Diversity-oriented synthesis of 13- to 18-membered macrolactams via ring-closing metathesis

Article abstract of DOI:10.1021/jo2011957

An efficient build/couple/pair approach to diversity-oriented synthesis was employed to access several structurally complex macrolactams. In this paper, we describe the successful evaluation of ring-closing metathesis toward the systematic generation of skeletal diversity. By appropriately varying the nature and chain length of the alkenol fragment, a diverse collection of 13- to 18-membered macro-lactams were obtained.

Full text of DOI:10.1021/jo2011957

NOTE
pubs.acs.org/joc
Diversity-Oriented Synthesis of 13- to 18-Membered Macrolactams via
Ring-Closing Metathesis
Sivaraman Dandapani, Jason T. Lowe, Eamon Comer, and Lisa A. Marcaurelle*,†
Chemical Biology Platform, Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States
S Supporting Information
b
ABSTRACT: An efficient build/couple/pair approach to diversity-
oriented synthesis was employed to access several structurally complex
macrolactams. In this paper, we describe the successful evaluation of
ring-closing metathesis toward the systematic generation of skeletal
diversity. By appropriately varying the nature and chain length of the
alkenol fragment, a diverse collection of 13- to 18-membered macro-
lactams were obtained.
iversity-oriented synthesis (DOS) has been a topic of
increasing interest among both academic and industrial
D
sectors.1 This interest has stemmed, in large extent, from the
apparent lack of structural complexity in known screening collec-
tions.2,3 It has been suggested that this lack of diversity has
limited the number of drugs to come to market in the recent past
due to the narrow cross section of biological space accessible by
these small molecules.4 This leaves a large area of potential mole-
cular targets such as transcription factors, regulatory RNA, and
proteinÀprotein and proteinÀDNA interactions relatively
underexplored in the arena of drug discovery/development.5
In an effort to access these so-called undruggable targets, several
DOS-based libraries have recently been created to help increase
the overall complexity of the screening collections in the hopes of
modulating some of these more elusive targets.6
The build/couple/pair (B/C/P) algorithm has found increasing
use in the development of DOS-based chemical libraries.7 Our
attempts to incorporate this strategy in recent library design focused
on a diastereoselective aldol reaction to access 2 in the initial stages
of the synthesis (build phase) (Figure 1).7a By coupling this amino
acid with a complementary amino alcohol, 1, we were able to access
all stereochemical combinations of amine 3, which has been applied
in several library campaigns7a,8 to gain access to stereo/structure
Àactivity relationships (SSAR).9 In our initial study7a we applied
ring-closing metathesis (RCM)10,11 as a pairing strategy to access
the 14-membered macrolactams in all stereochemical combinations
(16 stereoisomers total). Macrocycles in general are appealing in
the context of drug discovery as they have been used successfully on
a variety of important target classes, including proteases, G protein-
coupled receptors (GPCRs), and proteinÀprotein interactions.12
The goal of the present study is to explore the feasibility of accessing
different macrocyclic ring sizes using RCM as a pairing strategy.
The ability to systematically vary the ring size of the RCM-derived
macrocycle would potentially be useful in exploring the influence of
skeletal diversity on biological activity.
Figure 1. Build/couple/pair strategy for the synthesis of stereochemi-
cally diverse macrolactams.
a single stereoisomer (2S,5R,6R) for this study, the pair phase
involves the application of an intermolecular SNAr reaction with
aryl fluoride 513 and commercially available alkenols.14 Our plan
called for systematically varying the alkenols to gain access to
increasingly larger rings (Scheme 1). This approach would allow
for the direct access to a number of ring sizes without the need for
changing the overall synthetic strategy.
It was found that exposure of enantio-enriched 5 to a solution
of sodium hydride and requisite alcohols in THF at 0 °C pro-
vided the desired SNAr products in excellent yields (82À91%).
The reaction was found to work well with several different alcohols,
Herein we demonstrate that 13- to 18-membered rings can be
successfully formed with the RCM pairing strategy. Focusing on
Received: June 16, 2011
Published: August 29, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2011957 J. Org. Chem. 2011, 76, 8042–8048
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Synthesis of RCM Precursorsa
a Reagents and conditions: (aÀg) alcohol, NaH, THF, 0À23 °C, [(a) allyl alcohol, 88%; (b) (S)-4-penten-2-ol, 82%; (c) (R)-5-hexen-2-ol, 89%;
(d) 5-hexenol, 91%; (e) 6-heptenol, 91%; (f) 7-octenol, 91%; (g) 2-allyl phenol, 83%]; (h) TBAF, THF, 0À25 °C (82À99%); (i) NaH, allyl bromide,
DMF, 0À25 °C (80À95%).
including primary, secondary, and aryl systems. Deprotection
of the TBS silyl ether using TBAF followed by allylation of
the resulting secondary alcohol with allyl bromide afforded the
respective RCM precursors 6À12 in excellent overall yields
(80À95%).
