Diverse synthesis of marine cyclic depsipeptide lagunamide A and its analogues

Article abstract of DOI:10.1021/jo401687s

The asymmetric total synthesis of lagunamide A (3.0%, 20 steps longest linear sequence) and its five analogues, including the structure dehydrated at the C37 position, are detailed in this report. The key feature in this diverse synthesis includes the ela

Full text of DOI:10.1021/jo401687s

Article
pubs.acs.org/joc
Diverse Synthesis of Marine Cyclic Depsipeptide Lagunamide A and
Its Analogues
Wei Huang,† Rong-Guo Ren,† Han-Qing Dong,‡,§ Bang-Guo Wei,*,† and Guo-Qiang Lin†,‡
†Department of Chemistry and Institutes of Biomedical Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: The asymmetric total synthesis of lagunamide A (3.0%, 20 steps longest
linear sequence) and its five analogues, including the structure dehydrated at the C37
position, are detailed in this report. The key feature in this diverse synthesis includes the
elaboration of four consecutive chiral centers at C37−40 and the final macrocyclization.
Starting from chiral aldehyde 10, we synthesized both 1,3-anti and 1,3-syn homoallylic
alcohols 20a and 20b through asymmetric aldol condensation and stereoselective
allylation. The following esterification to introduce the L-N-Me-Ala unit resulted in
significant epimerization. This problem was finally overcome by coupling the alcohols
with the corresponding acid chloride of the L-alanine derivative. The key α,β-unsaturated
carboxylic acid unit was produced by cross-metathesis (CM) of methacrylaldehyde and
related olefins. Interestingly, we found that the C7 configuration dramatically affected the
ring closure. Natural lagunamide A (1a), its 39-epimer (1c), and its 2-epimer (1d) were
obtained through macrolactamization between alanine and isoleucine moieties.
INTRODUCTION
■
Cyanobacteria, predominantly with structural skeletons as
modified peptides, depsipeptides, polyketides, and peptide−
polyketide hybrids,1 have emerged as a valuable source of
marine natural products with remarkable biological activities.2
As a class of promising compounds in drug discovery, most of
these secondary metabolites display a variety of physiological
activities, including antimicrobial, antimalarial, cytotoxic, and
neurotoxic properties.2b,3 Although a few of them have been
advanced to phase-II clinical trials for treating cancers,4 most
cyanobacterial metabolites have not been well-studied and thus
require further investigation of either their structural
modifications or their modes of action. In the past decade,
dolastatin 10,5a,b apratoxins,5c palau’amide,5d aurilide,5e,f
kulokekahilide,5g,h and largazole5i,j have been applied or
considered for further clinical development as anticancer
drugs because of their potent cytotoxic activities.
Lagunamides A−C (1−3) (Figure 1) were isolated from the
marine cyanobacterium Lyngbya majuscula collected in Pulau
Hantu Beser, Singapore.6 These cyclic depsipeptides exhibit
potent cytotoxic activity against P388 murine leukemia cell
lines (IC50 = 6.4, 20.5, and 24.4 nM, respectively) and selective
Figure 1. Structures of lagunamides A−C.
2012. Its high efficacy for P388 murine leukemia cell lines and
intriguing structure prompted us to develop a general synthetic
approach for a series of lagunamides and to study their
structure−activity relationship. As one part of our continuous
interest in pursuing some diverse syntheses of piperidine
growth inhibitory activities against a panel of other cancer cell
lines, including A549, PC3, HCT8, and SK-OV3 (IC50 = 1.6−
3.8 nM).1 6 In addition, they show moderate antiswarming
h,
activity against Pseudomonas aeruginosa PA10.6 The structure of
lagunamide A was originally assigned on the basis of extensive
NMR studies and LC−MS techniques,6a but the absolute
configurations of the two chiral centers at C7 and C39 were
revised by Dai et al.7 after the asymmetric total synthesis in
Received: August 8, 2013
© XXXX American Chemical Society
A
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Scheme 1. Retrosynthetic Analysis of Lagunamide A (1a)
alkaloids,8 ceramides,9 and depsipeptides,10 herein we present a
general method for the diverse synthesis of lagunamide A (1a).
Scheme 2. Preparation of Homoallylic Alcohols 16a and
16b
a
RESULTS AND DISCUSSION
■
Our synthetic strategy for the diverse synthesis of lagunamide A
(1a) is illustrated in Scheme 1, with the stereoselective
synthesis of non-peptide fragment 6 and the effective
macrocyclization as our main focus in constructing our target
molecule. As we aimed to achieve a convenient method for the
diverse synthesis of 1a and to study further the structure−
activity relationship, we proposed an RCM11 reaction to form
the double bond between C34 and C35 and certainly kept
macrolactamization as an alternative approach for ring closure.
The key fragment 6 could be prepared from the 1,3-diol moiety
8 and alanine derivative 7, in which the C2 chirality should be
closely monitored in the esterification step.12
Our strategy to construct the 1,3-diol moiety 8 was through
an asymmetric Paterson anti-aldol13 reaction of 10 and
subsequent allylation of 15a, as outlined in Scheme 2. The
trans-enolate of ketone 11, preformed by treatment with (c-
hex)2BCl in the presence of Me2NEt, reacted with aldehyde 10,
prepared by Swern oxidation14 of commercially available (S)-2-
methylbutan-1-ol, to produce the desired anti product 12 with
high diastereoselectivity (dr > 99:1) in 74% yield. After alcohol
12 was protected as its tert-butyldimethylsilyl (TBS) ether 13 in
82% yield, ketone 13 was reduced by NaBH4, and subsequent
hydrolysis of the benzoate moiety afforded 1,2-diol 14 as a
mixture of two diastereomers in 56% overall yield. The key
aldehyde 15a was generated by oxidative cleavage of 14
(NaIO4, MeOH) and then subjected to asymmetric allylation
using allylmagnesium chloride. Unfortunately, the diastereose-
lectivities in forming the homoallylic alcohols 16a and 16b were
quite low in both cases, slightly favoring the formation of 16b
(16a:16b = 39:61). Attempts at further improvement using
Lewis acids turned out to be unhelpful, probably because of the
unfavorable orientation of the C3 substituent in the transition
state.
a
Reagents and conditions: (a) (COCl)2, DMSO, TEA, −78 °C. (b)
(c-hex)2BCl, Me2NEt, −78 to −26 °C, 74% (two steps), dr > 99:1. (c)
TBSOTf, 2,6-lutidine, 0 °C, 82%. (d) (1) NaBH4, MeOH/THF, 0 °C;
(2) K2CO3, MeOH, rt, 56% (two steps). (e) NaIO4, MeOH/H2O (2/
1, v/v), rt, 84%. (f) AllylMgCl, THF, −78 °C, 84% (dr 39:61). (g)
AllylMgCl, ZnCl2, THF, −78 °C, 59% (dr 40:60).
desired syn product 17 with high diastereoselectivity (dr >
99:1) in 93% yield. Protection of the hydroxy group (TBSOTf,
2,6-lutidine) and subsequent reductive cleavage of the
auxiliary16 (LiBH4, MeOH) produced alcohol 19, which was
subjected to Swern oxidation [DMSO, (COCl)2] to generate
the key aldehyde 15b in 87% overall yield over three steps. The
allylation of aldehyde 15b with allylmagnesium chloride is
summarized in Table 1. The reaction in the absence of Lewis
acid produced a mixture of two diastereomers with dr = 11:89,
albeit in favor of the undesired isomer 20b (Table 1, entry 1).
Because of the steric TBS protective group at the C3 position,
most Lewis acids did not show any positive effect, although
AlMe2Cl and InCl3 slightly improved the formation of the
desired isomer 20a (Table 1, entries, 2−11). To our delight,
zinc chloride could reverse the selectivity, giving the desired
product with dr = 90:10 (Table 1, entry 12). The two
diastereomers 20a and 20b could be separated by silica gel
chromatography, and their stereochemistries were assigned
through chemical transformations to give acetonides 22a and
At the time we initiated our synthetic efforts, we had the
originally proposed structure 1 as our target molecule. In this
case, an alternative aldehyde 15b was required as a properly
assembled substrate for the asymmetric allylation. As shown in
Scheme 3, the aldol condensation with the above aldehyde 10,
through Evans’ chiral oxazolidinone auxiliary,15 afforded the
B
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shifts of the ketal methyl groups in the 13C NMR spectra.17 For
the syn-1,3-diol, the full chair conformation of 22b resulted in
significantly different chemical shifts for the two methyl groups
(i.e., 19.5 and 30.0 ppm for the equatorial and axial methyls,
respectively). On the other hand, the anti isomer adopted a
twisted chair conformation, having the two methyl groups in
similar orientations. The close chemical shifts of 25.0 and 25.4
ppm in compound 22a clearly demonstrated the anti-1,3-diol
structure in compounds 20a and 21a.
Scheme 3. Preparation of Homoallylic Alcohols 20a and
20b
a
As for the reactions of aldehydes 15a and 15b with
allylmagnesium chloride, the difference in diastereoselectivities
could be explained by the transition states shown in Figure 2. In
a
Reagents and conditions: (a) (R)-4-benzyl-3-propionyloxazolidin-2-
one, Bu2BOTf, TEA, CH2Cl2, −78 °C, 93%; (b) TBSOTf, 2,6-lutidine,
0 °C, 95%; (c) LiBH4, MeOH/THF, 0 °C; (d) (COCl)2, DMSO,
TEA, −78 °C, 92% (two steps); (e) AllylMgCl, THF, −78 °C, 11%
(20a), 81% (20b); (f) 40% aqueous HF, CH3CN, rt, 95% (21a), 92%
(21b); (g) TsOH, 2,2-dimethoxypropane, acetone, rt, 89% (22a), 92%
(22b).
Table 1. Allylation of Aldehyde 15b
Figure 2. Stereochemistry for the allylation of aldehydes 15a and 15b.
c
d
the absence of Lewis acid, the stereochemistry was controlled
by the Felkin−Anh model.20 In the reaction with 15b, both 2-
methyl and 3-OTBS groups in the transition state C blocked
the same side and allowed the allyl group to favorably attack
from the other side, affording 1,3-syn diol 20b as the
predominant product. In transition state A for the reaction
with 15a, the 2-methyl and 3-OTBS groups stayed at either side
for nucleophilic attack. As a result, the reaction produced a
mixture of two stereoisomers 16a and 16b, with slight favor for
16b, which was formed through the attack from the less
hindered 3-OTBS side in model A. When the reaction was
conducted in the presence of the strong Lewis acid ZnCl2, the
zinc cation could coordinate with both the carbonyl and OTBS
groups, forming a six-membered-ring transition state.18 In the
reaction with 15b, one side was blocked by the 2-methyl and
TBS groups, and thus, the nucleophilic attack preferred to take
place from the less hindered side in transition state D, forming
the 1,3-anti-diol 20a. On the other hand, in the case of 15a,
either side presented some steric hindrance for allylation,
leading to low diastereoselectivity in affording a mixture of 16a
and 16b. Our observation of the stereochemistry in this
allylation process agreed well with the theory of semiempirical
calculations (PM3) by Evans.19
entry
reagent
Lewis acid
yield (%)
20a:20b
a
1
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
AllylMgCl
−
92
87
85
89
90
82
85
78
88
89
90
90
11:89
16:84
17:83
14:86
25:75
33:67
14:86
20:80
17:83
14:86
15:85
90:10
b
2
Et2BOMe
b
3
CeCl3
b
4
Cu(OTf)2
AlMe2Cl
InCl3
b
5
b
6
b
7
SnCl2
b
8
NiCl2(PPh3)2
LiBr
b
9
b
10
Pd(OAc)2
BF3·Et2O
ZnCl2
b
11
b
12
a
b
AllylMgCl (1.5 equiv), THF, −78 °C. Lewis acid (2.5 equiv),
AllylMgCl (1.5 equiv), THF, −78 °C. Combined yields. Determined
c
d
by isolated products.
22b. Both isomers 20a and 20b were treated with a 40%
aqueous solution of hydrogen fluoride (40% HF) to remove the
TBS group, and the resulting 1,3-diols were protected with 2,2-
dimethoxypropane in the presence of a catalytic amount of 4-
methylbenzenesulfonic acid (cat. TsOH) to provide acetonides
22a and 22b, respectively. The stereochemistries of the syn- and
anti-1,3-diols were determined on the basis of the chemical
The enantioselective synthesis of anti-1,3-diol 21a estab-
lished all four stereocenters for the originally proposed
C
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a
Scheme 4. Preparation of 25a
a
Reagents and conditions: (a) TBSOTf, 2,6-lutidine, −78 °C, 76%; (b) Dess−Martin periodinane, CH2Cl2, rt, 92%; (c) Et3BHLi, THF, −78 °C,
94%.
structure of lagunamide A (1). However, we needed to invert
one hydroxyl group to achieve the key syn-1,3-diol intermediate
8 (P = TBS) for the total synthesis of the revised structure of
lagunamide A (1a). As shown in Scheme 4, silylation with tert-
butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) in the
presence of 2,6-lutidine afforded compound 23a with high
regioselectivity (dr > 99:1) in 76% yield. Dess−Martin
oxidation21 and subsequent reduction with lithium triethylbor-
ohydride (Et3BHLi) gave the desired steroisomer 25a with high
stereoselectivity (dr > 99:1) in 86% overall yield.
The formation of intermediate 27aa involved the coupling of
25a and alanine moiety 26. In spite of many effective methods
for such esterification, the classical method with L-N-Me-Fmoc-
Ala-OH under Yamaguchi conditions22 resulted in a mixture of
diastereomers 27aa and 27ab (dr = 24:76) in 92% combined
yield (Table 2, entry 1). It is worth mentioning that the major
product was the wrong isomer with epimerization at the
position α to the carbonyl group. Interestingly, when D-N-Me-
Fmoc-Ala-OH was used for the coupling, almost no
epimerization was observed, and the desired diastereomer
27ab was generated with high diastereoselectivity (dr = 98:2) in
89% yield (Table 2, entry 2). The above results suggested that
the epimerization likely occurred after the formation of the
ester bond. The replacement of N-Fmoc with N-Boc protection
for the L-alanine derivative in the esterification resulted in no
improvement under the same coupling conditions (Table 2,
entry 3). When other coupling reagents were used, 2-methyl-6-
nitrobenzoic anhydride (MNBA)23 and EDC, showed similar
results and 2-chloro-1-methylpyridinium iodide24 afforded no
desired product (Table 2, entries 4−6). As the base DMAP
might be the cause for the epimerization, we attempted the
coupling using the acid chloride N-Me-Fmoc-Ala-Cl.7,12 It
clearly showed that the reaction proceeded with less
epimerization when less DMAP was employed in the
esterification (Table 2, entries 7 and 8). Finally, the desired
optically pure ester 27aa was obtained through coupling with L-
N-Me-Fmoc-Ala-Cl in the absence of DMAP (Table 2, entry
9).
Next, we turned our attention to the preparation of the
peptide unit of lagunamide A (1a) (Scheme 5). Removal of the
a
Scheme 5. Preparation of the Peptide Fragment
Table 2. Esterification of Alcohol 25a.
26
i
j
entry
R1
R2
X
P
27aa:27ab
yield (%)
a
1
Me
H
H
Me
H
H
H
H
H
H
H
OH
OH
OH
OH
OH
OH
Cl
Fmoc
Fmoc
Boc
24:76
2:98
92
89
73
69
NR
48
57
56
55
a
2
b
3
Me
Me
Me
Me
Me
Me
Me
24:76
23:77
−
33:67
58:42
70:30
>99:1
c
a
4
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Fmoc
Reagents and conditions: (a) (1) TFA/CH2Cl2, 0 °C to rt; (2) D-
d
Boc-N-Me-Phe-OH, HATU, DIPEA, CH2Cl2, 0 °C to rt, 89% (two
steps). (b) (1) TFA/CH2Cl2, 0 °C to rt; (2) L-Boc-Ala-OH, HATU,
DIPEA, CH2Cl2, 0 °C to rt, 68% (two steps). (c) (1) TFA/CH2Cl2, 0
°C to rt; (2) (2R,3S)-2-hydroxy-3-methylpentanoic acid, HOBt, EDC,
DMF, −15 °C to rt, 56% (two steps). (d) Methacrylic acid,
Cl3C6H2COCl, TEA, toluene, 87%. (e) Pd(PPh3)4, PhNHMe, THF,
95%.
5
e
6
f
7
g
8
Cl
h
9
Cl
a
Cl3C6H2COCl (1.2 equiv), acid (1.2 equiv), TEA (1.5 equiv), DMAP
b
(2.0 equiv), rt, 30 min. (1) Conditions in footnote a; (2) TMSOTf,
2,6-lutidine, DCM; (3) FmocOsu, DIPEA, DCM. MNBA (1.2 equiv),
acid (2 equiv), TEA (3 equiv), DMAP (0.2 equiv), rt, 30 min. 2-
Chloro-1-methylpyridinium iodide (2.2 equiv), acid (2 equiv), DIPEA
(5 equiv), DCM reflux. EDCI (2 equiv), acid (2 equiv), TEA (2
equiv), DMAP (1 equiv) DCM, rt, 12 h. Acid chloride (5.0 equiv),
DIPEA (5.5 equiv), DMAP (0.5 equiv), DCM, −15 °C, 5 h. Acid
chloride (5.0 equiv), colidine (10 equiv), DMAP (0.2 equiv), toluene,
c
Boc group in 28 with TFA and subsequent condensation with
D-Boc-N-Me-Phe-OH in the presence of HATU/DIPEA
afforded dipeptide 29 in 89% yield. Tripeptide 30 was obtained
in 68% yield in a similar sequence. Treatment of compound 30
with TFA and subsequent coupling with (2R,3S)-2-hydroxy-3-
methylpentanoic acid in the presence of EDC/HOBt produced
a 56% yield of 31, which was subjected to esterification with
methacrylic acid under Yamaguchi conditions to generate 32 in
87% yield. Removal of the allylic group gave free carboxylic acid
d
e
f
g
h
60 °C, 8 h. Acid chloride (2.5 equiv), DIPEA (5 equiv), DCM, reflux,
8 h. Determined by HPLC of the crude products. Combined yields of
27aa and 27ab.
i
j
D
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a
33, which could be used in the following condensation without
further purification.
