Total synthesis of emericellamides A and B

Article abstract of DOI:10.1016/j.tet.2009.01.082

The total synthesis of emericellamides A and B is reported. A convergent, flexible strategy employing peptide chemistry, asymmetric alkylations, and culminating in macrolactamization is described. The previously reported structure of both compounds is confirmed.

Full text of DOI:10.1016/j.tet.2009.01.082

Tetrahedron 65 (2009) 2695–2702
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis of emericellamides A and B
,
,
b
,
a,b,
*
Shuo Li a, Shuo Liang a, Wenfei Tan a b, Zhengshuang Xu a , Tao Ye
*
a Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China
b Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The total synthesis of emericellamides A and B is reported. A convergent, flexible strategy employing
peptide chemistry, asymmetric alkylations, and culminating in macrolactamization is described. The
previously reported structure of both compounds is confirmed.
Received 9 November 2008
Received in revised form 13 January 2009
Accepted 16 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 14 February 2009
Keywords:
Total synthesis
Emericellamides A and B
Structure confirmation
1. Introduction
di- or trimethyl hydroxy acid. The absolute configurations of the
amino acids, and those of the stereogenic centers on the side chain,
Marine organisms have provided chemists with a wealth of
structurally diverse compounds over recent years, and many of
these compounds have shown considerable biological activities.1 To
date, antimicrobial, antiviral, antitumor, and anti-inflammatory
action has been identified amongst this range of secondary me-
tabolites. Some of these compounds are in advanced clinical trials,
and others have proven useful in studies directed toward the elu-
cidation of biochemical pathways.1,2 The structures vary from
cyclopeptides to cyclodepsipeptides that embody both polypeptide
and polyketide domains displaying conformational flexibility.3 This
combination of unusual structures and promising biological activ-
ity makes these compounds an attractive target for synthetic and
medicinal chemists alike. We have been interested for some time in
marine cyclopeptides and cyclodepsipeptides,4 and view their
syntheses as a key route to structural modification and subsequent
activity control. Here we report on our efforts in the total synthesis
of emericellamides A and B.5
were established by application of the Marfey’s method, by J-based
configuration analysis, and by application of the modified Mosher
method. There was also considerable reliance on NOE data for the
configurations on the side chain. Emericellamides A and B showed
antibacterial activities against methicillin-resistant Staphylococcus
aureus with MIC values of 3.8 and 6.0 mM, respectively.
It can be seen from the retrosynthetic analysis that there are
a number of possible positions to close the macrocyclic portion of
the molecule (Scheme 1). We chose to close the cyclodepsipeptide
via macrolactamization between the two alanine residues because
it allowed versatility in the construction of the cyclization pre-
cursor (3, 4a), in terms of the b-hydroxy acid portion of the mole-
cule. Disconnection at this point gives a polyketide fragment (6, 7a),
which can be prepared from the substituted alcohol (10a, 11a). It
was envisaged that the peptide couplings would be carried out
under standard conditions, which left the disconnection of the acid.
There are two target emericellamides and so a versatile approach to
each, allowing modification of the acid chain, was sought (10a,11a).
The desired stereochemistry was to be obtained using a combina-
tion of alkylations following Evans’ protocol7 and asymmetric
crotylations8 carried out with enantiopure diisopinocampheylbor-
ane derived reagents.
Given the small sample available to Fenical and the difficulty in
unequivocally interpreting NOE data for side-chains due to possible
modes of folding, we took the view that the correct structure for 2
could possibly have been the C-25 epimer, instead of that pub-
lished. With this in mind, it was decided to make both enantiomers
of key alcohols 10a, 10b to ensure that both C-25 epimers could be
made, as well as the reported structure of emericellamide A.
2. Results and discussion
Emericellamides A and B were isolated from marine-derived
fungus Emericella sp. with the proposed stereochemistry as shown
in Scheme 1 (1, 2).6 Structurally, the emericellamides (Scheme 1, 1,
2) contain two main portions: a pentapeptide and an adjoining
* Corresponding authors. Tel.: þ86 755 26032697; fax: þ86 755 26032290.
E-mail address: bctaoye@inet.polyu.edu.hk (T. Ye).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.082

2696
S. Li et al. / Tetrahedron 65 (2009) 2695–2702
H
N
16
15
19
1, (COCl)2, DMSO, DIPEA, -78 °C
20
O
22
O
24
H
N
21
25
18
23
t
n
n
2, KOBu , trans-2-butene, LiBu ,
(-)-Ipc2BOMe, BF3.OEt2, -78°C,
3 N NaOH, 30% H2O2
14
17
O
7
OH
OH
O
10a
8
O
3
13
O
1
H
NH
8
O
2
N
EDC, DMAP,
L-N-Boc-Ala-OH,
CH2Cl2
5
6
4
, Emericellamide A, n = 0
1
N
H
11
90%
75%; dr > 98:2
10
, Emericellamide B, n = 1
2
O
9
12
H
N
1, OsO4-NaIO4, 2,6-lutidine,
dioxane-H2O;
20
O
22
O
24
H
N
25
n
2, NaClO2, CH3SO2NH2,
O
O
OH
O
O
O
O
t
pH = 7.0, Bu OH-H2O
NH
O
HN
BocHN
76%
15
BocHN
O
6
t
OBu
Boc
3, n = 0
EDC, HOBt, DIPEA,
4a, n = 1
t
HN
L-Gly-Val-Leu-Ala-O Bu
O
HATU,
DIPEA,
DMF/
H
N
H
N
NHCbz
H
N
H
N
H
N
O
O
22
O
HO 20
O
24
O
CH2Cl2,
(72%)
O
O
O
O
O
O
n
25
O
O
+
NH
O
H
NH
NH
O
O
or
HN
t
N
O
DEPC,
DIPEA,
DMF,
(76%)
O
N
H
OBu
t
Boc
OBu
O
6, n = 0
HN
HN
Boc
3
HN
O
7a, n = 1
O
1, Emericellamide A
5
Scheme 3. Synthesis of emericellamide A.
20
22
24
22
HO
24
25
n
25
n
OH
8, n = 0; 9a, n = 1
10a, n = 0; 11a, n = 1
in 76% yield. Oxidative cleavage of the olefin of 15 using OsO4–
NaIO4 in the presence of 2,6-lutidine,11 followed by Pinnick
oxidation12 afforded the carboxylic acid 6, which was then
Scheme 1. Retrosynthetic analysis of emericellamides.
activated and coupled with L-Gly-L-Val-L-Leu-L
-Ala-OtBu, to give 3
in 76% yield over the three steps. Simultaneous removal of both
Boc and tert-butyl protecting groups using TFA in dichloro-
methane, followed by macrolactamization promoted with
O-(7-azabenzotriazol-1-yl)-N,N,N0,N0-tetramethyl-uronium hexa-
fluorophosphate (HATU)13 or diethyl cyanophosphonate (DEPC),14
gave emericellamide A (1) in 72% and 76% yield, respectively
(Scheme 3).
