An ester enolate-Claisen rearrangement route to substituted 4-alkylideneprolines. Studies toward a definitive structural revision of lucentamycin A

Article abstract of DOI:10.1021/jo201727g

Substituted 4-alkylideneprolines represent a rare class of naturally occurring amino acids with promising biological activities. Lucentamycin A is a cytotoxic, marine-derived tripeptide that harbors a 4-ethylidine-3-methylproline (Emp) residue unique among known peptide natural products. In this paper, we examine the synthesis of Emp and related 4-alkylideneprolines employing a versatile ester enolate-Claisen rearrangement. The scope and selectivity of the key rearrangement reaction are described with a number of diversely substituted glycine ester substrates. Treatment of the allyl esters with excess NaHMDS at ambient temperature gives rise to highly substituted α-allylglycine products with good to excellent diastereoselectivities. Resolution of dipeptide diastereomers and cyclization to form the pyrrolidine rings provide rapid access to stereopure prolyl dipeptides. We have applied this strategy to the synthesis of four Emp-containing isomers of lucentamycin A in pursuit of a definitive stereochemical revision of the natural product. Our studies indicate that the Emp stereogenic centers are not the source of structural misassignment. The current strategy should find broad utility in the synthesis of additional natural product analogues and related 3-alkyl-4-alkylidene prolines.

Full text of DOI:10.1021/jo201727g

Article
pubs.acs.org/joc
An Ester Enolate−Claisen Rearrangement Route to Substituted
4-Alkylideneprolines. Studies toward a Definitive Structural Revision
of Lucentamycin A
Sujeewa Ranatunga,†,‡ Jinsoo S. Kim,† Ujjwal Pal,† and Juan R. Del Valle*,†
†Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, United States
‡Department of Chemistry and Biochemistry, New Mexico State University, Las Cruces, New Mexico 88003, United States
S
* Supporting Information
ABSTRACT: Substituted 4-alkylideneprolines represent a
rare class of naturally occurring amino acids with promising
biological activities. Lucentamycin A is a cytotoxic, marine-
derived tripeptide that harbors a 4-ethylidine-3-methylproline
(Emp) residue unique among known peptide natural products.
In this paper, we examine the synthesis of Emp and related
4-alkylideneprolines employing a versatile ester enolate−
Claisen rearrangement. The scope and selectivity of the key rearrangement reaction are described with a number of diversely
substituted glycine ester substrates. Treatment of the allyl esters with excess NaHMDS at ambient temperature gives rise to
highly substituted α-allylglycine products with good to excellent diastereoselectivities. Resolution of dipeptide diastereomers and
cyclization to form the pyrrolidine rings provide rapid access to stereopure prolyl dipeptides. We have applied this strategy to the
synthesis of four Emp-containing isomers of lucentamycin A in pursuit of a definitive stereochemical revision of the natural
product. Our studies indicate that the Emp stereogenic centers are not the source of structural misassignment. The current
strategy should find broad utility in the synthesis of additional natural product analogues and related 3-alkyl-4-alkylidene prolines.
INTRODUCTION
■
Chimeric proline residues have long been used in the
elucidation of peptide structure−activity relationships.1 This
is due to their influence on the local conformation, recognition,
and biological activity of host peptidomimetics. Moreover, a
number of alkyl-substituted proline derivatives are present in
bioactive natural products,2 making their chemical synthesis a
key component in the discovery of new therapeutic leads.
In 2007, a new family of nonribosomal peptides, lucen-
tamycins A−D, was isolated from the fermentation broth of
Nocardiopsis lucentensis.3 Structure elucidation based on NMR
and degradation studies revealed unique tripeptides comprised
of an N-acylated homoarginine (Har), a C-terminal leucine
or tryptophan, and a central 4-ethylidene-3-methylproline
(Emp) residue unprecedented in the natural product literature
(Figure 1). Of the four closely related structures, lucentamycin
A showed potent in vitro growth inhibition of HCT-116 human
colon carcinoma cells (IC50 = 0.20 μM). The biological activity
and structural novelty of lucentamycin A, coupled with our
interest in substituted proline derivatives,4 prompted our group
to pursue its synthesis in the hopes of delivering sufficient
material for more comprehensive evaluation. In addition, the
development of a versatile synthetic strategy toward analogues
of 1 became central to a planned structure−activity relationship
campaign.
Figure 1. Originally proposed structures of lucentamycins A−D (1−4,
respectively).
A-315675.6 While 3-methylprolines are relatively common in
nature,2b 4-alkylideneproline derivatives are exceedingly rare
and have been encountered in only a few natural products,
including isodomoic acids G and H,7 tomaymycin,8 and the
recently isolated cytotoxic alkaloid eleganine A (Figure 2).9 The
contiguous pyrrolidine substituents in Emp, their stereo-
chemical relationship, and the C4 alkene geometry complicate
retrosynthetic disconnections. For example, selection of
4-oxoproline as a logical precursor leads to a host of potential
problems with regard to the relative stereochemistry and
regioselectivity of proline alkylation.10 Proposed biosyntheses
for Emp (via selective isoleucine oxidation or complex
enzymatic manipulations of L-DOPA)3 also fail to suggest a
The main challenge in synthesizing members of the lucen-
tamycin family lies in the Emp residue, which is reminiscent
of other complex polyalkylprolines such as kainic acid5 and
Received: August 17, 2011
Published: September 23, 2011
© 2011 American Chemical Society
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interested in evaluating the utility of the enolate−Claisen
rearrangement described above in the synthesis of diversely
substituted variants. At the outset, it was apparent that a
protected hydroxymethyl substituent on the alkene substrate
would be required for eventual pyrrolidine ring formation.
However, during our synthesis of 1, we encountered unexpected
difficulties in promoting the key reaction under the typical
glycine ester enolate−Claisen conditions described by Bartlett14
and Kazmaier.15
Figure 2. Emp and other naturally occurring 4-alkylideneproline
derivatives.
We screened various reaction conditions using different
model substrates to assess the impact of alkene substitution
on product yield (Table 1). In agreement with precedent, we
practical synthetic solution. Notably, a derivative of Emp was
prepared previously by Gais and co-workers as part
of a study on the synthetic utility of chiral vinyl amino-
sulfoxonium salts.11 Although intriguing because of the fact that
the Emp residue was unprecendented in nature, the described
route is not readily amenable to the preparation of other
isomers.
Table 1. Screening of Ester Enolate−Claisen Rearrangement
Conditions
We recently reported the synthesis of Emp and the putative
structure of lucentamycin A (1) relying on the ester enolate−
Claisen rearrangement strategy depicted in Scheme 1.12
Scheme 1. An Ester Enolate−Claisen Route to 3-Alkyl-4-
alkylideneprolines
acid
alcohol
b
a
b
entry ester
conditions
yield
yield
1
5
3 equiv of LDA, 1.2 equiv of ZnCl2,
−78 °C to rt
73
0
2
3
4
5
5
5
3 equiv of NaHMDS, rt
87
95
48
0
0
0
3 equiv of NaHMDS, −78 °C to rt
3 equiv of LiHMDS, 1.2 equiv of
ZnCl2, −78 °C to rt
5
5
3 equiv of LDA, 3 equiv of TMSCL,
−78 °C to rt
85
0
6
7
5
6
3 equiv of KHMDS, 0 °C to rt
3 equiv of LDA, 1.2 equiv of ZnCl2,
−78 °C to rt
83
0
0
78
8
6
6
6
6
3 equiv of KHMDS, 0 °C to rt
3 equiv of NaHMDS, −78 °C to rt
1.1 equiv of NaHMDS, rt
14
10
0
60
56
94
23
69
9
10
11
12
2.5 equiv of NaHMDS, rt
74
0
The key reaction presumably proceeds through a stereoselective
chairlike transition state13 to give the linear proline precursor,
setting both stereocenters and the pendant alkene geometry
in a single step. We anticipated that varying the R groups on
the glycine ester substrate would provide access to other
lucentamycin diastereomers as well as an array of complex
proline residues, depending on the availability of substituted
allylic diol precursors.
Here, we present an exploration into the scope and stereo-
selectivity of the key reaction in the context of 4-alkylidenepro-
line synthesis. The ester enolate−Claisen rearrangement route
to substituted allylglycines is amenable to the preparation of
various complex proline derivatives with moderate to high
diastereoselectivities. Application of this strategy to the total
synthesis of four lucentamycin A isomers revealed that the
structure of the natural product requires revision, and that
the Emp stereogenic centers are not the loci of structural
misassignment.
(S)-7 3 equiv of LDA, 1.2 equiv of ZnCl2,
−78 °C to rt
13
14
15
(S)-7 2.5 equiv of NaHMDS, −78 °C to rt
(S)-7 1.1 equiv of NaHMDS, rt
9
0
63
97
23
(S)-7 2.5 equiv of NaHMDS, rt
76
a
Reaction progress was monitored by TLC, and times ranged from
5 min to 18 h. Isolated yields.
b
found that ester 5,15 devoid of the silyloxymethyl substituent,
afforded good yields of the Boc-protected amino acid under
various conditions. However, ester 6, lacking the methyl
substituents and harboring a silyloxymethyl group, consistently
gave poor yields of the desired product along with the alcohol
precursor to 6. While the absence of a Lewis acid additive
seemed to improve the yield of the carboxylic acid, reducing the
equivalency of the base resulted in near quantitative recovery
of the fragmentation product (entry 10). On the basis of pKa
considerations, this result suggests that the N-Boc group
participates in ester cleavage because this anion is presumably
formed first. The ester cleavage pathway may be favored over
thermally induced rearrangement at lower temperatures, even
when the dianion is formed (>2 equiv of base). Indeed, we
found that temperature had a dramatic effect on the product
ratio (see entries 9 and 11). Fully elaborated substrate (S)-712
RESULTS AND DISCUSSION
■
Optimization, Scope, and Selectivity of the Enolate−
Claisen Rearrangement. Our plan to initiate an SAR
campaign around lucentamycin A required both confirmation
of its structure and access to analogues. We were particularly
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mirrored this trend, confirming that the silyloxymethyl alkene
substituent poses an obstacle to the desired pathway. In
contrast, the presence of the methyl substituents at R1 and R2
had no effect on the product distribution (entries 11 and 15).
Under optimized conditions, fragmentation was largely sup-
pressed, resulting in a 76% isolated yield of the desired acid
with 99% conversion (entry 15).
We then investigated the effects of other alkene substituents
on reaction diastereoselectivity and product distribution. A series
of substituted glycine allyl ester derivatives was synthesized
as shown in Scheme 2. Iodoacrylates were prepared via
passage through a short silica plug, isolated acids were obtained
as diastereomeric mixtures in moderate to high yields. We also
attempted to recover any alcohol byproduct during column
purification. Combined isolated yields varied from 54 to 89%,
with many of the more sterically demanding substrates giving
rise to significant amounts of fragmentation byproduct at the
expense of the desired acid. Table 2 also lists the isolated yields
of the pure recovered alcohol. In some cases (entries 4, 6, and 10),
the alcohol coeluted with unidentified impurities artificially sup-
pressing the overall yields. Typically, reaction conversions were
greater than 90%.
Although most substrates gave rise to amino acids with
good diastereoselectivities, some discernible trends could be
identified with respect to steric bulk. Increases in the size of R1
had a negative impact on dr when R2 was kept constant (entries
2−5 and 7−10). This result is somewhat counterintuitive
on the basis of A value considerations and may indicate that
large R1 substituents lead to disruption of an ordered chairlike
transition state. Variations in the size of R2 substituents
appeared to have a weaker effect, though some erosion in dr
was still observed (compare entries 6, 11, and 12). An allyl
ester with a Z alkene configuration appeared to be well-
tolerated despite a presumed axial disposition in the transition
state (entry 15). Only the reaction of esters 11h−j, featuring
two bulky substituents, resulted in diastereomeric ratios of
<4:1.
Scheme 2. Synthesis of Diversely Substituted Claisen
Rearrangement Substrates
To demonstrate the utility of racemic allylglycine derivatives
in the synthesis of diastereopure 3-alkyl-4-alkylideneproline-
containing peptides, we selected some N-Boc amino acids for
further elaboration (Scheme 3).18 Crude amino acid 13a was
Baylis−Hillman reaction16 and the alkenes functionalized through
either Suzuki or Gilman coupling in good yields.17 Ester
reduction, monosilylation, and condensation with Boc-Gly-OH
afforded racemic esters 11a−l.
The results of enolate−Claisen rearrangement reactions
employing 2.5 equiv of NaHMDS are shown in Table 2. After
Scheme 3. Synthesis of Polysubstituted Prolyl Dipeptides 16
and 17
Table 2. Effects of Substituents on Diastereoselectivity
a
b
entry
ester
R1
R2
Me
R3
acid
dr
yield
1
(S)-712
11a
11b
11c
11d
11e
11f
Me
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
1212
13a
13b
13c
13d
13e
13f
>95:5
>95:5
91:9
76 (23)
77 (18)
60 (10)
62 (7)
2
n-pentyl
n-pentyl
n-pentyl
n-pentyl
n-pentyl
Ph
3
4
iPr
tBu
Ph
Me
Et
90:10
83:17
87:13
>95:5
87:13
79:21
78:22
73:27
>95:5
>95:5
>95:5
94:6
5
52 (32)
74 (9)
6
7
85 (5)
8
11g
11h
11i
Ph
13g
13h
13i
76 (11)
54 (44)
61 (20)
69 (18)
78 (15)
89 (7)
9
iPr
tBu
Ph
Ph
Me
H
Ph
10
11
12
13
14
15
Ph
11j
Ph
13j
11k
11l
Me
13k
131
13m
13n
Et
11m
Me
82 (9)
thus reacted with L-leucine tert-butyl ester in the presence of
HBTU, triethylamine, and a catalytic amount of HOBt to afford
amides 14 and 15 in good yield. The diastereomeric dipeptides
could be readily separated by flash column chromatography.
c
11n
H
H
65 (32)
a
b
Determined by HPLC of a semicrude product mixture. Combined
isolated yield of the diastereomeric mixture (isolated yield of alcohol in
c
parentheses). R4 = TIPS.
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Scheme 4. Proposed Stereoselective SN1 Ring Closure to Form Phenylprolines 21 and 23
Removal of the silyl protecting groups was followed by
activation of the resulting allylic alcohol in the presence of
methanesulfonyl chloride and triethylamine. Stirring at room
temperature led to exclusive formation of the primary allylic
chloride intermediate in high yield.19 Acidolysis of the Boc
group and treatment with potassium carbonate afforded the
stereopure prolyl dipeptides 16 and 17 in 47 and 41% overall
yield, respectively.
When racemic 13e was used as a starting material, the
corresponding leucyl derivatives could likewise be separated
by column (Scheme 4). However, we found that the one-pot
mesylation/chlorination procedure gave rise to an equimolar
mixture of secondary allylic chlorides. The presence of a
terminal alkene in both 20 and 22 was confirmed by DEPT
NMR. Remarkably, treatment of each of the diastereomeric
mixtures with TFA followed by basification with K2CO3
afforded the corresponding 5-phenylproline derivatives (21
and 23) as single isomers. One-dimensional NOE studies were
used to establish the all-cis configuration about the pyrrolidine
rings. No other stereo- or regioisomers were detected in the
crude reaction mixtures. These results indicate that ring closure
occurs through an SN1 mechanism involving stereoselective
attack of the amine onto the incipient carbocation. This
pathway appears to be unique to the phenyl (R1)-substituted
substrate as elaboration of alkyl-substituted variants did not
give rise to any secondary allylic chlorides or the 5-substituted
prolines. The generality of this reaction for the synthesis of
other highly substituted 5-arylprolines warrants further
investigation.
Application to the Synthesis of Presumed Lucenta-
mycin A and Its Isomers. Our next goal was to apply the
methodology described above to the synthesis of Emp
diastereomers for incorporation into lucentamycin tripeptides.
In our initial synthesis of 1, we noted differences in NMR
chemical shifts between our material and the natural isolate.12
We have since obtained a crystal structure of the synthetic
compound, confirming the need for revision (Figure 3).
Lindsley and co-workers subsequently described the synthesis
of another unnatural diastereomer of lucentaymcin A as well as
the simplified proline-containing analogue, neither of which
exhibited activity toward HCT-116 cells.20 These potential
eudismic discrepancies underscored the need for efficient access
to each of the Emp diastereomers.
Figure 3. Crystal structure of 1.
the Emp residue was determined by Marfey derivatization of
the acid hydrolysate. Because this assignment relied on an
assumption of a typical HPLC elution order for 1-fluoro-2,4-
dinitrophenyl-5-L-leucinamide (FDLA) derivatives of known
amino acids, we hypothesized that the C8 stereochemistry of
the Emp residue may be in need of correction. In addition,
molecular models suggested that accessible proline conforma-
tions may give rise to HC8−HC9 Overhauser correlations, even
in the case of a trans relationship.
