), 1.23 (d,
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J = 4.0 Hz, 6H); C NMR (100 MHz, CDCl3) δ 174.4, 71.1, 42.1, 34.9, 27.6, 24.1, 21.8; TOF HRMS
(DART) m/z [M+H]+ calcd for C13H23O4 243.1596, found 243.1607.
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General epoxidation procedure. Following the literature procedure,7 to a solution of 3 (10 mg) in
acetone-H2O:DCM (1:1:1, 9 mL) was added excess amount of NaHCO3 (100 mg, 0.94 mmol) and
Oxone (120 mg, 0.19 mmol) at 0 °C. The resulting heterogeneous solution was stirred for 3 h at 0 °C,
and extracted with DCM. After removal of the solvent, the residue was purified by chromatography to
give the epoxide product.
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Compound 7a. Obtained according to the general procedure in 93% yield (10.0 mg) as a white solid.
m.p. 91-92 °C; Rf 0.56 (hexanes: EtOAc 7:3,); 1H NMR (400 MHz, CDCl3) 5.28 – 5.22 (m, 1H), δ 4.72
(td, J = 8.0, 4.0 Hz, 1H), 3.83– 3.79 (m, 1H), 2.78 (d, J = 8.0 Hz, 1H), 2.71 (d, J = 8.0 Hz, 1H), 2.42 –
2.39 (m, 4H), 2.23 – 2.07 (m, 3H), 1.82 – 1.75 (m, 1H), 1.58 – 1.48 (m, 2H), 1.26 (d, J = 4.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ 172.8, 69.0, 58.2, 34.6, 29.6, 26.9, 22.9; TOF HRMS (DART) m/z
[M+H]+ calcd for C12H18O5 243.1233, found 243.1221.
Compound 7b. The compound was prepared according to the general procedure in 88% yield (9.0 mg)
as a white solid. m.p. 105-106 °C; Rf 0.62 (hexanes: EtOAc 8:2); 1H NMR (400 MHz, CDCl3) δ 4.49 (d,
J = 8.0 Hz, 2H), 3.38 (d, J = 12.0 Hz, 2H), 2.72 (d, J = 8.0 Hz, 2H), 2.41 – 2.36 (m, 4H), 2.19 – 2.14
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(m, 2H),1. 60 – 1.54 (m, 2H), 1.02 (s, 6H); C NMR (100 MHz, CDCl3) δ 172.8, 69.0, 58.2, 34.6,
29.6, 26.9, 22.9; TOF HRMS (DART) m/z [M+H]+ calcd for C13H21O5 257.1389, found 257.1360.
Compound 7c. The compound was prepared according to the general procedure in 81% yield (9.0 mg)
as a white solid. m.p. 157-158 °C; Rf 0.20 (hexanes: EtOAc 6:4,); 1H NMR (400 MHz, CDCl3) δ 6.28 (s,
br, 2H), 3.43 (dd, J = 12.0, 8.0 Hz, 2H), 2.88 (dd, J = 12.0, 8.0 Hz, 2H), 2.76 (d, J = 8.0 Hz, 2H), 2.41
(t, J = 6.0 Hz, 2H), 2.38 – 2.34 (m, 2H), 2.23 – 2.16 (m, 2H), 1.90 – 1.66 (m, 2H), 1.47 – 1.43 (m, 2H),
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0.94 (s, 6H); C NMR (100 MHz, CDCl3) δ 172.9, 57.9, 48.8, 36.1, 32.8, 27.6, 25.0; TOF HRMS
(DART) m/z [M+H]+ calcd for C13H23N2O3 255.1709, found 255.1738.
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Compound 7d. The compound was prepared according to the general procedure in 77% yield (8.0 mg)
as a white solid. m.p. 83-84 °C; Rf 0.58 (hexanes: EtOAc 8:2); 1H NMR (400 MHz, CDCl3) δ 4.36 (q, J
= 4.0 Hz, 1H), 4.28 (q, J = 4.0 Hz, 1H), 2.86 (d, J = 8.0 Hz, 1H), 2.77 (d, J = 8.0 Hz, 1H), 2.39 – 2.23
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(m, 8H), 1. 59 – 1.50 (m, 2H), 1.45 (d, J = 8.0 Hz, 6H); C NMR (100 MHz, CDCl3) δ 173.0, 172.3,
81.1, 60.7, 57.7, 57.4, 37.9, 31.5, 31.2, 27.5, 27.3, 27.0, 26.3; TOF HRMS (DART) m/z [M+H]+ calcd
for C13H21O5 257.1389, found 257.1360.