Scheme 7. Macrolactamization Strategy
With the peptide unit 33 in hand, we started to evaluate our
RCM strategy for macrocyclization using the readily available
intermediate 20a, the correct stereoisomer for the originally
proposed structure of lagunamide A (1) (Scheme 6). The
a
Scheme 6. Preparation of RCM Precursor 38
a
Reagents and conditions: (a) TrocCl, DMAP (cat.), pyridine,
CH2Cl2, 96%. (b) 40% aqueous HF, CH3CN, 95%. (c) L-N-Me-
Fmoc-Cl, DIPEA, CH2Cl2, reflux, 61%. (d) (1) Et2NH/CH3CN, rt;
(2) L-Fmoc-aIle-OH, HATU, DIPEA, CH2Cl2, 0 °C to rt, 84% (two
steps). (e) (1) Et2NH/CH3CN, rt; (2) 33, HATU, DIPEA, CH2Cl2, 0
°C to rt, 73% (two steps). (f) Grubbs 2nd, CH2Cl2 (1 mM) at reflux
or toluene (1 mM) at 60 °C.
a
Reagents and conditions: (a) (1) Et2NH/CH3CN, rt; (2) Boc2O,
TEA, CH2Cl2, rt, 75% (two steps); (b) methacrylaldehyde, Grubbs
2nd, CH2Cl2, reflux, E:Z > 99:1, 81% for 41, 80% for 47; (c) NaClO2,
NaH2PO4, t-BuOH, 2-methylbut-2-ene, rt, 93% for 42, 87% for 48;
(d) 31, MNBA, DMAP, CH2Cl2, rt, 66% for 43, 60% for 49; (e) (1)
TFA/CH2Cl2, rt; (2) L-Boc-aIle-OH, HATU, DIPEA, CH2Cl2, 0 °C ∼
rt, 82% for 44 (two steps); (f) (1) Et2NH/CH3CN, rt; (2) L-Boc-aIle-
OH, HATU, DIPEA, CH2Cl2, 0 °C ∼ rt, 76% for 50 (two steps); (g)
(1) Pd(PPh3)4, PhNHMe, THF, rt; (2) TFA/CH2Cl2, 0 °C∼ rt; (3)
HATU, DIPEA, CH2Cl2 (1 mM), rt, 22% for 45, 30% for 1 (three
steps).
hydroxyl group of 20a could be protected by 2,2,2-
trichloroethyl carbonochloridate (TrocCl) in the presence of
pyridine, and subsequent removal of the silyl protecting group
with a solution of 40% hydrogen fluoride produced secondary
alcohol 35 in 91% overall yield. The N-Me-Fmoc-Ala moiety
was introduced through our optimized conditions using L-N-
Me-Fmoc-Ala-Cl to give ester 36 with high diastereoselectivity
(dr > 99:1) in 61% yield. Removal of the Fmoc protecting
group with Et2NH/CH3CN and subsequent condensation with
N-Fmoc-aIle-OH in the presence of HATU/DIPEA produced
37 in 84% overall yield. Finally, the precursor for the RCM
reaction, 38, was obtained after removal of the Fmoc protecting
group in 37 and subsequent coupling with carboxylic acid 33 in
the presence of HATU/DIPEA. Disappointingly, the RCM
reaction of 38 using the Grubbs second-generation catalyst
turned out to be unsuccessful. Although various conditions
(different solvents and temperature) were screened, no desired
cyclization product 39 was obtained.
easily converted from 36 by deprotection of the Fmoc group
(Et2NH/CH3CN) and Boc protection (Boc2O, TEA) in 75%
overall yield. Pinnick oxidation25 of aldehyde 41 generated
carboxylic acid 42, which was coupled with compound 31 using
MNBA/DMAP to give 43 in 66% yield. Removal of the Boc
protecting group in compound 43 and subsequent reaction
with L-Boc-aIle-OH in the presence of HATU/DIPEA
produced 44 in 82% overall yield. Sequential cleavage of the
allyl ester using Pd(PPh3)4/N-methylaniline and removal of the
Boc protecting group with TFA afforded the cyclization
precursor, which was subjected to macrolactamization (1 mM
in CH2Cl2) without further purification. Delightfully, the
cyclization proceeded smoothly under HATU/DIEA con-
ditions, but the elimination of OTroc was observed, giving
An alternative strategy using macrolactamization by for-
mation of a peptide bond between C11 and C6 is shown in
Scheme 7. Cross-metathesis (CM) of terminal olefin 36 with
methacrylaldehyde proceeded smoothly in the presence of the
Grubbs second-generation catalyst, giving the desired product
(E/Z > 99:1) in 80% yield. For practical reasons, the N-Fmoc
protection in 36 was replaced by N-Boc. Compound 40 was
E
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a
diene 45 in 22% yield over three steps. The structure of 45 was
unambiguously assigned by NMR spectroscopic data of the
pure sample from preparative HPLC.
Scheme 8. Synthesis of 1b
As the Troc protecting group of the hydroxyl, an ester
moiety, was easily eliminated under the basic conditions for the
macrolactamization, we considered using silyl protection (TBS)
of the hydroxyl group at the C37 position (Scheme 7). Starting
from compound 46, prepared by esterification of 23a and L-N-
Me-Fmoc-Ala-Cl under our optimized conditions, the key
intermediate 50 was prepared in 32% overall yield through
similar operations. Cleavage of the allyl ester using Pd(PPh3)4/
N-methylaniline and subsequent removal of the Boc protecting
group with TFA generated the cyclization precursor, in which
the TBS group was also removed to give a free OH at C37. The
final macrolactamization (1 mM in CH2Cl2) was performed
under HATU/DIEA conditions, successfully yielding the
desired product 7,39-epi-lagunamide A, that is, the originally
proposed structure for natural lagunamide A (1), in 30% yield
over three steps. The crude 7,39-epi-lagunamide A (1) was
further purified by preparative HPLC, and the NMR
spectroscopic data and optical rotation were consistent with
the literature values7 {[α]D25 −32.9 (c 0.2, MeOH); lit [α]D20
−31.0 (c 0.5, CH3OH)}.
=
With the readily available diol 21b, we conducted the
synthesis of 7,37,39-epi-lagunamide A (1b) (Scheme 8).
Coupling of secondary alcohol 51, which was prepared by
selective O-TBS protection of 21b, with L-N-Me-Boc-Ala-Cl in
the presence of DIPEA afforded 52 in 53% yield. Following the
previous synthetic sequence (CM reaction, Pinnick oxidation,
esterification, and subsequent amidation), the fully protected
cyclization precursor 56 was obtained in 30% overall yield.
Deprotection of the allyl ester using Pd(PPh3)4/N-methylani-
line and removal of both the N-Boc and O-TBS protecting
groups using TFA afforded the cyclization precursor, which was
treated with HATU/DIEA (1 mM in CH2Cl2) to yield the
desired product 7,37,39-epi-lagunamide A (1b) in 32% yield
over three steps. The crude 1b was further purified by
preparative HPLC. Although the optical rotation {[α]2D5 −33.2
(c 0.18, MeOH); lit [α]D20 = −4.6 (c 0.2, CH3OH)} differed
from the literature value, the NMR spectroscopic data were
consistent.7
Starting with diol 21a, we prepared the fully protected
cyclization precursor 57 through the previous intermediate 49
(Scheme 9). Unfortunately, after sequential deprotection of the
allyl ester and the N-Boc and O-TBS protecting groups, the
macrocyclization (1 mM in CH2Cl2) to generate the desired
39-epi-lagunamide A (1c) did not proceed under HATU/
DIPEA conditions. This surprising unsuccessful ring closure led
us to reconsider another site for macrolactamization.
a
Reagents and conditions: (a) TBSOTf, 2,6-lutidine, −78 °C, 75%.
(b) L-N-Me-Fmoc-Cl, DIPEA, CH2Cl2, reflux, 58%. (c) Methacry-
laldehyde, Grubbs 2nd, CH2Cl2, reflux, 83%, E:Z > 99:1. (d) NaClO2,
NaH2PO4, t-BuOH, 2-methylbut-2-ene, rt, 78%. (e) 31, MNBA,
DMAP, CH2Cl2, rt, 63%. (f) (1) Et2NH/CH3CN, rt; (2) L-Boc-aIle-
OH, HATU, DIPEA, CH2Cl2, 0 °C to rt, 75% (two steps). (g) (1)
Pd(PPh3)4, PhNHMe, THF, rt; (2) TFA/CH2Cl2, 0 °C to rt; (3)
HATU, DIPEA, CH2Cl2 (1 mM), rt, 32% (three steps).
a
Scheme 9. Preparation of 57
Scheme 10 shows the synthesis of 39-epi-lagunamide A (1c),
with macrolactamization between the alanine and isoleucine
moieties as the key step. In this case, compound 49 was treated
with Pd(PPh3)4 and N-methylaniline to cleave the allyl ester,
and the resulting free carboxylic acid was coupled with L-lle-O-
allyl in the presence of HATU/DIPEA to generate the fully
protected cyclization precursor 58 in 85% overall yield. After
deprotection of the allyl ester using Pd(PPh3)4/N-methylani-
line and the N-Fmoc protecting group with Et2NH/CH3CN,
the macrolactamization (1 mM in CH2Cl2) proceeded
smoothly under HATU/DIPEA conditions. The desired
cyclization product was treated with 40% hydrogen fluoride
aqueous solution, successfully giving 39-epi-lagunamide A (1c)
in 38% yield over four steps. The crude 1c was further purified
a
Reagents and conditions: (a) (1) Et2NH/CH3CN, rt; (2) L-Boc-Ile-
OH, HATU, DIPEA, CH2Cl2, 0 °C to rt, 79% (two steps). (b) (1)
Pd(PPh3)4, PhNHMe, THF, rt; (2) TFA/CH2Cl2, 0 °C to rt; (3)
HATU, DIPEA, CH2Cl2 (1 mM), rt.
by preparative HPLC, and the optical rotation was to be [α]D25
−64.7 (c 0.04, MeOH).
Finally, we accomplished the synthesis of revised structure
for natural lagunamide A (1a) and its 2-epimer (1d) starting
from the intermediates 27aa and 27ab, respectively. As shown
in Scheme 11, the macrolactamization (1 mM in CH2Cl2)
F
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a
1
The spectroscopic data of H and 13C NMR of lagunamide A
(1a) agreed with that of the reported data,6a,7 and the structure
of 2-epi-Lagunamide A (1d) was unambiguously confirmed by
two-dimensional NMR.
Scheme 10. Synthesis of 1c
CONCLUSION
■
We have completed the enantioselective total synthesis of
natural lagunamide A (1a) and its five analogues (1, 1b−d, and
45) starting from commercially available (S)-2-methylbutan-1-
ol (9). Although the original strategy of using RCM for the
macrocyclization did not work, several key homoallylic alcohols
could still be applied in cross-metathesis (CM) to produce
different C33−C44 units, from which an alternative approach
for ring closure was realized through macrolactamization.
Further efforts to extend this strategy to synthesize other
analogues of lagunamide A are ongoing in our laboratory. The
chemistry and related biological data will be published in due
course.
a
Reagents and conditions: (a) (1) Pd(PPh3)4, PhNHMe, THF, rt; (2)
L-lle-O-allyl, HATU, DIPEA, CH2Cl2, rt, 85% (two steps). (b) (1)
Pd(PPh3)4, PhNHMe, THF, rt; (2) Et2NH/CH3CN, rt; (3) HATU,
DIPEA, CH2Cl2, rt; (4) 40% aqueous HF, CH3CN, 38% (four steps).
a
Scheme 11. Synthesis of 1a and 1d
EXPERIMENTAL SECTION
■
General. THF was distilled from sodium/benzophenone. Reac-
tions were monitored by thin-layer chromatography (TLC) on glass
plates coated with silica gel with fluorescent indicator. Flash
chromatography was performed on silica gel (300−400) with
petroleum ether/EtOAc (PE/EA) as the eluent. Optical rotations
were measured on a polarimeter with a sodium lamp. HRMS was
performed on a LCMS-IT-TOF apparatus. IR spectra were recorded
using films on a Fourier transform infrared spectrometer. NMR spectra
were recorded at 400, 500, or 600 MHz, and chemical shifts (δ) are
reported in parts per million referenced to an internal standard [TMS
for H NMR and CDCl3 (77.0 ppm) for 13C NMR].
1
(R)-4-Benzyl-3-((2R,3S,4S)-3-hydroxy-2,4-dimethylhexanoyl)-
oxazolidin-2-one (17). (COCl)2 (9.8 mL, 0.112 mol) was stirred in
CH2Cl2 (150 mL) at −78 °C, and then a solution of DMSO (15.9 mL,
0.224 mol) in CH2Cl2 (30 mL) was slowly added dropwise. After the
mixture was stirred for 1 h, a solution of (S)-2-methylbutan-1-ol (9)
(4.92 g, 0.056 mol) in CH2Cl2 (5 mL) was slowly added dropwise, and
the resulting mixture was stirred for 2 h. Once TEA (46.5 mL, 0.336
mol) was added dropwise, the mixture was allowed to warm to room
temperature, and the reaction was quenched with a saturated NH4Cl
aqueous solution. The organic layer was separated, and the aqueous
layer was extracted with DCM (50 mL × 2). The combined organic
layers were washed with a 1 M HCl aqueous solution and brine. The
resulting organic layer was dried, filtered, and concentrated at 0 °C to
give crude aldehyde 10 (ca.10 mL) without further purification. To a
cooled (0 °C) solution of (R)-4-benzyl-3-propionyloxazolidin-2-one
(6.514 g, 28 mmol) in CH2Cl2 (100 mL) were added Bu2BOTf (1 M
in CH2Cl2, 33.6 mL, 33.6 mmol) and TEA (4.24 g, 42 mmol). The
mixture was stirred for 1 h and then cooled to −78 °C, and crude
aldehyde 10 was slowly added dropwise. After the mixture was stirred
for 2 h, it was allowed to warm to room temperature and stirred
overnight. A mixture of MeOH (10 mL) and 30% H2O2 (30 mL) was
slowly added dropwise, and the resulting solution was stirred for 8 h at
room temperature.The mixture was diluted with water, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2 (50
mL × 2), and the combined organic layers were washed with brine,
dried, filtered, and concentrated. The resulting residue was purified by
flash chromatography on silica gel (PE/EA = 6/1) to give 17 (8.29 g,
93%). [α]2D5 = −36.8 (c 2.87, CHCl3). IR (film) νmax: 3512, 2965,
2921, 2870, 1781, 1691, 1454, 1386, 1210 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.43−7.17 (m, 5H), 4.73 (ddd, J = 10.7, 6.9, 3.2 Hz, 1H),
4.30−4.16 (m, 2H), 4.01−3.96 (m, 1H), 3.67−3.64 (m, 1H), 3.28 (dd,
J = 13.4, 3.3 Hz, 1H), 3.03−2.97 (m, 1H), 2.82 (dd, J = 13.4, 9.4 Hz,
1H), 1.90−1.75 (m, 1H), 1.61−1.48 (m, 1H), 1.26 (d, J = 7.0 Hz,
3H), 1.24−1.16 (m, 1H), 0.94 (t, J = 7.4 Hz, 3H), 0.90 (d, J = 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 178.1, 152.9, 135.1, 129.5,
129.0, 127.4, 74.8, 66.2, 55.2, 39.5, 37.8, 37.0, 25.2, 14.8, 10.9, 9.7.
a
Reagents and conditions: (a) Methacrylaldehyde, Grubbs 2nd,
CH2Cl2, reflux, 87% for 59, 83% for 63, E:Z > 99:1. (b) NaClO2,
NaH2PO4, t-BuOH, 2-methylbut-2-ene, rt, 80% for 60, 81% for 64. (c)
31, MNBA, DMAP, CH2Cl2, rt, 56% for 61, 58% for 65. (d) (1)
Et2NH/CH3CN, rt; (2) L-Boc-aIle-OH, HATU, DIPEA, CH2Cl2, 0 °C
to rt, 91% for 62, 80% for 66 (two steps). (e) (1) Pd(PPh3)4,
PhNHMe, THF, rt; (2) Et2NH/CH3CN, rt; (3) HATU, DIPEA,
CH2Cl2, rt; (4) 40% aqueous HF, CH3CN, 38% for 1a, 45% for 1d
(four steps).
between the alanine and isoleucine moieties was conducted in
both cases using the same strategy that was applied for the
synthesis of 39-epi-lagunamide A (1c). Following a synthetic
sequence similar to that described above, both lagunamide A
(1a) and 2-epi-lagunamide A (1d) were successfully obtained in
parallel. The crude 1a and 1d were further purified by
preparative HPLC, with optical rotations of [α]2D5 −34.9 (c 0.04,
MeOH) {lit [α]D25 = −36 (c 0.5, CH3OH),6a [α]2D0 = −33.8 (c
0.1, CH3OH)7} and [α]2D5 +3.6 (c 0.46, MeOH), respectively.
G
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HRMS (ESI): calcd for [C18H25NO4 + Na+] 342.1681, found
342.1681.
NH4Cl aqueous solution and warmed to room temperature. Then the
mixture was extracted with EtOAc (50 mL × 3), and the combined
organic layers were washed with brine, dried, filtered, and
concentrated. The residue was purified by flash chromatography on
silica gel (PE/EA = 200/1) to give 20b (2.1 g, 86%) and 20a (0.29 g,
12%). Data for the major product 20b: [α]2D5 = +20.0 (c 1.07, CHCl3).
IR (film) νmax: 3469, 3078, 2959, 2930, 2858, 1463, 1382, 1361, 1255,
(R)-4-Benzyl-3-((2R,3S,4S)-3-(tert-butyldimethylsilyloxy)-2,4-
dimethylhexanoyl)oxazolidin-2-one (18). To a cooled (0 °C)
solution of 17 (4.0 g, 12.5 mmol) in CH2Cl2 (100 mL) was added
dropwise 2,6-lutidine (2.92 mL, 25 mmol) followed by TBSOTf (4.32
mL, 18.8 mmol). After the mixture was stirred for 1 h, it was warmed
to room temperature and stirred for 1 h, and then the reaction was
quenched with a saturated NaHCO3 aqueous solution. The organic
layer was separated, and the aqueous layer was extracted with CH2Cl2
(50 mL × 2). The combined organic layers were washed with brine
(30 mL × 2), dried, filtered, and concentrated. The resulting residue
was purified by flash chromatography on silica gel (PE/EA = 20/1) to
1
1096, 1051, 1024, 1005, 913, 835, 773 cm−1. H NMR (400 MHz,
CDCl3): δ 5.90−5.75 (m, 1H), 5.20−5.07 (m, 2H), 3.77−3.71 (m,
1H), 3.71−3.64 (m, 1H), 2.33−2.19 (m, 2H), 2.18−2.11 (m, 1H),
1.76−1.66 (m, 1H), 1.66−1.55 (m, 1H), 1.50−1.37 (m, 1H), 1.19−
1.05 (m, 1H), 0.99−0.89 (m, 18H), 0.13−0.08 (m, 6H). 13C NMR
(100 MHz, CDCl3): δ 135.4, 117.5, 78.5, 74.41, 40.8, 39.6, 40.0, 29.7,
26.1, 25.8, 18.3, 15.3, 12.3, 8.8, −3.5, −4.3. HRMS (ESI): calcd for
[C17H36O2Si + H+] 301.2563, found 301.2569.
General Procedure for the Synthesis of 21a and 21b.