The characterization data obtained for compound 1 agreed
satisfactorily with that of the natural product, thus confirming its
structure. In terms of specific optical rotation, we obtained a value
of ꢀ39 (c 0.28, MeOH) compared to a literature value of ꢀ43 (c 0.23,
MeOH).6 This result confirmed the stereochemistry of the 3-hy-
droxy-2,4-dimethyldecanoic acid (HDMD) portion within emer-
icellamide A. The HDMD fragment is known to appear in another
The synthesis commenced with formation of both enantiomers
of N-octanoyl-4-benzyloxazolidinone using standard procedures.
Starting from (S)-4-benzyloxazolidinone (12a), this afforded 13a in
78%, which was then treated with NaHMDS and methyl iodide in
THF at ꢀ78 ꢁC to give the alkylated product 14a9 in 76% yield as
a single diastereoisomer. Reductive cleavage of the chiral auxiliary
using LiBH4 gave an almost quantitative yield of substituted
alcohol 10a,10 which was a precursor to the substituted acid por-
tion of both emericellamide A and B. Alcohol 10b was prepared
from (R)-4-benzyloxazolidinone (12b) in a similar reaction se-
quence for the preparation of the C-25 epimer of emericellamide B
(Scheme 2).
Focusing on emericellamide A, a Swern oxidation of alcohol
10a, using Hunig’s base to minimize the chance of racemization,
gave the corresponding aldehyde in excellent yield. This was then
reacted with (ꢀ)-B-E-crotyl diisopinocampheylborane to give the
desired homoallylic alcohol 8 in a good yield and with 98:2 di-
natural product, LL-15G256g, but has been reported with the op-
posite absolute configuration.15 Given the common source of each
of our target molecules, it was strongly believed that the stereo-
chemistry of the side chain of emericellamide B (2) would be
analogous to that of 1. The only stereogenic center to confirm was
that at C-25.
astereomeric ratio. The alcohol 8 was coupled with L-N-Boc-Ala-
OH in the presence of EDC and DMAP in DCM to give the ester 15
For emericellamide B, alcohols 10a and 10b were treated with
triflic anhydride and the product used to alkylate with (R)-
(ꢀ)-4-benzyl-3-propionyl-2-oxazolidinone (16), again following
Evans’ methodology, thus incorporating the extra methyl sub-
stituent on the side chain. Reductive cleavage, Swern oxidation, and
asymmetric crotylation as previously employed, secured alcohols
9a and 9b in comparable yield as single diastereomers, ready for
inclusion into the rest of the synthesis (Scheme 4).
Bn
Bn
Bn
Et3N, DMAP,
O
Octanoyl Chloride
N
O
NH
12a
O
NH
78%
O
O
13a
O
12b
O
NaHMDS,
MeI, THF,
- 78 °C
76%
Thus, alcohol 9a was coupled with L-N-Boc-Ala-OH in the same
way as 8 and this gave the ester 18a in 85% yield. Further elabo-
ration of 18a as was performed on 15 provided the cyclization
precursor 4a (78%, three steps), which was closed to give 2 and this
proceeded in 75% yield. However, the data obtained for 2 was not
wholly consistent with that published. The synthetic material gave
specific optical rotation value of ꢀ31 (c 0.066, MeOH), it disagreed
with the literature value of ꢀ34 (c 0.076, MeOH).6 There were also
Bn
LiBH4
95%
O
N
O
O
OH
10b
OH
10a
14a
Scheme 2. Synthesis of intermediates 10a and 10b.

S. Li et al. / Tetrahedron 65 (2009) 2695–2702
2697
33
R1
Bn
R2
33
23
R1 R2
R1
R2
27
22
24
26
27
26
23
28
29
22
25
24
26
LiBH4
27
1, Tf2O, Py., CH2Cl2, -78 °C,
O
N
25
25
OH
THF
29
OH
2, LiHMDS, 16 , THF, -78 °C
O
O
29
MeOH,
31
1, (COCl)2, DMSO, DIPEA, -78 °C
31
31
t
n
1
: R = C , R2 = H; 96%
17a: R1 = CH3, R2 = H; 45%
17b: R1 = H, R2 = CH3; 40%
H3
2, KOBu , trans-2-butene, LiBu ,
10a: R1 = CH3, R2 = H
10b: R1 = H, R2 = CH3
11a
Bn
11b: R1 = H, R2 = CH3; 95%
(-)-Ipc2BOMe, BF3 OEt2, -78 °C,
3 N NaOH, 30% H2O2
O
N
O
O
16
32
21
32
33
33
23
R1 R2
R1
32
21
33
R2
R1
1, OsO4-NaIO4, 2,6-lutidine,
dioxane-H2O;
R2
22
24
26
20
22
24
26
EDC, DMAP,
HO
20
28
29
22
28
29
23
24
25
21
20
26
27
25
27
23
27
25
L-N-Boc-Ala-OH,
O
O
O
O
O
2, NaClO2, CH3SO2NH2,
OH
CH2Cl2, rt.
t
pH = 7.0, Bu OH-H2O
31
31
31
BocHN
BocHN
18a: R1 = CH3, R2 = H; 85%
18b: R1 = H, R2 = CH3; 83%
9a: R1 = CH3, R2 = H; 65% (dr > 95:5)
7a: R1 = CH3, R2 = H;
7b: R1 = H, R2 = CH3;
9b: R1 = H, R2 = CH3; 68% (dr > 97:3)
EDC, HOBt, DIPEA,
t
L-Gly-Val-Leu-Ala-O Bu
32
21
33
23
R1 R2
32
33
H
N
R1 R2
19
16
15
20
22
24
16
15
H
19
H
N
26
27
25
22
20
18
24
N
H
N
26
27
18
23
25
21
O
O
14
17
O
O
13
O
O
1
2
28
29
DEPC, DIPEA, DMF, rt.
14
1
O
17
O
13
28
29
2
NH
11 O
O
30
31
H
NH
8
8
HN
O
O
30
31
5
3
7
N
t
OBu
4
7
N
10
12
9
Boc
11
3
H
5
HN
O
10
12
9
6
4
O
4a: R1 =6CH3, R2 = H; 78%
2, Emericellamide B (R1 = CH3, R2 = H; 75%)
19, epi-Emericellamide B (R1 = H, R2 = CH3; 73%)
4b: R1 = H, R2 = CH3; 75%
Scheme 4. Synthesis of emericellamide B and epi-emericellamide B.
slight differences in both the 1H and 13C NMR spectra, with certain
signals marginally out of place. Synthesis of the C-25 epimer in
exactly the same way starting with 10b, and relying on the reagent-
control of the stereochemistry during the crotylation reaction,
provided compound 19, which had a specific optical rotation value
of ꢀ33 (c 0.1, MeOH), close to the natural material. However, the
differences in the NMR spectra provided sufficient evidence that
the epimer at C-25 (19) was not the correct structure of the natural
product. The analysis data for 19 were even more inconsistent with
the natural material than for 2. A comparison of the Dd values for
the C-13 spectra (Fig. 1) shows that there are more differences
between 19 and the natural product than those for compound 2.