We first prepared Bz-Har-(8R,9S,10Z)-Emp-Leu-OH (27)
using (+)-methyl lactate as a chiral progenitor (Scheme 5).
As expected, the enolate−Claisen rearrangement of (R)-7
proceeded with high enantio- and diastereoselectivity on the
basis of HPLC analysis of acid 24 and dipeptide 25. Formation
of the pyrrolidine ring over three steps was followed by
condensation with Fmoc-(L)Har(Boc)2-OH, N-terminal group
interconversion, and global deprotection. Unfortunately, the 1H
NMR spectrum of 27 did not correlate with that of the natural
product. In particular, the α-proton at C8 appeared significantly
downfield relative to that in lucentamycin A. The protons at C9
and C12, in contrast, were shifted slightly upfield.
Access to the 8,9-trans Emp isomers required extension of
the Claisen rearrangement to a trisubstituted Z alkene substrate.
As with 7, this reaction would presumably proceed through a
chairlike transition state but with the terminal methyl group
forced to occupy an axial position. We pursued the synthesis of
the requisite racemic glycine ester in hopes of again resolving
the diastereomeric leucyl derivatives (Scheme 6). Thus, enoate
29 was prepared in multigram quantities following a known
procedure.21 Hydride reduction, selective silyl ether formation,
and condensation with Boc-glycine then provided ester 30 in
good yield. Treatment of 30 with 2.5 equiv of NaHMDS at
room temperature led to the formation of (±)-31 in 78% yield
and >95:5 dr, as judged by HPLC.
The original structure elucidation of natural lucentamycin
A relied on ROESY correlations to establish the Z alkene
geometry as well as the cis relationship between the Emp
methine protons on C8 and C9.3 The absolute configuration of
As with racemic N-Boc amino acids 13a and 13e, coupling of
31 to L-leucine tert-butyl ester afforded diastereomers 32 and
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33, respectively, which could be readily separated by flash
column chromatography (Scheme 7). Each of these compounds
was cyclized to form intermediates 34 and 36, respectively, and
converted to their corresponding tripeptides according to our
previous protocol. Notably, the syntheses of these compounds
are considerably shorter than our previous route toward 1 (12 vs
17 steps from commercially available starting materials)
primarily because of the rapid and scalable preparation of
known enoate 29. Enantiopure 29 could also be obtained by
isomerization of the lactate-derived chiral (Z)-enoate12 in the
presence of DBU. However, we have found the route described
in Scheme 7 to be more practical for the synthesis of large
quantitites of Emp-containing peptides.
Scheme 5. Synthesis of Bz-Har-(8R,9S,10Z)-Emp-Leu-OH
(27)
Following the purification of 35 and 37 by RP-HPLC,
we carried out complete characterization for comparison with
the natural product. As expected, the NMR data for one of the
tripeptides (27) matched those previously reported by Lindsley
and co-workers20 and exhibited significant chemical shift dif-
ferences relative to those of natural lucentamycin A. We were
surprised to find that compound 37 also failed to correspond to
the structure of the natural product, indicating that the Emp
stereochemical assignments are not solely responsible for the
structural misassignment. Examination of the 1H NMR
resonances for each compound also revealed some interesting
patterns. Figure 4 depicts the deviations in proton chemical
shifts for each synthetic isomer relative to natural lucentamycin
A. Tripeptides 27 and 35, which both harbor D-Emp (8R)
residues, exhibited the largest chemical shift differences,
particulary in the Emp region. The effect of the C8 configura-
tion on Har and Leu proton shifts was also quite pronounced,
indicating a considerable change in the global conformation.
This may be explained in part by the intramolecular head-to-tail
salt bridge observed in the X-ray structure of 1 (Figure 3).
A change in the stereochemistry at the Emp α-carbon may
result in a significant disruption of this macrocyclic con-
formation. Taken together, our data suggest that the natural
Emp residue is most likely 8S,9R, as originally proposed. Efforts
to systematically vary the alkene geometry as well as the Har
and Leu configurations are currently underway. Finally, com-
pounds 1, 27, 35, and 37 were evaluated for growth inhibition
of HCT-116 cells using a cell titer blue assay but did not exhibit
significant activity below 100 μM.
Scheme 6. Toward the trans Emp Diastereomers
Scheme 7. Expedient Synthesis of Tripeptides 35 and 37
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1
Figure 4. Deviation in nonexchangeable H NMR chemical shifts (in DMSO-d6) for isomers 1, 27, 35, and 37 relative to natural lucentamycin A.
The original numbering system was used. Only chemical shift differences for hydrogens on carbons are listed. In cases where proton shifts were
within a range, the minimum possible difference is shown.
precoated plates (0.25 mm). Flash chromatography was performed
using silica gel (60 μm particle size). The purity of all compounds was
CONCLUSIONS
■
We have investigated the scope and selectivity of a NaHMDS-
promoted ester enolate−Claisen rearrangement for the syn-
thesis of substituted 4-alkylidene prolines. The key reaction was
found to be tolerant of various alkene substituents, resulting
in good product yields and diastereomeric ratios in all but
the most sterically demanding cases. Selected α-allylglycine
products were elaborated into diversely subtituted prolyl
dipeptides. We have employed this approach to access each
of the possible diastereomers of 4-ethylidene-3-methylproline,
the central residue proposed for lucentamycin A. Resolution
of diastereomeric dipeptides en route to the final products
resulted in a streamlined synthesis of lucentamycin isomers,
starting from racemic enolate−Claisen substrates. While the
key reaction provides ready access to the target tripeptides,
compounds 1, 27, 35, and 37 each exhibit discrepancies with
the natural product by NMR. Efforts to exhaust other stereo-
centers as the source of structural misassignment are ongoing.
Given the importance of substituted prolines in bioactive
compounds, we anticipate that the described studies will find
utility in the synthesis of related natural products and constrained
peptidomimetics.
judged by TLC analysis (single spot/two solvent systems) using a UV
lamp, CAM (ceric ammonium molybdate), ninhydrin, or basic
KMnO4 stain(s) for detection purposes. NMR spectra were recorded
on a 400 MHz spectrometer. Mass spectral data were measured with
1
high-resolution ESI-TOF instrument in positive or negative mode. H
and 13C NMR chemical shifts are reported as δ using residual solvent
as an internal standard. Analytical RP-HPLC was performed on a C18
column (4 mm × 150 mm) with an acetonitrile/water (0.1% formic
acid) mixture as the eluent (1 mL/min flow rate). Semipreparative
RP-HPLC was performed on a C18 column (9.4 mm × 250 mm)
with an acetonitrile/water (0.1% formic acid) mixture as the eluent
(4 mL/min flow rate).
2-[(tert-Butyldiphenylsilyloxy)methyl]allyl 2-(tert-
Butoxycarbonylamino)acetate (6). A solution of 2-[(tert-butyl-
diphenylsilyloxy)methyl]prop-2-en-1-ol22 (142 mg, 0.435 mmol) in
10 mL of CH2Cl2 at rt was treated with Boc-Gly-OH (0.099 g, 0.565
mmol), DMAP (0.027 g, 0.218 mmol), and EDC (108 mg, 565
mmol). The mixture was stirred for 20 h, the reaction quenched with
saturated aq NH4Cl, and the mixture extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated under reduced
pressure. Purification by flash chromatography (10% EtOAc/hexanes)
afforded 6 as a thick colorless oil (206 mg, 98%): 1H NMR (400 MHz,
CDCl3) δ 7.66 (m, 1H), 7.41 (m, 1H), 5.33 (m, 1H), 5.18 (m, 1H),
4.95 (bs, 1H), 4.66 (s, 2H), 4.18 (s, 2H), 3.86 (d, J = 5.6 Hz, 2H),
1.44 (s, 9H), 1.06 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 170.2,
155.8, 142.3, 135.6, 133.4, 129.9, 127.9, 113.9, 80.2, 65.5, 64.5, 42.5,
28.4, 26.9, 19.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C27H37NO5Si 484.25138, found 484.25193.
EXPERIMENTAL SECTION
■
General. Unless stated otherwise, reactions were performed in
flame-dried glassware under a positive pressure of argon or nitrogen
gas using dry solvents. Commercial grade reagents and solvents were
used without further purification except where noted. Diethyl ether,
toluene, dimethylformamide dichloromethane, and tetrahydrofuran
were purified by solvent purification system. Other anhydrous solvents
were purchased directly from chemical suppliers. Thin layer
chromatography (TLC) was performed using silica gel 60 F254
(Z)-Ethyl 3-Hydroxy-2-(iodomethylene)butanoate (9a). A
flask charged with dry CH2Cl2 (10 mL) and MgI (1.33 g, 4.80
mmol) was cooled to 0 °C over an ice bath and treated dropwise
with ethyl propiolate (0.49 mL, 4.80 mmol). Acetaldehyde (0.23 mL,
4.00 mmol) was then added dropwise, and the reaction mixture was
allowed to warm to rt while being stirred overnight. The reaction was
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quenched with 10% aq Na2S2O3 and the mixture stirred vigorously
until the layers separated. The phases were separated, and the organic
phase was dried over Na2SO4, filtered, and concentrated with a rotary
evaporator for purification by flash chromatography (5−10% EtOAc/
hexanes). Pure 9a was isolated as an orange oil (0.80 g, 74%) in
addition to the corresponding E isomer (0.13 g, 12%). Data for major
Z isomer 9: 1H NMR (400 MHz, CDCl3) δ 7.17 (d, J = 1.1 Hz, 1H),
4.61 (q, J = 6.4 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.31 (bs, 1H), 1.38
(m, 6H); 13C NMR (101 MHz, CDCl3) δ 166.6, 148.0, 83.7, 70.3,
61.6, 22.4, 14.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C7H11IO3Na 292.9645, found 292.9653.
22.6, 19.8, 18.8, 14.4, 14.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd
for C14H26O3Na 265.17742, found 265.17885.
(Z)-Ethyl 2-(1-Hydroxy-2,2-dimethylpropyl)oct-2-enoate
(10d). Prepared from 9d as described for the 9a → 10a reaction
1
(87%): H NMR (400 MHz, CDCl3) δ 6.02 (t, J = 7.6 Hz, 1H), 4.23
(q, J = 7.1 Hz, 2H), 4.04 (s, 1H), 3.02 (bs, 1H), 2.34 (q, J = 15.0,
7.5 Hz, 2H), 1.48−1.38 (m, 2H), 1.35−1.27 (m, 7H), 0.88 (s, 12H);
13C NMR (101 MHz, CDCl3) δ 169.2, 142.9, 132.0, 82.3, 60.7, 36.3,
31.7, 29.6, 29.1, 26.1, 22.6, 14.3, 14.1; HRMS (ESI-TOF) m/z [M +
Na]+ calcd for C15H28O3Na 279.1931, found 279.1949.
(Z)-Ethyl 2-[Hydroxy(phenyl)methyl]oct-2-enoate (10e). Pre-
pared from 9e as described for the 9a → 10a reaction (75%). Spectral
data matched those previously reported for enantiopure 10e.17
(Z)-Ethyl 2-Benzylidene-3-hydroxybutanoate (10f). A stir bar
was added to a round-bottom flask containing 9a (0.803 g, 2.97 mmol)
and a 1:1 dimethoxyethane/H2O mixture (10 mL). Solid Na2CO3
(0.944 g, 8.91 mmol) was added in a single portion to the stirring
solution, followed by phenylboronic acid (0.398 g, 3.27 mmol).
Pd(OAc)2 (0.067 g, 0.297 mmol) was added in a single portion and
the solution stirred overnight at rt. The reaction mixture was diluted
with H2O (10 mL) and extracted with EtOAc. The combined extracts
were dried over Na2SO4, filtered, and concentrated with a rotary
evaporator for purification by flash chromatography (10% EtOAc/
hexanes, flushed with 10% MeOH/EtOAc) to afford 10f as a colorless
(Z)-Ethyl 3-Hydroxy-2-(iodomethylene)pentanoate (9b). Pre-
pared as described for 9a using 1-propanal in place of acetaldehyde
1
(72%): H NMR (400 MHz, CDCl3) δ 7.10 (d, J = 1.0, 1H), 4.32
(q, J = 7.1 Hz, 3H), 2.35 (d, J = 6.4 Hz, 1H), 1.75−1.59 (m, 2H), 1.37
(t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 166.6, 146.7, 84.4, 76.6, 61.6, 29.2, 14.3, 10.0; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C8H13IO3Na 306.9802, found
306.9790.
(Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4-methylpentanoate
(9c). Prepared as described for 9a using isobutyraldehyde in place of
acetaldehyde (74%). Spectral data matched those previously reported
for enantiopure 9c.17
(Z)-Ethyl 3-Hydroxy-2-(iodomethylene)-4,4-dimethylpenta-
noate (9d). Prepared as described for 9a using pivaldehyde in
place of acetaldehyde (82%). Spectral data matched those previously
reported for enantiopure 9d.23
(Z)-Ethyl 2-[Hydroxy(phenyl)methyl]-3-phenylacrylate (9e). Pre-
pared as described for 9a using benzaldehyde in place of acetaldehyde
(74%). Spectral data matched those previously reported for
enantiopure 9e.17
1
oil (0.498 g, 76%): H NMR (400 MHz, CDCl3) δ 7.35−7.24 (m,
5H), 6.90 (s, 1H), 4.65 (m, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.51 (bs,
1H), 1.47 (d, J = 6.5 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 169.2, 137.7, 135.6, 132.6, 128.4, 128.3, 128.2, 70.1,
61.1, 22.5, 13.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C13H16O3Na 243.0992, found 243.1005.
(Z)-Ethyl 2-Benzylidene-3-hydroxypentanoate (10g). Pre-
1
(Z)-Ethyl 2-(1-Hydroxyethyl)oct-2-enoate (10a). A flame-dried
flask was cooled and purged with argon. LiBr (0.09 g, 1.00 mmol) and
CuBr (0.14 g, 1.00 mmol) were added in a single portion and
dissolved in dry THF (2 mL). A stir bar was added to a separate
round-bottom flask containing 9a (0.71 g, 2.61 mmol) in dry THF
(15 mL), and the contents were cooled to −40 °C and stirred. The
LiCuBr2 solution described above (0.5 M in THF, 1.04 mL, 0.522
mmol) was added followed by dropwise addition of pentylmagnesium
bromide (2 M solution in Et2O, 3.92 mL, 7.84 mmol) over 10 min.
The reaction mixture was allowed to stir for an additional 20 min and
the reaction quenched by dropwise addition of saturated aq. NH4Cl
(CAUTION: gas evolution). The mixture was diluted with water
and the solution stirred until the aqueous phase turned deep blue
(∼10 min). The phases were separated, and the aqueous layer was
extracted with EtOAc. The combined extracts were dried over Na2SO4,
filtered, and concentrated with a rotary evaporator for purification by
flash chromatography (5−10% EtOAc/hexane) to afford 10a as a pale
pared from 9b as described for the 9a → 10f reaction (69%): H
NMR (400 MHz, CDCl3) δ 7.34−7.25 (m, 5H), 6.86 (s, 1H), 4.32 (t,
J = 6.7 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 1.80−1.70 (m, 2H), 1.11 (t,
J = 7.1 Hz, 3H), 1.01 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 169.1, 136.5, 135.6, 133.6, 128.4, 128.3, 128.2, 76.2, 61.1,
29.3, 13.9, 10.3; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C14H18O3Na 257.1148, found 257.1170.
(Z)-Ethyl 2-Benzylidene-3-hydroxy-4-methylpentanoate
(10h). Prepared from 9c as described for the 9a → 10f reaction
1
(72%): H NMR (400 MHz, CDCl3) δ 7.35−7.24 (m, 5H), 6.83 (s,
1H), 4.14 (q, J = 7.1 Hz, 2H), 4.03 (d, J = 7.5 Hz, 1H), 2.48 (bs, 1H),
1.91 (m, 1H), 1.10 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 0.96
(d, J = 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.3, 135.8,
135.6, 134.5, 128.4, 128.3, 128.2, 80.8, 61.1, 33.1, 19.6, 18.3, 13.8;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C15H20O3Na 271.1305,
found 271.1301.
(Z)-Ethyl 2-Benzylidene-3-hydroxy-4,4-dimethylpentanoate
1
orange oil (0.47 g, 84%): H NMR (400 MHz, CDCl3) δ 6.14 (t, J =
(10i). Prepared from 9d as described for the 9a → 10f reaction
1
7.5 Hz, 1H), 4.47 (q, J = 6.4 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.41
(m, J = 15.0, 7.5 Hz, 2H), 1.48−1.38 (m, 2H), 1.37−1.23 (m, 11H),
0.89 (t, J = 7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 141.8,
135.2, 69.9, 60.6, 31.7, 29.5, 29.1, 22.8, 22.6, 14.4, 14.2; HRMS
(ESI-TOF) m/z [M + Na]+ calcd for C12H22O3Na 237.1461, found
237.1471.