Compound 20a or 20b (300 mg, 1 mmol) was dissolved in CH3CN (5
mL), and the solution was stirred in a plastic bottle at 0 °C. Then a
40% HF (1 mL) aqueous solution was added dropwise, and the
mixture was stirred for 5 h at 0−25 °C. The mixture was diluted with
EtOAc (100 mL) and washed with brine (50 mL × 2). The organic
layer was dried and concentrated to afford a residue that was purified
by flash chromatography on silica gel (PE/EA = 6/1) to give the
desired compound.
give 18 (5.16 g, 95%). [α]2D5 = −47.1 (c 1.40, CHCl3). IR (film) νmax
:
2959, 2930, 2881, 2857, 1783, 1698, 1462, 1383, 1350, 1252, 1209,
1121, 1103, 1050, 1019, 969, 837, 775, 702 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.41−7.22 (m, 5H), 4.66 (ddd, J = 9.6, 8.4, 4.8 Hz, 1H),
4.23−4.18 (m, 2H), 4.05−3.95 (m, 2H), 3.31 (dd, J = 13.3, 3.2 Hz,
1H), 2.79 (dd, J = 13.3, 9.7 Hz, 1H), 1.58−1.45 (m, 2H), 1.26 (d, J =
6.5 Hz, 3H), 1.08−1.00 (m, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.95 (s,
9H), 0.90 (t, J = 7.2 Hz, 3H), 0.11 (s, 3H), 0.08 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 176.1, 152.9, 135.4, 129.5, 129.0, 127.4, 76.2,
66.0, 55.7, 41.1, 40.9, 37.7, 26.1, 24.9, 18.4, 15.3, 14.0, 12.4, −3.9, −4.2.
HRMS (ESI): calcd for [C24H39NO4Si + Na+] 456.2546, found
456.2552.
(4S,5S,6S,7S)-5,7-Dimethylnon-1-ene-4,6-diol (21a). Colorless oil
(177 mg, 95%). [α]D25 = −3.0 (c 0.36, CHCl3). IR (film) νmax: 3358,
(2S,3S,4S)-3-(tert-Butyldimethylsilyloxy)-2,4-dimethylhexan-
1-ol (19). To a cooled (0 °C) solution of 18 (4.0 g, 9.24 mmol) in
THF (30 mL) was added dropwise a solution of LiBH4 (0.3 g, 13.9
mmol) in THF (10 mL). Then MeOH (5 mL) was carefully added
dropwise, and the mixture was stirred for 1 h. The reaction was
quenched with water, and the mixture was extracted with EtOAc (50
mL × 3). The combined organic layers were washed with brine (50
mL), dried, filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (PE/EA = 20/1) to give 19 (2.2 g,
1
3077, 2967, 2933, 2878, 1463, 1382, 1339, 1083, 966, 914 cm−1. H
NMR (400 MHz, CDCl3): δ 5.89−5.75 (m, 1H), 5.17−5.08 (m, 2H),
3.73−3.62 (m, 2H), 3.29−3.05 (m, 2H), 2.39−2.30 (m, 2H), 1.84−
1.74 (m, 1H), 1.74−1.65 (m, 1H), 1.53−1.42 (m, 1H), 1.19−1.05 (m,
1H), 0.98 (d, J = 7.1 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H), 0.76 (d, J = 6.7
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 135.2, 117.8, 75.3, 74.5,
40.1, 37.5, 37.5, 25.4, 14.7, 10.9, 10.3. HRMS (ESI): calcd for
[C11H22O2 + Na+] 209.1517, found 209.1522.
92%) as a colorless oil. [α]2D5 = +6.8 (c 0.62, CHCl3). IR (film) νmax
:
(4R,5S,6S,7S)-5,7-Dimethylnon-1-ene-4,6-diol (21b). Colorless oil
(171 mg, 92%). [α]2D5 = −17.2 (c 1.14, CHCl3). IR (film) νmax: 3362,
3346, 2959, 2930, 2858, 1463, 1382, 1361, 1253, 1100, 1047, 1006,
862, 835, 773, 673 cm−1. 1H NMR (400 MHz, CDCl3): δ 3.66 (dd, J =
5.1, 2.5 Hz, 1H), 3.60 (dd, J = 10.3, 7.9 Hz, 1H), 3.49 (dd, J = 10.4, 6.1
Hz, 1H), 1.97−1.85 (m, 2H), 1.63−1.51 (m, 2H), 1.16−1.05 (m, 1H),
0.95−0.88 (m, 18H), 0.09 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
76.6, 66.7, 39.4, 38.6, 26.1, 25.8, 18.3, 16.1, 12.1, 11.9, −4.0, −4.3.
HRMS (ESI): calcd for [C14H32O2Si + Na+] 283.2069, found
283.2075.
(4S,5S,6S,7S)-6-(tert-Butyldimethylsilyloxy)-5,7-dimethyl-
non-1-en-4-ol (20a). To a solution of aldehyde 15b (2.0 g, 7.75
mmol) in THF (40 mL) was added dropwise ZnCl2 (1.0 M in THF,
19.4 mL, 19.4 mmol) at −78 °C, and then allylmagnesium chloride
(6.9 mL, 1.0 M in THF, 11.6 mmol) was added dropwise. After the
mixture was stirred for 1 h, the reaction was quenched with water, and
the solution was warmed to room temperature and acidified with 1 M
aqueous citric acid solution. The mixture was extracted with EtOAc
(50 mL × 3). The combined organic layers were washed with brine
(50 mL), dried, and concentrated to give a crude residue, which was
purified by flash chromatography on silica gel (PE/EA = 50/1) to give
20a (2.02 g, 87%) and 20b (223 mg, 9.6%) as a colorless oil. Data for
1
2968, 2932, 2877, 1642, 1463, 1382, 1152, 1086, 966, 914 cm−1. H
NMR (400 MHz, CDCl3): δ 5.83−5.71 (m, 1H), 5.14−5.04 (m, 2H),
3.87−3.81 (m, 1H), 3.43 (dd, J = 9.5, 1.4 Hz, 1H), 3.28−3.16 (m,
2H), 2.33−2.23 (m, 1H), 2.23−2.14 (m, 1H), 1.78−1.65 (m, 2H),
1.52−1.42 (m, 1H), 1.16−1.04 (m, 1H), 0.92−0.83 (m, 6H), 0.76 (d, J
= 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 135.0, 117.7, 81.0,
76.4, 39.9, 37.6, 37.1, 25.2, 14.8, 10.7, 4.1. HRMS (ESI): calcd for
[C11H22O2 + H+] 187.1698, found 187.1700.
General Procedure for the Synthesis of 22a and 22b. A
solution of compound 21a or 21b (169 mg, 0.91 mmol) and PTSA·
H2O (17 mg, 0.09 mmol) in acetone (10 mL) was stirred at room
temperature, and then 2,2-dimethylpropane (1.1 mL, 9.2 mmol) was
added dropwise. After the mixture was stirred for 2.5 h, the reaction
was quenched with a saturated NaHCO3 aqueous solution, and the
mixture was diluted with ether. The organic layer was separated, and
the aqueous layer was extracted with ether (30 mL × 2). The
combined organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated. The resulting residue was purified by flash
chromatography on silica gel (PE/EA = 100/1) to give the desired
product.
(4S,5S,6S)-4-Allyl-6-((S)-sec-butyl)-2,2,5-trimethyl-1,3-dioxane
(22a). Colorless oil (183 mg, 89%). [α]2D5 = +43.8 (c 0.02, CHCl3). IR
(film) νmax: 3399, 2963, 2927, 2855, 1740, 1599, 1460, 1252, 1191,
1081 cm−1. 1H NMR (400 MHz, CDCl3): δ 5.96−5.83 (m, 1H),
5.17−5.10 (m, 1H), 5.09−5.04 (m, 1H), 3.46−3.39 (m, 1H), 3.35 (dd,
J = 13.2, 6.3 Hz, 1H), 2.31 (t, J = 6.5 Hz, 2H), 1.85−1.70 (m, 2H),
1.54−1.44 (m, 1H), 1.37 (s, 3H), 1.35 (s, 3H), 1.09−0.98 (m, 1H),
0.93−0.88 (m, 6H), 0.82 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 135.3, 116.5, 100.7, 74.9, 72.9, 39.2, 37.9, 34.0, 25.4, 25.0,
23.9, 14.3, 11.8, 10.7.
(4R,5S,6S)-4-Allyl-6-((S)-sec-butyl)-2,2,5-trimethyl-1,3-dioxane
(22b). Colorless oil (189 mg, 92%). [α]2D5 = +1.6 (c 0.13, CHCl3). IR
(film) νmax: 3358, 2957, 2911, 2855, 1597, 1458, 1427, 1119 cm−1. 1H
NMR (400 MHz, CDCl3): δ 5.86−5.74 (m, 1H), 5.13 (dd, J = 17.2,
the major product 20a: [α]2D5 = +6.4 (c 0.78, CHCl3). IR (film) νmax
:
3490, 2958, 2929, 2858, 1462, 1383, 1254, 1028, 835, 773 cm−1. H
NMR (400 MHz, CDCl3): δ 5.92 (dddd, J = 14.4, 12.1, 8.2, 6.1 Hz,
1H), 5.21−5.13 (m, 2H), 3.84 (dd, J = 5.4, 2.1 Hz, 1H), 3.66−3.57
(m, 1H), 2.76 (s, 1H), 2.49−2.37 (m, 1H), 2.16−2.05 (m, 1H), 1.77−
1.54 (m, 3H), 1.18−1.04 (m, 1H), 0.96−0.90 (m, 15H), 0.87 (d, J =
7.0 Hz, 3H), 0.14−0.09 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
135.1, 117.8, 77.6, 72.4, 41.4, 39.6, 39.0, 26.1, 25.7, 18.3, 16.5, 12.2,
12.1, −4.2. HRMS (ESI): calcd for [C17H36O2Si + Na+] 323.2382,
found 323.2368.
1
(4R,5S,6S,7S)-6-(tert-Butyldimethylsilyloxy)-5,7-dimethyl-
non-1-en-4-ol (20b). To a cooled (−78 °C) solution of aldehyde
15b (2.09 g, 8.1 mmol) in anhydrous THF (40 mL) was added
allylmagnesium chloride (1.7 M in THF, 7.2 mL, 12.2 mmol). After
the mixture was stirred for 30 min, it was quenched with a saturated
H
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The Journal of Organic Chemistry
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1.3 Hz, 1H), 5.09−5.03 (m, 1H), 3.92−3.87 (m, 1H), 3.44 (dd, J =
9.8, 1.8 Hz, 1H), 2.37−2.28 (m, 1H), 2.21−2.11 (m, 1H), 1.80−1.67
(m, 1H), 1.59−1.46 (m, 2H), 1.41 (s, 6H), 1.17−1.05 (m, 1H), 0.92−
0.84 (m, 6H), 0.79 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 134.6, 116.7, 98.8, 77.1, 73.4, 37.4, 35.2, 32.3, 30.0, 25.2, 19.5, 13.4,
10.4, 4.4.
MHz, CDCl3): δ 5.81−5.67 (m, 1H), 5.15−5.04 (m, 2H), 3.94−3.88
(m, 1H), 3.44−3.37 (m, 1H), 2.78−2.70 (m, 1H), 2.41−2.29 (m, 2H),
1.84−1.72 (m, 2H), 1.57−1.45 (m, 1H), 1.22−1.10 (m, 1H), 0.95−
0.89 (m, 15H), 0.80 (d, J = 6.8 Hz, 3H), 0.18−0.12 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 134.4, 117.2, 78.9, 77.5, 39.7, 37.6, 36.6,
25.9, 25.0, 18.0, 15.0, 10.9, 5.5, −3.7, −4.6. HRMS (ESI): calcd for
[C17H36O2Si + H+] 301.2563, found 301.2563.
(4S,5S,6S,7S)-6-(tert-Butyldimethylsilyloxy)-5,7-dimethyl-
non-1-en-4-yl 2,2,2-Trichloroethyl Carbonate (34). A solution of
compound 20a (2.0 g, 6.67 mmol) and DMAP (81 mg, 0.7 mmol) in
CH2Cl2 (50 mL) was treated with pyrrolidine (1.05 g, 13.4 mmol) and
TrocCl (1.7 g, 8 mmol) at 0 °C. After the mixture was stirred for 1 h, it
was warmed to room temperature and diluted with CH2Cl2 (50 mL).
The resulting mixture was washed with 1 M aqueous HCl, sat.
NaHCO3, and brine successively and then dried and concentrated.
The residue was purified by flash chromatography on silica gel (PE/EA
= 150/1) to give 34 (3.03 g, 96%). [α]2D5 = +31.3 (c 1.23, CHCl3). IR
(film) νmax: 2958, 2921, 2855, 1758, 1462, 1380, 1245, 1096, 834
cm−1. 1H NMR (400 MHz, CDCl3): δ 5.90−5.77 (m, 1H), 5.20−5.10
(m, 2H), 4.85 (d, J = 11.9 Hz, 1H), 4.76 (d, J = 12.0 Hz, 1H), 4.76−
4.69 (m, 1H), 3.68 (dd, J = 4.6, 1.8 Hz, 1H), 2.59−2.50 (m, 1H),
2.41−2.31 (m, 1H), 2.04−1.94 (m, 1H), 1.57−1.42 (m, 2H), 1.18−
1.07 (m, 1H), 0.97−0.90 (m, 18H), 0.09 (s, 3H), 0.06 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ 153.9, 132.9, 118.4, 94.8, 81.6, 76.6, 74.1,
41.7, 37.7, 35.6, 26.1, 25.8, 18.4, 14.9, 12.2, 11.0, −4.0, −4.4.
(4S,5R,6S,7S)-6-Hydroxy-5,7-dimethylnon-1-en-4-yl 2,2,2-
Trichloroethyl Carbonate (35). A solution of compound 34 (2.5
g, 5.27 mmol) in CH3CN (30 mL) was treated with 40% aqueous HF
(5 mL) solution at 0 °C. After the mixture was stirred for 5 h, it was
warmed to room temperature and diluted with EtOAc (150 mL).
Then the mixture was washed with brine (50 mL × 2) and a saturated
NaHCO3 aqueous solution (30 mL), dried, filtered, and concentrated,
and the residue was purified by flash chromatography on silica gel
(3S,5S,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-8-
en-4-one (24a). Compound 23a (1.2 g, 4 mmol) and DMP (2.04 g,
4.8 mmol) were stirred in CH2Cl2 (80 mL) for 1 h, and then the
reaction was quenched with saturated NaHCO3 and Na2S2O3 aqueous
solution. The organic layer was separated, washed with brine, dried,
filtered, and concentrated, and the residue was purified by flash
chromatography on silica gel (PE/EA = 100/1) to give 24a (1.1 g,
92%) as a colorless oil. [α]2D5 = +123.6 (c 0.47, CHCl3). IR (film) νmax
:
1
3514, 2959, 2855, 1460, 1463, 1255, 1087, 1021, 837, 776 cm−1. H
NMR (400 MHz, CDCl3): δ 5.95−5.83 (m, 1H), 5.11−5.00 (m, 2H),
4.03−3.95 (m, 1H), 2.90−2.79 (m, 1H), 2.56−2.44 (m, 1H), 2.32−
2.24 (m, 1H), 2.24−2.16 (m, 1H), 1.77−1.63 (m, 1H), 1.38−1.25 (m,
1H), 1.00 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.88−0.81 (m,
12H), 0.04 (s, 3H), −0.04 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
216.0, 133.8, 117.2, 72.8, 49.3, 48.1, 38.1, 25.8, 25.2, 17.9, 14.9, 12.5,
11.7, −4.6, −4.8. HRMS (ESI): calcd for [C17H34O2Si + Na+]
321.2226, found 321.2224.
(3S,4R,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethyl-
non-8-en-4-ol (25a). A solution of 24a (0.94 g, 3.13 mmol) in
anhydrous THF (20 mL) was treated with Et3BHLi (1 M in THF, 4.7
mL, 4.7 mmol) at −78 °C. After the mixture was stirred for 30 min,
the reaction was carefully quenched with MeOH (5 mL), and the
mixture was stirred for another 5 min at −78 °C. Once a saturated
NaHCO3 aqueous solution was added dropwise, the mixture was
warmed to room temperature and extracted with EtOAc (50 mL × 3).
The combined organic layers were washed with brine, dried, filtered,
and concentrated, and the residue was purified by flash chromatog-
raphy on silica gel (PE/EA = 100/1) to give 25a (0.89 g, 94%) as a
colorless oil. [α]2D5 = +26.3 (c 1.29, CHCl3). IR (film) νmax: 3517, 3077,
2960, 2931, 2858, 1463, 1380, 1255, 1073, 991, 940, 911, 836, 776
cm−1. 1H NMR (400 MHz, CDCl3): δ 5.90−5.77 (m, 1H), 5.07−4.99
(m, 2H), 3.82 (dd, J = 10.7, 5.4 Hz, 1H), 3.42 (d, J = 9.3 Hz, 1H), 2.68
(s, 1H), 2.36−2.27 (m, 1H), 2.27−2.17 (m, 1H), 1.81−1.69 (m, 1H),
1.48−1.36 (m, 2H), 1.35−1.25 (m, 1H), 0.92−0.85 (m, 12H), 0.81 (d,
J = 6.5 Hz, 3H), 0.75 (d, J = 6.9 Hz, 3H), 0.10−0.04 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 135.3, 116.9, 76.2, 75.8, 40.6, 39.0, 36.5,
27.2, 25.8, 18.0, 12.8, 12.1, 11.8, −4.3, −4.7. HRMS (ESI): calcd for
[C17H36O2Si + Na+] 323.2382, found 323.2384.
(PE/EA = 15/1) to give 35 as a colorless oil (1.8 g, 95%). [α]D25
=
+14.8 (c 0.76, CHCl3). IR (film) νmax: 2962, 1761, 1653, 1591, 1247,
1119 cm−1. 1H NMR (400 MHz, CDCl3): δ 5.90−5.78 (m, 1H),
5.22−5.11 (m, 2H), 4.92 (td, J = 8.3, 3.7 Hz, 1H), 4.87 (d, J = 11.9 Hz,
1H), 4.78 (d, J = 12.0 Hz, 1H), 3.45−3.35 (m, 1H), 2.64−2.54 (m,
1H), 2.48−2.36 (m, 1H), 2.02 (d, J = 4.9 Hz, 1H), 2.01−1.94 (m,
1H), 1.88−1.75 (m, 1H), 1.57−1.45 (m, 1H), 1.20−1.08 (m, 1H),
0.97−0.89 (m, 6H), 0.82 (d, J = 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 154.6, 132.9, 118.6, 94.7, 81.5, 73.5, 38.2, 37.3, 36.5, 25.7,
14.8, 10.9, 8.6. HRMS (ESI): calcd for [C14H23Cl3O4 + Na+]
383.0560, found 383.0560.
General Procedure for the Synthesis of 23a and 51. A
solution of 21a or 21b (1.0 g, 5.4 mmol) and 2,6-lutidine (10.8 mmol)
in CH2Cl2 (50 mL) was treated with TBSOTf (1.18 mL, 5.1 mmol)
dropwise over 30 min at −78 °C. After the mixture was stirred for 1 h,
the reaction was quenched with water, and the mixture was warmed to
room temperature. The organic layer was separated, and the aqueous
layer was extracted with CH2Cl2 (30 mL × 2). The combined organic
layers were washed with 1 M HCl (20 mL) aqueous solution and brine
(20 mL), dried, filtered, and concentrated, and the residue was purified
by flash chromatography on silica gel (PE/EA = 100/1) to give the
desired 23a or 51, respectively.