Consequently, 2 was thus assumed to have the correct stereo-
chemistry for emericellamide B. Although there are some discrep-
ancies between the data for our synthetic sample of emericellamide
B (2) and the natural material, we feel that this is most likely to have
arisen out of either a concentration or pH effect during the re-
cording of the spectra.
5
2.5
0
-2.5
-5
1
6
11
16
21
26
31
E mericellamide A
5
2.5
0
-2.5
-5
1
6
11
16
21
26
31
E mericellamide B
5
2.5
0
3. Conclusions
-2.5
In summary, the total synthesis of emericellamide A (1) was
accomplished in an overall yield of 22% in eight reaction vessels.
From the same intermediate 10a employed for the preparation of 1,
the synthesis of emericellamide B (2) was completed in 14% overall
yield. Through the stereochemically controlled synthesis, we can
unambiguously confirm that the originally proposed structures for
emericellamides A and B are correct.
-5
1
6
11
16
21
26
31
C-25-epi-Emericellamide B
Figure 1. Differences in 13C NMR shifts of natural products between synthetic samples
of emericellamides A, B, and C25-epi-B. X-axis for carbon number and Y-axis for Dd
(ppm).

2698
S. Li et al. / Tetrahedron 65 (2009) 2695–2702
4. Experimental
Na2S2O3 (100 mL), and brine (100 mL), dried over anhydrous
Na2SO4, and concentrated. The residue was purified by flash chro-
4.1. General methods
matography on silica gel, using ethyl acetate–hexane (5%) as eluent,
25
providing the desired compound (4.82 g, 76%) as clear oil. [
a
]
þ82
D
All non-aqueous reactions were run under an inert atmosphere
(nitrogen or argon) with rigid exclusion of moisture from reagents
and all reaction vessels were oven-dried. Solvents were distilled
prior to use: THF from Na/benzophenone, dichloromethane, DMF,
triethylamine and diisopropylethylamine from CaH2. NMR spectra
were recorded on Bruker Avance DPX 300 MHz, AV 500 MHz
spectrometers. Chemical shifts are reported in parts per million
(ppm), relative to either a tetramethylsilane internal standard or
the signals due to the solvent. Data are reported as follows:
chemical shift, multiplicity (s¼singlet, d¼doublet, t¼triplet,
q¼quartet, br¼broad), coupling constants, and integration. Low-
and high-resolution EI and ESI mass spectra were obtained using
a Finnigan MAT 95 mass spectrometer. Specific optical rotations
were recorded on a Perkin–Elmer 343 polarimeter. TLC was carried
out using pre-coated sheets (Qingdao silica gel 60-F250, 0.2 mm)
and compounds were visualized at 254 nm, and/or staining in
p-anisole, ninhydrin or phosphomolybdic acid solution followed by
heating. Flash column chromatography was performed using the
indicated solvents (with Rf¼1.5–3.0 for the desired component) on
Qingdao silica gel 60 (230–400 mesh ASTM).
(c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3) dH: 7.35–7.32 (2H, m),
7.29–7.28 (1H, m), 7.23–7.21 (2H, m), 4.71–4.66 (1H, m), 4.22–4.16
(2H, m), 3.75–3.68 (1H, m), 3.28 (1H, dd, J 13.3, 3.1), 2.78 (1H, dd,
J 13.3, 9.6), 1.75–1.71 (1H, m), 1.43–1.39 (1H, m), 1.26 (8H, br s), 1.23
(3H, d, J 6.8), 0.88 (3H, t, J 6.9); 13C NMR (125 MHz, CDCl3) dC: 177.4,
153.1, 135.4, 129.5, 129.0, 127.4, 65.9, 55.3, 37.8, 37.8, 33.4, 31.6, 29.2,
27.1, 22.5, 17.3, 14.0; m/z (EI) 318.2055 (C19H28NO3 [MþH]þ requires
318.2069).
4.4. (S)-2-Methyl-1-octanol (10a)
To a cold (0 ꢁC) solution of imide 14a (3.17 g, 10 mmol) in THF
(200 mL) was added 0.5 ml of methanol followed by a solution of
LiBH4 (10 mL, 20 mmol, 2.0 M in THF). The reaction was stirred at
0 ꢁC for 2 h and then allowed to warm to room temperature. After
4 h, a solution of 2 M NaOH (20 mL) was added. The resulted so-
lution was stirred until both phases were clear. The organic layer
was separated and the aqueous phase was then extracted with Et2O
(3ꢂ100 mL). The combined extracts was washed with water and
brine, dried over anhydrous Na2SO4, filtered, and concentrated in
vacuo. The residue was purified by flash chromatography on silica
gel, using 10% ethyl acetate–hexane as eluent, to produce the de-
sired product (1.37 g, 95%) as a clear colorless oil. 1H NMR
(500 MHz, CDCl3) dH: 3.51 (1H, dd, J 10.5, 5.8), 3.42 (1H, dd, J 10.5,
6.6),1.63–1.59 (1H, m), 1.43 (1H, s), 1.41–1.37 (1H, m),1.26 (8H, br s),
1.13–1.09 (1H, m), 0.91 (3H, d, J 6.7), 0.88 (3H, t, J 6.6); 13C NMR
(125 MHz, CDCl3) dC: 68.4, 35.8, 33.2, 31.8, 29.6, 26.9, 22.6, 16.6,
14.0; m/z (EI) 145.1590 (C9H21O [MþH]þ requires 145.1592).
4.2. (S)-N-Octanoyl-4-benzyl-2-oxazolidinone (13a)
To a solution of n-octanoic acid (4.32 g, 30 mmol) in dichloro-
methane (200 mL) at 0 ꢁC was added oxalyl chloride (13.1 mL,
150 mmol), followed by DMF (0.24 mL, 3 mmol). The reaction was
monitored with TLC. After the starting material had been consumed
(5 h), the mixture was concentrated in vacuo to provide the cor-
responding acylchloride, which was used in next step without
purification. The chiral auxiliary (12a) (3.54 g, 20 mmol) and DMAP
(183 mg, 1.5 mmol) were dissolved in dichloromethane (120 mL) at
0 ꢁC, to this solution was added triethylamine (8.3 mL, 60 mmol),
followed by the above acylchloride in dichloromethane (50 mL).