(56%): H NMR (400 MHz, CDCl3) δ 7.3−7.19 (m, 5H), 6.89 (s,
1H), 4.19 (s, 1H), 2.81 (bs, 1H), 4.11−4.02 (m, 2H), 1.04 (m, J = 7.1,
3.5 Hz, 3H), 0.97 (d, J = 3.5 Hz, 9H); 13C NMR (101 MHz, CDCl3) δ
170.2, 136.4, 136.0, 134.7, 128.3, 128.2, 128.1, 82.5, 61.1, 36.6, 26.0,
13.6; HRMS m/z (ESI-TOF) [M + Na]+ calcd for C16H22O3Na
285.1461, found 285.1476.
(Z)-Ethyl 2-(1-Hydroxypropyl)oct-2-enoate (10b). Prepared
(Z)-Ethyl 2-[Hydroxy(phenyl)methyl]-3-phenylacrylate
(10j). Prepared from 9d as described for the 9a → 10f reaction
(56%). Spectral data matched those previously reported for
enantiopure 10j.17
1
from 9b as described for the 9a → 10a reaction (88%): H NMR
(400 MHz, CDCl3) δ 6.10 (t, J = 7.5 Hz, 1H), 4.25 (q, J = 7.1 Hz,
2H), 4.12 (t, J = 6.8 Hz, 1H), 2.42 (m, J = 14.9, 7.5 Hz, 2H), 1.72−
1.59 (m, 2H), 1.48−1.38 (m, 2H), 1.31 (m, 8H), 0.90 (m, 6H); 13C
NMR (101 MHz, CDCl3) δ 168.0, 142.9, 133.8, 76.4, 60.6, 31.7, 29.6,
29.5, 29.1, 22.6, 14.4, 14.2, 10.6; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C13H24O3Na 251.1618, found 251.1633.
(Z)-Ethyl 2-[Hydroxy(phenyl)methyl]but-2-enoate (10k). Pre-
pared from 9e as described for the 9a → 10a reaction, using methyl-
1
magnesium bromide in place of pentylmagnesium bromide (47%): H
NMR (400 MHz, CDCl3) δ 7.39−7.23 (m, 5H), 6.31 (q, J = 7.2 Hz,
1H), 5.43 (d, J = 7.0 Hz, 1H), 4.23−4.08 (m, 2H), 3.13 (d, J = 7.1 Hz,
1H), 2.06 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 167.4, 142.3, 139.2, 134.7, 128.4, 127.6, 126.4, 75.6,
60.6, 15.7, 14.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C13H16O3Na 243.0992, found 243.0991.
(Z)-Ethyl 2-(1-Hydroxy-2-methylpropyl)oct-2-enoate (10c).
1
Prepared from 9c as described for the 9a → 10a reaction (75%): H
NMR (400 MHz, CDCl3) δ 6.04 (t, J = 7.6 Hz, 1H), 4.24 (qd, J = 7.1,
0.8 Hz, 2H), 3.79 (t, J = 8.0 Hz, 1H), 2.64 (dd, J = 17.5, 8.7 Hz, 1H),
2.39 (m, 2H), 1.83 (m, 1H), 1.43 (m, 2H), 1.35−1.26 (m, 7H), 0.98
(m, 3H), 0.89 (m, 3H), 0.82 (d, J = 6.8 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 168.2, 143.5, 133.2, 81.3, 60.6, 33.4, 31.7, 29.6, 29.1,
(Z)-Ethyl 2-(1-Hydroxyethyl)pent-2-enoate (10l). Prepared
from 9b as described for the 9a → 10a reaction, using ethylmagnesium
8968
dx.doi.org/10.1021/jo201727g|J. Org. Chem. 2011, 76, 8962−8976

The Journal of Organic Chemistry
Article
1
bromide in place of pentylmagnesium bromide (88%): H NMR (400
MHz, CDCl3) δ 6.12 (t, J = 7.4 Hz, 1H), 4.47 (q, J = 6.4 Hz, 1H), 4.26
(q, J = 7.1 Hz, 2H), 2.43 (m, J = 7.5 Hz, 2H), 1.33 (m, 6H), 1.04 (t,
J = 7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 142.9, 134.8,
69.7, 60.6, 22.9, 22.7, 14.4, 13.8; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C9H16O3Na 195.0992, found 195.1010.
(E)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2,2-dimethyldec-
4-en-3-yl 2-(tert-Butoxycarbonylamino)acetate (11d). Prepared
from 10d using the same three-step procedure described for the 10a
→ 11a reaction (45%): 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 4H),
7.46−7.35 (m, 6H), 5.54 (t, J = 7.3 Hz, 1H), 5.21 (s, 1H), 4.88 (m,
1H), 4.21 (d, J = 12.0 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 3.86 (m,
1H), 3.75 (m, 1H), 1.94 (q, J = 7.4 Hz, 2H), 1.44 (s, 9H), 1.33−1.11
(m, 6H), 1.05 (s, 9H), 0.89 (s, 9H), 0.84 (t, J = 7.1 Hz, 3H); 13C
NMR (101 MHz, CDCl3) δ 169.3, 155.7, 135.9, 134.9, 134.8, 133.62,
133.58, 129.79, 129.82, 127.77, 127.75, 83.5, 79.8, 60.4, 42.7, 35.4,
31.7, 29.3, 28.5, 27.9, 27.0, 26.9, 26.7, 26.4, 22.6, 19.4, 14.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C36H56NO5Si 610.39223, found
610.39431.
(E)-3-[(tert-Butyldiphenylsilyloxy)methyl]non-3-en-2-yl 2-
(tert-Butoxycarbonylamino)acetate (11a). Allylic alcohol 10a
(472 mg, 10.0 mmol) in 50 mL of Et2O was cooled to 0 °C and
treated with LAH (1 M solution in THF, 2.65 mmol, 2.65 mL). The
mixture was stirred from 0 to 10 °C for 1 h and the reaction quenched
carefully with saturated aq Rochelle salt. When no more gas evolution
was observed, the reaction mixture was diluted with 20 mL each of
saturated aq Rochelle salt and Et2O and stirred vigorously at rt for
20 h. The reaction mixture was diluted with brine and extracted
repeatedly with EtOAc. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. Purification by flash column
chromatography over silica gel (EtOAc/hexanes) gave the inetermedi-
ate diol as a colorless oil (278 mg, 73%).
The allylic diol mentioned above (475 mg, 2.76 mmol) in 10 mL
of CH2Cl2 under Ar at 0 °C was treated with DMAP (0.067 g,
0.550 mmol) and NEt3 (0.461 mL, 3.30 mmol) and TBDPSCl
(0.776 mL, 3.03 mmol). The mixture was stirred at rt for 23 h and the
reaction quenched with saturated aq NH4Cl. The aqueous layer was
extracted with CH2Cl2, and the combined extracts were dried over
Na2SO4 and evaporated. The crude residue was absorbed onto silica
gel and purified by flash column chromatography (5%−10% EtOAc/
hexanes) to afford the silyl ether as a colorless oil (1.040 g, 92%).
A solution of the silyl ether mentioned above (918 mg, 2.24 mmol)
in 10 mL of CH2Cl2 at rt was treated with Boc-Gly-OH (510 mg,
2.91 mmol), DMAP (137 mg, 1.12 mmol), and EDC (558 mg,
2.91 mmol). The mixture was stirred for 20 h, the reaction quenched
with saturated aq NH4Cl, and the mixture extracted with CH2Cl2. The
organic layer was dried over Na2SO4 and concentrated under reduced
pressure. Purification by flash chromatography (10% EtOAc/hexanes)
afforded 11a as a thick colorless oil (1.22 g, 96%): 1H NMR
(400 MHz, CDCl3) δ 7.7−7.58 (m, 4H), 7.47−7.31 (m, 6H), 5.61 (q,
J = 6.5 Hz, 1H), 5.55 (t, J = 7.3 Hz, 1H), 4.97 (m, 1H), 4.25−4.09 (m,
2H), 3.88 (m, 1H), 3.79 (m, 1H), 1.84 (dd, J = 14.9, 7.4 Hz, 2H), 1.43
(m, 11H), 1.30−1.06 (m, 7H), 1.04 (m, J = 2.6 Hz, 9H), 0.86 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 169.9, 155.9, 137.2, 136.1,
135.90, 135.87, 135.6, 135.1, 133.7, 133.6, 130.6, 130.0, 129.8, 127.94,
127.91, 127.8, 127.7, 80.1, 73.7, 59.6, 42.9, 32.0, 31.7, 29.8, 29.5, 29.3,
28.6, 27.7, 27.6, 27.2, 27.1, 27.0, 26.8, 22.7, 20.2, 19.5, 19.4, 19.3, 14.4,
14.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for C33H50NO5Si
568.34528, found 568.34500.
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-1-phenyloct-2-
enyl 2-(tert-Butoxycarbonylamino)acetate (11e). Prepared from
10e using the same three-step procedure described for the 10a → 11a
1
reaction (55%): H NMR (400 MHz, CDCl3) δ 7.65−7.52 (m, 4H),
7.45−7.28 (m, 11H), 6.63 (m, 1H), 5.59 (t, J = 7.4 Hz, 1H), 4.97 (m,
1H), 4.20 (m, 1H), 3.96 (m, 3H), 1.88 (m, 2H), 1.45 (s, 9H), 1.32−
1.06 (m, 6H), 1.01 (s, 9H), 0.85 (t, J = 7.1 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 169.4, 155.7, 138.5, 135.8, 135.7, 133.43, 133.36,
131.0, 129.8, 129.7, 128.4, 128.1, 127.78, 127.75, 127.7, 80.0, 59.4,
42.8, 31.6, 29.4, 28.5, 27.7, 27.0, 26.9, 22.6, 19.3, 14.2; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C38H51NO5SiNa 652.34287, found
652.34622.
(E)-3-[(tert-Butyldiphenylsilyloxy)methyl]-4-phenylbut-3-en-
2-yl 2-(tert-Butoxycarbonylamino)acetate (11f). Prepared from
10f using the same three-step procedure described for the 10a → 11a
1
reaction (35%): H NMR (400 MHz, CDCl3) δ 7.62 (m, 4H), 7.44−
7.31 (m, 7H), 7.18 (m, 4H), 6.67 (s, 1H), 5.76 (q, J = 6.6 Hz, 1H),
4.97 (m, 1H), 4.35 (s, 2H), 3.95−3.51 (m, 2H), 1.51 (d, J = 6.6 Hz,
3H), 1.45 (s, 9H), 1.06 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
169.7, 155.8, 139.9, 136.2, 135.8, 135.8, 133.32, 133.27, 129.8, 129.1,
129.0, 128.2, 127.8, 127.3, 80.0, 73.2, 60.2, 42.8, 28.5, 27.0, 20.4, 19.4;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C34H43NO5SiNa
596.28027, found 596.28242.
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-1-phenylpent-1-
en-3-yl 2-(tert-Butoxycarbonylamino)acetate (11g). Prepared
from 10g using the same three-step procedure described for the 10a
1
→ 11a reaction (30%): H NMR (400 MHz, CDCl3) δ 7.64 (dt, J =
8.0, 1.6 Hz, 4H), 7.44−7.31 (m, 7H), 7.20 (s, 4H), 6.64 (s, 1H), 5.54
(t, J = 6.6 Hz, 1H), 4.96 (m, 1H), 4.33 (q, J = 11.7 Hz, 2H), 4.03−3.76
(m, 2H), 1.98−1.75 (m, 2H), 1.45 (s, 9H), 1.07 (s, 9H), 0.95 (t, J =
7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 169.7, 155.7, 138.2,
136.2, 135.77, 135.75, 133.3, 133.2, 130.4, 129.79, 129.77, 129.0,
128.1, 127.8, 127.2, 79.9, 78.8, 60.1, 42.7, 28.4, 27.2, 27.0, 19.3, 10.1;
HRMS (ESI-TOF) m/z [M + Na]+ calcd for C35H45NO5SiNa
610.29592, found 610.29312.
(E)-4-[(tert-Butyldiphenylsilyloxy)methyl]dec-4-en-3-yl 2-
(tert-Butoxycarbonylamino)acetate (11b). Prepared from 10b
using the same three-step procedure described for the 10a → 11a
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-4-methyl-1-phe-
nylpent-1-en-3-yl 2-(tert-Butoxycarbonylamino)acetate
(11h). Prepared from 10h using the same three-step procedure
1
reaction (62%): H NMR (400 MHz, CDCl3) δ 7.68 (d, J = 7.6 Hz,
4H), 7.46−7.35 (m, 6H), 5.53 (t, J = 7.3 Hz, 1H), 5.36 (t, J = 6.7 Hz,
1H), 4.95 (m, 1H), 4.17 (m, 2H), 3.89 (d, J = 18.3 Hz, 1H), 3.81 (d,
J = 18.3 Hz, 1H), 1.92−1.67 (m, 4H), 1.44 (s, 9H), 1.3 −1.11 (m,
6H), 1.04 (s, 9H), 0.87 (dt, J = 19.9, 7.3 Hz, 6H); 13C NMR (101
MHz, CDCl3) δ 169.8, 155.7, 135.81, 135.77, 135.5, 133.6, 133.5,
132.1, 129.8, 127.8, 79.4, 59.4, 42.7, 31.6, 29.4, 28.5, 27.5, 26.9, 22.6,
19.3, 14.2, 10.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C34H52NO5Si 582.36093, found 582.36179
(E)-4-[(tert-Butyldiphenylsilyloxy)methyl]-2-methyldec-4-en-
3-yl 2-(tert-Butoxycarbonylamino)acetate (11c). Prepared from
10c using the same three-step procedure described for the 10a → 11a
reaction (69%): H NMR (400 MHz, CDCl3) δ 7.69 (m, 4H), 7.47−
7.35 (m, 6H), 5.51 (t, J = 7.4 Hz, 1H), 5.16 (d, J = 7.6 Hz, 1H), 4.94
(m, 1H), 4.20 (d, J = 11.8 Hz, 1H), 4.10 (d, J = 11.8 Hz, 1H), 3.87 (m,
1H), 3.82 (m, 1H), 2.10 (m, 1H), 1.90 (q, J = 7.3 Hz, 2H), 1.44 (s,
9H), 1.32−1.11 (m, 6H), 1.04 (s, 9H), 0.93−0.82 (m, 9H); 13C NMR
(101 MHz, CDCl3) δ 169.7, 155.7, 135.9, 135.8, 134.6, 133.6, 133.5,
133.3, 129.8, 129.8, 127.8, 127.8, 83.6, 79.9, 59.3, 42.7, 31.6, 30.6, 29.4,
28.5, 27.6, 26.9, 22.6, 19.7, 19.3, 18.1, 14.2; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C35H54NO5Si 596.37658, found 596.37937.
1
described for the 10a → 11a reaction (35%): H NMR (400 MHz,
CDCl3) δ 7.65 (m, 4H), 7.46−7.31 (m, 7H), 7.22 (m, 4H), 6.61 (s,
1H), 5.35 (d, J = 7.1, 1H), 4.95 (bs, 1H), 4.36 (d, J = 11.7 Hz, 1H),
4.25 (d, J = 11.7 Hz, 1H), 4.00−3.81 (m, 2H), 2.17 (m, 1H), 1.45 (s,
9H), 1.08 (s, 9H), 0.95 (m, 6H); 13C NMR (101 MHz, CDCl3) δ
169.7, 155.7, 137.2, 136.2, 135.9, 133.3, 133.2, 131.6, 129.9, 129.8,
129.1, 128.2, 127.78, 127.77, 127.3, 82.9, 80.0, 60.0, 42.6, 30.9, 28.4,
27.0, 19.8, 19.4, 17.9; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C36H47NO5SiNa 624.31157, found 624.31511.