Allyl 2-((tert-Butoxycarbonyl)(methyl)amino)acetate (28).
Boc-N-Me-Gly-OH (2.0 g, 10.6 mmol), K2CO3 (2.92 g, 21.2
mmol), and TBAB (0.34 g, 1.06 mmol) were stirred in DMF (20
mL) at 0 °C, and allyl bromide (1.4 mL, 15.8 mmol) was added
dropwise, after which the mixture was stirred for 5 h. Then water (50
mL) was added dropwise, and the resulting mixture was extracted with
EtOAc (50 mL × 3). The combined organic layers were washed with
brine (100 mL × 3), dried, filtered, and concentrated, and the residue
was purified by flash chromatography on silica gel (PE/EA = 10/1) to
give 28 as a colorless oil (2.2 g, 91%). IR (film) νmax: 2977, 1754, 1702,
(3S,4S,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-8-
en-4-ol (23a). Colorless oil (1.22 g, 76%). [α]2D5 = −3.4 (c 0.28,
CHCl3). IR (film) νmax: 3514, 2960, 2931, 2859, 1641, 1464, 1382,
1
1481, 1451, 1391, 1367, 1246, 1192, 1150, 987 cm−1. H NMR (400
MHz, CDCl3): δ 5.97−5.83 (m, 1H), 5.36−5.28 (m, 1H), 5.27−5.20
(m, 1H), 4.67−4.58 (m, 2H), 4.02−3.97 (m, 1H), 3.93−3.89 (m, 1H),
2.98−2.85 (m, 3H), 1.51−1.37 (m, 9H). 13C NMR (100 MHz,
CDCl3): δ 169.6, 156.1, 155.4, 131.8, 131.7, 118.6, 118.4, 80.1, 65.5,
51.0, 50.3, 35.5, 28.3, 28.2. HRMS (ESI): calcd for [C11H19NO4 +
Na+] 252.1212, found 252.1210.
(R)-Allyl 2-(2-((tert-Butoxycarbonyl)(methyl)amino)-N-meth-
yl-3-phenylpropanamido)acetate (29). A cooled solution (0 °C)
of 28 (1.17 g, 5.1 mmol) in CH2Cl2 (5 mL) was treated with TFA (2
mL). After 2 h of stirring, the mixture was concentrated, and the
residue was azeotroped with toluene two times. The residue was
dissolved in CH2Cl2 (20 mL) and cooled to 0 °C. After HATU (2.91
g, 7.66 mmol) and DIPEA (2.53 mL, 15.3 mmol) were added, a
solution of D-Boc-N-Me-Phe-OH (1.40 g, 5.1 mmol) in CH2Cl2 (20
1
1255, 1087, 1021, 1004, 915, 837, 776 cm−1. H NMR (400 MHz,
CDCl3): δ 5.73−5.59 (m, 1H), 5.13−5.00 (m, 2H), 3.86−3.75 (m,
1H), 3.73 (s, 1H), 3.68 (d, J = 9.6 Hz, 1H), 2.54−2.44 (m, 1H), 2.42−
2.32 (m, 1H), 1.90−1.78 (m, 1H), 1.74 (q, J = 7.0 Hz, 1H), 1.50−1.39
(m, 1H), 1.16−1.03 (m, 1H), 0.96 (d, J = 7.1 Hz, 3H), 0.93−0.84 (m,
12H), 0.71 (t, J = 6.8 Hz, 3H), 0.09 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 134.3, 117.6, 78.7, 73.7, 40.0, 37.4, 35.1, 25.9, 25.2, 17.9,
14.4, 11.2, 10.9, −4.4, −4.9. HRMS (ESI): calcd for [C17H36O2Si +
H+] 301.2563, found 301.2569.
(3S,4S,5R,6R)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-8-
en-4-ol (51). Colorless oil (1.21 g, 75%). [α]2D5 = −33.6 (c 0.34,
CHCl3). IR (film) νmax: 3516, 3078, 2959, 2930, 2858, 1640, 1463,
1408, 1361, 1256, 1083, 1038, 912, 837, 775, 741 cm−1. 1H NMR (400
I
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mL) was added dropwise, and the resulting mixture was stirred for 2 h
at 0 °C to room temperature. The reaction was quenched with water,
and the organic layer was separated. The aqueous layer was extracted
with CH2Cl2 three times, and the combined organic layers were
washed with brine, dried, and concentrated. The residue was purified
by flash chromatography on silica gel (PE/EA = 6/1, 3/1) to give 29
as a colorless oil (1.77 g, 89%). [α]2D5 = +119.7 (c 0.98, CHCl3). IR
(film) νmax: 2973, 2932, 1751, 1691, 1658, 1453, 1388, 1317, 1191
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.35−7.10 (m, 5H), 6.00−5.79
(m, 1H), 5.38−5.23 (m, 2.5H), 5.08−4.99 (m, 0.3H), 4.92−4.84 (m,
0.2H), 4.71−4.61 (m, 1.7H), 4.59−4.51 (m, 0.3H), 4.39 (d, J = 17.6
Hz, 0.4H), 4.29 (d, J = 17.3 Hz, 0.4H), 4.21−4.03 (m, 0.5H), 3.98 (d,
J = 17.2 Hz, 0.3H), 3.82 (d, J = 17.2 Hz, 0.4H), 3.22−3.07 (m, 0.5H),
3.07−2.98 (m, 3.5H), 2.98−2.90 (m, 1H), 2.88−2.80 (m, 2H), 2.78−
2.71 (m, 1H), 1.36−1.11 (m, 9H). 13C NMR (100 MHz, CDCl3): δ
170.9, 170.6, 170.2, 168.7, 168.6, 168.4, 155.3, 154.3, 153.6, 138.1,
137.6, 131.7, 131.4, 129.5, 129.4, 128.4, 128.2, 126.4, 126.3, 119.4,
118.9, 118.7, 80.5, 80.1, 79.9, 66.3, 65.9, 65.8, 65.7, 58.1, 57.9, 55.8,
55.5, 51.0, 50.7, 50.2, 50.0, 36.06, 35.8, 35.2, 29.6, 29.4, 29.0, 28.2,
28.1, 28.0, 27.8. HRMS (ESI): calcd for [C21H30N2O5 + H+] 391.2233,
found 391.2227.
(6S,9R)-Allyl 9-Benzyl-2,2,6,8,11-pentamethyl-4,7,10-trioxo-
3-oxa-5,8,11-triazatridecan-13-oate (30). A solution of com-
pound 29 (2.60 g, 6.67 mmol) in CH2Cl2 (6 mL) was treated with
TFA (3 mL) at 0 °C. After 2 h of stirring, the mixture was
concentrated, and the residue was azeotroped with toluene two times.
The residue was dissolved in CH2Cl2 (50 mL) and cooled to 0 °C, and
then L-Boc-Ala-OH (1.26 g, 6.67 mmol), HATU (3.80 g, 10.0 mmol),
and DIPEA (3.3 mL, 20.0 mmol) were added. After the mixture was
stirred for 3 h, the reaction was quenched with water, and the organic
layer was separated. The aqueous layer was extracted with CH2Cl2
three times, and the combined organic layers were washed with brine,
dried, and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 4/1, 2/1) to give 30 as a
colorless oil (2.09 g, 68%). 1H NMR (400 MHz, CDCl3): δ 7.27−7.07
(m, 5H), 5.93−5.67 (m, 1H), 5.36−5.18 (m, 2H), 4.66−4.54 (m,
1.7H), 4.54−4.34 (m, 1H), 4.32−4.16 (m, 1.7H), 4.12−4.03 (m, 1H),
3.96−3.86 (m, 0.6H), 3.20−3.04 (m, 1.3H), 3.05−2.84 (m, 6.7H),
1.46−1.30 (m, 10H), 1.27−1.17 (m, 2H). 13C NMR (100 MHz,
CDCl3): δ 173.0, 172.9, 170.2, 169.8, 168.8, 168.4, 155.3, 154.9, 136.6,
136.5, 131.6, 131.5, 129.5, 129.3, 128.2, 128.2, 126.6, 119.0, 118.7,
79.4, 66.0, 65.7, 60.3, 53.8, 53.1, 51.1, 50.2, 46.5, 36.3, 35.3, 35.1, 35.1,
30.1, 29.9, 28.3, 28.2, 20.9, 17.6, 17.4, 14.1. HRMS (ESI): calcd for
[C24H35N3O6 + Na+] 484.2424, found 484.2425.
119.0, 118.9, 74.0, 73.8, 66.1, 65.9, 53.9, 53.2, 51.2, 50.2, 45.2, 44.8,
38.6, 38.5, 36.3, 35.3, 35.2, 35.0, 30.4, 30.1, 26.2, 26.1, 17.5, 17.4, 12.7,
12.6, 11.9. HRMS (ESI): calcd for [C25H37N3O6 + H+] 476.2761,
found 476.2757.
Compound 32. A solution of methacrylic acid (74 mg, 0.86 mmol)
and TEA (0.18 mL, 1.29 mmol) in anhydrous THF (1.5 mL) was
treated with Cl3C6H2COCl (0.16 mL, 1.0 mmol) at room temperature
for 30 min. Then a solution of 31 (205 mg, 0.43 mmol) in toluene and
DMAP (105 mg, 0.86 mmol) were added. After the mixture was
stirred for 30 min, the reaction was quenched with water, and the
mixture was extracted with EtOAc (20 mL × 3). The combined
organic layers were washed with brine (30 mL), dried (MgSO4),
filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 2/1) to give 32 (204 mg,
87%). [α]2D5 = +23.1 (c 0.71, CHCl3). IR (film) νmax: 3314, 3028, 2965,
2934, 2878, 1748, 1725, 1647, 1497, 1456, 1411, 1294, 1191, 1129,
1049, 986, 942, 700 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.26−7.11
(m, 5H), 6.66 (d, J = 7.3 Hz, 1H), 6.18 (s, 1H), 5.90−5.81 (m, 1H),
5.70−5.62 (m, 1H), 5.36−5.17 (m, 3H), 4.77−4.67 (m, 1H), 4.65−
4.53 (m, 2H), 4.26 (d, J = 17.2 Hz, 1H), 3.92 (d, J = 17.2 Hz, 1H),
3.68 (dd, J = 14.0, 7.0 Hz, 1H), 3.20−3.06 (m, 2H), 3.05−2.90 (m,
6H), 2.05−1.91 (m, 4H), 1.40−1.28 (m, 1H), 1.26−1.11 (m, 3H),
0.92−0.77 (m, 7H). 13C NMR (100 MHz, CDCl3): δ 172.4, 172.2,
170.0, 169.8, 169.1, 169.0, 168.8, 168.4, 166.1, 166.0, 136.5, 136.4,
135.6, 135.6, 131.6, 131.4, 129.4, 129.2, 128.3, 128.3, 126.8, 126.7,
126.7, 118.9, 118.9, 76.1, 66.1, 65.8, 53.8, 53.1, 51.2, 50.2, 45.3, 44.9,
37.5, 37.4, 36.3, 35.3, 35.2, 35.0, 30.3, 30.1, 29.7, 26.1, 26.1, 18.4, 18.4,
17.4, 17.2, 13.9, 13.8, 11.7. HRMS (ESI): calcd for [C29H41N3O7 +
Na+] 566.2842, found 566.2848.
General Procedure for the Synthesis of 27aa, 36, 46, and 52.
To a cooled (0 °C) solution of L-Fmoc-Ala-Cl (457 mg, 1.33 mmol) in
CH2Cl2 (15 mL) was added dropwise DIPEA (0.44 mL, 2.67 mmol)
followed by the secondary alcohol (0.67 mmol) in CH2Cl2 (5 mL).
Then the mixture was warmed to reflux for 8 h and cooled to room
temperature again, and water was added. The organic phase was
separated, and the aqueous phase was extracted with CH2Cl2 (30 mL
× 2). The combined organic layers were washed with brine (30 mL),
dried (MgSO4), filtered, and concentrated. The residue was purified by
flash chromatography on silica gel (PE/EA = 30/1) to give the
corresponding title compound.
(S)-((3S,4R,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-
8-en-4-yl) 2-(((9H-Fluoren-9-yl)methoxy)carbonyl)propanoate
(27aa). Colorless oil (224 mg, 55%). [α]2D5 = −25.8 (c 0.96,
CHCl3). IR (film) νmax: 2958, 2921, 2856, 1736, 1703, 1452, 1400,
1
1316, 1250, 1159, 1077, 775, 757, 739 cm−1. H NMR (400 MHz,
Compound 31. A solution of compound 30 (2.07 g, 4.49 mmol)
in CH2Cl2 (5 mL) was treated with TFA (2.5 mL) at 0 °C. The
mixture was stirred for 2 h and then concentrated, and the residue was
azeotroped with toluene two times to give the crude amine without
further purification. (2R,3S)-2-Hydroxy-3-methylpentanoic acid (0.71
g, 5.39 mmol) and HOBt (0.86 g, 6.4 mmol) were stirred in DMF (10
mL) at −15 °C, and then EDC·HCl (0.79 g, 4.11 mmol) was added.
After 15 min of stirring, a solution of the above crude amine in DMF
(2 mL) and TEA (3.1 mL, 22.4 mmol) were added dropwise. After the
mixture was stirred for 18 h at 0 °C to room temperature, it was
diluted with water (40 mL) and extracted with EtOAc (40 mL × 3).
The combined organic layers were washed with brine (25 mL × 3),
dried, and concentrated, and the residue was purified by flash
chromatography on silica gel (PE/EA = 1/1, 1/2) to give 31 as a
colorless oil (1.21 g, 56%). [α]2D5 = +123.4 (c 1.19, CHCl3). IR (film)
νmax: 3397, 2963, 2934, 2876, 1748, 1642, 1497, 1456, 1411, 1268,
CDCl3): δ 7.77 (d, J = 7.5 Hz, 2H), 7.66−7.53 (m, 2H), 7.40 (t, J =
7.4 Hz, 2H), 7.35−7.28 (m, 2H), 5.83−5.70 (m, 1H), 5.09−4.83 (m,
4H), 4.58−4.50 (m, 0.5H), 4.44−4.34 (m, 1.5H), 4.31−4.21 (m, 1H),
3.69−3.55 (m, 1H), 3.02−2.89 (m, 3H), 2.25−2.16 (m, 1H), 2.08−
1.96 (m, 2H), 1.66−1.56 (m, 1H), 1.46 (d, J = 7.4 Hz, 3H), 1.32−1.23
(m, 1H), 1.19−1.04 (m, 1H), 0.95−0.76 (m, 18H), 0.14− −0.07 (m,
6H). 13C NMR (100 MHz, CDCl3): δ 171.8, 156.5, 143.9, 141.3,
136.9, 127.7, 127.0, 125.0, 119.9, 116.3, 78.1, 72.1, 67.8, 54.1, 47.3,
41.0, 36.2, 35.9, 30.0, 26.9, 25.84, 18.0, 15.2, 12.5, 11.9, 9.8, −4.4, −4.5.
HRMS (ESI): calcd for [C36H53NO5Si + Na+] 630.3591, found
630.3599.
(S)-((3S,4S,5S,6S)-3,5-Dimethyl-6-((2,2,2-trichloroethoxy)-
carbonyloxy)non-8-en-4-yl) 2-(((9H-Fluoren-9-yl)methoxy)-
carbonyl)propanoate (36). Colorless oil (273 mg, 61%). [α]D25
=
+0.5 (c 0.88, CHCl3). IR (film) νmax: 3065, 2967, 2875, 1757, 1704,
1
1451, 1382, 1314, 1247, 1155, 1095, 758, 740 cm−1. H NMR (400
1
1194, 1098, 1052, 985 cm−1. H NMR (400 MHz, CDCl3): δ 7.33−
MHz, CDCl3): δ 7.81 (d, J = 7.5 Hz, 2H), 7.69−7.57 (m, 2H), 7.44 (t,
J = 7.4 Hz, 2H), 7.35 (t, J = 7.3 Hz, 2H), 5.88−5.74 (m, 1H), 5.23−
5.12 (m, 2H), 5.12−4.95 (m, 1.7H), 4.94−4.82 (m, 1.3H), 4.74−4.63
(m, 2H), 4.54−4.37 (m, 2H), 4.35−4.26 (m, 1H), 3.01−2.94 (m, 3H),
2.65−2.53 (m, 1H), 2.49−2.36 (m, 1H), 2.20−2.07 (m, 1H), 1.72−
1.63 (m, 1H), 1.55−1.49 (m, 3H), 1.48−1.43 (m, 1H), 1.16−1.04 (m,
1H), 1.03−0.96 (m, 3H), 0.94−0.84 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 171.5, 156.6, 153.8, 144.2, 144.0, 141.4, 132.5, 127.7, 127.1,
125.1, 120.0, 118.8, 94.6, 79.8, 75.8, 67.7, 54.3, 47.3, 36.8, 36.3, 30.3,
6.99 (m, 6H), 6.00−5.65 (m, 2H), 5.32 (d, J = 17.2 Hz, 1H), 5.25 (d, J
= 10.4 Hz, 1H), 4.82−4.72 (m, 0.7H), 4.68−4.57 (m, 2H), 4.57−4.49
(m, 0.3H), 4.36−4.32 (m, 0.1H), 4.27 (d, J = 16.2 Hz, 0.9H), 4.16−
4.07 (m, 0.3H), 4.07−4.00 (m, 1H), 3.92 (d, J = 17.2 Hz, 0.7H),
3.62−3.35 (m, 1H), 3.22−3.07 (m, 1.4H), 3.07−2.92 (m, 6.6H),
1.87−1.73 (m, 1H), 1.52−1.40 (m, 1H), 1.36−1.22 (m, 1H), 0.92 (t, J
= 7.0 Hz, 3H), 0.84 (d, J = 6.7 Hz, 2.3H), 0.78−0.69 (m, 3.7H). 13C
NMR (100 MHz, CDCl3): δ 173.2, 172.6, 170.1, 169.8, 168.8, 168.4,
136.6, 136.4, 131.6, 131.4, 129.4, 129.3, 128.3, 128.2, 126.8, 126.7,
J
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
26.9, 25.0, 14.8, 10.9, 9.8. HRMS (ESI): calcd for [C33H40Cl3NO7 +
H+] 668.1949, found 668.1951.
give 40 (266 mg, 75%) as a colorless oil. [α]2D5 = −0.42 (c 0.86,
CHCl3). IR (film) νmax: 2973, 1758, 1698, 1453, 1389, 1247, 1152
cm−1. 1H NMR (400 MHz, CDCl3): δ 5.85−5.72 (m, 1H), 5.20−5.09
(m, 2H), 5.07−4.98 (m, 1H), 4.94−4.83 (m, 1.5H), 4.76−4.59 (m,
2.5H), 2.90−2.79 (m, 3H), 2.62−2.51 (m, 1H), 2.44−2.34 (m, 1H),
2.18−2.06 (m, 1H), 1.73−1.60 (m, 1H), 1.51−1.42 (m, 12H), 1.35−
1.26 (m, 1H), 1.14−1.02 (m, 1H), 1.02−0.95 (m, 3H), 0.92−0.86 (m,
6H). 13C NMR (100 MHz, CDCl3): δ 171.9, 155.8, 155.4, 153.8,
132.5, 118.7, 94.6, 80.0, 79.7, 79.5, 76.0, 75.6, 54.2, 53.5, 36.8, 36.3,
35.4, 30.5, 30.3, 29.9, 28.4, 26.9, 24.9, 22.7, 15.4, 14.8, 14.1, 10.9, 9.7,
9.7. HRMS (ESI): calcd for [C23H38Cl3NO7 + Na+] 568.1612, found
568.1612.