The reaction was allowed to warm to room temperature and stirred
16 h before being concentrated in vacuo. The residue was then
dissolved in ethyl acetate (300 mL) and successively washed with
saturated NH4Cl solution (100 mL), saturated NaHCO3 solution
(100 mL), and brine (100 mL). This solution was dried over anhy-
drous Na2SO4 and concentrated to leave a brown oil. The oil was
purified by silica gel chromatography using 5%–10% ethyl acetate–
4.5. (3S,4R,5S)-3,5-Dimethyl-undec-1-en-4-ol (8)
To a solution of oxalyl chloride (1.05 mL, 12 mmol) in dry CH2Cl2
(60 mL) at ꢀ78 ꢁC was slowly added a solution of DMSO (1.52 mL,
16 mmol) in dry CH2Cl2 (60 mL). After stirring for 1 h at ꢀ78 ꢁC,
alcohol (10a) (0.58 g, 4 mmol) in dry CH2Cl2 (40 mL) was slowly
added to the above solution. 30 min later, diisopropylethylamine
(10.4 mL, 60 mmol) was introduced via a syringe. The reaction was
then stirred at ꢀ78 ꢁC for 30 min and further at ꢀ50 ꢁC for 20 min,
prior to the addition of aqueous saturated NH4Cl solution (100 mL).
The organic phase was separated and then washed with saturated
NaHCO3 solution (100 mL) and brine (100 mL), dried over anhy-
drous Na2SO4, and concentrated in vacuo to afford the desired
(S)-2-methyloctanal (0.56 g, quantitative yield) as a clear oil, which
was used in the next step without further purification. Potassium
tert-butoxide (1.16 g, 10.4 mmol, prior dried at 0.5 mm/80 ꢁC/8 h) in
THF (8 mL) was cooled at ꢀ78 ꢁC, trans-2-butene (1.16 mL,
20.8 mmol) was introduced to the reaction vessel, followed by the
addition of n-BuLi (2.2 M, 4.73 mL, 10.4 mmol). The resulting or-
ange solution was stirred at ꢀ45 ꢁC for 10 min and re-cooled to
ꢀ78 ꢁC before (ꢀ)-methoxydiisopinocampheylborane [1.0 M in
hexane as eluent to produce the desired compound (13a) (4.7 g,
25
78%) as a clear oil. [
a
]
þ65 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) dH: 7.28–7.25 (2H, m), 7.22–7.19 (1H, m), 7.15–7.13 (2H, m),
4.62–4.59 (1H, m), 4.15–4.08 (2H, m), 3.23 (1H, dd, J 13.4, 3.2),
2.94–2.80 (2H, m), 2.70 (1H, dd, J 13.4, 10.6), 1.66–1.57 (2H, m),
1.30–1.22 (8H, m), 0.82 (3H, t, J 6.6); 13C NMR (125 MHz, CDCl3) dC
:
173.5, 153.4, 135.4, 129.4, 128.9, 127.3, 66.2, 55.2, 38.0, 35.5, 31.7,
29.1, 29.0, 24.3, 22.6, 14.0; m/z (EI) 304.1910 (C18H26NO3 [MþH]þ
requires 304.1913).
4.3. (S)-N-[(S)-(2-Methyl)octanoyl]-4-benzyl-2-
oxazolidinone (14a)
THF, 11.2 mL, 11.2 mmol, derived from (þ)-
a-pinene] was dropwise
added. 30 min later at ꢀ78 ꢁC, boron trifluoride etherate (1.52 mL,
12 mmol) was added, followed by the above crude (S)-2-methyl-
octanal (0.56 g, 8 mmol) in THF (10 mL). This mixture was stirred at
ꢀ78 ꢁC for 6 h and then treated with NaOH (3 M, 4.2 mL,
12.6 mmol) and H2O2 (30% solution, 1.8 mL) under refluxing tem-
perature for 3 h. Volatiles were removed in vacuo and the aqueous
residue was extracted with Et2O (3ꢂ50 mL). The combined extracts
were washed with water (30 mL) and brine (30 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo to leave a residue.
This was purified by silica gel chromatography, using ethyl 2%–5%
ethyl acetate–hexane as eluent, to provide the desired homoallylic
To a solution of NaHMDS (12 mL, 24 mmol, 2.0 M solution in
THF) in THF (100 mL) at ꢀ78 ꢁC was added dropwise a solution of
13a (6.06 g, 20 mmol) in THF (100 mL). After 1 h, iodomethane
(6.24 mL, 100 mmol) was added slowly via a syringe. The reaction
mixture was stirred at ꢀ78 ꢁC for 10 h and was quenched by adding
saturated aqueous NH4Cl (150 mL). Volatiles were removed under
reduced pressure and the aqueous layer was extracted with
dichloromethane (3ꢂ100 mL). The combined organic layers were
successively washed with 5% KHSO4 (100 mL), aqueous saturated

S. Li et al. / Tetrahedron 65 (2009) 2695–2702
2699
alcohol (8) (1.04 g, 75%, dr >98:2 as measured by 1H NMR spec-
crude aldehyde, which was subjected to next reaction immediately.
The above crude aldehyde was dissolved in tert-butanol–water
(5 mL, 1:1) at 0 ꢁC, and treated with a pre-mixed aqueous solution
of NaClO2 (80%, 125 mg, 1.36 mmol) and NaH2PO4 (pH¼7), in the
presence of CH3SO2NH2 (78 mg, 0.82 mmol) for 2.5 h. The mixture
was then poured into ethyl acetate (20 mL) and organic layer was
separated. The aqueous layer was further extracted with ethyl ac-
etate (2ꢂ20 mL). The combined extracts were washed with brine
(15 mL), dried over anhydrous Na2SO4, and concentrated in vacuo
to afford the desired acid (6, 110 mg, 85%, 2 steps) as a viscous oil,
which was used directly in the next step.
25
trum) as clear oil. [
a
]
þ1.1 (c 0.4, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) dH: 5.79–5.71 (1H, m), 5.14–5.11 (2H, m), 3.20 (1H, dd, J 8.8,
3.7), 2.29 (1H, dd, J 14.0, 7.6), 1.63–1.60 (1H, m), 1.51 (1H, s),
1.47–1.41 (1H, m), 1.28 (9H, s), 0.98 (3H, d, J 6.8), 0.88 (3H, t, J 7.2),
0.87 (3H, d, J 6.9); 13C NMR (125 MHz, CDCl3) dC: 141.5, 116.1, 77.2,
42.0, 34.7, 34.3, 31.9, 29.6, 27.2, 22.6, 16.7, 14.0, 12.8; m/z 221.1881
(EI) (C13H26ONa [MþNa]þ requires 221.1881).