Compound 7e. The compound was prepared according to the general procedure in 93% yield (10.0 mg)
as a white solid. m.p. 101-102 °C; Rf 0.55 (hexanes: EtOAc 6:4); 1H NMR (400 MHz, CDCl3) δ 5.58 (d,
J = 4.0 Hz, 0.25H), 5.22 (d, J = 8.0 Hz, 0.75H), 4.69 (td, J = 12.0, 4.0 Hz, 1H), 4.66 – 4.10 (m, 1H),
3.89 (td, J = 8.0, 4.0 Hz, 1H), 2.84 – 2.81 (m, 1H), 2.67 – 2.64 (m, 1H), 2.45 – 2.41 (m, 1H), 2.39 – 2.06
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(m, 5H), 1.75 – 1.40 (m, 4H), 1.20 (d, J = 4.0 Hz, 0.8H), 1.16 (d, J = 4.0 Hz, 2.2H); C NMR (100
MHz, CDCl3) δ 170.6, 60.1, 58.9, 58.4, 41.9, 34.1, 31.5, 29.8, 27.0, 26.7, 22.0; TOF HRMS (DART)
m/z [M+H]+ calcd for C12H20NO4 242.1392, found 242.1416.
Compound 7f. The compound was prepared according to the general procedure in 76% yield (8.0 mg)
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as a white solid. m.p. 115-116 °C; Rf 0.11 (DCM: EtOAc: methanol 80:15:5); H NMR (400 MHz,
CDCl3) δ 5.35 (d, J = 4.0 Hz, 1H), 5.24 (td, J = 8.0, 4.0 Hz, 1H), 3.91 – 3.85 (m, 1H), 3.04 (dd, J =
12.0, 8.0 Hz, 1H), 2.78 (t, J = 8.0 Hz, 2H), 2.44 (q, J = 4.0 Hz, 2H), 2.32 – 2.30 (m, 1H), 2.20 – 2.11 (m,
3H), 1.86 – 1.80 (m, 2H), 1.69 – 1.59 (m, 2H), 1.22 (d, J = 4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
172.8, 171.3, 66.8, 59.2, 58.5, 35.2, 33.6, 31.8, 29.6, 27.2, 26.5, 20.8; TOF HRMS (DART) m/z [M+H]+
calcd for C12H20NO4 242.1392, found 242.1417.
Compound 7h. (racemate) The compound was prepared according to the general procedure in 94%
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yield (10.0 mg) as a white solid. m.p. 97-98 °C; Rf 0.70 (hexanes: EtOAc 7:3); H NMR (400 MHz,
CDCl3) δ 5.23 – 5.18 (m, 2H), 2.73 (d, J = 8.0 Hz, 2H), 2.43 – 2.35 (m, 4H), 2.15 (td, J = 12.0, 4.0 Hz,
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2H), 1.82 (t, J = 8.0 Hz, 2H), 1.54 – 1.51 (m, 2H), 1.22 (d, J = 8.0 Hz, 6H); C NMR (100 MHz,
CDCl3) δ 172.4, 161.4, 66.8, 59.0, 29.6, 26.8, 20.4; HRMS m/z [M+H]+ calcd for C13H21O5 257.1389,
found 257.1365.
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Compound 7i. (meso) The compound was prepared according to the general procedure in 91% yield
(10.0 mg) as a white solid. m.p. 109-110 °C Rf 0.75 (hexanes: EtOAc 7:3); 1H NMR (400 MHz, CDCl3)
δ 5.22 – 5.18 (m, 2H), 2.96 (q, J = 4.0 Hz, 1H), 2.72 (q, J = 4.0 Hz, 1H), 2.50 – 2.17 (m, 6H), 2.02 –
1.96 (m, 1H), 1.65 – 1.53 (m, 3H),1.24 (d, J = 8.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 176.6, 71.0,
70.8, 57.0, 56.6, 42.4, 32.0, 30.7, 27.1, 26.4, 21.9, 21.8; TOF HRMS (DART) m/z [M+H]+ calcd for
C13H21O5 257.1389, found 257.1367.
Acknowledgement. The authors thank Daniel Terwilliger for initial experiments on this project. The
NSF supported of this work through a grant to MWP (CHE-0957626). 400MHz/100MHz 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 3h, 3i, 7b and 7d. Carlos Pacheco is acknowledged for assistance collecting NMR spectra,
especially the VT 1H NMR data on 3h and 6h.
Supporting Information Available: Crystallographic data for 3h, 3i, 7b and 7d are in the Cambridge
Crystallographic Data Centre (CCDC), No. 924286, 924287, 924284, and 924285. Copies of this
information 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:
1
deposit@ccdc.cam.ac.uk). VT HNMR data for 3h and 6h and characterization data including H and
1
13C NMR spectra of all new compounds. This material is available free of charge via the Internet at
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References
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Reactions of [13]-macrodilactones (e.g. 3a, 3b, and 3d) were slightly lower than the in situ DMDO
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