(S)-((3S,4S,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-
8-en-4-yl) 2-(((9H-Fluoren-9-yl)methoxy)carbonyl)propanoate (46).
Colorless oil (240 mg, 59%). [α]2D5 = −1.2 (c 0.98, CHCl3). IR (film)
νmax: 2958, 2927, 2857, 1737, 1707, 1451, 1400, 1313, 1250, 1210,
1158, 1078, 836, 757 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.81 (d, J
= 7.5 Hz, 2H), 7.68−7.58 (m, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.36 (t, J
= 7.4 Hz, 2H), 5.96−5.82 (m, 1H), 5.14−5.06 (m, 2H), 5.04−4.94 (m,
1.6H), 4.88−4.79 (m, 0.4H), 4.55−4.38 (m, 2H), 4.35−4.26 (m, 1H),
3.69−3.59 (m, 1H), 3.00−2.93 (m, 3H), 2.27−2.18 (m, 2H), 2.02−
1.91 (m, 1H), 1.76−1.62 (m, 1H), 1.55−1.44 (m, 4H), 1.20−1.07 (m,
1H), 0.98−0.84 (m, 18H), 0.13−0.05 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 171.7, 156.5, 144.2, 144.0, 141.4, 135.0, 127.7, 127.1, 125.1,
120.0, 116.9, 79.2, 79.0, 73.3, 67.8, 54.3, 47.3, 39.9, 37.5, 37.1, 37.0,
31.5, 30.3, 29.7, 26.0, 24.1, 23.8, 18.1, 15.9, 15.8, 15.0, 11.5, 9.9, −4.1,
−4.2, −4.6. HRMS (ESI): calcd for [C36H53NO5Si + H+] 608.3771,
found 608.3774.
(S)-((3S,4S,5R,6R)-6-(tert-Butyldimethylsilyloxy)-3,5-dimethylnon-
8-en-4-yl) 2-(((9H-Fluoren-9-yl)methoxy)carbonyl)propanoate (52).
Colorless oil (236 mg, 58%). [α]2D5 = −23.5 (c 0.40, CHCl3). IR (film)
νmax: 2963, 2932, 2855, 1750, 1704, 1597, 1458, 1309, 1252, 1165,
1129, 1083 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.76−7.70 (m, 2H),
7.60−7.49 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.1 Hz, 2H),
5.80−5.64 (m, 1H), 5.07−4.98 (m, 2H), 4.96−4.86 (m, 1.7H), 4.84−
4.75 (m, 0.3H), 4.42−4.29 (m, 2H), 4.27−4.17 (m, 1H), 3.52 (dd, J =
10.9, 5.5 Hz, 1H), 2.96−2.84 (m, 3H), 2.35−2.18 (m, 2H), 1.92−1.79
(m, 1H), 1.73−1.59 (m, 1H), 1.48−1.33 (m, 4H), 1.07−0.94 (m, 1H),
0.90−0.76 (m, 18H), 0.05−0.03 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 171.8, 171.6, 156.5, 155.9, 144.1, 143.9, 141.3, 134.4, 127.7,
127.0, 125.1, 120.0, 117.4, 117.3, 79.2, 79.0, 72.5, 67.9, 67.7, 54.2, 54.0,
47.2, 39.0, 38.0, 36.1, 30.3, 29.7, 25.9, 23.7, 23.5, 18.1, 15.6, 15.5, 15.1,
11.4, 9.8, −4.0, −4.7. HRMS (ESI): calcd for [C36H53NO5Si + Na+]
630.3591, found 630.3591.
Compound 37. Compound 36 (450 mg, 0.67 mmol) and Et2NH
(1.5) were stirred in CH3CN (3 mL) at room temperature for 10 min,
and then the mixture was concentrated under reduced pressure. The
residue, L-Fmoc-aIle (300 mg, 0.85 mmol), HATU (380 mg, 1.0
mmol), and DIPEA (0.22 mL, 1.3 mmol) were stirred in CH2Cl2 (10
mL) for 1 h. The reaction was quenched with saturated NH4Cl
aqueous solution, and the mixture was separated. The aqueous layer
was extracted with CH2Cl2 two times, and the compound organic
layers were washed with brine, dried, and concentrated. The residue
was purified by flash chromatography on silica gel (PE/EA = 10/1) to
give 37 (438 mg, 84%). [α]2D5 = −4.7 (c 0.84, CHCl3). IR (film) νmax
:
3304, 2966, 2932, 1737, 1643, 1450, 1450, 1410, 1381, 1247, 1084,
1
740 cm−1. H NMR (400 MHz, CDCl3): δ 7.80−7.72 (m, 2H), 7.60
(d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.34−7.27 (m, 2H),
5.84−5.70 (m, 1H), 5.65 (d, J = 9.2 Hz, 1H), 5.32 (dd, J = 14.5, 7.2
Hz, 1H), 5.20−5.08 (m, 2H), 5.08−4.98 (m, 1H), 4.83 (d, J = 11.9
Hz, 1H), 4.73 (dd, J = 9.2, 3.9 Hz, 1H), 4.68−4.58 (m, 2H), 4.43−
4.36 (m, 1H), 4.36−4.28 (m, 1H), 4.26−4.19 (m, 1H), 3.10−2.99 (m,
2.5H), 2.86 (s, 0.5H), 2.60−2.48 (m, 1H), 2.47−2.35 (m, 1H), 2.14−
2.03 (m, 1H), 1.85−1.73 (m, 1H), 1.67−1.62 (m, 1H), 1.56−1.49 (m,
1H), 1.45 (d, J = 7.3 Hz, 3H), 1.28−1.23 (m, 2H), 1.10−0.94 (m,
6.4H), 0.92−0.78 (m, 8.6H). 13C NMR (100 MHz, CDCl3): δ 172.1,
171.0, 156.5, 153. 8, 143.9, 143.8, 141.3, 132.3, 127.7, 127.6, 127.0,
125.2, 125.1, 124.7, 120.0, 119.9, 118.9, 94.5, 79.8, 76.7, 75.7, 67.0,
53.9, 52.2, 47.2, 37.5, 36.6, 36.3, 36.1, 31.2, 26.7, 24.9, 14.8, 14.2, 13.8,
11.9, 10.8, 9.7. HRMS (ESI): calcd for [C39H51Cl3N2O8 + Na+]
803.2609, found 803.2612.
Compound 38. To a solution of compound 32 (100 mg, 0.18
mmol) and Pd(PPh3)4 (42 mg, 0.04 mmol) in anhydrous THF (5 mL)
was added PhNHMe (48 mg, 0.45 mmol). The resulting mixture was
stirred for 1 h, diluted with EtOAc (30 mL), washed with 1 M aqueous
HCl (20 mL × 2), dried, filtered, and concentrated to give crude 33 as
a yellow oil without further purification. Then compound 37 (140 mg,
0.18 mmol) and Et2NH (1 mL) were stirred in CH3CN (2 mL) for 10
min. After the mixture was concentrated, the residue was dissolved in
CH2Cl2 (5 mL) and crude 33, HATU (103 mg, 0.27 mmol), and
DIPEA (100 μL, 0.54 mmol) were added successively. The mixture
was stirred for another 1 h and then concentrated under reduced
pressure. The resulting residue was purified by flash chromatography
on silica gel (PE/EA = 1/1) to give 38 as a colorless oil (141 mg,
73%). [α]2D5 = −0.32 (c 0.48, CHCl3). IR (film) νmax: 3311, 2967,
2878, 1757, 1633, 1535, 1463, 1411, 1381, 1248, 1092 cm−1. 1H NMR
(400 MHz, CDCl3): δ 7.32−7.07 (m, 5H), 6.90−6.74 (m, 2H), 6.28−
6.09 (m, 1H), 5.86−5.68 (m, 2H), 5.68−5.58 (m, 1H), 5.35−5.28 (m,
1H), 5.23−5.13 (m, 1.3H), 5.13−5.03 (m, 2H), 5.04−4.93 (m, 1.7H),
4.85−4.77 (m, 1H), 4.77−4.67 (m, 1H), 4.67−4.54 (m, 2H), 4.15−
3.92 (m, 2H), 3.23−2.75 (m, 11H), 2.58−2.46 (m, 1H), 2.44−2.31
(m, 1H), 2.12−2.02 (m, 3H), 2.00−1.93 (m, 3H), 1.82−1.71 (m, 1H),
1.68−1.55 (m, 1H), 1.52−1.30 (m, 5.4H), 1.27−1.13 (m, 2.6H),
1.09−0.61 (m, 24H). 13C NMR (100 MHz, CDCl3): δ 172.5, 172.0,
170.9, 170.3, 169.2, 167.9, 166.1, 153.8, 136.5, 135.6, 132.3, 129.3,
129.2, 128.3, 128.2, 126.7, 118.9, 94.5, 79.7, 76.2, 75.8, 53.9, 52.0, 52.0,
45.0, 38.6, 37.5, 37.4, 36.6, 36.4, 36.3, 36.1, 35.1, 31.1, 30.4, 26.6, 26.0,
24.9, 20.7, 18.3, 17.3, 14.9, 14.7, 14.5, 14.2, 14.0, 13.9, 13.8, 11.9, 11.8,
11.6, 10.8, 9.7. HRMS (ESI): calcd for [C50H76Cl3N5O12 + H+]
1044.4634, found 1044.4632.
(R)-((3S,4R,5R,6S)-6-(tert-Butyldimethylsilyloxy)-3,5-dime-
thylnon-8-en-4-yl) 2-(((9H-Fluoren-9-yl)methoxy)carbonyl)-
propanoate (27ab). A solution of D-N-Me-Fmoc-Ala-OH (1.37 g,
4.20 mmol) and TEA (0.73 mL, 5.30 mmol) in anhydrous THF (10
mL) was treated with Cl3C6H2COCl (0.66 mL, 4.20 mmol) for 30
min, and then a mixture of compound 25a (1.05 g, 3.50 mmol) and
DMAP (0.85 g, 7.00 mmol) in toluene was added dropwise. After the
mixture was stirred for 30 min, the reaction was quenched with water,
and the mixture was extracted with EtOAc (30 mL × 3). The mixture
was separated, and the organic layer was washed with brine (30 mL),
dried, filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 30/1) to give 27ab (1.89 g,
89%) as a colorless oil. [α]2D5 = −17.8 (c 0.67, CHCl3). IR (film) νmax
:
2958, 2932, 2857, 1737, 1706, 1452, 1400, 1312, 1251, 1157, 1077,
1
835, 774, 740 cm−1. H NMR (400 MHz, CDCl3): δ 7.76 (d, J = 7.5
Hz, 2H), 7.65−7.51 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.2
Hz, 2H), 5.88−5.69 (m, 1H), 5.08−4.88 (m, 3.6H), 4.85−4.74 (m,
0.4H), 4.50−4.33 (m, 2H), 4.31−4.20 (m, 1H), 3.67−3.54 (m, 1H),
2.98−2.87 (m, 3H), 2.26−2.14 (m, 1H), 2.09−1.95 (m, 2H), 1.66−
1.55 (m, 1H), 1.45−1.38 (m, 3H), 1.35−1.22 (m, 1H), 1.20−1.07 (m,
1H), 0.96−0.82 (m, 18H), 0.07−0.02 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 171.4, 156.4, 144.1, 143.9, 141.3, 137.0, 127.7, 127.0, 125.0,
119.9, 116.2, 78.2, 72.3, 67.8, 54.1, 47.2, 40.9, 36.2, 35.8, 30.4, 26.9,
25.8, 18.0, 15.0, 12.4, 12.0, 9.7, −4.4, −4.5. HRMS (ESI): calcd for
[C36H53NO5Si + Na+] 630.3591, found 630.3582.
(S)-(3S,4S,5S,6S)-3,5-Dimethyl-6-(((2,2,2-trichloroethoxy)-
carbonyl)oxy)non-8-en-4-yl 2-((tert-Butoxycarbonyl)(methyl)-
amino)propanoate (40). Compound 36 (434 mg, 0.65 mmol)
and Et2NH (2 mL) were stirred in CH3CN (4 mL) for 10 min at room
temperature, and then the solvent was evaporated under reduced
pressure. The residue was dissolved in CH2Cl2 (5 mL), Boc2O (170
mg, 0.78 mmol), and TEA (0.13 mL, 0.98 mmol) were added. The
mixture was stirred for 2 h and then diluted with water and extracted
with CH2Cl2 (30 mL × 3). The combined organic layers were washed
with brine (50 mL), dried, filtered, and concentrated, and the residue
was purified by flash chromatography on silica gel (PE/EA = 30/1) to
General Procedure for the Synthesis of 41, 47, 53, 59, and
63. A solution of terminal olefin (4.0 mmol), Grubbs second-
K
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
generation catalyst (4 mg, 0.1%), and methacrylaldehyde (80%, 4.2
mL, 40.0 mmol) was refluxed for 2 days in CH2Cl2 (100 mL) (catalyst
was reloaded about 2 mg/10 h). The mixture was concentrated under
reduced pressure, and the resulting residue was purified by flash
chromatography on silica gel (PE/EA = 15/1) to give the desired
compound.
(m, 1H), 1.18−1.07 (m, 1H), 0.98−0.77 (m, 18H), 0.06− −0.10 (m,
6H). 13C NMR (100 MHz, CDCl3): δ 195.3, 171.7, 156.2, 153.2,
143.9, 141.3, 140.1, 127.7, 127.0, 125.0, 120.0, 78.0, 70.9, 67.7, 54.5,
47.2, 41.1, 36.2, 30.8, 26.8, 25.7, 17.9, 15.0, 12.3, 12.0, 9.5, 9.3, −4.5,
−4.7. HRMS (ESI): calcd for [C38H55NO6Si + Na+] 672.3696, found
672.3694.
General Procedure for the Synthesis of 42, 48, 54, 60, and
64. A solution of aldehyde (1.76 mmol) in t-BuOH/2-methyl-2-
butene (10/5 mL) was treated with a solution of NaClO2 (80%, 1.58
g, 14.1 mmol) and NaH2PO4 (2.75 g, 17.6 mmol) in water (50 mL).
After 2 h of stirring, the mixture was extracted with EtOAc (30 mL ×
3), and the combined organic layers were washed with brine (30 mL),
dried, filtered, and concentrated. The residue was purified by flash
chromatography on silica gel (PE/EA = 5/1) to give the
corresponding title compound.
Compound 41. Colorless oil (1.90 g, 81%). [α]2D5 = +16.8 (c 1.24,
CHCl3); IR (film): νmax 3369, 2971, 2916, 2875, 1758, 1693, 1454,
1
1390, 1367, 1322, 1247, 1154, 1078, 991, 821 cm−1. H NMR (400
MHz, CDCl3): δ 9.43 (s, 1H), 6.57−6.47 (m, 1H), 5.11−4.98 (m,
1H), 4.95−4.74 (m, 3H), 4.70−4.62 (m, 1H), 2.90−2.75 (m, 3H),
2.23−2.11 (m, 1H), 1.81 (s, 3H), 1.77−1.61 (m, 2H), 1.52−1.42 (m,
14H), 1.15−1.06 (m, 1H), 1.03 (d, J = 7.0 Hz, 3H), 0.94−0.87 (m,
6H); 13C NMR (100 MHz, CDCl3): δ 194.6, 172.3, 172.1, 155.8,
155.4, 154.6, 153.8, 147.1, 146.7, 142.1, 94.4, 80.1, 79.8, 79.1, 79.0,
76.8, 75.8, 75.4, 54.4, 54.2, 53.5, 37.4, 36.3, 31.5, 31.3, 30.5, 30.3, 29.7,
28.4, 24.9, 24.7, 15.5, 14.8, 10.9, 9.8, 9.5. HRMS (ESI): calcd for
[C25H40Cl3NO8 + Na+] 610.1717, found 610.1716.
Compound 42. Colorless oil (0.986 g, 93%). [α]2D5 = +64.2 (c
0.076, CHCl3). IR (film) νmax: 2972, 2937, 1759, 1693, 1454, 1390,
1368, 1324, 1247, 1154, 1093, 996 cm−1. 1H NMR (400 MHz,
CDCl3): δ 6.93−6.85 (m, 1H), 5.07−4.97 (m, 1H), 4.96−4.84 (m,
1.5H), 4.82−4.70 (m, 1.5H), 4.70−4.60 (m, 1H), 2.91−2.80 (m, 3H),
2.72−2.61 (m, 2H), 2.20−2.08 (m, 1H), 1.89 (s, 3H), 1.74−1.61 (m,
1H), 1.53−1.41 (m, 12H), 1.33−1.24 (m, 1H), 1.14−1.04 (m, 1H),
1.01 (d, J = 6.9 Hz, 3H), 0.93−0.85 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 172.4, 172.0, 171.2, 155.8, 153.7, 137.7, 137.5, 130.4, 94.5,
80.2, 79.8, 79.5, 79.3, 76.8, 75.8, 75.4, 60.4, 54.2, 53.6, 37.2, 36.3, 31.2,
30.3, 29.7, 28.4, 24.8, 22.7, 21.0, 15.4, 14.8, 14.2, 14.1, 12.3, 10.9, 9.8.
HRMS (ESI): calcd for [C25H40Cl3NO9 + Na+] 626.1666, found
626.1662.
Compound 47. Colorless oil (2.08 g, 80%). [α]2D5 = −4.7 (c 0.94,
CHCl3). IR (film) νmax: 2958, 2930, 2857, 1737, 1705, 1452, 1401,
1
1316, 1251, 1211, 1159, 1077, 1006, 934, 836, 775, 740 cm−1. H
NMR (400 MHz, CDCl3): δ 9.46−9.42 (m, 1H), 7.80 (d, J = 7.5 Hz,
2H), 7.67−7.57 (m, 2H), 7.43 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.3 Hz,
2H), 6.67−6.56 (m, 1H), 5.00−4.89 (m, 1.6H), 4.88−4.78 (m, 0.4H),
4.58−4.49 (m, 0.3H), 4.49−4.36 (m, 1.7H), 4.35−4.23 (m, 1H),
3.84−3.74 (m, 1H), 3.01−2.90 (m, 3H), 2.61−2.49 (m, 1H), 2.45−
2.33 (m, 1H), 2.04−1.91 (m, 1H), 1.83−1.74 (m, 3H), 1.69−1.59 (m,
1H), 1.54−1.43 (m, 4H), 1.20−1.06 (m, 1H), 0.95−0.84 (m, 18H),
0.13−0.01 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 195.0, 171.8,
156.5, 151.0, 144.1, 143.9, 141.4, 140.6, 127.7, 127.1, 125.0, 120.0,
78.7, 72.6, 67.8, 54.4, 47.3, 40.4, 37.2, 32.5, 30.3, 29.7, 26.1, 25.8, 24.1,
18.0, 15.8, 14.9, 11.5, 9.5, −4.4, −4.6. HRMS (ESI): calcd for
[C38H55NO6Si + Na+] 672.3696, found 672.3702.