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-4,4-dimethyl-1-
phenylpent-1-en-3-yl 2-(tert-Butoxycarbonylamino)acetate
(11i). Prepared from 10i using the same three-step procedure
1
1
described for the 10a → 11a reaction (51%): H NMR (400 MHz,
CDCl3) δ 7.64 (m, 4H), 7.44−7.29 (m, 6H), 7.25−7.16 (m, 5H), 6.64
(s, 1H), 5.47 (s, 1H), 4.93 (bs, 1H), 4.45 (d, J = 12.2 Hz, 1H), 4.23 (d,
J = 12.2 Hz, 1H), 3.97−3.71 (m, 2H), 1.45 (s, 9H), 1.05 (s, 9H), 0.93
(s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.2, 155.7, 138.0, 136.4,
136.0, 135.8, 133.4, 133.3, 132.1, 129.8, 129.7, 129.1, 128.2, 127.8,
127.7, 127.2, 81.9, 79.9, 61.6, 42.8, 35.9, 28.5, 27.0, 26.5, 19.4; HRMS
8969
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Article
(ESI-TOF) m/z [M + Na]+ calcd for C37H49NO5SiNa 638.32722,
found 638.32163.
presumably provides an inseparable mixture of diastereomeric
carboxylic acids. This semicrude mixture was used in the next step
without further purification. Spectral data given for the mixture of
rotamers and diastereomers (>95:5 dr): 1H NMR (400 MHz, CDCl3)
δ 7.73 (m, 4H), 7.49−7.38 (m, 6H), 5.48 (m, 1H), 5.33 (d, J = 8.6 Hz,
1H), 4.53 (m, 1H), 4.25 (m, 1H), 4.06 (m, 1H), 2.63 (m, 1H), 1.59−
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-1,3-diphenylallyl
2-(tert-Butoxycarbonylamino)acetate (11j). Prepared from 10j
using the same three-step procedure described for the 10a → 11a
reaction (52%): 1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 20.2, 7.8
Hz, 4H), 7.41−7.27 (m, 12H), 7.23−7.15 (m, 5H), 6.78 (s, 1H), 6.73
(s, 1H), 4.98 (m, 1H), 4.36 (d, J = 11.9 Hz, 1H), 4.07 (d, J = 12.0 Hz,
1H), 3.97 (d, J = 5.3 Hz, 2H), 1.44 (d, J = 6.5 Hz, 9H), 1.03 (s, 9H);
13C NMR (101 MHz, CDCl3) δ 169.3, 155.7, 138.4, 138.1, 136.1,
136.0, 135.8, 135.7, 133.3, 133.1, 129.8, 129.7, 129.5, 129.0, 128.9,
128.6, 128.4, 128.2, 128.0, 127.76, 127.75, 127.6, 127.3, 126.7, 80.1,
60.0, 42.8, 28.5, 27.1, 26.9, 19.3; HRMS (ESI-TOF) m/z [M + Na]+
calcd for C39H45NO5SiNa 658.29592, found 658.29583.
1.35 (m, 15H), 1.32−1.12 (m, 3H), 1.05 (m, 11H), 0.83 (m, 3H); 13
C
NMR (101 MHz, CDCl3) δ 175.3, 155.7, 135.9, 135.8, 135.3, 132.4,
130.2, 130.1, 128.1, 128.0, 79.8, 60.2, 57.5, 48.2, 31.8, 31.1, 28.7, 28.5,
28.4, 27.2, 27.0, 22.6, 19.2, 14.2, 13.5; HRMS (ESI-TOF) m/z [M −
H]− calcd for C33H48NO5Si 566.33072, found 566.33285.
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-3-[(Z)-1-(tert-
butyldiphenylsilyloxy)pent-2-en-2-yl]octanoic Acid (13b). Pre-
pared from 11b using the same procedure described for the 11a →
13a reaction (60%). Spectral data given for the mixture of rotamers
(E)-2-[(tert-Butyldiphenylsilyloxy)methyl]-1-phenylbut-2-
enyl 2-(tert-Butoxycarbonylamino)acetate (11k). Prepared from
10k using the same three-step procedure described for the 10a → 11a
1
and diastereomers (91:9 dr): H NMR (400 MHz, CDCl3) δ 7.81−
7.65 (m, 4H), 7.50−7.36 (m, 6H), 5.44 (t, J = 7.4 Hz, 1H), 5.27 (m,
1H), 4.58 (m, 1H), 4.32−4.15 (m, 1H), 4.08−3.92 (m, 1H), 2.40 (m,
1H), 1.97−1.78 (m, 2H), 1.56 (m, 1H), 1.43 (m, 11H), 1.33−1.11 (m,
2H), 1.06 (m, 12H), 0.91−0.77 (m, 6H); 13C NMR (101 MHz,
CDCl3) δ 176.0, 155.7, 135.9, 135.8, 134.9, 134.3, 134.1, 132.8, 132.7,
130.0, 130.0, 128.0, 127.9, 127.8, 79.7, 60.7, 57.4, 46.8, 31.8, 28.8, 28.5,
27.1, 27.0, 22.6, 21.1, 19.2, 14.3, 14.1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C34H52NO5Si 582.3609, found 582.3664.
1
reaction (72%): H NMR (400 MHz, CDCl3) δ 7.63 (dd, J = 7.9, 1.4
Hz, 2H), 7.56 (dd, J = 7.9, 1.3 Hz, 2H), 7.47−7.27 (m, 11H), 6.64 (s,
1H), 5.65 (m, 1H), 4.98 (m, 1H), 4.21 (d, J = 12.1 Hz, 1H), 4.03 (d,
J = 12.1 Hz, 1H), 3.94 (d, J = 5.3 Hz, 2H), 1.52 (d, J = 6.9 Hz, 3H),
1.44 (s, 9H), 1.02 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 169.3,
155.7, 138.5, 136.9, 135.7, 135.6, 133.42, 133.35, 129.73, 129.67,
128.4, 128.1, 127.74, 127.71, 127.6, 125.2, 79.9, 77.3, 59.2, 42.7, 28.4,
26.8, 19.2, 13.2; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C34H43NO5SiNa 596.28027, found 596.28307.
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-3-[(Z)-1-(tert-butyl-
diphenylsilyloxy)-4-methylpent-2-en-2-yl]octanoic Acid
(13c). Prepared from 11c using the same procedure described for
the 11a → 13a reaction (62%). Spectral data given for the mixture of
(E)-3-[(tert-Butyldiphenylsilyloxy)methyl]hex-3-en-2-yl 2-
(tert-Butoxycarbonylamino)acetate (11l). Prepared from 10l
using the same three-step procedure described for the 10a → 11a
1
rotamers and diastereomers (90:10 dr): H NMR (400 MHz, CDCl3)
1
δ 7.73 (m, 4H), 7.42 (m, 6H), 5.74−5.46 (m, 0.5H), 5.39 (d, J = 8.3
Hz, 0.5H), 5.29−5.03 (m, 1H), 4.67−4.39 (m, 1H), 4.31−3.90 (m,
2H), 2.82−2.48 (m, 1H), 2.28 (m, 1H), 1.71−1.37 (m, 10H), 1.36−
1.02 (m, 16H), 1.01−0.66 (m, 9H); 13C NMR (101 MHz, CDCl3) δ
177.7, 176.9, 158.2, 156.5, 155.7, 139.1, 136.0, 135.81, 135.76, 135.7,
134.9, 133.3, 133.0, 132.9, 132.3, 129.9, 127.9, 127.81, 127.77, 127.7,
80.5, 79.8, 79.7, 61.1, 57.2, 45.6, 40.6, 31.8, 31.6, 31.5, 28.8, 28.49,
28.45, 28.3, 26.97, 26.92, 26.9, 26.9, 26.7, 23.11, 23.06, 22.9, 22.6, 22.5,
19.2, 14.1; HRMS (ESI-TOF) m/z [M + H]+calcd for C35H54NO5Si
596.3766, found 596.3808.
reaction (53%): H NMR (400 MHz, CDCl3) δ 7.74−7.61 (m, 4H),
7.47−7.35 (m, 6H), 5.61 (q, J = 6.4 Hz, 1H), 5.54 (t, J = 7.3 Hz, 1H),
4.92 (bs, 1H), 4.21 (m, 2H), 3.92−2.73 (m, 2H), 1.87 (m, 2H), 1.43
(m, 12H), 1.04 (s, 9H), 0.88 (t, J = 7.5 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 169.6, 155.7, 136.71, 135.67, 135.7, 134.9, 133.54,
133.47, 131.8, 129.8, 127.8, 79.8, 73.4, 59.5, 42.8, 28.4, 26.9, 20.8, 20.0,
19.3, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H44NO5Si
526.29833, found 526.29901.
(Z)-2-[(tert-Butyldiphenylsilyloxy)methyl]but-2-enyl 2-(tert-
Butoxycarbonylamino)acetate (11m). Prepared from 10m24
using the same three-step procedure described for the 10a → 11a
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-3-[(Z)-1-(tert-butyl-
diphenylsilyloxy)-4,4-dimethylpent-2-en-2-yl]octanoic Acid
(13d). Prepared from 11d using the same procedure described for
the 11a → 13a reaction (52%). Spectral data given for the mixture of
1
reaction (95%): H NMR (400 MHz, CDCl3) δ 7.68 (m, 4H), 7.46−
7.36 (m, 6H), 5.65 (q, J = 7.0 Hz, 1H), 4.98 (bs, 1H), 4.76 (s, 2H),
4.25 (s, 2H), 3.92−3.76 (m, 2H), 1.50−1.43 (m, 12H), 1.04 (m, 9H);
13C NMR (101 MHz, CDCl3) δ 170.3, 155.7, 135.7, 133.6, 133.5,
1
rotamers and diastereomers (83:17 dr): H NMR (400 MHz, CDCl3)
δ 7.81−7.66 (m, 4H), 7.43 (m, 6H), 5.44 (m, 1H), 5.24 (m, 1H), 4.61
(m, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.02 (m, 1H), 2.24 (m, 1H), 1.55
(m, 1H), 1.43 (m, 10H), 1.26 (m, 1H), 1.18 (m, 1H), 1.07 (m, 13H),
0.88 (m, 9H), 0.81 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 176.9,
155.6, 136.0, 134.9, 133.6, 132.8, 130.0, 127.9, 127.8, 79.6, 61.0, 57.3,
32.5, 31.8, 31.3, 28.8, 28.5, 27.1, 27.0, 22.7, 19.2, 14.1; HRMS (ESI-
TOF) m/z [M − H]− calcd for C36H54NO5Si 608.37767, found
608.37878.
129.9, 127.8, 127.4, 80.1, 67.4, 59.2, 42.6, 28.5, 26.9, 19.4, 13.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C28H40NO5Si 498.26703, found
498.26692.
(E)-2-[(Triisopropylsilyloxy)methyl]but-2-enyl 2-(tert-
Butoxycarbonylamino)acetate (11n). Prepared from 10n24 using
the same three-step procedure described for the 10a → 11a reaction
(99%): 1H NMR (400 MHz, CDCl3) δ 5.81 (q, J = 7.0 Hz, 1H), 5.00
(s, 1H), 4.74 (s, 2H), 4.19 (s, 2H), 3.89 (d, J = 5.0 Hz, 2H), 1.73 (d,
J = 7.0 Hz, 3H), 1.44 (s, 9H), 1.16−1.01 (m, 21H); 13C NMR (101
MHz, CDCl3) δ 170.4, 155.8, 133.7, 126.3, 80.1, 65.5, 60.5, 42.5, 28.4,
18.1, 13.2, 12.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C21H42NO5Si 416.28268, found 416.28138.
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-3-[(Z)-3-(tert-butyl-
diphenylsilyloxy)-1-phenylprop-1-en-2-yl]octanoic Acid
(13e). Prepared from 11e using the same procedure described for
the 11a → 13a reaction (74%). Spectral data given for the mixture of
1
rotamers and diastereomers (87:13 dr): H NMR (400 MHz, CDCl3)
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-3-[(Z)-1-(tert-
butyldiphenylsilyloxy)but-2-en-2-yl]octanoic Acid (13a). A
solution of NaHMDS (1 M in THF, 3.43 mL, 3.43 mmol) was
diluted with 3 mL of additional THF at rt and treated with a solution
of 11a (690 mg, 1.35 mmol) in 5 mL of THF. After TLC indicated
consumption of the starting material (typically within 20 min), the
reaction was quenched with 1 M aq HCl and the mixture evaporated
under reduced pressure. The residue was taken up in 1 M aq HCl and
extracted with EtOAc. The combined organic layers were dried over
Na2SO4, concentrated, and purified by flash column chromatography
(10% EtOAc/hexane) to give alcohol (0.082 mg, 18%) and then 10%
MeOH/EtOAc to afford carboxylic acid 13a as a sticky foam (501 mg,
77%). It should be noted that column chromatography was performed
only to remove the byproduct and that the column flushing stage
δ 7.77−7.27 (m, 10H), 7.21 (m, 3H), 7.09 (m, 2H), 6.56 (s, 1H), 5.30
(m, 1H), 4.71 (m, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.15 (d, J = 11.1 Hz,
1H), 2.69 (m, 1H), 1.62 (m, 1H), 1.45 (m, 10H), 1.30−1.12 (m, 4H),
1.08 (m, 11H), 0.82 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 176.5, 155.7, 138.2, 136.9, 135.9, 135.8, 134.9, 132.8, 130.7,
130.0, 129.9, 129.8, 128.9, 128.1, 127.9, 127.8, 126.9, 79.9, 61.7, 56.8,
53.5, 45.8, 31.9, 28.44, 28.35, 27.1, 27.0, 22.7, 19.3, 14.2; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C38H51NO5SiNa 652.3429, found
652.3426.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-phenylhex-4-enoic Acid
(13f). Prepared from 11f using the same procedure described for
the 11a → 13a reaction (85%). Spectral data given for the mixture of
rotamers and diastereomers (>95:5 dr): 1H NMR (400 MHz, CDCl3)
8970
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Article
δ 7.70 (m, 2H), 7.60 (m, 2H), 7.50−7.30 (m, 8H), 7.25−7.10 (m,
4H), 5.79 (q, J = 6.9 Hz, 1H), 5.08 (m, 1H), 4.81 (d, J = 8.2 Hz, 1H),
4.08−3.87 (m, 3H), 1.52 (d, J = 6.9 Hz, 3H), 1.41 (m, 9H), 1.09 (s,
9H); 13C NMR (101 MHz, CDCl3) δ 176.3, 155.6, 138.1, 137.2,
135.8, 135.6, 134.9, 133.0, 132.9, 129.8, 129.8, 129.1, 128.6, 127.82,
127.77, 127.3, 125.0, 80.2, 80.1, 60.1, 55.9, 51.0, 31.0, 28.4, 28.3, 26.9,
26.7, 19.2, 13.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C34H44NO5Si 574.2983, found 574.3026.
1H), 4.48 (q, J = 12.5 Hz, 2H), 3.36 (m, 1H), 1.34 (m, 9H), 1.17 (d,
J = 6.9 Hz, 3H), 1.06 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 176.4,
155.7, 140.7, 136.8, 135.8, 135.7, 133.1, 133.0, 129.8, 129.7, 129.1,
128.9, 128.6, 128.0, 127.9, 127.8, 126.8, 79.9, 61.4, 56.3, 39.4, 28.43,
28.38, 27.0, 19.4, 14.2; HRMS (ESI-TOF) m/z [M − H]− calcd for
C34H42NO5Si 572.28377, found 572.28566.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-ethylhex-4-enoic Acid (13l). Pre-
pared from 11l using the same procedure described for the 11a → 13a
reaction (89%). Spectral data given for the mixture of rotamers and
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-phenylhept-4-enoic Acid
(13g). Prepared from 11g using the same procedure described for
the 11a → 13a reaction (76%). Spectral data given for the mixture of
1
diastereomers (>95:5 dr): H NMR (400 MHz, CDCl3) δ 9.79 (bs,
1H), 7.74 (m, 4H), 7.43 (m, 6H), 5.52 (m, 1H), 4.57 (m, 1H), 4.33
(m, 1H), 4.13 (m, 1H), 2.74 (m, 1H), 1.61 (m, 1H), 1.42 (m, 13H),
1.09 (s, 9H), 0.90 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ
175.5, 155.7, 135.9, 135.8, 135.0, 132.6, 132.5, 130.1, 128.03, 127.97,
125.3, 104.9, 79.8, 60.2, 57.3, 49.8, 28.5, 27.0, 21.8, 19.3, 13.5, 12.2;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C30H44NO5Si 526.29833,
found 526.29965.
1
rotamers and diastereomers (87:13 dr): H NMR (400 MHz, CDCl3)
δ 7.66 (m, 2.5H), 7.57 (m, 1.5H), 7.47−7.31 (m, 7H), 7.30−7.16 (m,
4H), 5.66 (t, J = 7.3 Hz, 1H), 5.04 (m, 1H), 4.83 (m, 1H), 4.18−3.87
(m, 3H), 1.89 (m, 2H), 1.39 (m, 9H), 1.08 (m, 9H), 0.90 (t, J = 7.5
Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.3, 174.4, 156.0, 155.5,
138.1, 135.8, 135.7, 134.9, 134.1, 133.0, 132.9, 132.8, 129.9, 129.8,
129.1, 128.6, 128.4, 127.9, 127.82, 127.77, 127.3, 80.6, 80.3, 80.1, 60.3,
56.0, 51.1, 42.4, 28.4, 28.3, 27.0, 26.9, 21.3, 21.2, 19.2, 19.1, 14.3;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C35H46NO5Si 588.3140,
found 588.3180.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-6-methyl-3-phenylhept-4-enoic
Acid (13h). Prepared from 11h using the same procedure described
for the 11a → 13a reaction (54%). Spectral data given for the mixture
of rotamers and diastereomers (79:21 dr): 1H NMR (400 MHz,
CDCl3) δ 7.70−7.57 (m, 4H), 7.39 (m, 7H), 7.26−7.14 (m, 4H), 5.51
(d, J = 9.7 Hz, 1H), 5.46−5.16 (m, 1H), 5.15−4.96 (m, 1H), 4.78 (m,
0.5H), 4.55 (m, 0.5H), 3.99 (m, 2H), 2.62 (m, 0.5H), 2.29 (m, 0.5H),
1.39 (m, 9H), 1.05 (m, 9H), 1.00−0.80 (m, 6H); 13C NMR (101
MHz, CDCl3) δ 177.0, 176.5, 156.5, 155.3, 143.8, 139.4, 138.5, 138.1,
136.0, 135.81, 135.76, 135.7, 133.8, 133.2, 133.1, 132.9, 132.0, 129.9,
129.8, 129.1, 128.6, 128.4, 128.0, 127.9, 127.82, 127.76, 127.2, 126.6,
80.1, 80.0, 67.4, 60.5, 55.9, 55.2, 51.0, 45.4, 28.5, 28.3, 27.21, 27.16,
27.0, 26.9, 23.2, 23.0, 22.7, 19.2, 19.1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C36H48NO5Si 602.3296, found 602.3332.