We chose to focus on Grubbs first generation catalyst since this
reagent performed best in our initial screening for this ring
system (Table 1, entries 1À3). In an attempt to improve the
product to dimer ratio, we carried out the reaction in a range of
solvents, and the results are summarized in Table 2. Aromatic
solvents, including benzene, chlorobenzene, trifluorotoluene and
xylenes, gave product to dimer ratios similar to that observed for
toluene (Table 2, entries 2À5) as did the non-aromatic solvent
ethyl acetate (entry 6). Finally it was found that DCM provided
full conversion of the starting materials, albeit with product
to dimer ratios identical to those for toluene (Table 2, entry 7).
Though the product to dimer ratio remained the same, the
overall isolated yield was significantly improved (from 55% to
79%).
We next surveyed the role of known additives that have been
shown to affect the outcome of metathesis reactions.16 Unfortu-
nately, neither 1,4-benzoquinone nor acetic acid improved the
overall selectivity of the reaction and in fact lowered the overall
conversion (Table 2, entries 8 and 9).
In an effort to add additional structural diversity to the
backbone of the macrocycle, we sought to incorporate a biaryl
ether linkage. This is a common structural motif in a number of
biologically active compounds, including vancomycin, K-13,
bouvardin, OF4949-III, or biphenomycin-A.17 Exposure of 8 to
G1, G2, or GH2 provided excellent conversion and minimal
dimer formation (Table 3).
At this stage we began to investigate the scope and limitations
of the RCM reaction. To this end, we tested the metathesis
reaction on all our substrates with three commercially available
ruthenium-based catalysts. Compounds 6À12 were subjected to
Grubbs first generation (G1) and second generation (G2) and
GrubbsÀHoveyda second generation (GH2) catalysts at 65 °C
in toluene (Table 1). Little variation was noticed among the three
catalysts with respect to overall chemical conversion for each
of the ring sizes (Table 1, entries 1À18). Moreover, the product
to dimer ratio was found to be independent of the catalyst
employed in the reaction.15 The 14- through 18-membered ring
systems gave the best product to dimer ratios (98:2 to 100:0)
using G1 catalyst with isolated yields ranging from 69À88%
(Table 1, entries 7, 10, 13, and 16). A notable exception to this
trend was the 13-membered ring system, which was found to
give 85À88% conversion using various catalysts (Table 1, entries
1À3). Also, the 13-membered ring was found to be the most
difficult system to close, with substantial amounts of dimers
observed under all three catalyst conditions. G1 proved to be the
best catalyst, with nearly 20% dimer and a 55% overall yield for the
desired macrocycle (Table 1, entry 1).
Further optimization of the 13-membered system was under-
taken in an effort to improve the yield and decrease dimerization.
In summary, application of the ring-closing metathesis reac-
tion provided rapid entry to complex macrocyclic core systems
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The Journal of Organic Chemistry
NOTE
Table 1. Ring Size Variation via RCM
entrya
SM f P (ring size, X)
6 f 13 (13, H)
catalystb
time (h)
conversionc (%)
UV ratio product:dimersc
yieldd (%)
55
1
2
G1
1
1
1
1
1
1
3
2
2
3
2
2
1
1
1
1
1
1
88
88
81:19
60:40
54:46
100:0
100:0
100:0
98:2
G2
3
GH2
G1
85
4
7 f 14 (14, Me)
8 f 15 (15, Me)
9 f 16 (16, H)
10 f 17 (17, H)
11 f 18 (18, H)
100
100
100
100
99
5
G2
6
GH2
G1
85
73
7
8
G2
95:5
9
GH2
G1
98
90:10
98:2
10
11
12
13
14
15
16
17
18
99
88
83
69
G2
100
100
98
95:5
GH2
G1
90:10
98:2
G2
98
98:2
GH2
G1
98
98:2
100
100
100
98:2
G2
98:2
GH2
91:9
a Reactions run on 20 mg of material, 0.01 M in toluene, 65 °C, and 10 mol % catalyst. b G1 = Grubbs catalyst (first generation), G2 = Grubbs catalyst
(second generation), and GH2 = GrubbsÀHoveyda catalyst (second generation). c From LCÀMS analysis. d Yields based on products isolated after
flash chromatography.
starting from a common intermediate, 5. This synthetic sequence
has been shown to be general for varying ring sizes (13- through
18-membered) and structural types (linear and branched alkyl and
biaryl ethers). The twokey steps of our approach are (i) an efficient
intermolecular SNAr reaction of a number of commercially avail-
able alkenyl alcohols to allow direct access to any number of
bisallylated building blocks and (ii) a high-yielding ring-closing
metathesis showing utility over a wide range of ring sizes. The
ability to access a collection of such related ring systems is beneficial
for library development and for providing structureÀactivity
relationships once a hit is identified from one of the ring sizes.
accomplished with UV light and aqueous potassium permanganate
(KMnO4) stain followed by heating.
General Procedure for the Synthesis of RCM Precursors.