4.6. N-tert-Butyloxycarbonyl-L-alanine-(1R,2S)-2-methyl-1-
[(1S)-1-methyl-2-propen-1-yl]-octyl ester (15)
Alcohol 8 (0.2 g, 1 mmol) and N-Boc-Alanine (0.85 g, 5 mmol)
were dissolved in dichloromethane (30 mL) at 0 ꢁC, after EDC
(0.99 g, 5 mmol) and DMAP (1.22 g, 10 mmol) were added, the re-
action was stirred at room temperature for 16 h before it was
concentrated in vacuo to give a viscous oil, which was dissolved in
Et2O (100 mL) and successively washed with saturated NH4Cl so-
lution (40 mL), saturated NaHCO3 solution (40 mL), and brine
(40 mL), dried over anhydrous Na2SO4, and concentrated. The crude
product was purified by silica gel chromatography, using 5% ethyl
4.9. 1-[N-[N-[N-[(2R,3R,4S)-(2,4-Dimethyl)-3-[(2S)-2-[[tert-
butyloxycarbonyl]amino]-1-oxopropoxy]decanoyl]glycyl]-
L-
valyl]- -leucyl]- -alanine-tert-butyl ester (3)
L
L
Tetrapeptide
Cbz-Gly-
L-Val-L-Leu-
L
-Ala-OtBu
(5)
(1.1 g,
2.0 mmol) in dry methanol (15 mL) was treated with hydrogen in
the presence of catalytic amount of Pd/C (10%) at ambient tem-
perature for 2 h. The solution was then filtered through a pad of
Celite to remove the catalyst powder, the cake was washed with
methanol (15 mL). The combined solution was concentrated in
vacuo to afford the crude amine in quantitative yield, which was
pure enough for the next reaction. The above crude acid 6 (110 mg,
0.28 mmol) in CH2Cl2 (2 mL) was treated with EDC (140 mg,
0.71 mmol) and HOBt (96 mg, 0.71 mg) at 0 ꢁC for 10 min, before
a solution of above amine (5) (177 mg, 0.43 mmol) in CH2Cl2 (3 mL)
was added via a cannula, followed by DIPEA (0.25 mL, 1.42 mmol).
The reaction was then allowed to warm to room temperature and
stirred for 24 h. The solution was diluted to 50 mL with CH2Cl2,
washed successively with HCl (0.5 N, 15 mL), saturated NaHCO3
solution (15 mL), and brine (15 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo to give a viscous oil. The residue was
purified by silica gel chromatography, using 2%–5% methanol–
dichloromethane as eluent, to produce the key precursor (3)
acetate–hexane as eluent, to afford the desired ester (15) (0.33 g,
25
90%) as clear oil. [
a]
þ3.2 (c 0.44, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) dH: 5.70–5.62 (1H, m), 5.05–4.96 (3H, m), 4.77 (1H, dd, J 7.0,
4.8), 4.28 (1H, br s), 2.50–2.43 (1H, m), 1.74 (1H, br s), 1.65 (1H, br s),
1.44 (9H, br s), 1.38 (3H, d, J 7.1), 1.25 (8H, br s), 1.12–1.05 (1H, m),
0.98 (3H, d, J 6.9), 0.87 (3H, t, J 6.5), 0.87 (3H, d, J 6.9); 13C NMR
(125 MHz, CDCl3) dC: 172.9, 155.0, 140.1, 115.3, 80.4, 78.5, 40.3, 34.1,
33.6, 31.7, 29.4, 28.3, 26.8, 22.6, 17.2, 14.0, 13.8; m/z (EI) 392.2780
(C21H39NO4Na [MþNa]þ requires 392.2777).
4.7. Cbz-Gly-Val-Leu-Ala-OtBu (5)
Cbz-Gly-
treated with EDC (1.19 g, 6.0 mmol) and HOBt (810 mg, 6.0 mg) at
0 ꢁC for 10 min, then H- -Ala-OtBu (851 mg, 3.3 mmol) in
-Leu-
L-Val-OH (942 mg, 3.0 mmol) in CH2Cl2 (20 mL) was
L
L
(200 mg, 92% or 76% total yield from 15) as light yellow viscous oil.
25
CH2Cl2 (20 mL) was added via a cannula followed by DIPEA
(1.74 mL, 10 mmol). The reaction was allowed to warm to room
temperature and stirred for 24 h. The solution was then diluted to
150 mL with CH2Cl2, and successively washed with HCl (0.5 N,
25 mL), saturated NaHCO3 solution (25 mL), and brine (25 mL),
dried over anhydrous Na2SO4, and concentrated to give a yellow oil.
The oil was purified by silica gel chromatography, eluting with 60%
ethyl acetate–hexane, to give the titled tetrapeptide (1.93 g, 82%) as
a viscous oil. 1H NMR (300 MHz, CDCl3) dH: 7.54 (1H, d, J 8.7), 7.44
(1H, d, J 8.4), 7.32 (5H, br s), 7.14 (1H, d, J 8.3), 5.94 (1H, br s), 5.10
(2H, s), 4.65–4.61 (1H, m), 4.49–4.40 (2H, m), 4.02 (2H, br s),
2.06–2.00 (1H, m), 1.66–1.60 (2H, m), 1.54–1.50 (1H, m), 1.51 (9H, br
s), 1.29 (3H, d, J 6.9), 0.91–0.85 (12H, m); 13C NMR (75 MHz, CDCl3)
dC: 171.8, 171.5, 171.1, 169.0, 156.6, 136.3, 128.5, 128.1, 128.0, 81.7,
67.0, 58.3, 51.6, 48.7, 44.4, 41.3, 31.7, 27.9, 24.7, 22.7, 22.2, 19.0, 18.3,
18.0; m/z (EI) 571.3104 (C28H44N4O7Na [MþNa]þ requires
571.3108).
[a
]
ꢀ42.1 (c 1.0, CH2Cl2); 1H NMR (500 MHz, CDCl3) dH: 7.62 (1H,
D
d, J 7.9), 7.80 (1H, br s), 7.70 (1H, br s), 7.35 (1H, br s), 5.57 (1H, br s),
5.11 (1H, d, J¼5.6), 4.73–4.68 (1H, m), 4.45–4.41 (1H, m), 4.44–4.40
(1H, m), 4.24–4.14 (2H, m), 3.86 (1H, d, J 10.4), 2.79–2.74 (1H, m),
2.02–1.97 (1H, m),1.70–1.60 (2H, m),1.50 (1H, br s),1.42 (9H, s),1.38
(9H, s),1.32 (3H, d, J 7.0),1.29 (3H, d, J 7.1),1.27 (3H, d, J 7.3),1.22 (8H,
br s), 1.08 (3H, d, J 6.8), 0.87–0.81 (15H, m, 5ꢂMe), 0.82 (3H, d, J 7.0);
13C NMR (125 MHz, CDCl3) dC: 174.2, 172.3, 171.7 (2ꢂC), 171.1, 169.2,
155.2, 81.4 (2ꢂC), 78.3, 58.4, 51.5, 48.7, 43.1, 41.4, 34.2, 33.7, 31.8,
31.7, 29.6, 29.3, 28.4, 27.9, 27.8, 27.0, 24.7, 22.7, 22.5, 22.4, 19.1, 18.5,
18.4, 17.9, 14.7, 13.9, 13.3; m/z (EI) 806.5265 (C40H73N5O10Na
[MþNa]þ requires 806.5255).