(2S*,3R*)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-methylpent-4-enoic Acid
(13m). Prepared from 11m using the same procedure described for
the 11a → 13a reaction (82%). Spectral data given for the mixture of
rotamers and diastereomers (>95:5 dr): 1H NMR (400 MHz, CDCl3)
δ 10.16 (bs, 1H), 7.67 (m, 4H), 7.41 (m, 6H), 5.22 (s, 1H), 5.10 (m,
1H), 4.95 (m, 1H), 4.70−4.40 (m, 1H), 4.40−4.04 (m, 2H), 2.90 (m,
1H), 1.49−1.31 (m, 9H), 1.15−0.99 (m, 12H); 13C NMR (101 MHz,
CDCl3) δ 176.9, 155.6, 148.1, 135.7, 133.4, 129.8, 127.85, 127.82,
111.9, 80.1, 66.1, 56.3, 38.0, 28.4, 26.9, 19.4, 14.5; HRMS (ESI-TOF)
m/z [M − H]− calcd for C28H38NO5Si 496.25247, found 496.25222.
(2S*,3S*)-2-(tert-Butoxycarbonylamino)-3-methyl-4-
[(triisopropylsilyloxy)methyl]pent-4-enoic Acid (13n). Prepared
from 11n using the same procedure described for the 11a → 13a
reaction (65%). Spectral data given for the mixture of rotamers and
1
diastereomers (94:6 dr): H NMR (400 MHz, CDCl3) δ 5.89−5.63
(m, 1H), 5.22 (s, 1H), 5.04 (s, 1H), 4.32−4.12 (m, 3H), 2.84 (m, 1H),
1.44 (m, 9H), 1.15 (m, 3H), 1.07 (m, 21H); 13C NMR (101 MHz,
CDCl3) δ 175.6, 156.1, 147.8, 134.8, 114.8, 80.1, 65.9, 58.0, 39.1, 28.4,
18.1, 16.7, 12.1, 12.0; HRMS (ESI-TOF) m/z [M − H]− calcd for
C21H40NO5Si 414.26812, found 414.26687.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-6,6-dimethyl-3-phenylhept-4-
enoic Acid (13i). Prepared from 11i using the same procedure
described for the 11a → 13a reaction (61%). Spectral data given
(S)-tert-Butyl 2-{(2R,3S,Z)-2-(tert-Butoxycarbonylamino)
-4-[(tert-butyldiphenylsilyloxy)methyl]-3-methylhex-4-enami-
do}-4-methylpentanoate (14) and (S)-tert-Butyl 2-{(2S,3R,Z)-2-
(tert-Butoxycarbonylamino)-4-[(tert-butyldiphenylsilyloxy)-
methyl]-3-methylhex-4-enamido)-4-methylpentanoate (15). A
solution of 13a (810 mg, 1.43 mmol) in 12 mL of MeCN was treated
with HBTU (0.704 g, 1.86 mmol), HOBt (0.039 g, 0.285 mmol), NEt3
(1.19 mL, 8.57 mmol), and H-Leu-OtBu-HCl (0.415 g, 1.86 mmol).
After being stirred at rt for 20 h, the mixture was concentrated under
reduced pressure. The residue was diluted with EtOAc and washed
with 1 M aq HCl followed by 10% aq Na2CO3. The organic layer was
dried over Na2SO4 and evaporated. Purification by flash column
chromatography over silica gel (5−7.5% EtOAc/hexanes and then
1
for the mixture of rotamers and diastereomers (78:22 dr): H NMR
(400 MHz, CDCl3) δ 7.63 (m, 4H), 7.48−7.30 (m, 7H), 7.24−7.08
(m, 4H), 5.74 (s, 1H), 5.12 (t, J = 9.6 Hz, 1H), 4.78 (d, J = 9.4 Hz,
1H), 4.14 (d, J = 11.5 Hz, 1H), 3.99 (d, J = 12.0 Hz, 1H), 3.90 (d, J =
9.6 Hz, 1H), 1.37 (s, 9H), 1.12 (s, 9H), 0.92 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 176.9, 155.3, 140.6, 138.2, 136.0, 135.9, 135.5, 133.0,
132.9, 129.9, 129.8, 129.1, 128.6, 127.8, 127.7, 127.2, 80.0, 60.4, 56.1,
50.9, 32.7, 31.4, 28.4, 27.0, 19.2; HRMS (ESI-TOF) m/z [M − H]−
calcd for C37H48NO5Si 614.33072, found 614.33277.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3,5-diphenylpent-4-enoic Acid
(13j). Prepared from 11j using the same procedure described for
the 11a → 13a reaction (69%). Spectral data given for the mixture of
30%) afforded the diastereomeric dipeptides in 76% combined yield.
1
Data for 14 (37%): [α]24 −6.3 (c 0.58, CHCl3); H NMR (400
D
1
MHz, CDCl3) δ 7.84−7.59 (m, 4H), 7.41 (m, 6H), 6.33 (d, J = 8.4 Hz,
1H), 5.35 (q, J = 6.7 Hz, 2H), 4.47 (td, J = 8.7, 5.7 Hz, 1H), 4.38−
4.07 (m, 3H), 2.77 (m, 1H), 1.63 (m, 1H), 1.52 (m, 2H), 1.57−1.34
(m, 26H), 1.32−1.13 (m, 4H), 1.13−1.01 (m, 10H), 0.89 (m, 6H),
0.83 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 172.0, 171.3, 155.6,
136.7, 135.9, 135.8, 133.4, 133.2, 129.9, 129.8, 127.9, 127.8, 124.6,
81.7, 61.1, 51.2, 46.2, 42.1, 32.1, 28.4, 28.1, 27.4, 27.2, 24.8, 22.9, 22.7,
22.1, 19.3, 14.2, 13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
rotamers and diastereomers (73:27 dr): H NMR (400 MHz, CDCl3)
δ 7.67 (m, 1H), 7.58 (m, 1H), 7.50−7.07 (m, 18H), 6.82 (s, 1H), 5.16
(m, 0.5H), 4.94 (m, 0.5H), 4.87−4.63 (m, 1H), 4.35 (m, 1H), 4.23
(m, 1H), 4.06 (m, 1H), 1.39 (m, 9H), 1.06 (s, 9H); 13C NMR (101
MHz, CDCl3) δ 176.7, 156.1, 155.6, 139.6, 138.5, 137.5, 136.9, 136.7,
135.9, 135.8, 135.7, 133.5, 133.13, 133.09, 132.9, 130.0, 129.9, 129.74,
129.65, 129.3, 128.9, 128.8, 128.6, 128.6, 128.3, 128.1, 128.0, 127.9,
127.8, 127.7, 127.5, 127.3, 127.0, 80.2, 65.7, 61.2, 55.8, 55.1, 50.1, 45.5,
28.5, 28.3, 28.1, 27.0, 26.9, 19.3, 19.2, 19.2; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C39H46NO5SiNa 658.2959, found 658.2968.
(2S*,3R*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-methyl-5-phenylpent-4-enoic
Acid (13k). Prepared from 11k using the same procedure described
for the 11a → 13a reaction (78%). Spectral data given for the mixture
of rotamers and diastereomers (>95:5 dr): 1H NMR (400 MHz,
CDCl3) δ 7.71−7.53 (m, 4H), 7.43−7.23 (m, 7H), 7.20−6.96 (m,
4H), 6.40 (s, 1H), 5.28 (d, J = 8.8 Hz, 1H), 4.77 (d, J = 8.5, 4.2 Hz,
C43H69N2O6Si 737.49249, found 737.49350.
1
Data for 15 (38%): [α]24 −0.5 (c 0.67, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.89−7.64 (m, 4H), 7.41 (m, 6H), 6.49 (d, J = 7.6 Hz,
1H), 5.37 (q, J = 6.8 Hz, 1H), 5.25 (bs, 1H), 4.44 (dd, J = 14.2, 8.3 Hz,
1H), 4.39−4.19 (m, 1H), 4.08 (d, J = 12.0 Hz, 1H), 2.63 (m, 1H),
1.62 (m, 1H), 1.55−1.35 (m, 25H), 1.30−1.15 (m, 3H), 1.15−1.01
(m, 12H), 0.89 (m, 6H), 0.82 (t, J = 6.9 Hz, 3H); 13C NMR (101
MHz, CDCl3) δ 171.8, 171.5, 155.7, 136.1, 136.0, 134.9, 133.5, 133.2,
129.9, 129.7, 127.9, 127.8, 125.5, 81.5, 60.8, 58.0, 51.3, 47.6, 42.4, 32.0,
8971
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The Journal of Organic Chemistry
Article
28.6, 28.5, 28.1, 27.3, 27.2, 26.7, 24.9, 22.8, 22.7, 22.4, 19.3, 14.2, 13.5;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C43H69N2O6Si 737.49249,
found 737.49130.
22.7, 22.0, 14.2, 13.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C27H51N2O6 499.37471, found 499.37470.
Data for the allylic chloride intermediate (86%): [α]24D +6.9 (c 0.83,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 6.20 (m, 1H), 5.61 (q, J = 6.9
Hz, 1H), 5.07 (d, J = 8.4 Hz, 1H), 4.44 (td, J = 8.5, 5.6 Hz, 1H), 4.17
(m, 2H), 4.04 (d, J = 11.5 Hz, 1H), 2.52 (m, 1H), 1.73 (d, J = 6.9 Hz,
3H), 1.68−1.50 (m, 3H), 1.46 (m, 20H), 1.36−1.08 (m, 6H), 0.92 (m,
6H), 0.85 (t, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 171.7,
170.9, 155.8, 134.5, 130.2, 82.0, 80.0, 58.0, 51.5, 48.4, 42.3, 41.5, 32.0,
28.4, 28.1, 27.0, 25.0, 22.9, 22.6, 22.3, 14.2, 13.8; HRMS (ESI-TOF)
(R)-tert-Butyl 2-[(2R,3S,Z)-4-Ethylidene-3-pentylpyrrolidine-
2-carboxamido]-4-methylpentanoate (16). A solution of 14
(375 mg, 0.509 mmol) in 4 mL of THF and 1.5 mL of pyridine in
a polypropylene flask was cooled to 0 °C and treated with HF (70%
solution in pyridine, 1.50 mL). After the mixture had been stirred for
5 h at rt, TLC indicated completion and the reaction was quenched by
careful addition of saturated aq NaHCO3. The mixture was extracted
with EtOAc, and the organic layers were dried over Na2SO4 and
concentrated. Purification by flash chromatography (10−20% EtOAc/
m/z [M + H]+ calcd for C27H50ClN2O5 517.34083, found 517.34350.
1
Data for 17 (56%): [α]24 −32.5 (c 2.08, CHCl3); H NMR (400
D
hexanes) afforded the intermediate alcohol as a white foam (220 mg,
MHz, CDCl3) δ 7.42 (d, J = 7.6 Hz, 1H), 5.49 (d, J = 6.9 Hz, 1H),
4.61 (m, 1H), 4.43 (dd, J = 13.4, 7.5 Hz, 1H), 4.02 (m, 2H), 2.91 (m,
1H), 1.71−1.49 (m, 6H), 1.44 (s, 9H), 1.40−1.16 (m, 8H), 1.00−0.79
(m, 9H); 13C NMR (101 MHz, CDCl3) δ 171.5, 166.0, 134.5, 121.1,
82.3, 63.7, 52.0, 45.5, 45.2, 40.9, 31.5, 28.0, 27.9, 26.5, 24.9, 22.7,
22.6, 21.7, 14.7, 14.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H41N2O3 381.31172, found 381.31310.
1
87%): [α]24 −8.5 (c 2.17, CHCl3); H NMR (400 MHz, CDCl3) δ
D
6.95 (d, J = 6.7 Hz, 1H), 5.42 (q, J = 6.8 Hz, 1H), 5.29 (d, J = 8.0 Hz,
1H), 4.41 (m, 1H), 4.32 (m, 1H), 4.21 (d, J = 11.5 Hz, 1H), 4.12 (d,
J = 11.5 Hz, 1H), 3.12 (bs, 1H), 2.49−2.26 (m, 1H), 1.66 (d, J = 6.8
Hz, 3H), 1.64−1.36 (m, 24H), 1.31−1.00 (m, 6H), 0.91 (m, 6H), 0.83
(t, J = 6.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 171.7,
156.0, 137.1, 127.3, 82.0, 80.1, 67.8, 59.3, 57.9, 51.4, 49.4, 42.0, 31.9,
29.3, 28.4, 28.1, 27.2, 24.9, 24.1, 22.9, 22.7, 22.1, 14.2, 13.6; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C27H51N2O6 499.37471, found
499.37534.
(S)-tert-Butyl 2-{(2R,3S,Z)-2-(tert-Butoxycarbonylamino)
-4-[(tert-butyldiphenylsilyloxy)methyl]-3-methyl-5-phenyl-
pent-4-enamido}-4-methylpentanoate (18) and (S)-tert-Butyl
2-{(2S,3R,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-methyl-5-phenylpent-4-en-
amido}-4-methylpentanoate (19). Prepared from racemic 13e
following the same procedure described for the 13a → 14/15 reaction.
Careful flash chromatography over silica gel afforded the diastereo-
A solution of alcohol described above (215 mg, 0.431 mmol) in
2 mL of CH2Cl2 was cooled to 0 °C and treated with NEt3 (0.430 mL,
3.09 mmol) and methanesulfonyl chloride (0.203 mL, 2.65 mmol).
The reaction mixture was stirred at rt for 18 h, diluted with CH2Cl2,
and washed with 1 M aq HCl. The organic layer was dried over
Na2SO4, concentrated under reduced pressure, and purified by flash
meric dipeptides in 77% combined yield.
1
Data for 18 (37%): [α]24 +8.1 (c 2.67, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.69 (m, 2H), 7.60 (d, J = 7.3 Hz, 2H), 7.48−7.27 (m,
6H), 7.21−6.98 (m, 5H), 6.40 (s, 1H), 6.34 (d, J = 8.2 Hz, 1H), 5.37
(m, 1H), 4.58−4.19 (m, 4H), 3.02 (m, 1H), 1.71−1.45 (m, 4H), 1.41
(m, 20H), 1.31−1.13 (m, 5H), 1.09 (s, 9H), 0.98−0.75 (m, 9H); 13C
NMR (101 MHz, CDCl3) δ 171.9, 171.1, 155.6, 138.9, 136.9, 135.9,
135.8, 133.21, 133.17, 129.8, 129.7, 129.0, 128.0, 127.9, 127.8, 126.7,
81.8, 62.1, 57.5, 51.3, 46.2, 42.0, 32.1, 28.4, 28.3, 28.1, 28.0, 27.3, 27.2,
24.8, 22.7, 22.1, 19.4, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd
chromatography to give the intermediate allylic chloride as a white
1
solid (210 mg, 94%): [α]24 −20.5 (c 2.25, CHCl3); H NMR (400
D
MHz, CDCl3) δ 6.34 (d, J = 8.2 Hz, 1H), 5.58 (q, J = 6.9 Hz, 1H),
5.08 (d, J = 41.4 Hz, 1H), 4.45 (dd, J = 13.9, 8.4 Hz, 1H), 4.29−4.12
(m, 2H), 4.05 (d, J = 11.5 Hz, 1H), 2.66−2.54 (m, 1H), 1.73 (d, J =
6.9 Hz, 3H), 1.69−1.50 (m, 3H), 1.49−1.39 (m, 21H), 1.31−1.05 (m,
6H), 0.92 (m, 6H), 0.84 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 171.8, 170.8, 155.7, 134.6, 129.9, 82.1, 80.0, 57.4, 51.5, 48.4,
42.1, 41.2, 31.9, 28.4, 28.1, 27.8, 27.0, 25.0, 22.9, 22.6, 22.2, 14.2, 13.8;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H50ClN2O5
517.34083, found 517.33905.
for C48H71N2O6Si 799.50759, found 799.50832.