Compound 48. Colorless oil (1.02 g, 87%). [α]2D5 = −6.3 (c 0.76,
CHCl3). IR (film) νmax: 2959, 2855, 1736, 1706, 1451, 1401, 1316,
1252, 1212, 1158, 1077, 836, 740 cm−1. 1H NMR (400 MHz, CDCl3):
δ 7.80 (d, J = 7.5 Hz, 2H), 7.68−7.57 (m, 2H), 7.44 (t, J = 7.4 Hz,
2H), 7.35 (t, J = 7.3 Hz, 2H), 7.08−6.97 (m, 1H), 5.02−4.90 (m,
1.7H), 4.86−4.77 (m, 0.3H), 4.58−4.37 (m, 2H), 4.36−4.24 (m, 1H),
3.82−3.70 (m, 1H), 3.01−2.92 (m, 3H), 2.46−2.33 (m, 1H), 2.32−
2.21 (m, 1H), 2.04−1.93 (m, 1H), 1.87 (s, 3H), 1.69−1.58 (m, 1H),
1.55−1.43 (m, 4H), 1.20−1.08 (m, 1H), 0.96−0.85 (m, 18H), 0.13−
0.03 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 173.0, 156.6, 144.0,
141.4, 128.4, 127.7, 127.1, 125.1, 120.0, 79.0, 72.6, 67.8, 54.4, 53.4,
47.3, 40.4, 37.2, 32.4, 30.3, 25.8, 24.0, 18.0, 15.9, 14.9, 12.3, 11.5, 9.7,
−4.5, −4.6. HRMS (ESI): calcd for [C38H55NO7Si + H+] 666.3826,
found 666.3821.
Compound 53. Colorless oil (2.15 g, 83%). [α]2D5 = −7.2 (c 0.37,
CHCl3). IR (film) νmax: 2958, 2857, 1736, 1692, 1452, 1400, 1313,
1252, 1206, 1164, 1076, 836, 775, 740, 758 cm−1. 1H NMR (400 MHz,
CDCl3): δ 9.38 (s, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.62−7.48 (m, 2H),
7.38 (t, J = 7.4 Hz, 2H), 7.33−7.25 (m, 2H), 6.61−6.47 (m, 1H),
4.91−4.75 (m, 2H), 4.50−4.29 (m, 2H), 4.28−4.17 (m, 1H), 3.74−
3.60 (m, 1H), 2.99−2.87 (m, 3H), 2.84−2.67 (m, 1H), 2.50−2.38 (m,
1H), 1.85−1.72 (m, 4H), 1.71−1.55 (m, 2H), 1.47−1.39 (m, 3H),
1.07−0.95 (m, 1H), 0.93−0.73 (m, 18H), 0.07−0.04 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 195.2, 195.0, 172.2, 156.5, 150.5, 149.9,
144.0, 143.9, 141.3, 140.7, 127.7, 127.0, 125.0, 120.0, 78.5, 78.1, 72.2,
67.8, 54.3, 54.0, 47.2, 39.3, 36.2, 34.0, 30.3, 29.7, 25.8, 24.1, 23.8, 18.0,
15.3, 15.0, 11.2, 11.1, 10.3, 9.6, −4.2, −4.6. HRMS (ESI): calcd for
[C38H55NO6Si + Na+] 672.3696, found 672.3695.
Compound 54. Colorless oil (0.913 g, 78%). [α]2D5 = −10.0 (c 1.39,
CHCl3). IR (film) νmax: 2959, 2857, 1736, 1704, 1452, 1401, 1316,
1
1253, 1213, 1161, 1076, 836, 775, 740 cm−1. H NMR (400 MHz,
CDCl3): δ 7.80 (d, J = 7.4 Hz, 2H), 7.69−7.56 (m, 2H), 7.43 (t, J =
7.4 Hz, 2H), 7.35 (t, J = 7.1 Hz, 2H), 7.08−6.93 (m, 1H), 5.01−4.90
(m, 1.6H), 4.88−4.78 (m, 0.4H), 4.57−4.38 (m, 2H), 4.35−4.23 (m,
1H), 3.78−3.65 (m, 1H), 3.01−2.92 (m, 3H), 2.65−2.51 (m, 1H),
2.46−2.33 (m, 1H), 1.96−1.84 (m, 4H), 1.77−1.67 (m, 1H), 1.54−
1.40 (m, 4H), 1.15−1.02 (m, 1H), 0.98−0.82 (m, 18H), 0.14−0.05
(m, 6H). 13C NMR (100 MHz, CDCl3): δ 173.2, 171.8, 156.6, 144.0,
141.4, 141.1, 128.6, 127.7, 127.1, 125.1, 120.0, 78.3, 72.6, 67.8, 54.4,
47.3, 39.4, 36.5, 34.0, 30.4, 25.9, 24.1, 18.1, 15.4, 15.0, 12.4, 11.3, 10.3,
−4.2, −4.5. HRMS (ESI): calcd for [C38H55NO7Si + Na+] 688.3645,
found 688.3650.
Compound 59. Colorless oil (2.26 g, 87%). [α]2D5 = −24.1 (c 1.19,
CHCl3). IR (film) νmax: 3356, 2959, 2930, 2857, 1737, 1689, 1452,
1399, 1323, 1252, 1206, 1168, 1075, 1007, 948, 837, 776, 758, 740
1
cm−1. H NMR (400 MHz, CDCl3): δ 9.31 (s, 1H), 7.76 (d, J = 7.4
Hz, 2H), 7.64−7.51 (m, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.3
Hz, 2H), 6.55−6.40 (m, 1H), 4.95−4.82 (m, 2H), 4.43−4.33 (m, 2H),
4.31−4.19 (m, 1H), 3.87−3.66 (m, 1H), 3.05−2.87 (m, 3H), 2.54−
2.33 (m, 2H), 2.13−2.00 (m, 1H), 1.77−1.68 (m, 3H), 1.68−1.57 (m,
1H), 1.52−1.40 (m, 3H), 1.35−1.22 (m, 1H), 1.20−1.09 (m, 1H),
0.98−0.81 (m, 18H), 0.09− −0.16 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 195.3, 172.3, 156.6, 153.5, 144.0, 143.8, 141.3, 140.1, 127.7,
127.1, 125.0, 120.0, 77.8, 70.8, 67.8, 54.1, 47.17, 41.3, 36.1, 30.9, 29.9,
26.9, 25.7, 17.9, 15.2, 12.3, 12.0, 9.5, 9.3, −4.4, −4.6. HRMS (ESI):
calcd for [C38H55NO6Si + Na+] 672.3696, found 672.3695.
Compound 60. Colorless oil (0.936 g, 80%). [α]2D5 = −25.9 (c 1.05,
CHCl3). IR (film) νmax: 2960, 2927, 2857, 1737, 1692, 1452, 1384,
1319, 1256, 1208, 1165, 1077, 953, 837, 776, 758, 740 cm−1. 1H NMR
(400 MHz, CDCl3): δ 7.75 (d, J = 7.5 Hz, 2H), 7.64−7.51 (m, 2H),
7.38 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.4 Hz, 2H), 6.95−6.84 (m, 1H),
4.95−4.79 (m, 2H), 4.45−4.34 (m, 2H), 4.28−4.20 (m, 1H), 3.81−
3.65 (m, 1H), 2.93 (s, 3H), 2.37−2.21 (m, 2H), 2.11−1.99 (m, 1H),
1.79 (s, 3H), 1.66−1.58 (m, 1H), 1.44 (d, J = 7.4 Hz, 3H), 1.28−1.25
(m, 1H), 1.17−1.09 (m, 1H), 0.97−0.80 (m, 18H), 0.09− −0.07 (m,
6H). 13C NMR (100 MHz, CDCl3): δ 173.0, 172.1, 159.4, 156.5,
144.0, 143.9, 143.3, 142.7, 141.3, 139.6, 127.8, 127.6, 127.0, 125.0,
119.9, 115.7, 78.3, 77.9, 72.8, 70.8, 68.3, 68.0, 67.7, 54.1, 47.2, 41.1,
36.2, 31.9, 30.7, 30.0, 27.7, 26.8, 26.4, 25.7, 24.5, 23.8, 20.5, 20.4, 20.1,
17.9, 15.7, 15.2, 14.5, 12.3, 12.2, 11.9, 11.6, 9.6, 8.1, −4.6, −4.7, −4.8.
Compound 63. Colorless oil (2.15 g, 83%). [α]2D5 = −16.4 (c 0.78,
CHCl3). IR (film) νmax: 3400, 2958, 2927, 2857, 1736, 1703, 1452,
1401, 1315, 1251, 1156, 1077, 837, 774, 758, 740 cm−1. 1H NMR (400
MHz, CDCl3): δ 9.42−9.28 (m, 1H), 7.75 (d, J = 7.5 Hz, 2H), 7.64−
7.48 (m, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.2 Hz, 2H), 6.57−
6.39 (m, 1H), 4.90 (dd, J = 10.5, 1.7 Hz, 1H), 4.87−4.69 (m, 1H),
4.59−4.29 (m, 2H), 4.30−4.17 (m, 1H), 3.83−3.59 (m, 1H), 2.96−
2.84 (m, 3H), 2.53−2.43 (m, 1H), 2.43−2.29 (m, 1H), 2.14−1.99 (m,
1H), 1.74 (s, 3H), 1.68−1.55 (m, 1H), 1.50−1.35 (m, 3H), 1.33−1.20
L
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI): calcd for [C38H55NO7Si + Na+] 688.3645, found
688.3645.
(m, 0.6H), 2.04−1.98 (m, 1.8H), 1.95 (s, 3H), 1.92−1.81 (m, 1H),
1.77−1.63 (m, 1H), 1.52−1.42 (m, 3H), 1.37−1.32 (m, 1H), 1.29−
1.25 (m, 1H), 1.24−1.14 (m, 1H), 1.12−1.00 (m, 1H), 0.97−0.81 (m,
27H), 0.12−0.02 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 172.5,
172.3, 172.2, 171.8, 170.1, 169.9, 169.4, 168.9, 168.4, 166.5, 156.5,
144.0, 141.3, 140.1, 136.7, 131.7, 131.5, 129.5, 129.3, 128.3, 128.3,
127.7, 127.1, 126.7, 125.0, 120.0, 118.9, 78.1, 76.1, 67.8, 66.1, 65.8,
54.4, 53.8, 53.2, 50.3, 47.3, 45.2, 44.9, 42.8, 41.2, 39.3, 37.5, 36.3, 35.3,
35.1, 33.9, 30.4, 30.3, 26.1, 25.9, 18.2, 18.0, 17.4, 15.6, 15.0, 14.2, 14.0,
13.9, 12.9, 11.7, 11.2, 10.9, 10.3, −3.8, −4.2, −4.6, −4.9. HRMS (ESI):
calcd for [C63H90N4O12Si + Na+] 1145.6222, found 1145.6193.
Compound 61. Colorless oil (396 mg, 56%). [α]2D5 = +25.6 (c 0.46,
CHCl3). IR (film) νmax: 2962, 2932, 1741, 1708, 1649, 1453, 1402,
Compound 64. Colorless oil (0.948 g, 81%). [α]2D5 = −15.2 (c 0.93,
CHCl3). IR (film) νmax: 2959, 2932, 2855, 1736, 1702, 1452, 1401,
1311, 1257, 1158, 1077 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.75 (d,
J = 7.5 Hz, 2H), 7.64−7.48 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.30 (t, J
= 7.3 Hz, 2H), 7.05−6.83 (m, 2H), 4.95−4.71 (m, 2H), 4.55−4.32 (m,
2H), 4.29−4.18 (m, 1H), 3.77−3.61 (m, 1H), 3.00−2.84 (m, 3H),
2.39−2.18 (m, 2H), 2.11−1.99 (m, 1H), 1.87−1.78 (m, 3H), 1.66−
1.56 (m, 1H), 1.48−1.35 (m, 3H), 1.31−1.21 (m, 1H), 1.20−1.06 (m,
1H), 1.00−0.76 (m, 18H), 0.11−0.05 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 173.4, 171.6, 156.3, 144.0, 143.9, 143.4, 141.3, 127.9, 127.6,
127.0, 125.0, 119.9, 78.1, 71.0, 67.8, 54.3, 47.2, 41.1, 36.3, 30.7, 30.6,
26.8, 25.7, 17.9, 15.0, 12.3, 12.2, 12.0, 9.6, −4.6, −4.8. HRMS (ESI):
calcd for [C38H55NO7Si + Na+] 688.3645, found 688.3646.
1
1317, 1250, 1209, 1094, 741 cm−1. H NMR (400 MHz, CDCl3): δ
7.75 (d, J = 7.5 Hz, 2H), 7.65−7.50 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H),
7.29 (t, J = 8.4 Hz, 2H), 7.24−7.07 (m, 5H), 6.92−6.79 (m, 1H),
5.96−5.78 (m, 1H), 5.36−5.15 (m, 3H), 4.95−4.80 (m, 2H), 4.71−
4.53 (m, 3H), 4.47−4.34 (m, 2H), 4.31−4.19 (m, 2H), 4.10 (q, J = 7.2
Hz, 1H), 3.99−3.88 (m, 1H), 3.82−3.66 (m, 1H), 3.20−3.07 (m, 2H),
3.05−2.87 (m, 9H), 2.40−2.21 (m, 2H), 2.10−2.03 (m, 1H), 2.00−
1.91 (m, 1H), 1.87 (s, 3H), 1.66−1.56 (m, 1H), 1.48−1.38 (m, 3H),
1.33−1.11 (m, 7H), 0.97−0.62 (m, 24H), 0.12− −0.12 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 172.4, 172.1, 172.0, 171.0, 170.1, 169.9,
169.6, 168.9, 168.4, 166.7, 156.4, 144.1, 143.9, 142.3, 141.3, 136.7,
136.5, 131.6, 131.5, 129.4, 129.3, 128.3, 128.2, 127.9, 127.6, 127.1,
127.0, 126.6, 125.1, 119.9, 118.8, 77.9, 75.9, 70.8, 67.9, 67.7, 66.0, 65.8,
60.3, 54.1, 53.8, 53.1, 51.1, 50.2, 47.2, 45.2, 44.9, 41.2, 37.5, 36.3, 36.2,
35.2, 35.2, 35.1, 31.9, 30.9, 30.2, 30.1, 29.7, 29.3, 27.0, 26.8, 26.2, 26.1,
25.8, 22.7, 21.0, 17.9, 17.2, 16.9, 15.7, 15.2, 14.2, 14.1, 14.0, 13.9, 12.8,
12.4, 11.9, 11.6, 9.8, −4.5, −4.7. HRMS (ESI): calcd for
[C63H90N4O12Si + Na+] 1145.6222, found 1145.6201.
General Procedure for the Synthesis of 43, 49, 55, 61, and
65. To a solution of the carboxylic acid (0.63 mmol) in CH2Cl2 (10
mL) were added successively 31 (600 mg, 1.26 mmol), DMAP (384
mg, 3.15 mmol), and 2-methyl-6-nitrobenzoic anhydride (368 mg,
1.07 mmol). The mixture was stirred for 5 h and then concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel (PE/EA = 2/1) to give the
corresponding title compound.
Compound 43. Colorless oil (441 mg, 66%). [α]2D5 = +38.3 (c 1.54,
CHCl3). IR (film) νmax: 3409, 3302, 2967, 2934, 2873, 1747, 1650,
1456, 1390, 1246, 1154, 1097, 980, 939, 744, 693 cm−1. 1H NMR (400
MHz, CDCl3): δ 7.29−7.15 (m, 5H), 6.88−6.80 (m, 0.6H), 6.69−6.58
(m, 1H), 6.46−6.36 (m, 0.4H), 6.06−5.82 (m, 2H), 5.40−5.16 (m,
3H), 5.04−4.58 (m, 7H), 4.29 (d, J = 17.1 Hz, 1H), 3.98 (d, J = 17.1
Hz, 1H), 3.25−3.11 (m, 1.5H), 3.09−2.95 (m, 7.5H), 2.88−2.82 (m,
2H), 2.75−2.64 (m, 1H), 2.14−1.92 (m, 5H), 1.88−1.80 (m, 1H),
1.74−1.61 (m, 1H), 1.51−1.42 (m, 12H), 1.34−1.16 (m, 4H), 1.06
(dd, J = 18.1, 6.6 Hz, 3H), 0.95−0.82 (m, 15H). 13C NMR (100 MHz,
CDCl3): δ 172.3, 170.6, 170.0, 169.8, 169.6, 169.2, 168.9, 168.4, 167.2,
166.2, 153.8, 136.7, 131.7, 131.5, 129.4, 129.3, 128.3, 128.3, 126.7,
118.9, 94.4, 79.8, 76.8, 76.2, 66.1, 65.8, 53.9, 50.3, 45.0, 37.6, 37.3,
36.4, 36.3, 35.3, 35.1, 30.3, 30.1, 29.7, 28.4, 26.1, 17.4, 15.8, 14.0, 13.9,
12.8, 11.68, 11.4, 10.9, 10.0. HRMS (ESI): calcd for [C50H75Cl3N4O14
+ Na+] 1083.4243, found 1083.4249.
Compound 65. Colorless oil (410 mg, 58%). [α]2D5 = +34.8 (c 0.56,
CHCl3). IR (film) νmax: 2962, 2927, 2850, 1740, 1708, 1648, 1452,
1
1402, 1309, 1258, 1209, 1079 cm−1. H NMR (400 MHz, CDCl3): δ
7.75 (d, J = 7.5 Hz, 2H), 7.63−7.49 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H),
7.29 (t, J = 7.4 Hz, 2H), 7.25−7.09 (m, 5H), 6.90−6.76 (m, 1H),
6.66−6.52 (m, 1H), 5.94−5.70 (m, 2H), 5.36−5.11 (m, 2H), 4.94−
4.84 (m, 1H), 4.83−4.66 (m, 1H), 4.66−4.54 (m, 2H), 4.42−4.32 (m,
2H), 4.29−4.18 (m, 2H), 4.16−4.05 (m, 1H), 3.92 (d, J = 17.1 Hz,
1H), 3.78−3.61 (m, 1H), 3.20−3.07 (m, 2H), 3.05−2.83 (m, 9H),
2.36−2.21 (m, 2H), 2.10−1.91 (m, 2H), 1.88 (s, 3H), 1.68−1.54 (m,
1H), 1.48−1.36 (m, 3H), 1.35−1.07 (m, 7H), 0.96−0.80 (m, 21H),
0.79−0.74 (m, 2H), 0.70−0.63 (m, 1H), 0.07− −0.08 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 172.1, 171.7, 170.0, 169.8, 169.5, 168.9,
168.4, 166.8, 156.3, 144.0, 143.9, 142.3, 141.3, 136.6, 131.6, 131.5,
129.4, 129.2, 128.3, 128.2, 128.0, 127.7, 127.0, 126.6, 125.0, 119.9,
118.9, 78.1, 76.0, 70.9, 67.8, 66.1, 65.8, 54.2, 53.8, 50.2, 47.2, 45.2,
44.9, 41.1, 37.4, 36.3, 35.3, 35.2, 35.1, 30.8, 30.5, 30.3, 30.1, 26.8, 26.2,
26.1, 25.7, 17.9, 17.3, 15.0, 14.1, 13.9, 12.8, 12.4, 11.9, 11.6, 9.7, −4.6,
−4.5. HRMS (ESI): calcd for [C63H90N4O12Si + H+] 1123.6403,
found 1123.6412.