SNAr Reaction. A solution of the alcohol (4.0 equiv) in THF (0.38 M)
was cooled to 0 °C in an ice bath. Sodium hydride (60% dispersion in
mineral oil, 4.0 equiv) was added portionwise, and the reaction was
stirred for 20 min at 0 °C. A solution of compound 57a (2.45 mmol) in
THF (2 M) was added via cannula over 2 min. The solution turned
yellow over the addition of the amine. The reaction was allowed to warm
to room temperature and stirred for 2 h. The reaction mixture was
quenched with water, and the aqueous layer was extracted two times
with EtOAc. The combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure to provide the crude
product, which was purified by chromatography over silica gel to provide
the SNAr product.
’ EXPERIMENTAL SECTION
General Experimental Methods. All oxygen- and/or moisture-
sensitive reactions were carried out under a N2 atmosphere in glassware
that had been flame-dried under vacuum (∼0.5 mmHg) and purged
with N2 prior to use. All reagents and solvents were purchased from
commercial vendors and used as received or synthesized according to
the footnoted references. NMR spectra were recorded on a 300 MHz
(1H)/75 MHz (13C) or 500 MHz (1H)/125 MHz (13C) spectrometer.
Unless otherwise indicated, NMR data were collected at 25 °C. Flash
chromatography was performed using 40À60 μm silica gel (60 Å mesh)
on an automated medium-pressure liquid chromatography instrument.
Analytical thin layer chromatography (TLC) was performed on com-
mercially available plates with 0.25 mm of silica gel. Visualization was
TBS Deprotection. A solution of SNAr product from the previous step
(1.0 equiv) in THF (0.1 M) was cooled to 0 °C in an ice bath. A solution
of tetrabutylammonium fluoride in THF (1.0 M, 2.0 equiv) was added
dropwise over 3 min, and the reaction was stirred for 12 h, slowly warm-
ing to room temperature. The reaction was quenched with saturated
aqueous NH4Cl and water and extracted three times with EtOAc. The
combined organic layers were dried (MgSO4), filtered, and concentrated
to provide the crude product, which could be purified by flash
chromatography on silica gel to get a pure secondary alcohol.
Allylation. A solution of the secondary alcohol (1.0 equiv) in DMF
(0.1 M) was cooled to 0 °C in an ice bath. Allyl bromide (10.0 equiv) was
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NOTE
Table 2. Optimization of the RCM To Form the 13-Membered Macrolactam
entrya
solventb
additive
T (°C)
time (h)
conversionc (%)
UV ratio product:dimersc
yieldd (%)
55
1
2
3
4
5
6
7
8
9
PhMe
65
65
65
65
65
40
40
40
40
3
3
3
3
3
3
4
5
5
85
84
81:19
73:27
78:22
72:28
77:23
74:26
85:15
81:19
85:15
PhH
PhCI
86
PhCF3
xylenes
EtOAc
CH2CI2
CH2CI2
CH2CI2
71
77
78
100
93
79
BQ
AcOH
89
a Reactions run on 20 mg of material, 0.01 M in toluene, 65 °C, and 10 mol % catalyst. b G1 = Grubbs catalyst (first generation), G2 = Grubbs catalyst
(second generation), and GH2 = GrubbsÀHoveyda catalyst (second generation). c From LCÀMS analysis. d Yields based on products isolated after
flash chromatography.
1484, 1454, 1391, 1365, 1340, 1270, 1247, 1157, 1077; 1H NMR
Table 3. Accessing Macrocyclic Biaryl Ether through RCM
(500 MHz, DMSO-d6, 140 °C) δ 8.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.97
(d, J = 3.0 Hz, 1H), 7.27 (d, J = 9.5, Hz, 1H), 7.20 (br s, 2H), 6.90 (d, J =
8.0 Hz, 2H), 6.02 (ddt, J = 16.5, 11.0, 5.5 Hz, 1H), 5.85 (br s, 1H), 5.43
(dd, J = 17, 1.5 Hz, 1H), 5.30 (d, J = 10.5 Hz, 1H), 5.20 (br s, 1H), 5.10
(s, 1H), 4.75 (d, J = 5.0 Hz, 1H), 4.40 (br s, 2H), 3.96 (br s, 2H),
3.90À3.70 (obsc br s, 1H), 3.79 (s, 3H), 3.70À3.00 (br, 4H), 3.35 (d, J =
11 Hz, 1H), 2.84 (s, 3H), 2.17 (br s, 1H), 1.44 (s, 9H), 1.23 (br s, 3H),
0.96 (br s, 3H); 13C NMR (125 MHz, DMSO) δ 166.4, 158.5, 158.3,
154.4, 140.6, 134.8, 134.8, 131.6, 129.8, 128.1, 128.1, 124.8, 122.9, 117.5,
114.8, 113.3, 112.6, 79.9, 77.9, 71.5, 70.7, 70.1, 69.2, 54.6, 53.6, 49.3, 42.6,
34.9, 34.5, 27.5, 15.0, 12.7; HRMS (ESI) m/z calcd for C35H49N3O9
time conversionc UV ratio product:
yieldd
(%)
[M + H]+ 656.3542, found 656.3549.