1
Data for 19 (40%): [α]24 −10.7 (c 2.33, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.72 (m, 2H), 7.62 (m, 2H), 7.48−7.28 (m, 6H),
7.24−7.03 (m, 5H), 6.40 (m, 2H), 5.32 (d, J = 7.5 Hz, 1H), 4.43 (m,
3H), 4.28 (m, 1H), 3.00 (m, 1H), 1.58 (m, 4H), 1.49−1.32 (m, 21H),
1.30−1.17 (m, 4H), 1.09 (m, 9H), 0.84 (m, 9H); 13C NMR (101
MHz, CDCl3) δ 171.7, 171.2, 155.7, 139.0, 137.0, 136.0, 135.9, 133.3,
129.9, 129.8, 129.7, 129.0, 128.8, 128.6, 127.9, 127.8, 127.7, 126.7,
81.7, 62.2, 57.6, 51.5, 46.2, 42.2, 32.1, 28.5, 28.4, 28.1, 28.0, 27.2, 27.1,
24.9, 22.8, 22.7, 22.4, 19.4, 14.2; HRMS (ESI-TOF) m/z [M + H]+
calcd for C48H70N2O6Si 799.50759, found 799.50980; HRMS (ESI-
TOF) m/z [M + Na]+ calcd for C48H70N2O6SiNa 821.48954, found
821.49194.
The allylic chloride mentioned above (160 mg, 0.309 mmol) was
treated with a solution of 15% TFA in CH2Cl2 (2.5 mL) precooled to
0 °C. The mixture was stirred at 0 °C for 3 h, diluted with EtOAc, and
concentrated under reduced pressure. The dilution−concentration
sequence was repeated two more times, and the crude TFA salt was
dried under vacuum. The residue was then taken up in 3.0 mL of
acetone, and K2CO3 (426 mg, 3.09 mmol) was added. After being
stirred at rt for 20 h, the mixture was filtered through Celite, con-
centrated, and purified by flash chromatography (90−100% EtOAc/
hexanes eluent) to afford 16 as a thick colorless oil (67.0 mg, 58%, two
1
steps): [α]24 −54.0 (c 1.58, CHCl3); H NMR (400 MHz, CDCl3)
(S)-tert-Butyl 2-[(2R,3S)-2-(tert-Butoxycarbonylamino)-3-(3-
chloro-3-phenylprop-1-en-2-yl)octanamido]-4-methylpenta-
noate (20). Prepared from 18 following the same desilylation/
chlorination sequence described for the 14 → 16 reaction.
D
δ 8.26 (d, J = 6.8 Hz, 1H), 6.09 (bs, 2H), 5.46 (m, 1H), 4.64 (m, 1H),
4.41 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 2.91 (m, 1H), 1.79−1.51
(m, 6H), 1.42 (m, 11H), 1.35−1.16 (m, 6H), 0.89 (m, 9H); 13C NMR
(101 MHz, CDCl3) δ 173.6, 166.9, 134.8, 119.6, 83.1, 63.0, 51.8, 46.4,
45.1, 40.6, 31.9, 27.9, 27.2, 25.0, 22.9, 22.5, 21.5, 14.7, 14.1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C22H41N2O3 381.31172, found
381.31360.
Data for the primary alcohol intermediate (88%): [α]24 −19.4 (c
D
1
1.17, CHCl3); H NMR (400 MHz, CDCl3) δ 7.40−7.25 (m, 5H),
7.21 (m, 1H), 6.45 (s, 1H), 5.44 (d, J = 8.7 Hz, 1H), 4.52 (t, J = 8.8
Hz, 1H), 4.41 (m, 2H), 4.24 (d, J = 10.8 Hz, 1H), 4.08 (m, 1H), 2.55
(m, 1H), 1.73−1.47 (m, 2H), 1.40 (m, 21H), 1.31−1.10 (m, 6H),
0.92−0.67 (m, 9H); 13C NMR (101 MHz, CDCl3) δ 171.9, 171.7,
156.1, 138.8, 136.6, 132.8, 129.1, 128.2, 127.1, 81.8, 80.1, 59.9, 57.9,
51.6, 50.3, 42.0, 31.9, 29.5, 28.4, 28.0, 27.1, 24.8, 22.6, 22.6, 22.0, 14.1;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C32H53N2O6 561.39037,
found 561.38990.
(R)-tert-Butyl 2-[(2R,3S,Z)-4-Ethylidene-3-pentylpyrrolidine-
2-carboxamido]-4-methylpentanoate (17). Prepared from 15
following the same three-step procedure used for the 14 → 16
reaction.
Data for the primary alcohol intermediate (85%): [α]24 −15.2
D
1
(c 2.00, CHCl3); H NMR (400 MHz, CDCl3) δ 6.68 (d, J = 8.5 Hz,
Data for the diastereomeric mixture of allylic chlorides 20 (87%):
1H NMR (400 MHz, CDCl3) δ 7.39−7.16 (m, 6H), 6.14 (d, J = 8.3
Hz, 0.5H), 5.91 (d, J = 8.2 Hz, 0.5H), 5.48 (s, 0.5H), 5.35 (s, 0.5H),
5.24 (d, J = 1.8 Hz, 0.5H), 5.12 (d, J = 1.5 Hz, 0.5H), 4.90 (dd, J = 7.9,
1.5 Hz, 1H), 4.68 (d, J = 8.6 Hz, 0.5H), 4.52 (m, 1.5H), 2.99 (m, 1H),
1.74−1.51 (m, 3H), 1.47 (m, 11H), 1.38 (m, 5H), 1.33−1.16 (m, 4H),
1H), 5.43 (q, J = 6.8 Hz, 1H), 5.11 (d, J = 9.0 Hz, 1H), 4.48 (td, J =
9.1, 5.2 Hz, 1H), 4.26 (m, 2H), 4.02 (m, 1H), 2.66 (bs, 1H), 2.33 (t,
J = 8.8 Hz, 1H), 1.64 (m, 4H), 1.60−1.48 (m, 2H), 1.44 (m, 20H),
1.33−0.98 (m, 6H), 0.91 (m, 6H), 0.84 (t, J = 7.0 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 172.9, 171.9, 156.0, 136.9, 128.6, 82.3, 79.9,
67.8, 58.3, 58.2, 51.1, 50.4, 42.1, 31.9, 28.8, 28.4, 28.1, 27.2, 24.9, 23.0,
8972
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The Journal of Organic Chemistry
Article
1.11 (s, 5H), 0.93 (m, 6H), 0.86 (m, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 172.0, 170.0, 169.8, 154.0, 153.6, 151.9, 150.5, 144.1,
142.6, 128.9, 128.7, 128.6, 128.5, 127.3, 127.1, 125.1, 124.8, 107.4,
106.9, 82.1, 81.8, 81.0, 80.3, 66.9, 66.6, 65.1, 64.0, 51.6, 51.3, 51.3,
47.9, 43.9, 43.7, 43.4, 42.8, 42.2, 42.0, 32.3, 32.2, 28.4, 28.2, 28.1, 28.0,
26.9, 26.5, 26.2, 24.9, 24.8, 22.9, 22.7, 22.6, 22.5, 22.2, 14.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C32H52ClN2O5 579.35593, found
579.35436; HRMS (ESI-TOF) m/z [M + Na]+ calcd for
C32H51ClN2O5Na 601.33787, found 601.33641.
by 10% aq Na2CO3. The organic layer was dried over Na2SO4 and
evaporated. Purification by flash column chromatography over silica
gel (10−20% EtOAc/hexanes) afforded 25 as a white foam (268 mg,
1
77%): [α]24 −10.3 (c 2.00, CHCl3); H NMR (400 MHz, CDCl3) δ
D
7.79−7.62 (m, 4H), 7.49−7.32 (m, 6H), 6.32 (d, J = 8.3 Hz, 1H),
5.38−5.14 (m, 2H), 4.49 (m, 1H), 4.35 (d, J = 12.4 Hz, 1H), 4.21 (d,
J = 12.4 Hz, 1H), 3.08 (m, 1H), 1.68−1.50 (m, 2H), 1.44 (m, 10H),
1.38 (m, 12H), 1.11−1.03 (m, 12H), 0.95−0.86 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 172.0, 171.2, 155.7, 139.2, 135.8, 135.7, 133.5,
133.4, 129.8, 129.8, 127.9, 127.8, 127.7, 122.8, 81.8, 60.8, 57.5, 51.2,
41.9, 39.3, 28.4, 28.1, 27.1, 24.9, 22.9, 22.0, 19.4, 13.3; HRMS (ESI-
TOF) m/z [MH]+ calcd for C39H61N2O6Si 681.42989, found
681.43066.
(R)-tert-Butyl 4-Methyl-2-[(2R,3S,5S)-4-methylene-3-pentyl-
5-phenylpyrrolidine-2-carboxamido]pentanoate (21). Prepared
from 20 following the same deprotection/cyclization procedure
described for the 14 → 16 reaction (60%): [α]26 +7.3 (c 2.08,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 9.0 Hz, 1H), 7.34
(m, 2H), 7.26 (m, 3H), 4.98 (m, 1H), 4.86 (s, 1H), 4.55 (m, 2H), 4.19
(d, J = 6.7 Hz, 1H), 2.95 (dd, J = 13.4, 6.8 Hz, 1H), 1.93 (bs, 1H), 1.61
(m, 2H), 1.51 (m, 1H), 1.43 (m, 12H), 1.28 (m, 5H), 0.93 (m, 6H),
0.86 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 172.1,
155.0, 144.6, 128.9, 127.7, 109.1, 81.7, 64.7, 64.4, 50.7, 48.0, 42.2, 31.9,
28.5, 28.1, 27.2, 25.1, 23.0, 22.7, 22.2, 14.2; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C27H43N2O3 443.32682, found 443.32668.
(R)-tert-Butyl 2-[(2S,3R)-2-(tert-Butoxycarbonylamino)-3-(3-
chloro-3-phenylprop-1-en-2-yl)octanamido]-4-methylpenta-
noate (22). Prepared from 19 following the same desilylation/
chlorination sequence described for the 14 → 16 reaction.
(S)-tert-Butyl 2-[(2R,3S,Z)-2-(tert-Butoxycarbonylamino)-4-
(hydroxymethyl)-3-methylhex-4-enamido]-4-methylpenta-
noate (26). Prepared from 25 following the same three-step
procedure described for the 14 → 16 reaction.
Data for the allylic alcohol intermediate (90%): [α]24 −12.3 (c
D
1
1.50, CHCl3); H NMR (400 MHz, CDCl3) δ 6.90 (d, J = 7.8 Hz,
1H), 5.44 (q, J = 6.8 Hz, 1H), 5.34 (d, J = 8.4 Hz, 1H), 4.48−4.29 (m,
3H), 4.11 (d, J = 11.3 Hz, 1H), 3.55 (bs, 1H), 2.63 (m, 1H), 2.10 (bs,
1H), 1.66 (d, J = 6.8 Hz, 3H), 1.63−1.46 (m, 2H), 1.44 (m, 10H),
1.41 (s, 9H), 1.03 (d, J = 6.7 Hz, 3H), 0.92 (dd, J = 6.3, 5.3 Hz, 6H);
13C NMR (101 MHz, CDCl3) δ 172.2, 171.3, 156.2, 139.3, 125.6, 82.0,
80.2, 77.5, 76.8, 59.9, 57.6, 51.5, 43.1, 42.0, 28.4, 28.1, 25.0, 22.9, 22.1,
15.2, 13.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H43N2O6
443.31156, found 443.31136.
Data for the primary alcohol intermediate (93%): [α]24 +4.1 (c
D
1.17, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 5H), 7.21 (m,
1H), 6.83 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 5.26 (d, J = 9.0 Hz, 1H),
4.44 (m, 2H), 4.26 (m, 2H), 3.98 (s, 1H), 2.63 (t, J = 8.0 Hz, 1H),
2.03 (s, 1H), 1.71−1.47 (m, 3H), 1.43 (m, 11H), 1.35 (s, 9H), 1.32−
1.09 (m, 6H), 0.94−0.80 (m, 9H); 13C NMR (101 MHz, CDCl3) δ
172.3, 171.7, 156.1, 139.0, 136.7, 132.7, 129.1, 128.2, 127.1, 82.2, 80.2,
60.2, 58.4, 51.4, 49.7, 42.0, 34.8, 31.9, 29.3, 28.4, 28.1, 28.0, 27.1, 25.4,
24.9, 22.9, 22.7, 22.1, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C32H53N2O6 561.39037, found 561.38930.
Data for the intermediate allylic chloride (97%): [α]24 −27.9 (c
D
1
1.25, CHCl3); H NMR (400 MHz, CDCl3) δ 6.43−6.32 (m, 1H),
5.58 (q, J = 6.8 Hz, 1H), 4.99 (bs, 1H), 4.52−4.40 (m, 1H), 4.31−4.21
(m, 2H), 4.12 (d, J = 11.5 Hz, 1H), 2.93−2.81 (m, 1H), 1.71 (d, J =
6.8 Hz, 3H), 1.68−1.46 (m, 3H), 1.44 (s, 9H), 1.40 (s, 9H), 1.05 (d,
J = 7.1 Hz, 3H), 0.92 (m, 6H); 13C NMR (101 MHz, CDCl3) δ 171.9,
170.8, 155.8, 137.0, 127.9, 82.1, 80.0, 57.1, 51.4, 42.0, 41.4, 41.2, 28.4,
28.1, 25.0, 22.9, 22.1, 14.3, 13.7; HRMS (ESI-TOF) m/z [M + H]+
Data for the diastereomeric mixture of allylic chlorides 22 (84%):
calcd for C23H42ClN2O5 461.27768, found 461.27780.
1H NMR (400 MHz, CDCl3) δ 7.41−7.18 (m, 6H), 6.23 (d, J = 8.6
1
Data for 26 (70%, two steps): [α]24 −22.0 (c 0.75, CHCl3); H
D
Hz, 0.5H), 6.02 (d, J = 8.2 Hz, 0.5H), 5.50 (s, 0.5H), 5.38 (s, 0.5H),
5.18 (m, 0.5H), 5.05 (s, 0.5H), 4.85 (m, 1H), 4.63−4.45 (m, 2H), 2.99
(m, 1H), 1.73 (m, 0.5H), 1.63−1.48 (m, 3H), 1.46 (m, 9.5H), 1.40
(m, 6H), 1.34−1.18 (m, 4H), 1.12 (m, 5H), 0.94 (m, 6H), 0.85 (m,
3H); 13C NMR (101 MHz, CDCl3) δ 172.2, 172.0, 169.8, 169.6,
154.3, 152.6, 151.0, 144.5, 142.7, 128.91, 128.88, 128.7, 128.6, 128.4,
127.3, 127.0, 125.2, 124.9, 106.7, 106.2, 82.2, 81.9, 80.9, 80.3, 67.0,
66.5, 65.2, 64.1, 51.3, 51.2, 44.0, 43.7, 42.9, 42.7, 32.3, 32.2, 28.4, 28.3,
28.2, 28.1, 28.04, 28.00, 26.6, 26.3, 25.0, 24.7, 23.1, 22.8, 22.6, 22.5,
22.3, 22.2, 14.2; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C32H52ClN2O5 579.35593, found 579.35374; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C32H51ClN2O5Na 601.33787, found 601.33532.
(R)-tert-Butyl 4-Methyl-2-[(2S,3R,5R)-4-methylene-3-pentyl-
5-phenylpyrrolidine-2-carboxamido]pentanoate (23). Prepared
from 22 following the same deprotection/cyclization procedure
NMR (400 MHz, CDCl3) δ 7.80 (bs, 1H), 5.31 (m, 1H), 4.59 (bs,
1H), 4.42 (dd, J = 14.9, 7.5 Hz, 1H), 4.08 (d, J = 6.6 Hz, 1H), 3.87 (d,
J = 14.5 Hz, 1H), 3.65 (d, J = 14.4 Hz, 1H), 2.92 (m, 1H), 1.72−1.59
(m, 1H), 1.55 (m, 5H), 1.42 (m, 9H), 1.02 (d, J = 7.1 Hz, 3H), 0.91
(m, 6H); 13C NMR (101 MHz, CDCl3) δ 173.4, 169.4, 139.9, 116.7,
82.5, 64.0, 51.5, 47.2, 41.0, 40.0, 28.0, 25.9, 22.9, 21.7, 14.7, 14.5;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C18H33N2O3 325.24857,
found 325.25005.
(S)-2-{(2R,3S,Z)-1-[(S)-2-Benzamido-6-guanidinohexanoyl]-4-
ethylidene-3-methylpyrrolidine-2-carboxamido}-4-methyl-
pentanoic Acid (27). To a solution of 26 (70.0 mg, 0.215 mmol)
and Fmoc-Har(Boc)2-OH (158 mg, 0.259 mmol) in 3 mL of THF at 0
°C were added DEPBT (96.5 mg, 0.322 mmol) and NEt3 (60.0 μL,
0.431 mol). The mixture was stirred at 0 °C for 6 h, the reaction
quenched with saturated aq NH4Cl, and the THF removed under
reduced pressure. The crude residue was taken up in EtOAc and
washed with 1 M HCl and saturated aq NaHCO3. The organic layer
was dried over Na2SO4 and concentrated under reduced pressure.