4.10. Emericellamide A (1)
Precursor 3 (80 mg, 0.1 mmol) was treated with a solution of dry
TFA–CH2Cl2 (40% 2.5 mL) at 0 ꢁC for 3 h. The reaction was allowed
to warm to room temperature and stirred for a further 4 h. The
solvents were evaporated under reduced pressure to give the crude
product, which was then dissolved in DMF (100 mL) and treated
4.8. N-tert-Butyloxycarbonyl-L-alanine-(1R,2S)-2-methyl-1-
[(1R)-1-carboxyethyl]octyl ester (6)
with DEPC (66 m
L, 0.4 mmol) at 25 ꢁC for 30 min, and then DIPEA
To a solution of ester 15 (127 mg, 0.34 mmol) in dioxane–water
(3:1, 5 mL) were added 2,6-lutidine (0.08 mL, 0.68 mmol), OsO4
(2.5 wt % in 2-methylpropan-2-ol, 0.3 mL, 0.015 mmol), and NaIO4
(335 mg, 1.5 mmol) at 0 ꢁC. The reaction mixture was stirred at 0 ꢁC
and monitored by TLC. After the starting material is consumed, the
reaction was quenched with saturated Na2SO3 solution (15 mL) for
30 min before it was concentrated in vacuo and extracted with
CH2Cl2 (3ꢂ20 mL). The combined extracts were washed with brine,
dried over anhydrous Na2SO4, and concentrated to produce the
(0.11 mL, 0.6 mmol) was added to the reaction mixture. The re-
action mixture was allowed to stir at this temperature for 48 h and
DMF was then removed by distillation under vacuum at the tem-
perature below 50 ꢁC. The resulting crude product was purified by
flash column chromatography on silica gel, using 2% MeOH in
dichloromethane as eluent to afford the emericellamide A (1)
25
(46 mg, 76% over two steps) as a white solid. [
a
]
ꢀ39 (c 0.28,
D
25
MeOH); lit. [
a]
ꢀ43 (c 0.23, MeOH); 1H NMR (500 MHz, DMSO-d6)
D
dH: 8.00 (1H, br s), 7.98 (1H, br s), 7.86 (1H, d, J 8.6 Hz), 7.44 (1H, br s),

2700
S. Li et al. / Tetrahedron 65 (2009) 2695–2702
7.36 (1H, d, J 7.0), 4.91 (1H, d, J 9.8), 4.30 (1H, dd, J 17.5, 5.5),
4.09–3.96 (4H, m), 3.61 (1H, d, J 10.4), 2.87–2.81 (1H, m), 1.90–1.85
(1H, m), 1.68–1.63 (1H, m), 1.60–1.52 (3H, m), 1.31–1.20 (14H, m),
1.14–1.09 (1H, m), 1.04–1.00 (1H, m), 0.99–0.78 (21H, m); 13C NMR
(125 MHz, DMSO-d6) dC: 172.6, 171.2, 171.0, 170.9, 170.5, 168.4, 76.4,
59.7, 51.6, 48.0, 47.0, 42.2, 40.9, 39.2, 33.1, 33.0, 30.8, 29.8, 28.5, 26.2,
24.2, 22.8, 21.7, 20.5, 18.7, 18.4, 17.9, 16.0, 14.0, 13.5, 12.6; m/z (EI)
632.4008 (C31H55N5O7Na [MþNa]þ requires 632.3999).
LiBH4 (4 mL, 8 mmol, 2.0 M in THF). The reaction was stirred at 0 ꢁC
for 2 h and then allowed to warm to room temperature. After 4 h,
a solution of 2 M NaOH (20 mL) was added and stirring was con-
tinued until both phases were clear. The organic layer was sepa-
rated and the aqueous layer was extracted with Et2O (3ꢂ100 mL).
The combined organic extracts were washed successively with
water and brine, dried over anhydrous Na2SO4, filtered, and con-
centrated in vacuo. Purification by flash chromatography on silica
gel, using 10% acetate–hexane as eluent, to afford (2S,4S)-
4.11. (R)-N-[(2S,4S)-(2,4-Dimethyl)decanoyl]-4-benzyl-2-
oxazoli-dinone (17a)
2,4-dimethyldecan-1-ol (11a) (0.71 g, 96%) as a clear, colorless oil.
25
[a
]
ꢀ1.9 (c, 0.9, CH2Cl2); 1H NMR (500 MHz, CDCl3) dH: 3.52 (1H,
D
dd, J 10.5, 5.2), 3.38 (1H, dd, J 10.5, 6.7), 1.75–1.69 (1H, m), 1.52–1.46
(1H, m), 1.41 (1H, br s), 1.33–1.27 (11H, m), 1.08–1.03 (1H, m), 0.92
(3H, d, J 6.7), 0.89 (3H, d, J 6.8), 0.88 (3H, t, J 6.6); 13C NMR (125 MHz,
CDCl3) dC: 68.5, 41.2, 36.8, 33.3, 31.9, 30.2, 29.7, 26.9, 22.7, 20.4, 17.3,
14.1; m/z (EI) 209.1885 (C12H26ONa [MþNa]þ requires 209.1881).