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(N-((S)-1-((4-methoxybenzyl)-
oxy)prop-2-yl)-5-nitro-2-((S)-pent-4-en-2-yloxy)benzamido)-3-
methylbutyl)(methyl)carbamate (7). Synthesis and characteriza-
tion of this compound has been previously reported.7a
entry
catalysta,b
(h)
(%)
dimersc
1
2
3
G1
1
1
1
100
100
100
98:2
98:2
91:9
87
G2
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(2-((R)-hex-5-en-2-yloxy)-N-
((S)-1-((4-methoxybenzyl)oxy)prop-2-yl)-5-nitrobenzamido)-3-
methylbutyl)(methyl)carbamate (8). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À63.4
(c 1.13, CHCl3); IR (cmÀ1) 2976, 2934, 1688, 1635, 1610, 1587, 1513,
1481, 1452, 1390, 1365, 1337, 1268, 1247, 1152, 1111, 1075, 1034;
1H NMR (500 MHz, DMSO-d6, 140 °C) δ 8.20 (dd, J = 9.0, 3.0 Hz,
1H), 7.98 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 9.0, Hz, 2H), 7.22 (br s, 1H),
6.90 (d, J = 8.5 Hz, 2H), 5.85 (ddt, J = 17.0, 10.5, 6.5 Hz, 2H), 5.19 (br s,
1H), 5.08 (br s, 1H), 5.01 (dd, J = 17.0, 1.5 Hz, 1H), 4.96 (d, J = 10.0 Hz,
1H), 4.72 (q, J = 6.5 Hz, 1H), 4.41 (br s, 2H), 3.98 (br s, 2H), 3.87À3.78
(br s, 1H), 3.78 (s, 3H), 3.74À3.00 (br s, 4H), 3.35 (d, J = 11.5 Hz, 2H),
2.86 (s, 3H), 2.16 (m, 3H), 1.81 (m, 1H), 1.73 (m, 1H), 1.42 (s, 9H),
1.34 (d, J = 6.0 Hz, 3H), 1.26 (obsc br s, 3H), 1.01 (br s, 3H); 13C NMR
(125 MHz, CDCl3) δ 166.5, 158.5, 157.9, 154.4, 140.1, 137.0, 134.7, 128.5,
128.0, 124.7, 123.2, 114.7, 114.0, 113.3, 112.6, 80.0, 77.9, 74.3, 71.5, 70.8,
70.2, 54.5, 53.4, 49.4, 42.3, 35.5, 34.5, 34.4, 27.9, 27.4, 18.4, 15.1, 12.8; HRMS
(ESI) m/z calcd for C38H55N3O9 [M + H]+ 698.4011, found 698.4002.
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(2-(hex-5-en-1-yloxy)-N-((S)-
1-((4-methoxybenzyl)oxy)-prop-2-yl)-5-nitrobenzamido)-3-
methylbutyl)(methyl)carbamate (9). This compound was synthesized
GH2
a G1 = Grubbs catalyst (first generation), G2 = Grubbs catalyst (second
generation), GH2 = GrubbsÀHoveyda catalyst (second generation).
b Reactions run on 20 mg of material, 0.01 M in toluene, 65 °C, and 10
mol % catalyst. c From LCÀMS analysis. d Yields based on products
isolated after flash chromatography.
then added, followed by sodium hydride (60% dispersion in mineral oil,
2.4 equiv) as a solid in one portion, and the reaction was stirred for 12 h,
slowly warming to room temperature. The reaction mixture was
quenched with aqueous saturated NH4Cl solution and extracted three
times with ethyl acetate. The combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure to provide
the crude product, which was purified by chromatography on silica gel to
give pure allylated products 6À12.
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(2-(allyloxy)-N-((S)-1-
((4-methoxybenzyl)oxy)prop-2-yl)-5-nitrobenzamido)-3-
methylbutyl)(methyl)carbamate (6). This compound was
synthesized by the general procedure described above: [α]2D0 = À40.9
(c 1.02, CHCl3); IR (cmÀ1) 2974, 2934, 1690, 1635, 1612, 1587, 1514,
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NOTE
by the general procedure described above: [α]2D0 =À39.2 (c1.27, CHCl3);IR
(cmÀ1) 2935, 1689, 1635, 1611, 1587, 1513, 1454, 1391, 1365, 1338, 1269,
1246, 1153, 1075, 1033; 1H NMR (500 MHz, DMSO-d6, 140 °C) δ 8.20
(dd, J = 9.5, 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 7.24 (d, J = 9.5, Hz, 2H),
7.21 (br s, 1H), 6.90 (d, J= 9.0 Hz, 2H), 5.85 (ddt, J= 17.5, 10.5, 7.0 Hz, 2H),
5.20 (br s, 1H), 5.08 (br s, 1H), 5.02 (dd, J = 17.0, 1.5 Hz, 1H), 4.97 (d, J =
9.5, 0.5 Hz, 1H), 4.41 (br s, 2H), 4.18 (m, 1H), 3.97 (br s, 2H), 3.84 (br s,
1H),3.78(s,3H),3.74À3.00 (br s, 4H), 3.37 (d, J= 11.5 Hz, 2H), 2.86 (br, s,
3H), 2.16 (br s, 1H), 2.11 (q, J = 7.5 Hz, 2H), 1.79 (pent, J = 7 Hz, 1H), 1.55
(pent, J = 7.5 Hz, 1H), 1.44 (s, 9H), 1.25 (br s, 3H), 0.98 (br s, 3H); 13C
NMR (125 MHz, CDCl3) δ 166.4, 158.8, 158.5, 154.4, 140.3, 137.4, 134.4,
129.8, 128.0, 127.9, 124.8, 122.9, 114.7, 113.8, 113.3, 112.2, 80.0, 77.9, 71.5,
70.8, 70.1, 68.7, 54.5, 53.5, 49.3, 42.2, 35.0, 34.5, 31.8, 27.4, 27.3, 23.9, 14.9,
12.7; HRMS (ESI) m/z calcd for C38H55N3O9 [M + H]+ 698.4011, found
698.4005.