Purification by flash chromatography over slica gel (30% EtOAc/
described for the 14 → 16 reaction (59%): [α]26 −7.4 (c 1.42,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 9.0 Hz, 1H), 7.33
(m, 2H), 7.26 (m, 3H), 4.98 (d, J = 1.3 Hz, 1H), 4.82 (s, 1H), 4.56
(m, 2H), 4.21 (d, J = 6.8 Hz, 1H), 2.95 (m, 1H), 1.70 (m, 1H), 1.65−
1.50 (m, 2H), 1.43 (m, 12H), 1.37−1.20 (m, 5H), 0.93 (m, 6H), 0.87
(t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.5, 172.1,
154.8, 144.5, 128.9, 127.7, 127.6, 109.4, 81.9, 64.7, 64.5, 50.8, 47.7,
42.0, 32.0, 29.0, 28.1, 27.1, 25.1, 23.1, 22.7, 22.0, 14.3; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C27H43N2O3 443.32682, found
443.32647.
hexanes) gave the desired tripeptide as a sticky white foam (148 mg,
1
75%): [α]24 +2.8 (c 0.92, CHCl3); H NMR (400 MHz, CDCl3) δ
D
11.49 (d, J = 5.9 Hz, 1H), 8.30 (m, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.59
(dd, J = 7.0, 4.5 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz,
2H), 6.35 − 6.27 (m, 1H), 5.67 (d, J = 7.6 Hz, 1H), 5.39−5.26 (m,
1H), 4.62−4.32 (m, 5H), 4.31−4.02 (m, 3H), 3.45−3.33 (m, 2H),
3.03−2.83 (m, 1H), 1.89−1.75 (m, 1H), 1.75−1.54 (m, 5H), 1.52−
1.37 (m, 33H), 1.18−1.06 (m, 3H), 0.96−0.83 (m, 6H). 13C NMR
(101 MHz, CDCl3, mixture of rotomers) δ 171.8, 170.9, 168.7, 163.7,
156.3, 156.2, 153.4, 144.0, 143.9, 141.4, 138.3, 127.8, 127.22, 127.18,
125.3, 120.1, 116.6, 83.2, 81.8, 79.4, 79.2, 67.3, 64.1, 52.4, 51.4, 49.1,
47.3, 41.8, 40.7, 38.8, 32.5, 29.0, 28.44, 28.42, 28.2, 28.09, 28.05, 25.2,
24.9, 22.7, 22.3, 14.7, 12.2, 11.9; HRMS (ESI-TOF) m/z [M + H]+
calcd for C50H73N6O10 917.53882, found 917.53804.
(S)-tert-Butyl 2-{(2R,3S,Z)-2-(tert-Butoxycarbonylamino)-4-
[(tert-butyldiphenylsilyloxy)methyl]-3-methylhex-4-enamido)-
4-methylpentanoate (25). A solution of 24 (260 mg, 0.508 mmol)
in 3.5 mL of MeCN was treated with HBTU (250 mg, 0.661 mmol),
HOBt (13.7 mg, 0.102 mmol), NEt3 (354 μL, 2.54 mmol), and
H-Leu-OtBu-HCl (136 mg, 0.609 mmol). After being stirred at rt for
20 h, the mixture was concentrated under reduced pressure. The
residue was diluted with EtOAc and washed with 1 M aq HCl followed
8973
dx.doi.org/10.1021/jo201727g|J. Org. Chem. 2011, 76, 8962−8976

The Journal of Organic Chemistry
Article
Butoxycarbonylamino)-4-[(tert-butyldiphenylsilyloxy)methyl]-
3-methylhex-4-enamido}-4-methylpentanoate (33). Prepared
from racemic 31 following the same procedure described for the
13a → 14/15 reaction. Careful flash chromatography over silica gel
The tripeptide described above (80.0 mg, 87.2 μmol) in 2 mL of
THF was treated with diethylamine (0.362 mL, 3.49 mmol) and
stirred for 5 h at rt. The mixture was evaporated under reduced
pressure. The crude was dissolved in 1.5 mL of CH2Cl2 and treated
with benzoyl chloride (20.0 μL, 0.174 mmol). After 1.5 h, the mixture
was concentrated. The crude was adsorbed onto silica gel and purified
by flash column chromatography over silica gel (50% EtOAc/hexanes
and then 10% MeOH/EtOAc) to give the benzoyl tripeptide as a
afforded the diastereomeric dipeptides in 76% combined yield.
1
Data for 32 (37%): [α]24 +0.3 (c 0.83, CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.81−7.65 (m, 4H), 7.48−7.33 (m, 6H), 6.58 (dd, J =
30.1, 7.6 Hz, 1H), 5.92 (dd, J = 19.7, 5.8 Hz, 1H), 5.49 (q, J = 6.7 Hz,
1H), 4.44 (td, J = 8.7, 5.6 Hz, 1H), 4.30−4.22 (m, 1H), 4.15 (t, J = 6.6
Hz, 1H), 4.05 (dd, J = 11.5, 4.7 Hz, 1H), 2.87 (m, 1H), 1.72− 1.49
(m, 2H), 1.44 (m, 13H), 1.38 (s, 9H), 1.12−1.04 (m, 12H), 0.92 (m,
6H); 13C NMR (101 MHz, CDCl3) δ 171.8, 171.0, 155.8, 138.8,
136.0, 135.8, 133.2, 133.0, 130.0, 129.9, 127.9, 127.8, 125.4, 81.5, 79.6,
61.1, 59.3, 51.5, 41.6, 40.2, 28.4, 28.1, 27.2, 24.9, 22.9, 22.0, 19.3, 16.9,
13.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H61N2O6Si
white foam (61.0 mg, 87%, two steps): [α]24 +6.8 (c 2.40, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 11.46 (bs, 1H), 8.30 (m, 1H), 8.07 (m,
1H), 7.81 (m, 2H), 7.50−7.35 (m, 3H), 7.19 (dd, J = 22.7, 8.0 Hz,
1H), 6.46 (d, J = 7.9 Hz, 1H), 5.43−5.24 (m, 1H), 5.12−4.93 (m,
0.5H), 4.86 (q, J = 7.0 Hz, 0.5H), 4.76 (d, J = 13.9 Hz, 1H), 4.58 (d,
J = 8.9 Hz, 1H), 4.38 (m, 1H), 4.32−4.17 (m, 1H), 3.46−3.32 (m,
2H), 2.95 (m, 1H), 2.00−1.76 (m, 2H), 1.73−1.55 (m, 4H), 1.54−
1.34 (m, 32H), 1.19−1.08 (m, 3H), 0.98−0.89 (m, 2H), 0.78 (d, J =
6.3 Hz, 2H), 0.66 (d, J = 6.4 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ
171.8, 171.7, 171.3, 171.0, 169.7, 168.7, 167.7, 167.5, 163.6, 163.7,
156.3, 156.2, 153.4, 153.3, 138.2, 137.8, 133.7, 133.6, 133.1, 132.0,
131.9, 130.1, 128.7, 128.6, 128.4, 127.4, 116.8, 116.0, 83.2, 83.0, 81.8,
81.5, 79.4, 79.2, 64.7, 64.3, 51.5, 51.4, 51.0, 49.3, 49.2, 41.4, 40.9, 40.6,
40.6, 38.9, 32.1, 32.0, 29.0, 28.4, 28.2, 28.1, 28.0, 25.2, 24.7, 23.0, 22.9,
22.8, 22.6, 22.1, 22.0, 14.7, 14.6, 12.2, 12.0; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C42H67N6O9 799.49696, found 799.49680.
The benzoylated tripeptide mentioned above (30.0 mg, 37.5 μmol)
was treated with 3 mL of a TFA/TES/CH2Cl2 solution (90:5:5) at rt
and stirred for 8.5 h. The mixture was diluted with EtOAc and
evaporated under reduced pressure. The dilution and evaporation were
repeated two more times. The crude was purified by semipreparative
RP-HPLC (20−60% MeCN/H2O linear gradient over 30 min,
retention time of 9.3 min) to afford 27 as a white solid (19.0 mg,
93%): [α]24D +18.1 (c 0.50, MeOH); 1H NMR (400 MHz, DMSO-d6)
δ 10.47 (s, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.22 (d, J = 8.9 Hz, 1H), 7.92
(m, 2H), 7.57−7.43 (m, 3H), 6.89 (bs, 2H), 5.18 (m, 1H), 5.10 (m,
1H), 4.61 (m, 1H), 4.11−3.92 (m, 3H), 3.07 (m, 1H), 2.97 (m, 1H),
2.86 (m, 1H), 1.75−1.28 (m, 12H), 1.03 (d, J = 6.7 Hz, 3H), 0.86 (d,
J = 6.5 Hz, 3H), 0.80 (d, J = 6.4 Hz, 3H); 13C NMR (101 MHz,
DMSO-d6) δ 176.9, 170.8, 168.5, 166.5, 157.5, 139.9, 133.8, 131.4,
128.3, 127.6, 113.2, 63.8, 52.4, 51.5, 49.1, 41.6, 40.4, 30.6, 28.3, 24.6,
23.2, 22.7, 21.7, 14.2, 12.3; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C28H43N6O5 543.32894, found 543.32673.
681.42990, found 681.43009.
1
Data for 33 (39%): [α]24 −11.0 (c 1.00 CHCl3); H NMR (400
D
MHz, CDCl3) δ 7.79−7.66 (m, 4H), 7.50−7.32 (m, 6H), 6.60 (d, J =
8.0 Hz, 1H), 5.92 (d, J = 6.4 Hz, 1H), 5.50 (m, 1H), 4.48 (td, J = 8.4,
5.9 Hz, 1H), 4.26 (d, J = 11.4 Hz, 1H), 4.13 (t, J = 7.2 Hz, 1H), 4.03
(d, J = 11.4 Hz, 1H), 2.88 (m, 1H), 1.67−1.48 (m, 2H), 1.42 (m,
13H), 1.36 (s, 9H), 1.11−1.00 (m, 12H), 0.97−0.84 (m, 6H); 13C
NMR (101 MHz, CDCl3) δ 171.9, 171.0, 156.0, 138.6, 136.1, 135.9,
133.4, 133.1, 130.1, 130.0, 128.0, 127.9, 125.9, 81.7, 79.6, 61.2, 59.2,
51.5, 42.2, 40.3, 28.5, 28.2, 27.3, 27.2, 24.9, 23.0, 22.4, 19.4, 16.8, 13.6;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C39H61N2O6Si 681.42990,
found 681.43060.
(S)-tert-Butyl 2-[(2R,3R,Z)-4-Ethylidene-3-methylpyrrolidine-
2-carboxamido]-4-methylpentanoate (34). Prepared from 32
following the same three-step procedure described for the 14 → 16
reaction.
Data for the primary alcohol intermediate (89%): [α]24 −11.3 (c
D
1
1.46, CHCl3); H NMR (400 MHz, CDCl3) δ 6.66 (d, J = 8.3 Hz,
1H), 6.01 (d, J = 8.6 Hz, 1H), 5.48 (q, J = 6.7 Hz, 1H), 4.43 (m, 1H),
4.35 (dd, J = 8.6, 5.5 Hz, 1H), 4.24 (dd, J = 31.4, 12.0 Hz, 1H), 4.14−
3.99 (m, 1H), 3.69 (m, 1H), 2.86 (m, 1H), 2.13 (bs, 1H), 1.70−1.51
(m, 5H), 1.50−1.36 (m, 19H), 1.06 (m, 3H), 0.90 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 173.0, 170.9, 156.2, 138.0, 127.6, 82.3, 80.0,
58.3, 57.9, 51.4, 43.4, 41.5, 28.5, 28.2, 25.1, 23.1, 21.9, 15.0, 13.5;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H43N2O6 443.31156,
found 443.31154.
Data for the allylic chloride intermediate (87%): [α]24 −41.9 (c
D
(Z)-3-[(tert-Butyldiphenylsilyloxy)methyl]pent-3-en-2-yl 2-
(tert-Butoxycarbonylamino)acetate (30). Prepared according to
the three-step procedure described for the 10a → 11a reaction (58%):
1H NMR (400 MHz, CDCl3) δ 7.73−7.62 (m, 4H), 7.45−7.32 (m,
6H), 5.80 (q, J = 6.7 Hz, 1H), 5.71 (q, J = 7.1 Hz, 1H), 4.90 (m, 1H),
4.21 (m, 1H), 4.11 (m, 1H), 3.83 (dd, J = 18.2, 5.8 Hz, 1H), 3.67 (dd,
J = 18.3, 5.2 Hz, 1H), 1.73 (dt, J = 7.1, 1.3 Hz, 3H), 1.42 (s, 9H), 1.33
(d, J = 6.8 Hz, 3H), 1.06 (m, 9H); 13C NMR (101 MHz, CDCl3) δ
169.7, 155.8, 137.1, 135.8, 135.7, 133.8, 133.7, 130.0, 129.9, 127.9,
127.8, 123.6, 80.1, 69.8, 64.2, 42.6, 28.5, 27.0, 19.5, 19.5, 13.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C29H42NO5Si 512.28268, found
512.28215.
1
1.92, CHCl3); H NMR (400 MHz, CDCl3) δ 6.38 (dd, J = 51.4, 7.3
Hz, 1H), 5.63 (q, J = 6.8 Hz, 1H), 5.30 (m, 1H), 4.43 (m, 1H), 4.17
(m, 3H), 2.88−2.68 (m, 1H), 1.76 (dd, J = 7.9, 7.3 Hz, 3H), 1.69−
1.49 (m, 3H), 1.48−1.36 (m, 19H), 1.05 (d, J = 7.0 Hz, 3H), 0.92 (m,
6H); 13C NMR (101 MHz, CDCl3) δ 171.8, 169.9, 155.5, 136.8,
129.7, 82.0, 80.0, 57.2, 51.7, 42.7, 42.0, 28.5, 28.2, 25.1, 23.0, 22.1,
15.4, 13.9; HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H42ClN2O5
461.27768, found 461.27766.
Data for pyrrolidine 34 (65%, two steps): [α]24 +17.8 (c 0.92,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.57 (d, J = 8.6 Hz, 1H), 5.24
(m, 1H), 4.47 (td, J = 9.0, 5.0 Hz, 1H), 3.64 (m, 2H), 3.24 (d, J = 7.5
Hz, 1H), 2.63 (m, 1H), 2.05 (bs, 1H), 1.72−1.49 (m, 5H), 1.46−1.40
(m, 10H), 1.19 (d, J = 6.8, 3H), 0.93 (m, 6H); 13C NMR (101 MHz,
CDCl3) δ 173.4, 172.3, 144.2, 114.5, 81.7, 68.6, 51.0, 48.1, 43.0, 42.0,
28.2, 28.2, 25.2, 23.1, 22.2, 18.0, 14.7; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C18H33N2O3 325.24857, found 325.24875.
(2S*,3S*,Z)-2-(tert-Butoxycarbonylamino)-4-[(tert-
butyldiphenylsilyloxy)methyl]-3-methylhex-4-enoic Acid
(31). Prepared from 30 following the same procedure described for
the 11a → 13a reaction (78%). Spectral data given for the mixture of
1
rotamers and diastereomers (>95:5 dr): H NMR (400 MHz, CDCl3)
(S)-2-{(2R,3R,Z)-1-[(S)-2-Benzamido-6-guanidinohexanoyl]-
4-ethylidene-3-methylpyrrolidine-2-carboxamido}-4-methyl-
pentanoic Acid (35). Prepared from 16 according the same three-
step procedure described for the 26 → 27 reaction.
δ 7.75−7.65 (m, 4H), 7.49−7.31 (m, 6H), 5.90 (d, J = 6.9 Hz, 1H),
5.53 (q, J = 6.7 Hz, 1H), 4.31 (t, J = 7.2 Hz, 1H), 4.20 (d, J = 11.7 Hz,
1H), 4.04 (d, J = 11.6 Hz, 1H), 2.88 (m, 1H), 1.43 (d, J = 7.5 Hz, 1H),
1.38 (m, 9H), 1.13 (d, J = 6.9 Hz, 3H), 1.10−1.03 (m, 9H); 13C NMR
(101 MHz, CDCl3) δ 176.8, 156.3, 138.1, 136.0, 135.9, 133.2, 133.0,
130.1, 130.0, 128.0, 127.7, 126.3, 80.1, 60.4, 58.9, 40.4, 28.6, 28.5, 27.2,
19.4, 17.4, 13.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C29H42NO5Si 512.28268, found 512.28213; HRMS (ESI-TOF) m/z
[M + Na]+ calcd for C29H41NO5SiNa 534.26462, found 534.26382.