Compound 49. Colorless oil (424 mg, 60%). [α]2D5 = +40.3 (c 1.28,
CHCl3). IR (film) νmax: 3408, 2962, 2932, 2880, 2855, 1741, 1709,
1
1649, 1453, 1402, 1207, 1079 cm−1. H NMR (400 MHz, CDCl3): δ
7.79 (d, J = 7.5 Hz, 2H), 7.66−7.56 (m, 2H), 7.42 (t, J = 7.4 Hz, 2H),
7.33 (t, J = 7.3 Hz, 2H), 7.29−7.14 (m, 5H), 7.00−6.91 (m, 1H),
6.65−6.56 (m, 1H), 5.99−5.83 (m, 1H), 5.35 (d, J = 17.2 Hz, 1H),
5.28 (d, J = 10.4 Hz, 1H), 5.20 (dd, J = 13.7, 2.9 Hz, 1H), 4.99−4.89
(m, 1H), 4.83−4.72 (m, 1H), 4.71−4.59 (m, 3H), 4.54−4.38 (m, 2H),
4.34−4.23 (m, 2H), 4.06 (d, J = 18.2 Hz, 0.2H), 3.97 (d, J = 17.1 Hz,
0.8H), 3.82−3.73 (m, 1H), 3.25−3.12 (m, 1.5H), 3.10−2.90 (m,
10.5H), 2.49−2.36 (m, 1H), 2.33−2.20 (m, 1H), 2.03−1.87 (m, 5H),
1.70−1.60 (m, 1H), 1.42−1.33 (m, 1H), 1.32−1.18 (m, 2H), 1.17−
1.08 (m, 1H), 0.98−0.82 (m, 30H), 0.12−0.03 (m, 6H). 13C NMR
(100 MHz, CDCl3): δ 172.5, 172.2, 171.8, 170.1, 169.9, 169.4, 168.4,
166.6, 156.5, 144.1, 141.3, 140.4, 136.7, 131.7, 131.6, 129.5, 129.3,
128.3, 127.7, 127.1, 126.7, 125.0, 120.0, 118.9, 78.7, 76.2, 72.5, 67.8,
66.1, 65.8, 54.4, 53.8, 53.2, 50.3, 47.3, 45.3, 44.9, 40.3, 37.5, 37.1, 36.3,
35.1, 32.3, 30.3, 30.1, 26.1, 25.9, 18.0, 17.4, 15.9, 14.9, 14.0, 13.9, 12.9,
11.6, 11.5, 9.7, −4.3, −4.6. HRMS (ESI): calcd for [C63H90N4O12Si +
Na+] 1145.6222, found 1145.6223.
General Procedure for the Synthesis of 50, 56, and 57.
Compound 49 (for 50 and 57) or 55 (for 56) (0.25 mmol) and
Et2NH (2 mL) were stirred in CH3CN (4 mL) for 10 min. Then the
mixture was concentrated under reduced pressure, and the residue was
dissolved in CH2Cl2 (10 mL). To this solution were added
successively L-Boc-aIle-OH (for 50 and 56) or L-Boc-Ile-OH (for
57) (65 mg, 0.28 mmol), HATU (192 mg, 0.50 mmol), and DIPEA
(0.17 mL, 1.0 mmol). The mixture was stirred for 1 h and then
concentrated under reduced pressure. The crude product was purified
by flash chromatography on silica gel to give the desired compound.
Compound 50. Colorless oil (212 mg, 76%). [α]2D5 = +45.2 (c 0.69,
CHCl3). IR (film) νmax: 3325, 2964, 2927, 2875, 1718, 1648, 1498,
Compound 55. Colorless oil (445 mg, 63%). [α]2D5 = +39.0 (c 1.06,
CHCl3). IR (film) νmax: 3411, 2961, 2927, 1740, 1704, 1648, 1453,
1
1402, 1315, 1251, 1194, 1160, 1079, 836, 775, 741 cm−1. H NMR
(400 MHz, CDCl3): δ 7.79 (d, J = 7.4 Hz, 2H), 7.66−7.54 (m, 2H),
7.42 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.2 Hz, 2H), 7.28−7.14 (m, 5H),
7.00−6.89 (m, 1H), 6.74−6.58 (m, 1H), 6.00−5.83 (m, 1H), 5.35 (d, J
= 17.2 Hz, 1H), 5.30 (d, J = 3.9 Hz, 1H), 5.27−5.23 (m, 1H), 5.23−
5.16 (m, 0.5H), 4.96−4.87 (m, 1.5H), 4.80−4.72 (m, 0.7H), 4.68−
4.58 (m, 2.3H), 4.47−4.38 (m, 2H), 4.34−4.24 (m, 2H), 3.95 (d, J =
17.2 Hz, 1H), 3.73−3.65 (m, 1H), 3.32−3.24 (m, 0.3H), 3.23−3.12
(m, 1.5H), 3.08−2.92 (m, 10.2H), 2.69−2.55 (m, 0.6H), 2.43−2.31
1
1460, 1408, 1250, 1196, 1079 cm−1. H NMR (400 MHz, CDCl3): δ
7.28−7.12 (m, 5H), 6.99−6.87 (m, 1H), 6.63−6.52 (m, 1H), 5.96−
5.83 (m, 1H), 5.38−5.22 (m, 2H), 5.21−4.99 (m, 1.4H), 4.96−4.87
(m, 1H), 4.80−4.69 (m, 1H), 4.68−4.53 (m, 3.6H), 4.41 (d, J = 18.2
Hz, 0.2H), 4.27 (d, J = 17.1 Hz, 0.8H), 4.05 (d, J = 18.1 Hz, 0.2H),
3.95 (d, J = 17.1 Hz, 0.8H), 3.80−3.69 (m, 1H), 3.23−3.08 (m, 1.5H),
3.08−2.93 (m, 10.5H), 2.47−2.35 (m, 1H), 2.31−2.17 (m, 1H), 2.03−
M
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1.94 (m, 2H), 1.88 (s, 3H), 1.78−1.68 (m, 1H), 1.66−1.57 (m, 1H),
1.50−1.37 (m, 15H), 1.27−1.16 (m, 2H), 1.15−1.06 (m, 1H), 0.94−
0.79 (m, 33H), 0.11−0.01 (m, 6H). 13C NMR (100 MHz, CDCl3): δ
172.4, 172.2, 171.5, 170.1, 169.3, 168.8, 168.4, 166.6, 155.9, 140.4,
136.6, 131.6, 131.5, 129.4, 129.3, 128.6, 128.3, 126.6, 118.8, 79.4, 79.0,
76.2, 72.5, 66.1, 65.8, 53.8, 53.4, 53.2, 52.2, 51.2, 50.2, 45.2, 44.9, 40.2,
38.1, 37.4, 36.9, 36.3, 35.2, 35.1, 32.2, 31.3, 30.3, 30.1, 28.3, 26.7, 26.1,
25.8, 23.8, 18.0, 17.4, 17.2, 15.8, 14.3, 14.0, 13.9, 13.7, 12.9, 11.9, 11.6,
11.5, 9.8, −4.3, −4.7. HRMS (ESI): calcd for [C59H99N5O13Si + H+]
1114.7087, found 1114.7084.
7.31−7.24 (m, 2H), 7.22−7.08 (m, 5H), 6.67−6.58 (m, 1H), 5.87−
5.81 (m, 1H), 5.35−5.18 (m, 3H), 4.96−4.84 (m, 2H), 4.75−4.66 (m,
1H), 4.65−4.49 (m, 4H), 4.42−4.31 (m, 2H), 4.27−4.18 (m, 1H),
4.11−4.03 (m, 1H), 4.02−3.94 (m, 1H), 3.74−3.61 (m, 1H), 3.19−
3.07 (m, 2H), 3.05−2.94 (m, 6H), 2.92−2.84 (m, 3H), 2.51−2.41 (m,
1H), 2.39−2.27 (m, 1H), 2.00 (s, 3H), 1.96−1.87 (m, 2H), 1.85−1.82
(m, 2H), 1.48−1.36 (m, 4H), 1.24−1.19 (m, 3H), 1.16−1.11 (m, 1H),
1.06−1.00 (m, 1H), 0.98−0.65 (m, 33H), 0.11−0.03 (m, 6H). 13C
NMR (100 MHz, CDCl3): δ 172.9, 172.4, 171.3, 170.7, 169.9, 169.3,
169.3, 168.6, 168.1, 156.5, 143.9, 141.3, 136.4, 131.5, 129.3, 128.3,
128.2, 127.6, 127.0, 126.7, 125.0, 119.9, 118.9, 67.7, 65.8, 60.3, 56.4,
53.7, 52.6, 47.2, 45.0, 37.7, 37.4, 36.5, 35.1, 30.3, 29.6, 26.1, 26.0, 25.8,
25.1, 22.7, 21.0, 17.9, 17.3, 15.5, 14.2, 13.9, 12.88, 12.7, 12.2, 11.6,
11.5, 11.3, 10.7, 0.42, 0.39, −4.3. HRMS (ESI): calcd for
[C69H101N5O13Si + Na+] 1258.7063, found 1258.7060.
Compound 56. Colorless oil (209 mg, 75%). [α]2D5 = +36.1 (c 1.99,
CHCl3). IR (film) νmax: 3325, 2964, 2933, 1718, 1648, 1498, 1461,
1408, 1250, 1408, 1250, 1194, 1080 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.29−7.12 (m, 5H), 6.96−6.87 (m, 1H), 6.68−6.55 (m,
1H), 5.94−5.85 (m, 1H), 5.38−5.30 (m, 2H), 5.26−5.12 (m, 1.5H),
4.95−4.86 (m, 1H), 4.81−4.71 (m, 1H), 4.70−4.57 (m, 3.5H), 4.43
(d, J = 18.2 Hz, 0.2H), 4.29 (d, J = 17.1 Hz, 0.8H), 4.05 (d, J = 18.1
Hz, 0.2H), 3.95 (d, J = 17.1 Hz, 0.8H), 3.76−3.65 (m, 1H), 3.30−3.11
(m, 1.6H), 3.10−2.90 (m, 10.4H), 2.64−2.50 (m, 1H), 2.44−2.31 (m,
1H), 2.04−1.97 (m, 1H), 1.93 (s, 3H), 1.90−1.80 (m, 2H), 1.79−1.65
(m, 2H), 1.52−1.34 (m, 15H), 1.24−1.17 (m, 1H), 1.11−1.03 (m,
1H), 0.99−0.78 (m, 33H), 0.10−0.03 (m, 6H). 13C NMR (100 MHz,
CDCl3): δ 172.5, 172.2, 171.5, 170.1, 169.8, 169.3, 169.2, 168.8, 168.4,
166.5, 156.0, 139.9, 136.7, 131.6, 131.5, 129.4, 129.3, 128.6, 128.3,
128.3, 126.7, 118.9, 79.4, 78.3, 76.1, 72.5, 66.1, 65.8, 60.3, 53.8, 53.4,
52.3, 51.2, 50.3, 45.2, 44.9, 39.3, 37.5, 37.5, 36.3, 36.3, 35.2, 35.1, 33.9,
31.3, 30.3, 30.1, 28.3, 26.7, 26.1, 25.8, 24.0, 21.0, 18.0, 17.4, 15.4, 14.4,
14.2, 14.0, 13.9, 13.7, 12.9, 11.9, 11.6, 11.2, 10.3, −3.9, −4.1, −4.6.
HRMS (ESI): calcd for [C59H99N5O13Si + H+] 1114.7087, found
1114.7079.
Compound 62. Colorless oil (281 mg, 91%). [α]2D5 = +19.5 (c 1.02,
CHCl3). IR (film) νmax: 3349, 2964, 2927, 1730, 1694, 1648, 1453,
1252, 1209, 1150, 1094 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.74 (d,
J = 7.5 Hz, 2H), 7.63−7.49 (m, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.29 (t, J
= 7.4 Hz, 2H), 7.24−7.09 (m, 5H), 6.89−6.80 (m, 1H), 5.92−5.84 (m,
1H), 5.36−5.16 (m, 3H), 4.91−4.80 (m, 2H), 4.68−4.48 (m, 5H),
4.45−4.32 (m, 2H), 4.28−4.19 (m, 1H), 4.12−4.02 (m, 1H), 3.98−
3.89 (m, 1H), 3.79−3.69 (m, 1H), 3.19−3.07 (m, 2H), 3.07−2.88 (m,
9H), 2.37−2.23 (m, 2H), 2.05−1.89 (m, 4H), 1.85 (s, 3H), 1.73−1.54
(m, 2H), 1.49−1.37 (m, 4H), 1.29−1.07 (m, 6H), 0.97−0.70 (m,
30H), 0.07− −0.03 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 172.4,
172.0, 171.9, 171.3, 170.7, 169.6, 168.1, 166.8, 156.4, 144.0, 143.9,
142.3, 141.2, 136.4, 131.5, 129.3, 128.3, 127.9, 127.6, 127.0, 126.7,
125.1, 119.9, 118.9, 78.0, 75.9, 70.8, 67.7, 65.8, 56.4, 54.1, 53.7, 52.7,
47.2, 44.9, 41.2, 38.0, 37.7, 37.4, 36.5, 36.2, 35.1, 30.9, 30.3, 30.1, 26.8,
26.1, 25.8, 25.2, 25.1, 23.3, 17.9, 17.1, 15.5, 15.4, 15.2, 13.9, 12.8, 12.4,
11.9, 11.7, 11.6, 11.6, 9.8, −4.5, −4.7. HRMS (ESI): calcd for
[C69H101N5O13Si + Na+] 1258.7063, found 1258.7063.
Compound 57. Colorless oil (220 mg, 79%). [α]2D5 = +30.4 (c 0.46,
CHCl3). IR (film) νmax: 2964, 2933, 2875, 1735, 1718, 1654, 1649,
1513, 1497, 1460, 1250, 1195, 1079 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.25−7.09 (m, 5H), 6.94−6.84 (m, 1H), 6.64−6.53 (m,
1H), 5.94−5.78 (m, 2H), 5.30−5.23 (m, 2H), 5.19−5.10 (m, 1H),
4.94−4.85 (m, 1H), 4.75−4.68 (m, 1H), 4.63−4.54 (m, 3H), 4.52−
4.44 (m, 1H), 4.24 (d, J = 17.3 Hz, 1H), 3.94 (d, J = 17.1 Hz, 1H),
3.76−3.68 (m, 1H), 3.21−3.07 (m, 2H), 3.06−2.79 (m, 10H), 2.45−
2.34 (m, 1H), 2.26−2.17 (m, 1H), 2.00−1.90 (m, 2H), 1.86 (s, 3H),
1.77−1.69 (m, 1H), 1.62−1.55 (m, 1H), 1.50−1.30 (m, 15H), 1.21−
1.14 (m, 1H), 1.12−1.03 (m, 2H), 0.99−0.67 (m, 33H), 0.09− −0.02
(m, 6H). 13C NMR (100 MHz, CDCl3): δ 172.8, 172.5, 172.2, 171.4,
170.0, 169.8, 169.4, 169.2, 168.8, 168.4, 166.6, 155.8, 140.4, 136.6,
136.5, 131.6, 131.5, 129.4, 129.2, 128.5, 128.3, 128.2, 126.6, 118.9,
79.5, 78.9, 76.1, 72.3, 66.1, 65.8, 54.7, 53.8, 52.3, 50.2, 44.9, 40.5, 37.9,
37.4, 36.8, 36.3, 35.3, 35.2, 35.0, 32.2, 31.6, 30.3, 30.1, 28.3, 26.1, 25.9,
25.8, 23.9, 23.8, 18.0, 17.3, 17.1, 15.8, 15.6, 14.4, 13.9, 13.9, 12.9, 12.8,
11.6, 11.4, 11.3, 9.8, −4.3, −4.7. HRMS (ESI): calcd for
[C59H99N5O13Si + H+] 1114.7087, found 1114.7080.
Compound 66. Colorless oil (247 mg, 80%). [α]2D5 = +25.2 (c 1.82,
CHCl3). IR (film) νmax: 3338, 2964, 2927, 2875, 1737, 1686, 1648,
1453, 1402, 1251, 1211, 1149, 1079 cm−1. 1H NMR (400 MHz,
CDCl3): δ 7.74 (d, J = 7.5 Hz, 2H), 7.69−7.48 (m, 2H), 7.37 (t, J =
7.4 Hz, 2H), 7.28 (t, J = 7.3 Hz, 2H), 7.23−7.05 (m, 5H), 6.89−6.72
(m, 1H), 5.94−5.75 (m, 1H), 5.36−5.13 (m, 2H), 4.95−4.81 (m, 2H),
4.73−4.49 (m, 6H), 4.43−4.31 (m, 2H), 4.29−4.16 (m, 1H), 4.14−
3.90 (m, 2H), 3.75−3.59 (m, 1H), 3.19−3.07 (m, 2H), 3.08−2.82 (m,
9H), 2.35−2.20 (m, 2H), 2.10−1.92 (m, 4H), 1.86 (s, 3H), 1.67−1.52
(m, 2H), 1.47−1.27 (m, 6H), 1.27−1.11 (m, 4H), 0.98−0.69 (m,
30H), 0.06− −0.07 (m, 6H). 13C NMR (100 MHz, CDCl3): δ 172.9,
172.4, 171.8, 171.7, 171.3, 171.2, 170.7, 169.5, 168.1, 166.8, 156.3,
144.0, 143.9, 142.2, 141.3, 136.4, 131.5, 129.3, 129.2, 128.3, 128.2,
127.7, 127.0, 126.7, 125.0, 119.9, 118.9, 78.1, 75.9, 70.9, 67.8, 65.8,
65.7, 56.6, 56.4, 54.2, 53.7, 52.6, 47.2, 45.0, 41.1, 38.0, 37.7, 37.4, 36.5,
36.2, 35.1, 30.8, 30.5, 30.3, 26.8, 26.1, 25.8, 25.7, 25.2, 25.1, 17.9, 17.2,
15.5, 15.5, 15.4, 15.0, 14.0, 12.8, 12.4, 12.0, 11.6, 11.6, 11.5, 9.7, −4.5,
−4.6. HRMS (ESI): calcd for [C69H101N5O13Si + Na+] 1258.7063,
found 1258.7055.