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(2-(hept-6-en-1-yloxy)-N-((S)-
1-((4-methoxybenzyl)-oxy)prop-2-yl)-5-nitrobenzamido)-3-
methylbutyl)(methyl)carbamate (10). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À36.1 (c 1.42,
CHCl3); IR (cmÀ1) 2932, 1689, 1636, 1611, 1587, 1513, 1455, 1391, 1365,
1338, 1269, 1246, 1154, 1110, 1075, 1034; 1H NMR (500 MHz, DMSO-d6,
130 °C) δ 8.20 (dd, J = 9.5, 3.0 Hz, 1H), 7.98 (d, J = 3.0 Hz, 1H), 7.25 (d,
J = 9.5, Hz, 2H), 7.21 (br s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 5.83 (ddt, J= 17.5,
10.5, 7.0 Hz, 2H), 5.20 (br s, 1H), 5.08 (br s, 1H), 5.01 (dd, J = 17.0, 1.5 Hz,
1H), 4.95 (d, J = 9.5, Hz, 1H), 4.41 (br s, 2H), 4.17 (m, 2H), 3.97 (br s,
2H), 3.84 (br s, 1H), 3.78 (s, 3H), 3.74À3.00 (br s, 4H), 3.37 (d, J = 11.5
Hz, 2H), 2.86 (br, s, 3H), 2.18 (br s, 1H), 2.07 (apt. d, J = 6.5 Hz, 2H), 1.77
(pent, J = 7 Hz, 2H), 1.55 (pent, J = 6.5 Hz, 2H), 1.45 (s, 13H), 1.25 (br s,
3H), 0.98 (br s, 3H); 13C NMR (125 MHz, CDCl3) δ 166.4, 158.8, 158.4,
154.3, 140.3, 137.7, 134.7, 129.8, 128.0, 128.0, 124.8, 122.8, 114.7, 113.5,
113.3, 112.2, 79.9, 77.9, 71.5, 70.8, 70.1, 68.8, 54.5, 53.5, 49.4, 42.2, 35.0,
34.5, 32.1, 27.7, 27.4, 27.2, 24.1, 14.8, 12.7; HRMS (ESI) m/z calcd for
C39H57N3O9 [M + H]+ 711.4095, found 711.4157.
(br s, 1H), 2.87 (s, 3H), 2.21 (br s, 1H), 1.43 (s, 9H), 1.30 (br s, 3H), 0.99
(br s, 3H); 13C NMR (125 MHz, DMSO) δ 166.0, 158.5, 157.6, 154.3,
151.5, 141.8, 135.1, 134.7, 131.3, 130.2, 129.7, 128.7, 128.0, 127.3, 125.0,
124.7, 123.5, 119.6, 115.3, 115.3, 114.8, 113.3, 79.9, 77.9, 71.6, 70.7, 70.2, 54.5,
53.8, 49.4, 42.5, 35.0, 34.5, 32.4, 27.4, 15.0, 12.8; HRMS (ESI) m/z calcd for
C41H53N3O9Na [M + Na]+ 754.3679, found 754.3653.
General Procedure for RCM/Hydrogenation. RCM. A solu-
tion of allylated product synthesized by the first general procedure
described above (1.0 equiv) and G1, G2, or GH2 catalyst (0.10 equiv) in
toluene (0.01 M with respect to starting material) was degassed with dry
nitrogen. The reaction was heated and stirred for 4 h at 65 °C. The solvent
was evaporated under reduced pressure and purified by flash chroma-
tography on silica gel. The resulting products (a mixture of geometric
isomers) were redissolved in ethyl acetate (0.02 M) and stirred over-
night with activated carbon. The mixture was then filtered over Celite
and concentrated to provide the cyclized products 13À19. Since the
product was isolated as a mixture of E and Z isomers, full characterization
was carried out after hydrogenation.