(S)-tert-Butyl 2-{(2R,3R,Z)-2-(tert-Butoxycarbonylamino)-4-
[(tert-butyldiphenylsilyloxy)methyl]-3-methylhex-4-enamido}-
4-methylpentanoate (32) and (S)-tert-Butyl 2-{(2S,3S,Z)-2-(tert-
Data for the Fmoc-Har(Boc)2-Emp-Leu-OtBu intermediate (77%):
1
[α]24 +19.6 (c 0.67, CHCl3); H NMR (400 MHz, CDCl3) δ 11.49
D
(s, 1H), 8.32 (t, J = 4.2 Hz, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.57 (t, J =
7.3 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.29 (dd, J = 15.9, 8.4 Hz, 2H),
7.01 (d, J = 8.7 Hz, 1H), 5.70 (d, J = 7.5 Hz, 1H), 5.43 (m, 1H), 4.52−
4.29 (m, 5H), 4.29−4.15 (m, 3H), 3.42 (dd, J = 12.5, 6.8 Hz, 2H),
3.15 (m, 1H), 1.90−1.69 (m, 1H), 1.69−1.54 (m, 5H), 1.52−1.42 (m,
24H), 1.37 (s, 9H), 1.14 (d, J = 7.1 Hz, 3H), 0.9 (m, 6H); 13C NMR
8974
dx.doi.org/10.1021/jo201727g|J. Org. Chem. 2011, 76, 8962−8976

The Journal of Organic Chemistry
Article
(101 MHz, CDCl3) δ 172.0, 170.0, 163.7, 156.4, 156.3, 153.4, 143.9,
141.4, 139.1, 127.9, 127.3, 127.2, 125.3, 120.1, 118.2, 83.3, 81.6, 79.4,
77.5, 76.8, 67.4, 66.6, 52.7, 51.4, 47.8, 47.2, 41.7, 40.7, 40.6, 32.2, 29.1,
28.4, 28.2, 28.0, 24.9, 23.0, 22.1, 21.3, 14.8; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C50H73N6O10 917.53882, found 917.53662.
Data for the N-benzoyl tripeptide intermediate (79%): [α]24D +33.9
(c 0.42, CHCl3); 1H NMR (400 MHz, CDCl3) δ 11.47 (bs, 1H), 8.32
(m, 1H), 8.06 (m, 1H), 7.81 (m, 2H), 7.47 (m, 1H), 7.41 (q, J = 7.1
Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 6.9 Hz, 1H), 5.45 (m,
1H), 4.84 (q, J = 7.0 Hz, 1H), 4.51 (d, J = 14.4 Hz, 1H), 4.43 (td, J =
8.9, 5.1 Hz, 1H), 4.37 (d, J = 1.8 Hz, 1H), 4.30 (d, J = 14.4 Hz, 1H),
3.40 (m, 2H), 3.14 (m, 2H), 2.03−1.77 (m, 2H), 1.74−1.56 (m, 5H),
1.51−1.41 (m, 23H), 1.36 (s, 9H), 1.17 (d, J = 7.2 Hz, 3H), 0.82 (d,
J = 6.0 Hz, 3H), 0.69 (d, J = 6.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 172.1, 171.9, 169.9, 167.7, 163.7, 156.3, 153.4, 139.0, 133.4,
133.2, 132.0, 130.1, 128.6, 128.5, 127.4, 118.3, 83.3, 81.4, 79.4, 77.5,
76.8, 66.8, 51.9, 51.4, 48.0, 41.3, 41.2, 40.6, 31.8, 29.1, 28.4, 28.2, 28.0,
24.7, 23.1, 22.8, 21.9, 21.4, 14.9; HRMS (ESI-TOF) m/z [M + H]+
Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.4 Hz, 2H), 6.52 (d, J =
8.1 Hz, 1H), 5.65 (d, J = 8.7 Hz, 1H), 5.41 (m, 1H), 4.57 (td, J = 8.6,
4.7 Hz, 1H), 4.51−4.27 (m, 3H), 4.26−4.03 (m, 3H), 3.43 (dd, J =
13.5, 7.1 Hz, 2H), 3.03 (m, 1H), 1.88−1.55 (m, 8H), 1.48 (m, 32H),
1.19 (m, 3H), 0.97−0.80 (m, 6H); 13C NMR (101 MHz, CDCl3) δ
172.1, 172.1, 170.1, 163.8, 156.3, 156.3, 153.4, 144.0, 143.9, 141.4,
139.3, 127.8, 127.2, 125.3, 125.3, 120.1, 117.6, 83.2, 82.0, 79.3, 67.2,
67.1, 52.3, 51.6, 48.4, 47.3, 42.0, 40.7, 40.6, 32.8, 31.7, 29.0, 28.5, 28.2,
28.1, 28.0, 25.0, 23.0, 22.8, 22.7, 22.4, 21.5, 19.7, 14.8; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C50H73N6O10 917.53882, found
917.54052.
Data for the N-benzoyl tripeptide intermediate (85%): [α]24D −3.2
(c 1.75, CHCl3); 1H NMR (400 MHz, CDCl3) δ 11.47 (bs, 1H), 8.32
(d, J = 5.0 Hz, 1H), 8.07 (m, 1H), 7.80 (m, 2H), 7.59−7.32 (m, 5H),
7.25 (m, 1H), 6.55 (d, J = 8.2 Hz, 1H), 5.40 (m, 1H), 5.05 (td, J = 8.4,
4.8 Hz, 1H), 4.65 (dd, J = 23.8, 10.1 Hz, 1H), 4.46 (td, J = 8.4, 5.6 Hz,
1H), 4.24 (d, J = 14.1 Hz, 1H), 4.18 (d, J = 4.1 Hz, 1H), 3.41 (dd, J =
12.3, 6.8 Hz, 2H), 2.99 (m, 1H), 2.00−1.73 (m, 1H), 1.72−1.41 (m,
35H), 1.22−1.12 (m, 3H), 0.91 (m, 6H); 13C NMR (101 MHz,
CDCl3) δ 172.3, 172.2, 170.2, 167.3, 163.7, 156.2, 153.4, 139.3, 133.9,
133.2, 131.8, 128.6, 128.5, 128.4, 127.4, 127.3, 117.6, 83.1, 82.0, 79.3,
67.2, 51.6, 50.8, 48.6, 42.0, 40.8, 40.7, 32.6, 29.0, 28.4, 28.2, 28.1, 28.0,
25.0, 22.9, 22.8, 22.3, 19.6, 14.8; HRMS (ESI-TOF) m/z [M + H]+
calcd for C42H67N6O9 799.49696, found 799.49690.
1
Data for 35 (78%): [α]24 +22.4 (c 0.50, MeOH); H NMR (400
D
MHz, DMSO-d6) δ 10.19 (s, 1H), 8.66 (d, J = 7.1 Hz, 1H), 8.25 (d,
J = 9.0 Hz, 1H), 7.90 (m, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 6.99 (bs,
1H), 5.26 (dd, J = 13.6, 10.9 Hz, 1H), 4.70 (d, J = 2.0 Hz, 1H), 4.45
(m, 1H), 4.17 (d, J = 16.0 Hz, 1H), 4.01 (dt, J = 9.9, 3.8 Hz, 1H), 3.89
(d, J = 16.9 Hz, 1H), 3.06 (m, 1H), 2.93 (m, 1H), 2.63 (q, J = 6.6 Hz,
1H), 1.75−1.27 (m, 12H), 1.17 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.1
Hz, 3H), 0.80 (d, J = 6.0 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ
177.0, 171.3, 170.6, 166.4, 157.6, 140.4, 133.8, 131.3, 128.2, 127.6,
115.1, 66.6, 52.3, 51.5, 48.0, 45.2, 41.3, 40.7, 30.1, 28.1, 24.9, 23.3,
21.6, 21.3, 14.4; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C28H43N6O5 543.32894, found 543.32675.
calcd for C42H67N6O9 799.49696, found 799.49590.
1
Data for 37 (84%, two steps): [α]24 −31.4 (c 0.67, MeOH); H
D
NMR (400 MHz, DMSO-d6) δ 10.37 (bs, 1H), 8.59 (d, J = 6.7 Hz,
1H), 8.21 (s, 0.5H), 7.88 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H),
7.45 (t, J = 7.5 Hz, 2H), 7.04 (d, J = 6.7 Hz, 2.5H), 5.35 (t, J = 16.2
Hz, 1H), 4.88−4.68 (m, 2H), 4.31 (d, J = 14.4 Hz, 1H), 3.96 (d, J =
3.1 Hz, 1H), 3.84 (q, J = 6.5 Hz, 1H), 3.18 (m, 1H), 3.03 (m, 1H),
2.73 (m, 1H), 2.02 (m, 1H), 1.79−1.24 (m, 12H), 1.09 (d, J = 6.9 Hz,
3H), 0.82 (dd, J = 6.4, 3.9 Hz, 6H); 13C NMR (101 MHz, DMSO-d6)
δ 175.7, 171.5, 168.8, 166.1, 157.1, 139.9, 133.7, 131.4, 128.2, 127.5,
116.4, 67.6, 52.3, 51.1, 47.3, 42.6, 42.0, 41.0, 40.2, 39.9, 39.7, 39.5,
39.3, 39.1, 38.9, 31.5, 28.9, 24.4, 23.1, 22.9, 20.1, 14.0; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C28H43N6O5 543.32894, found
543.32763.
(S)-tert-Butyl 2-[(2S,3S,Z)-4-Ethylidene-3-methylpyrrolidine-
2-carboxamido]-4-methylpentanoate (36). Prepared from 33
following the same three-step procedure described for the 14 → 16
reaction.
Data for the primary alcohol intermediate (92%): [α]24 −11.3 (c
D
1
1.21, CHCl3); H NMR (400 MHz, CDCl3) δ 6.78 (d, J = 7.8 Hz,
1H), 5.62 (d, J = 8.3 Hz, 1H), 5.48 (q, J = 6.8 Hz, 1H), 4.39 (td, J =
8.3, 5.9 Hz, 1H), 4.26 (m, 2H), 4.18 (m, 1H), 3.70 (t, J = 5.1 Hz, 1H),
2.60 (m, 1H), 1.66 (d, J = 6.9 Hz, 3H), 1.64−1.50 (m, 1H), 1.47 (m,
Cell Growth Inhibition Assay. Compounds 1, 27, 35, and 38
were evaluated using a CellTiter-Blue cell viability assay with doxoru-
bicin as a positive control. For the assays, 0.8−3 × 103 HCT-116 cells
in a 24 μL volume were plated in 384-well plates and incubated
overnight at 37 °C in 5% CO2. The next day, the compounds were
diluted in media, and 6 μL of these dilutions was added to the
appropriate wells. Four replicate wells were used for each compound
concentration, and four additional negative control wells received a
diluent control without compounds. Compound dilutions consisted of
2-fold dilutions from a maximum final concentration of 100 μM. The
cells were incubated with compounds for 72 h. At this time, 5 μL of
CellTiter-Blue reagent (Promega Corp., Madison, WI) was added to
each well. Cell viability was assessed by the ability of the remaining
viable cells to bioreduce resazurin to resorufin. Resazurin is dark blue
in color and has little intrinsic fluorescence until it is reduced to
resorufin (excitation at 579 nm and emission at 584 nm). The change
in fluoresence was measured with a Synergy 4 microplate reader (Bio-
Tek Instruments, Inc., Winooski, VT). The fluorescence data were
then transferred to a spreadsheet program to calculate the percent
viability relative to the four replicate cell wells that did not receive
compounds. The positive control, doxorubicin, exhibited an IC50 of
268 nM. Compunds 1, 27, 35, and 38 did not inhibit cell viability
more than 15% at the largest dose tested (100 μM).
1H), 1.44−1.34 (m, 20H), 1.06 (d, J = 7.0 Hz, 3H), 0.89 (m, 6H); 13
C
NMR (101 MHz, CDCl3) δ 171.9, 170.6, 156.2, 138.5, 126.7, 82.0,
80.1, 58.8, 57.8, 51.8, 44.0, 42.0, 28.5, 28.2, 25.0, 22.9, 22.3, 14.5, 13.6;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H43N2O6 443.31156,
found 443.31124.
Data for the allylic chloride intermediate (94%): [α]24 +26.8 (c
D
1
1.67, CHCl3); H NMR (400 MHz, CDCl3) δ 6.30 (d, J = 7.8 Hz,
1H), 5.72 (q, J = 6.9 Hz, 1H), 5.33 (d, J = 7.3 Hz, 1H), 4.42 (td, J =
8.5, 5.5 Hz, 1H), 4.29−4.15 (m, 2H), 4.10 (d, J = 11.3 Hz, 1H), 2.72
(m, 1H), 1.79 (dd, J = 7.3, 3.5 Hz, 3H), 1.68−1.51 (m, 2H), 1.50−
1.37 (m, 19H), 1.07 (d, J = 7.0 Hz, 3H), 0.91 (m, 6H); 13C NMR
(101 MHz, CDCl3) δ 171.8, 170.0, 155.6, 136.5, 130.4, 81.9, 79.9,
57.1, 51.8, 43.1, 42.0, 41.8, 28.5, 28.2, 25.0, 23.0, 22.3, 15.3, 13.9;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C23H42ClN2O5
461.27768, found 461.27776.
Data for pyrrolidine 36 (64%, two steps): [α]24 −39.4 (c 0.83,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.6 Hz, 1H), 5.26
(m, 1H), 4.47 (td, J = 8.9, 5.0 Hz, 1H), 3.64 (m, 2H), 3.25 (d, J = 7.5
Hz, 1H), 2.56 (m, 1H), 2.37−2.17 (m, 1H), 1.68−1.49 (m, 5H), 1.45
(m, 10H), 1.21 (m, 3H), 0.92 (m, 6H); 13C NMR (101 MHz, CDCl3)
δ 173.4, 172.5, 143.9, 114.8, 81.9, 68.5, 51.0, 47.9, 43.6, 42.0, 28.2,
28.1, 25.2, 23.1, 22.2, 17.9, 14.6; HRMS (ESI-TOF) m/z [M + H]+
calcd for C18H33N2O3 325.24857, found 325.24865.
ASSOCIATED CONTENT
■
(S)-2-{(2S,3S,Z)-1-[(S)-2-Benzamido-6-guanidinohexanoyl]-4-
ethylidene-3-methylpyrrolidine-2-carboxamido}-4-methyl-
pentanoic Acid (37). Prepared from 37 according the same three-
step procedure described for the 26 → 27 reaction.
Data for the Fmoc-Har(Boc)2-Emp-Leu-OtBu intermediate (77%):
[α]24D −8.5 (c 0.50, CHCl3); 1H NMR (400 MHz, CDCl3) δ 11.50 (s,
1H), 8.34 (t, J = 4.9 Hz, 1H), 7.77 (d, J = 7.5 Hz, 2H), 7.61 (d, J = 7.4
S
* Supporting Information
1H and 13C NMR spectra of all new compounds, X-ray
structure data for 1, and NMR comparison table for natural
lucentamycin A and synthetic isomers. This material is available
free of charge via the Internet at http://pubs.acs.org.
8975
dx.doi.org/10.1021/jo201727g|J. Org. Chem. 2011, 76, 8962−8976

The Journal of Organic Chemistry
Article
(17) Senapati, B. K.; Hwang, G.-S.; Lee, S.; Ryu, D. H. Angew. Chem.,
Int. Ed. 2009, 48, 4398.
(18) The described synthesis is directly applicable to the preparation
of enantiopure N-Boc amino acids. Chiral Baylis−Hillman adducts and
esters corresponding to 9 and 11 are readily accessible as described in
ref 17.
(19) For previous examples of one-pot chlorination with
methanesulfonyl chloride, see: (a) Artman, G. D.; Grubbs, A. W.;
Williams, R. M. J. Am. Chem. Soc. 2007, 129, 6336. (b) Li, F.; Castle, S.
L. Org. Lett. 2007, 9, 4033.
(20) Daniels, R. N.; Melancon, B. J.; Wang, E. A.; Crews, B. C.;
Marnett, L. J.; Sulikowski, G. A.; Lindsley, C. W. J. Org. Chem. 2009,
74, 8852.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: juan.delvalle@moffitt.org.
ACKNOWLEDGMENTS
■
We thank Prof. William Fenical (University of California, San
Diego, La Jolla, CA) for providing original NMR spectra for
natural lucentamycin A. We thank Dr. Eileen Duesler
(University of New Mexico, Albuquerque, NM) for conducting
small molecule X-ray diffraction, and Dr. Chris Cubitt (Moffitt
Clinical Trials Core Facility, Tampa, FL) for conducting cell
viability assays. This work was supported by a grant from the
Bankhead-Coley Biomedical Research Program, Florida
Department of Health (1BN03).
(21) Cha, J. H.; Pae, A. M.; Choi, K. I. I.; Cho, Y. S.; Koh, H. Y.; Lee,
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