General Procedure for the Synthesis of 45, 1, and 1b.
Compound 44, 50, or 56 (0.023 mmol), Pd(PPh3)4 (5 mg, 4.6 μmol),
and PhNHMe (6 mg, 0.057 mmol) were stirred in anhydrous THF (3
mL) for 1 h and diluted with EtOAc (50 mL). The mixture was
washed with 1 M aqueous HCl (20 × 2), dried (MgSO4), filtered, and
concentrated under reduced pressure. Then the residue was treated
with TFA (1 mL) in CH2Cl2 (2 mL) for 1 h and concentrated. The
residue was dissolved in CH2Cl2 (23 mL), and HATU (87 mg, 0.23
mmol) and DIPEA (57 μL, 0.35 mmol) were added successively. After
the mixture was stirred for 3 days, the solvent was evaporated, and the
residue was purified by flash chromatography on silica gel (PE/acetone
= 2/1) to give the corresponding title compound, which was further
purified by preparative HPLC (Waters 2535 quaternary gradient
module, Waters 2707 autosampler, and Waters 2489 UV/vis detector;
SunFire C18 column, 10 μm, 19 mm × 250 mm).
General Procedure for the Synthesis of 58, 62, and 66.
Compound 49, 61, or 65 (280 mg, 0.25 mmol) and Pd(PPh3)4 (58
mg, 0.05 mmol) in anhydrous THF (5 mL) were treated with
PhNHMe (69 mg, 0.63 mmol) at room temperature. After the mixture
was stirred for 30 min, the mixture was diluted with EtOAc (100 mL)
and then washed with 1 M aqueous HCl (20 mL × 2), dried, filtered,
and concentrated to give the crude carboxylic acid as a yellow oil. To a
cooled solution (0 °C) of L-Boc-Ile-OAllyl (136 mg, 0.50 mmol) in
CH2Cl2 (2 mL) was added TFA (1 mL), and the resulting solution
was stirred for 2 h. Then the mixture was concentrated under reduced
pressure, and the residue was dissolved in CH2Cl2 (5 mL). The above
crude carboxylic acid (in 5 mL of CH2Cl2), HATU (190 mg, 0.50
mmol), and DIPEA (0.12 mL, 0.75 mmol) were then added
successively. After the mixture was stirred for 1 h, it was concentrated
under reduced pressure, and the residue was purified by flash
chromatography on silica gel (PE/EA = 1/1) to give the desired
compound.
Compound 58. Colorless oil (263 mg, 85%). [α]2D5 = +36.4 (c 1.1,
CHCl3). IR (film) νmax: 2965, 2934, 2877, 1735, 1691, 1643, 1577,
Compound 45. Amorphous solid (4.2 mg, 22%; MeOH/H2O =
91/9, 10 mL/min, 270 nm, RT = 19.532 min). [α]2D5 = −37.9 (c 0.075,
CH3OH). 1H NMR (600 MHz, CD3OD): δ 7.56 (d, J = 11.1 Hz, 1H),
1
1514, 1453, 1397, 1328, 1150 cm−1. H NMR (400 MHz, CDCl3): δ
7.73 (d, J = 7.4 Hz, 2H), 7.60−7.47 (m, 2H), 7.36 (t, J = 7.4 Hz, 2H),
N
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.27−7.08 (m, 5H), 6.77 (dd, J = 14.8, 9.9 Hz, 1H), 6.37 (dd, J = 14.9,
11.1 Hz, 1H), 5.52 (dd, J = 10.8, 4.8 Hz, 1H), 4.92 (d, J = 7.8 Hz, 1H),
4.90 (dd, J = 4.8, 1.8 Hz, 1H), 4.73 (dd, J = 10.5, 2.3 Hz, 1H), 4.45 (q,
J = 7.0 Hz, 1H), 4.23 (d, J = 18.3 Hz, 1H), 3.90 (q, J = 6.9 Hz, 1H),
3.31 (s, 3H), 3.21 (d, J = 18.2 Hz, 1H), 3.11−3.04 (m, 1H), 3.03 (s,
3H), 2.94 (dd, J = 14.4, 4.8 Hz, 1H), 2.81 (s, 3H), 2.70−2.63 (m, 1H),
1.97 (s, 3H), 1.92−1.81 (m, 2H), 1.76−1.69 (m, 1H), 1.57 (d, J = 6.9
Hz, 3H), 1.51−1.40 (m, 3H), 1.37−1.30 (m, 2H), 1.26−1.20 (m, 1H),
1.06 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 1.00 (t, J = 7.4 Hz,
3H), 0.95−0.90 (m, 9H), 0.86 (t, J = 7.4 Hz, 3H), 0.80 (d, J = 7.0 Hz,
3H). 13C NMR (150 MHz, CD3OD): δ 173.6, 171.4, 171.3, 171.2,
170.4, 169.4, 169.0, 149.2, 142.1, 137.0, 129.2, 127.6, 126.0, 123.7,
123.4, 80.2, 75.6, 60.4, 53.7, 53.6, 52.7, 51.4, 45.1, 38.2, 37.4, 37.1,
35.2, 34.4, 34.3, 29.2, 26.2, 25.7, 25.0, 14.1, 13.6, 13.4, 12.9, 12.8, 11.7,
11.1, 10.5, 10.5, 9.5. HRMS (ESI): calcd for [C45H69N5O9 + Na+]
846.4993, found 846.4991.
7-epi-Lagunamide A (1c). Amorphous solid (4.5 mg, 38%;
MeOH/H2O = 90/10, 10 mL/min, 270 nm, RT = 17.690 min).
[α]2D1 = −64.7 (c 0.04, MeOH). 1H NMR (500 MHz, MeOD): δ 8.38
(d, J = 6.3 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.26−7.14 (m, 5H), 7.12
(dd, J = 10.1, 3.2 Hz, 1H), 5.54 (dd, J = 10.7, 5.0 Hz, 1H), 5.04 (d, J =
10.0 Hz, 1H), 4.93 (d, J = 3.1 Hz, 1H), 4.84 (t, J = 8.7 Hz, 1H), 4.49
(p, J = 7.0 Hz, 1H), 4.27 (d, J = 18.2 Hz, 1H), 4.06 (td, J = 9.7, 2.4 Hz,
1H), 3.94 (q, J = 6.8 Hz, 1H), 3.38 (s, 3H), 3.31−3.30 (m, 1H), 3.10−
3.06 (m, 1H), 3.05 (s, 3H), 2.97 (dd, J = 14.4, 5.0 Hz, 1H), 2.84 (s,
3H), 2.50−2.42 (m, 1H), 2.28−2.19 (m, 1H), 1.93 (s, 3H), 1.91−1.88
(m, 1H), 1.88−1.74 (m, 3H), 1.71−1.62 (m, 1H), 1.52 (d, J = 6.9 Hz,
3H), 1.51−1.45 (m, 2H), 1.40−1.31 (m, 2H), 1.16−1.09 (m, 1H),
0.98 (t, J = 5.9 Hz, 3H), 0.97−0.87 (m, 18H), 0.80 (d, J = 7.0 Hz, 3H).
13C NMR (125 MHz, MeOD): δ 173.5, 172.6, 172.1, 171.0, 170.9,
168.9, 168.5, 145.0, 136.8, 129.1, 127.5, 127.0, 125.9, 78.6, 75.6, 70.9,
60.7, 53.6, 52.9, 51.1, 44.9, 40.2, 37.5, 37.1, 36.4, 34.8, 34.2, 34.2, 32.5,
29.0, 26.0, 25.2, 23.8, 14.1, 14.0, 13.5, 12.7, 12.6, 11.2, 10.4, 9.6, 9.3,
8.3. HRMS (ESI): calcd for [C45H71N5O10 + H+] 842.5279, found
842.5277.
7,39-epi-Lagunamide A (1). Amorphous solid (5.8 mg, 30%;
MeOH/H2O = 86/14, 10 mL/min, 220 nm, RT = 28.132 min). [α]D25
7
= −32.9 (c 0.2, CH3OH) {lit [α]2D0 = −31.0 (c 0.5, CH3OH)}. H
NMR (500 MHz, MeOD): δ 7.28−7.12 (m, 6H), 5.53 (dd, J = 10.6,
5.1 Hz, 1H), 5.10 (dd, J = 10.3, 1.3 Hz, 1H), 4.98 (d, J = 6.1 Hz, 1H),
4.91−4.90 (m, 1H), 4.50 (q, J = 7.0 Hz, 1H), 4.27 (d, J = 18.3 Hz,
1H), 4.06 (td, J = 9.2, 3.5 Hz, 1H), 3.92 (q, J = 6.8 Hz, 1H), 3.34 (d, J
= 18.3 Hz, 1H), 3.33 (s, 3H), 3.09−3.02 (m, 1H), 3.05 (s, 3H), 2.97
(dd, J = 14.4, 5.1 Hz, 1H), 2.84 (s, 3H), 2.52−2.45 (m, 1H), 2.28−
2.20 (m, 1H), 1.93 (s, 3H), 1.91−1.87 (m, 1H), 1.85−1.76 (m, 3H),
1.56−1.46 (m, 3H), 1.50 (d, J = 6.9 Hz, 3H), 1.40−1.32 (m, 2H),
1.16−1.09 (m, 1H), 1.03 (t, J = 7.4 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H),
0.96−0.87 (m, 15H), 0.81 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz,
MeOD): δ 175.1, 174.0, 173.4, 172.7, 172.5, 170.4, 169.9, 146.4, 138.4,
130.7, 129.1, 128.5, 127.5, 80.0, 77.2, 72.6, 62.1, 55.2, 53.9, 52.8, 46.4,
42.2, 38.8, 38.7, 38.4, 36.5, 36.0, 35.8, 34.8, 30.6, 27.6, 27.4, 26.8, 15.7,
15.2, 14.8, 14.3, 14.2, 12.8, 12.2, 12.0, 10.9, 9.9. HRMS (ESI): calcd for
[C45H71N5O10 + Na+] 864.5099, found 864.5098.
1
Lagunamide A (1a). Amorphous solid (4.5 mg, 38%; MeOH/H2O
= 83/17, 10 mL/min, 220 nm, RT = 27.959 min). [α]2D5 = −34.9 (c
0.04 CH3OH) {lit [α]D25 = −36 (c 0.5, CH3OH),6a [α]D20 = −33.8 (c
7
1
0.1, CH3OH) }. H NMR (500 MHz, MeOD): δ 7.32 (dd, J = 10.5,
2.2 Hz, 1H), 7.22−7.12 (m, 5H), 5.46 (dd, J = 10.5, 5.1 Hz, 1H), 5.06
(d, J = 6.2 Hz, 1H), 4.93−4.92 (m, 1H), 4.87 (d, J = 3.7 Hz, 1H), 4.50
(q, J = 7.0 Hz, 1H), 4.20 (d, J = 18.4 Hz, 1H), 3.95 (q, J = 6.9 Hz,
1H), 3.75 (dd, J = 10.5, 1.8 Hz, 1H), 3.57 (d, J = 18.3 Hz, 1H), 3.30 (s,
3H), 3.08−3.02 (m, 1H), 3.05 (s, 3H), 2.94 (dd, J = 14.4, 5.1 Hz, 1H),
2.89 (s, 3H), 2.30−2.21 (m, 1H), 2.19−2.12 (m, 1H), 2.07−2.01 (m,
1H), 1.91 (s, 3H), 1.89−1.79 (m, 2H), 1.71−1.61 (m, 2H), 1.55−1.47
(m, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.38−1.29 (m, 3H), 1.17−1.09 (m,
1H), 1.05 (d, J = 6.8 Hz, 3H), 1.00−0.88 (m, 18H), 0.85 (d, J = 7.0
Hz, 3H). 13C NMR (125 MHz, MeOD): δ 174.9, 173.0, 172.9, 172.7,
172.6, 171.3, 170.4, 146.9, 138.4, 130.7, 129.1, 128.6, 127.5, 79.0, 77.6,
71.5, 60.3, 55.0, 54.7, 52.7, 46.5, 41.3, 39.4, 38.6, 38.4, 37.7, 36.6, 35.9,
30.6, 28.3, 27.5, 24.7, 16.0, 15.6, 14.6, 13.8, 12.9, 12.5, 12.4, 11.9, 11.7,
10.1. HRMS (ESI): calcd for [C45H71N5O10 + Na+] 864.5099, found
864.5101.
7,37,39-epi-Lagunamide A (1b). Amorphous solid (6.2 mg, 32%;
MeOH/H2O = 83/17, 10 mL/min, 220 nm, RT = 18.114 min). [α]D25
7
1
= −33.2 (c 0.18, CHCl3) {lit [α]2D0 = −4.6 (c 0.2, CH3OH)}. H
NMR (500 MHz, MeOD): δ 7.28 (dd, J = 11.2, 3.0 Hz, 1H), 7.25−
7.10 (m, 5H), 5.51 (dd, J = 10.6, 5.0 Hz, 1H), 4.96−4.94 (m, 1H),
4.94−4.91 (m, 2H), 4.48 (q, J = 7.0 Hz, 1H), 4.24 (d, J = 18.4 Hz,
1H), 3.91−3.83 (m, 2H), 3.31 (s, 3H), 3.22 (d, J = 18.4 Hz, 1H),
3.09−3.03 (m, 1H), 3.05 (s, 3H), 2.96 (dd, J = 14.4, 5.0 Hz, 1H), 2.86
(s, 3H), 2.67−2.61 (m, 1H), 2.23−2.15 (m, 1H), 1.94 (s, 3H), 1.93−
1.87 (m, 1H), 1.83−1.72 (m, 3H), 1.53 (d, J = 6.9 Hz, 3H), 1.50−1.42
(m, 2H), 1.41−1.31 (m, 3H), 1.27−1.20 (m, 1H), 1.11 (d, J = 6.7 Hz,
3H), 1.05 (d, J = 6.7 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H), 0.95 (t, J = 7.4
Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H), 0.89 (t, J =
7.3 Hz, 3H), 0.83 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, MeOD):
δ 175.1, 172.8, 172.7, 171.8, 170.6, 170.4, 146.2, 138.4, 130.7, 129.2,
129.1, 127.5, 79.3, 77.1, 73.1, 61.8, 55.2, 54.0, 52.8, 46.5, 42.2, 38.9,
38.8, 38.7, 36.0, 35.9, 35.8, 30.6, 27.7, 27.0, 26.4, 15.5, 15.1, 14.9, 14.4,
2-epi-Lagunamide A (1d). Amorphous solid (5.3 mg, 45%;
MeOH/H2O = 86/14, 10 mL/min, 220 nm, RT = 19.035 min).
[α]2D5 = +3.6 (c 0.46, CH3OH). 1H NMR (500 MHz, MeOD): δ 7.27−
7.13 (m, 5H), 7.06−7.02 (m, 1H), 5.50 (dd, J = 10.4, 5.3 Hz, 1H),
4.97 (d, J = 7.4 Hz, 1H), 4.90−4.88 (m, 1H), 4.87 (d, J = 3.5 Hz, 1H),
4.57−4.47 (m, 2H), 4.24 (d, J = 18.2 Hz, 1H), 3.87−3.81 (m, 1H),
3.53 (d, J = 18.1 Hz, 1H), 3.24 (s, 3H), 3.08−3.02 (m, 1H), 3.04 (s,
3H), 2.96 (dd, J = 14.4, 5.2 Hz, 1H), 2.89 (s, 3H), 2.33−2.24 (m, 1H),
2.21−2.14 (m, 1H), 2.06−2.00 (m, 1H), 1.91 (s, 3H), 1.90−1.86 (m,
2H), 1.77−1.68 (m, 2H), 1.55−1.50 (m, 1H), 1.48 (d, J = 7.3 Hz,
3H), 1.37−1.26 (m, 3H), 1.19−1.12 (m, 1H), 1.00−0.89 (m, 21H),
0.84 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, MeOD): δ 173.33,
172.28, 171.1, 170.9, 170.7, 169.9, 168.7, 144.4, 136.7, 129.1, 127.5,
125.9, 77.5, 76.0, 70.1, 55.9, 53.8, 53.5, 51.1, 44.7, 40.0, 37.6, 37.0,
36.4, 34.8, 34.2, 32.1, 29.5, 29.0, 26.5, 25.9, 23.4, 14.2, 14.1, 13.4, 12.9,
12.7, 12.0, 11.9, 11.1, 9.8. HRMS (ESI): calcd for [C45H71N5O10
+
Na+] 864.5099, found 864.5100.
General Procedure for the Synthesis of 1c, 1a, and 1d.
Compound 58, 62, or 66 (17 mg, 0.014 mmol), Pd(PPh3)4 (3.5 mg,
2.8 μmol), and PhNHMe (4 mg, 0.035 mmol) were stirred in
anhydrous THF (5 mL) for 30 min and diluted with EtOAc (50 mL).
The mixture was washed with 1 M aqueous HCl (20 mL × 2), dried,
filtered, and concentrated under reduced pressure. Then the residue
was treated with Et2NH (1 mL) in CH3CN (2 mL) for 15 min.
Volatiles were evaporated, and the residue was dissolved in CH2Cl2
(14 mL). To this solution were added HATU (54 mg, 0.14 mmol) and
DIPEA (35 μL, 0.21 mmol). After being stirred 3 days, the resulting
mixture was concentrated, and the residue was treated with 40%
aqueous HF (1 mL) in CH3CN (4 mL) for 1 h. Then the mixture was
diluted with EtOAc (100 mL), washed with saturated NaHCO3
aqueous solution (30 mL) and brine (50 mL × 2), dried, filtered,
and concentrated, and the residue was purified by flash chromatog-
raphy on silica gel (PE/acetone = 2/1) give the corresponding title
compound.
11.5, 11.0, 10.8, 10.4, 9.9, 8.7. HRMS (ESI): calcd for [C45H71N5O10
+
Na+] 864.5099, found 864.5098.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H and 13C NMR spectra of related compounds and
HPLC graphs for crude 27aa and 27ab in Table 2. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: bgwei1974@fudan.edu.cn. Fax: (+86)-21-5423-7757.
O
dx.doi.org/10.1021/jo401687s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4919. (d) Huang, W.; Ma, J.-Y.; Yuan, M.; Xu, L.-F.; Wei, B.-G.
Tetrahedron 2011, 67, 7829.
Present Address
§OSI Pharmaceuticals, 1 Bioscience Park Drive, Farmingdale,
NY 11735, USA.
(9) (a) Huang, W.-F.; Li, Q.-R.; Chao, L.-M.; Lei, X.-S.; Wei, B.-G.
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21272041, 21072034, 20832005) and the Key Laboratory of
Synthetic Chemistry of Natural Substances, SIOC, Chinese
Academy of Sciences, as well as the National Basic Research
Program (973 Program) of China (Grant 2010CB912600) for
financial support. The authors also thank Dr. Xin-Sheng Lei for
helpful suggestions.
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