Hydrogenation. To a solution of the RCM products 13À19 (1.0 equiv)
in methanol (0.02 M) was added 10% Pd on activated carbon (0.065À
0.10 equiv). Into the mixture was bubbled hydrogen gas for 30 min, after
which the reaction was placed under a static H2 environment (balloon
pressure) for 12À15 h. The reaction mixture was filtered through Celite,
washing the filter cake with EtOAc, DCM, and finally hot EtOAc. The
filtrate was concentrated, and the crude residue was purified by flash
chromatography on silica gel using MeOH in DCM to provide the pure
anilines 13HÀ19H (structures not shown), which were suitable for
characterization.
tert-Butyl (((7R,8R)-13-Amino-10-((S)-1-((4-methoxybenzyl)-
oxy)prop-2-yl)-8-methyl-11-oxo-3,4,5,7,8,9,10,11-octahydro-
2H-benzo[b][1,9,5]dioxaazacyclotridec-7-yl)methyl)(methyl)-
carbamate (13H). This compound was synthesized by the general
procedure described above: [α]2D0 = À27.4 (c 0.27, CHCl3); IR (cmÀ1
)
3348, 3232, 2964, 2931, 2871, 1683, 1610, 1512, 1455, 1245, 1157, 1085,
1033; 1H NMR (500 MHz, DMSO-d6) δ 8.01 (br s, 1H), 7.21 (d, J =
8.5 Hz, 2H), 6.89 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.5 Hz, 1H), 6.50 (dd,
J = 8.4, 2.6 Hz, 1H), 6.40 (d, J = 2.5 Hz, 1H), 4.38 (d, J = 3 Hz, 2H), 4.16
(s, 2H), 4.01 (dq, J = 13.1, 6.5, 1H), 3.77 (s, 3H), 3.64 (dd, J = 9.8, 6.8,
1H), 3.50 (dd, J = 10.0, 6.0, 1H), 3.39 (t, J = 6.3, 2H), 3.35 (dd, J = 8.1,
4.3 Hz, 1H), 3.32À3.22 (m, 3H), 3.15 (dd, J = 14.3, 8.1 Hz, 1H) 2.83
(s, 3H), 2.12 (m, 1H), 1.50À1.42 (obs. m, 2H), 1.43 (s, 9H), 1.34 (td,
J = 14.3, 7.0 Hz, 2H), 1.21 (d, J = 6.8 Hz, 3H), 0.89 (m, 5H); 13C NMR
(125 MHz, DMSO-d6) δ 170.1, 158.4, 154.4, 144.1, 139.9, 130.0, 128.1,
128.1, 125.0, 116.2, 115.7, 113.3, 113.3, 113.2, 113.1, 80.0, 77.8, 71.4,
69.0, 54.7, 54.6, 53.1, 53.0, 49.2, 44.8, 34.8, 34.5, 34.4, 31.3, 27.6, 27.5,
18.0, 15.2, 15.1, 12.7, 12.6; HRMS (ESI) m/z calcd for C33H49N3O7
[M + H]+ 600.3649, found 6 00.3640.
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(N-((S)-1-((4-methoxybenzyl)-
oxy)prop-2-yl)-5-nitro-2-(oct-7-en-1-yloxy)benzamido)-3-
methylbutyl)(methyl)carbamate (11). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À34.1 (c
1.44, CHCl3); IR (cmÀ1) 1931, 2857, 1690, 1636, 1611, 1587, 1513,
1455, 1391, 1365, 1337, 1269, 1246, 1154, 1110, 1076, 1034; 1H NMR
(500 MHz, DMSO-d6, 130 °C) δ 8.20 (dd, J = 9.5, 2.5 Hz, 1H), 7.97
(d, J = 3.0 Hz, 1H), 7.25 (d, J = 9.5, Hz, 2H), 7.21 (br s, 1H), 6.89 (d, J =
8.5 Hz, 2H), 5.83 (ddt, J = 17.5, 10.5, 7.0 Hz, 2H), 5.18 (br s, 1H), 5.09
(br s, 1H), 5.01 (dd, J = 17.0, 1.5 Hz, 1H), 4.95 (d, J = 10.5, Hz, 1H), 4.41
(br s, 2H), 4.17 (m, 2H), 3.97 (obsc br s, 2H), 3.83 (obsc br s, 1H), 3.78
(s, 3H), 3.74À3.00 (br s, 4H), 3.37 (d, J = 11.5 Hz, 2H), 2.85 (br, s, 3H),
2.18 (br s, 1H), 2.05 (q, J = 6.5 Hz, 2H), 1.76 (pent, J = 7 Hz, 2H), 1.45
(s, 15H), 1.25 (br s, 3H), 0.97 (br s, 3H); 13C NMR (125 MHz, DMSO)
δ 166.4, 158.8, 158.5, 154.3, 140.3, 137.9, 134.7, 129.7, 128.0, 127.9,
124.8, 122.9, 114.7, 113.4, 113.3, 112.2, 79.9, 77.9, 71.5, 70.8, 70.1, 68.8,
54.5, 53.5, 49.4, 42.2, 35.0, 34.5, 32.1, 27.8, 27.4, 27.4, 27.3, 24.4, 14.8,
12.7; HRMS (ESI) m/z calcd for C40H59N3O9 [M + H]+ 726.4324,
found 726.4311.