To a solution of alcohol (10a) (1.44 g, 10 mmol) and pyridine
(0.98 mL,12 mmol) in CH2Cl2 (50 mL) at ꢀ78 ꢁC was added dropwise
trifluromethanesulfonic anhydride (Tf2O) (1.85 mL, 11 mmol). The
reaction was stirred at ꢀ78 ꢁC for 3 h, quenched with brine (50 mL),
and warmed to room temperature. The organic layer was separated
and the aqueous phase was extracted with CH2Cl2 (50 mL). The
combined organic extracts were dried over anhydrous Na2SO4 and
concentrated in vacuo to give the corresponding triflate as a color-
less oil, which was subjected to next alkylation reaction without
further purification. To LiHMDS (16 mL, 16 mmol, 1.0 M in THF) in
THF (100 mL) at ꢀ78 ꢁC was added dropwise a solution of (R)-(ꢀ)-4-
benzyl-3-propionyl-2-oxazolidinone 16 (4.66 g, 20 mmol) in THF
(100 mL). After 1 h, the crude triflate in dry Et2O (20 mL) was added
slowlyvia a cannula. The reaction mixturewas then stirredat ꢀ78 ꢁC
for 4 h and room temperature for additional 1.5 h, before it was
poured into saturated NH4Cl solution (150 mL). Volatiles were
removed in vacuo and the aqueous phase was extracted with
dichloromethane (3ꢂ100 mL). The combined extracts was succes-
sively washed with 5% KHSO4 solution (100 mL), saturated NaHCO3
solution (100 mL), and brine (100 mL), dried over anhydrous
Na2SO4, and concentrated to leave a residue. The residue was
purified by silica gel chromatography, using 5% ethyl acetate–
hexane as eluent, to afford the desired compound (17a) (1.17 g, 45%
for two steps) as a clear oil. 1H NMR (500 MHz, CDCl3) dH: 7.34–7.31
(2H, m), 7.28–7.25 (1H, m), 7.22–7.21 (2H, m), 4.71–4.67 (1H, m),
4.20–4.13 (2H, m), 3.98–3.91 (1H, m), 3.30 (1H, dd, J 13.3, 3.4), 2.73
(1H, dd, J 13.3, 9.7), 1.90–1.86 (1H, m), 1.44 (1H, br s), 1.33 (2H, br s),
1.26 (8H, br s), 1.17 (3H, d, J 6.8), 1.16–1.11 (1H, m), 0.92 (3H, d, J 6.6),
0.87 (3H, t, J 6.8); 13C NMR (125 MHz, CDCl3) dC: 177.7, 153.1, 135.4,
129.4, 128.9, 127.3, 65.9, 55.3, 41.4, 38.0, 36.8, 35.2, 31.9, 30.8, 29.6,
26.8, 22.7, 19.9, 18.0, 14.1; m/z (EI) 382.2341 (C22H33NO3Na
[MþNa]þ requires 382.2358).
4.14. (2S,4R)-2,4-Dimethyldecanol (11b)
Alcohol 11b was prepared according to the procedure described
for the synthesis of 11a, 1.8 g (5 mmol) of 17b afforded 883 mg
25
(95%) of 11b as a clear oil. [
a
]
ꢀ17.3 (c 1.0, CH2Cl2); 1H NMR
D
(500 MHz, CDCl3) dH: 3.48 (1H, dd, J 10.3, 5.7), 3.39 (1H, dd, J 10.3,
6.7), 1.75–1.67 (1H, m), 1.49 (1H, br s), 1.27 (11H, m), 1.17–1.08 (2H,
m), 0.89 (3H, d, J 6.6), 0.88 (3H, d, J 6.9), 0.84 (3H, t, J 6.6); 13C NMR
(125 MHz, CDCl3) dC: 69.1, 40.7, 38.0, 33.2, 31.9, 29.9, 29.6, 27.0, 22.7,
19.4, 16.3, 14.1; m/z (EI) 209.1888 (C12H26ONa [MþNa]þ requires
209.1881).
4.15. (3S,4R,5S,7S)-3,5,7-Trimethyl-tridec-1-en-4-ol (9a)
Homoallylic alcohol (9a) was prepared according to the pro-
cedures described for the synthesis of 8. The yield for 2.0 mmol
scale reaction was 65% yield (as a single diastereoisomer, which was
determined by analysis of the 1H NMR of crude product). The
25
product is a clear oil. [
a]
þ2.0 (c 1.0, CH2Cl2); 1H NMR (500 MHz,
D
CDCl3) dH: 5.78–5.71 (1H, m), 5.15–5.11 (2H, m), 3.18 (1H, dd, J 8.2,
3.4), 2.34–2.25 (1H, m), 1.76–1.71 (1H, m), 1.57 (1H, br s), 1.55–1.51
(1H, m), 1.45–1.40 (1H, m), 1.32–1.27 (10H, m), 1.09–1.02 (1H, m),
0.99 (3H, d, J 6.8), 0.90–0.86 (9H, m, Meꢂ3); 13C NMR (125 MHz,
CDCl3) dC: 141.7, 116.1, 76.5, 42.1, 41.9, 36.9, 31.9, 31.6, 29.9, 29.7,
26.8, 22.6, 20.2, 16.6, 14.0, 13.0; m/z (EI) 263.2377 (C16H32ONa
[MþNa]þ requires 263.2351).
4.16. (3S,4R,5S,7R)-3,5,7-Trimethyl-tridec-1-en-4-ol (9b)
4.12. (R)-N-[(2S,4R)-(2,4-Dimethyl)decanoyl]-4-benzyl-2-
oxazo-lidinone (17b)
Homoallylic alcohol (9b) was prepared according to the pro-
cedures described for the synthesis of 8. The yield for 2.0 mmol
scale reaction was 68% yield (as a single diastereoisomer, which was
determined by analysis of the 1H NMR of crude product). The
product is a clear oil. 1H NMR (500 MHz, CDCl3) dH: 5.79–5.72 (1H,
m), 5.14–5.11 (2H, m), 3.14 (1H, dd, J 7.5, 3.9), 2.33–2.28 (1H, m),
1.74–1.69 (1H, m),1.48 (2H, br s),1.32–1.26 (10H, br s),1.18–1.11 (1H,
m), 1.02 (3H, d, J 6.8), 0.88–0.83 (9H, m, Meꢂ3); 13C NMR (125 MHz,
CDCl3) dC: 141.3, 116.1, 78.1, 41.9, 41.8, 37.8, 32.0, 31.9, 30.0, 29.6,
26.9, 22.7, 19.4, 16.8, 14.1, 12.7; m/z (EI) 263.2365 (C16H32ONa
[MþNa]þ requires 263.2351).
This compound was prepared according to the procedure de-
scribed for the synthesis of 17a, using 10b as a starting material. The
reaction was carried out at 8 mmol scale and the yield over two
steps was 40%. The product is a clear oil. [
25
a]
ꢀ44.2 (c 1.0, CH2Cl2);
D
1H NMR (500 MHz, CDCl3) dH: 7.35–7.32 (m, 2H), 7.29–7.27 (1H, m),
7.23–7.22 (2H, m), 4.72–4.67 (1H, m), 4.21–4.15 (2H, m), 3.91–3.84
(1H, m), 3.31 (1H, dd, J 13.3, 3.2), 2.73 (1H, dd, J 13.3, 9.9), 1.64–1.59
(1H, m), 1.52 (1H, br s), 1.44–1.39 (1H, m), 1.30 (9H, br s), 1.18–1.13
(1H, m), 1.16 (3H, d, J 6.7), 0.92 (3H, d, J 6.5), 0.89 (1H, t, J 6.9); 13C
NMR (125 MHz, CDCl3) dC: 177.9, 153.0, 135.4, 129.4, 128.9, 127.3,
66.0, 55.3, 40.9, 38.1, 37.5, 35.4, 31.9, 30.5, 29.6, 26.9, 22.6, 19.2, 16.7,
14.0; m/z (EI) 382.2349 (C22H33NO3Na [MþNa]þ requires
382.2358).