tert-Butyl (((2S,8R,9R)-14-Amino-11-((S)-1-((4-methoxybenzyl)-
oxy)prop-2-yl)-2,9-dimethyl-12-oxo-2,3,4,5,6,8,9,10,11,12-
decahydrobenzo[b][1,9,5]dioxaazacyclotetradec-8-yl)methyl)-
(methyl)carbamate (14H). Synthesis and characterization of this
compound has been previously reported.7a
tert-Butyl (((2R,9R,10R)-15-Amino-12-((S)-1-((4-methoxy-
benzyl)oxy)prop-2-yl)-2,10-dimethyl-13-oxo-3,4,5,6,7,9,10,11,
12,13-decahydro-2H-benzo[b][1,9,5]dioxaazacyclopentadec-
9-yl)methyl)(methyl)carbamate (15H). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À80.0 (c 0.36,
CHCl3); IR (cmÀ1) 3428, 3349, 2970, 2933, 2872, 1684, 1226, 1153, 1084;
1H NMR (500 MHz, DMSO-d6) δ7.20 (br s, 2H), 6.90 (d, J= 8.3 Hz, 2H),
6.70 (d, J = 8.6 Hz, 1H), 6.58 (d, J = 6.3 Hz, 1H), 6.41 (s, 1H), 4.37 (obsc br
s, 2H), 4.27 (obsc br s, 1H), 3.95 (br s, 1H), 3.78 (s, 3H), 3.50 (br s, 1H),
3.34 (br s, 2H), 2.85 (s, 3H), 1.53 (obsc br m, 3H), 1.43 (s, 9H), 1.23 (obsc
br s, 3H), 1.19 (d, J = 5.4, 3H), 0.88 (br s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 169.8, 158.4, 154.5, 144.2, 140.6, 130.0, 128.2, 128.1, 127.9,
tert-Butyl ((2R,3R)-2-(Allyloxy)-4-(2-(2-allylphenoxy)-N-((S)-
1-((4-methoxybenzyl)oxy)prop-2-yl)-5-nitrobenzamido)-3-
methylbutyl)(methyl)carbamate (12). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À33.7 (c 1.05,
CHCl3); IR (cmÀ1) 2974, 2934, 1690, 1635, 1612, 1514, 1454, 1340, 1270,
1
1247, 1157, 1077. H NMR (500 MHz, DMSO-d6, 130 °C) δ 8.16
(m, 2H), 7.38(d, J= 7.0 Hz, 1H), 7.32 (t, J= 6.0 Hz, 1H), 7.26 (t, J=6.5Hz,
1H), 7.22 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz,
2H), 6.83 (d, J = 10.5 Hz, 1H), 5.92 (ddt, J = 16.5, 10.5, 6.5 Hz, 1H), 5.84
(br s, 1H), 5.18 (br d, J = 14.5 Hz, 1H), 5.07 (apt. AB, JA = 12.0 Hz, 1H),
5.01 (apt. AB, JB = 10.0 Hz, 1H), 4.46 (s, 2H), 4.04 (q, J = 6.0 Hz, 1H), 3.97
(br s, 1H), 3.78 (s, 3H), 3.70À3.40 (br s, 4H), 3.35 (d, J= 6.0 Hz, 2H), 3.21
8046
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NOTE
114.9, 113.4, 113.3, 77.7, 71.4, 66.9, 54.7, 54.6, 53.2, 48.1, 34.8, 27.6, 27.5,
23.0, 21.6, 18.8, 15.1, 12.0; HRMS (ESI) m/z calcd for C36H56N3O7
[M + H]+ 642.4118, found 642.4111.
(s, 3H), 2.83 (s, 3H), 2.67 (s, 4H), 1.40 (s, 9H), 1.30 (br s, 3H), 0.83
(d, J = 6.5, 3H); 13C NMR (126 MHz, DMSO) δ 168.8, 158.4, 155.2,
154.5, 153.0, 143.6, 142.5, 134.4, 130.0, 128.2, 128.0, 126.1, 123.4, 121.6,
119.8, 118.7, 116.5, 115.0, 114.1, 113.3, 113.3, 82.1, 77.7, 75.8, 71.4, 68.4,
67.4, 54.7, 54.5, 53.2, 52.2, 50.7, 50.3, 47.6, 43.4, 36.8, 34.7, 31.0,
29.0, 27.6, 27.5, 26.6, 24.7, 21.1, 15.1, 14.5, 13.4, 12.7, 11.4; HRMS (ESI)
m/z calcd for C39H53N3O7 [M + H]+ 676.3962, found 676.3969.
tert-Butyl(((10S,11R)-16-Amino-13-((S)-1-((4-methoxybenzyl)-
oxy)propan-2-yl)-11-methyl-14-oxo-2,3,4,5,6,7,8,10,11,12,13,
14-dodecahydrobenzo[b][1,9,5]dioxaazacyclohexadec-10-yl)-
methyl)(methyl)carbamate (16H). This compound was synthe-
sized by the general procedure described above: [α]2D0 = À2.6 (c 0.30,
CHCl3); IR (cmÀ1) 3350, 2971, 2932, 2860, 1686, 1612, 1498, 1470,
1245, 1226, 1153, 1084; 1H NMR (500 MHz, DMSO-d6) δ 7.23 (d, J =
22.2 Hz, 2H), 6.90 (d, J = 7.3 Hz, 2H), 6.73 (s, 1H), 6.59 (dd, J = 8.6, 2.7
Hz 1H), 6.42 (s, 1H), 4.46 (obsc br s, 1H), 4.32 (obsc br s, 3H), 3.88 (s,
4H), 3.77 (s, 3H), 3.61 À 3.49 (m, 2H), 3.35 (d, J = 14.1, 3H), 3.14 (br s,
1H), 2.94 (obsc br s, 1H), 2.84 (br s, 3H), 1.83 (br s, 1H), 1.68 À 1.50
(br m, 4H), 1.43 (s, 12H), 1.15 (s, 3H), 1.01 À 0.86 (m, 3H), 0.70
(s, 1H); 13C NMR (125 MHz, DMSO-d6) δ 169.2, 158.4, 154.5, 145.6,
145.2, 141.4, 141.1, 130.2, 129.9, 128.8, 128.1, 127.3, 127.2, 114.7, 114.0,
113.4, 113.2, 112.6, 111.4, 81.8, 77.8, 71.4, 68.6, 67.7, 65.0, 54.7, 54.6,
52.8, 50.9, 50.4, 48.1, 44.2, 36.1, 35.3, 34.8, 34.1, 28.4, 28.1, 27.6, 27.5,
27.0, 26.3, 23.9, 23.2, 15.0, 14.5, 13.4; HRMS (ESI) m/z calcd for
C36H56N3O7 [M + H]+ 642.4118, found 642.4111.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: lisa_marcaurelle@h3biomedicine.com.
Present Addresses
†H3 Biomedicine Inc., 300 Technology Square, Cambridge,
MA 02142.
tert-Butyl(((11S,12R)-17-Amino-14-((S)-1-((4-methoxybenzyl)-
oxy)prop-2-yl)-12-methyl-15-oxo-3,4,5,6,7,8,9,11,12,13,14,
15-dodecahydro-2H-benzo[b][1,9,5]dioxaazacycloheptadec-
11-yl)methyl)(methyl)carbamate (17H). This compound was syn-
thesized by the general procedure described above: [α]2D0 = À12.3 (c 0.34,
CHCl3); IR (cmÀ1) 3431, 3349, 2961, 2929, 2856, 1688, 1612, 1496, 1258,
1154, 1086, 1031; 1H NMR (500 MHz, DMSO-d6) δ 7.20 (br s, 2H), 6.90
(d, J= 8.4 Hz, 2H), 6.73 (s, 1H), 6.57 (dd, J = 8.6, 2.8 Hz, 1H), 6.42 (s, 1H),
4.44 (obsc br s, 1H), 4.33 (br s, 3H), 3.87 (obsc br s, 2H), 3.83 (m, 2H),
3.77 (s, 3H), 3.66À3.26 (obsc br s, 2H), 3.59 (br s, 2H), 3.33 (s, 2H), 3.11
(s, 2H), 2.85 (br s, 3H), 1.63 (br s, 2H), 1.43 (s, 16H), 1.35 (s, 7H), 1.16
(br s, 3H), 0.97(brs, 3H), 0.75(brs, 1H);13C NMR (125 MHz, DMSO-d6)
δ 169.2, 158.4, 154.4, 145.5, 141.6, 130.0, 128.5, 128.1, 128.0, 127.6, 114.6,
114.2, 113.3, 113.3, 111.9, 80.9, 77.8, 71.6, 71.4, 69.1, 68.5, 54.7, 54.6, 54.5,
54.4, 53.0, 51.3, 49.7, 49.2, 44.6, 35.2, 34.6, 34.5, 28.5, 27.6, 27.5, 27.28, 26.8,
24.4, 23.9, 15.2, 14.2, 13.7, 12.4; HRMS (ESI) m/z calcd for C37H57Na-
N3O7 [M + Na]+ 678.4094, found 678.4096.
’ ACKNOWLEDGMENT
This work was funded in part by the generous gift of Eli and
Edith Broad to the Broad Institute, as well the NIGMS-sponsored
Center of Excellence in Chemical Methodology and Library
Development (Broad Institute CMLD; Grant P50 GM069721).
We thank Dr. Damian Young and Dr. Sarathy Kesavan for helpful
suggestions. We also thank Louise Walport for optimizing the
synthesis of intermediate 5.
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8047
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