4.17. N-tert-Butyloxycarbonyl-L-alanine-(1R,2S,4S)-2,4-
dimethyl-1-[(1S)-1-methyl-2-propen-1-yl]decanoyl ester (18a)
Ester 18a was prepared according to the procedure described for
4.13. (2S,4S)-2,4-Dimethyldecanol (11a)
the synthesis of 15,120 mg (0.5 mmol) of 9a and 189 mg (1.0 mmol)
25
of N-Boc-Ala-OH afforded 175 mg (85%) of 18a as a clear oil. [a]
D
To a cooled (0 ꢁC) solution of imide 17a (1.44 g, 4 mmol) in THF
(50 mL) was added 0.2 mL of methanol followed by a solution of
þ1.3 (c 0.44, CH2Cl2); 1H NMR (500 MHz, CDCl3) dH: 5.68–5.61 (1H,
m), 5.06 (1H, br s), 5.01–4.96 (2H, m), 4.75 (1H, dd, J 7.3, 4.1), 4.28

S. Li et al. / Tetrahedron 65 (2009) 2695–2702
2701
(1H, br s), 2.50–2.44 (1H, m), 1.89–1.85 (1H, m), 1.53–1.48 (1H, m),
4.21. Emericellamide B (2)
1.44 (9H, br s), 1.38 (3H, d, J 7.0), 1.25 (11H, br s), 1.02–0.98 (1H, m),
0.98 (3H, d, J 6.8), 0.96–0.92 (1H, m), 0.93–0.86 (6H, m, 2ꢂMe), 0.84
(3H, d, J 6.6); 13C NMR (125 MHz, CDCl3) dC: 172.9, 155.0, 140.2,
115.4, 79.9, 79.6, 49.5, 41.4, 40.5, 36.7, 36.5, 31.9, 31.4, 29.7, 29.6,
28.4 (3ꢂC), 26.7, 22.7, 20.2, 17.1, 14.2, 14.1; m/z (EI) 434.3265
(C24H45NO4Na [MþNa]þ requires 434.3246).
Emericellamide B (2) was prepared according to the procedure
described for the synthesis of emericellamide (1). 86 mg
(0.1 mmol) of precursor 4a afforded 49 mg (75%) of 2 as a white
A
25
25
solid. [
a
]
ꢀ31 (c 0.066, MeOH); lit. [
a
]
ꢀ34 (c 0.076, MeOH);
D
D
1H NMR (500 MHz, DMSO-d6) dH: 8.50 (br s, 1H), 8.47 (1H, br s),
8.06 (1H, br s), 7.44 (1H, br s), 7.36 (1H, d, J 6.0), 4.91 (1H, d, J 9.8),
4.25 (1H, dd, J 17.5, 5.5), 4.09–3.96 (4H, m), 3.61 (1H, d, J 10.4),
2.87–2.82 (1H, m), 1.90–1.85 (1H, m), 1.84–1.78 (2H, m), 1.60–1.50
(4H, m), 1.31–1.18 (15H, m), 1.14–1.09 (1H, m), 1.04–1.00 (1H, m),
0.99–0.78 (24H, m); 13C NMR (125 MHz, DMSO-d6) dC: 172.8, 171.2,
171.1, 170.8, 168.6, 75.9, 60.1, 51.8, 48.2, 47.2, 41.2, 40.8, 40.1, 39.6,
36.7, 31.2, 30.2, 30.1, 28.9, 28.8, 26.0, 24.4, 22.0, 20.7, 23.1, 19.4, 19.0,
18.7, 18.4, 16.3, 14.2, 13.9, 13.5; m/z (EI) 674.4449 (C34H61N5O7Na
[MþNa]þ requires 674.4469).
4.18. N-tert-Butyloxycarbonyl-L-alanine-(1R,2S,4R)-2,4-
dimethyl-1-[(1S)-1-methyl-2-propen-1-yl]decanoyl ester (18b)
Ester 18b was prepared according to the procedure described for
the synthesis of 15,120 mg (0.5 mmol) of 9b and 189 mg (1.0 mmol)
25
of N-Boc-Ala-OH afforded 175 mg (83%) of 18b as a clear oil. [a]
D
ꢀ2.8 (c 0.44, CH2Cl2); 1H NMR (500 MHz, CDCl3) dH: 5.70–5.63 (1H,
m), 5.07 (1H, br s), 5.02–4.98 (2H, m), 4.73 (1H, dd, J 6.9, 5.0), 4.29
(1H, br s), 2.55–2.45 (1H, m), 1.88–1.83 (1H, m), 1.44 (9H, br s), 1.38
(3H, d, J 7.2), 1.25 (11H, br s), 1.11–1.04 (2H, m), 0.98 (3H, d, J 7.4),
0.88 (3H, d, J 6.9), 0.84 (3H, d, J 6.7), 0.78 (3H, d, J 6.8); 13C NMR
(125 MHz, CDCl3) dC: 173.0, 155.1, 140.0, 115.4, 81.2, 79.7, 49.6, 41.0,
40.3, 37.9, 31.9, 31.7, 29.8, 29.6, 28.4 (4ꢂC), 26.9, 22.6, 19.3,17.3, 14.0,
13.6; m/z (EI) 434.3258 (C24H45NO4Na [MþNa]þ requires
434.3246).
4.22. C-25-epi-Emericellamide B (19)
C-25-epi-Emericellamide B (19) was prepared according to the
procedure described for the synthesis of emericellamide A (1),
83 mg (0.1 mmol) of precursor 4b afforded 47 mg (73%) of 19 as
25
a straw-yellow viscous oil. [
a
]
ꢀ33 (c 0.1, MeOH); 1H NMR
D
(500 MHz, DMSO-d6) dH: 7.98 (1H, d, J 8.6), 8.05 (1H, br s), 7.85 (1H,
d, J 8.9), 7.43 (1H, br s), 7.34 (1H, d, J 7.0), 4.86 (1H, d, J 10.0), 4.26
(1H, dd, J 17.5, 5.4), 4.10–3.98 (4H, m), 3.62 (1H, dd, J 17.5, 2.1),
2.88–2.83 (1H, m), 1.88–1.83 (1H, m), 1.82–1.77 (1H, m), 1.61–1.54
(4H, m), 1.44 (1H, br s), 1.22–1.19 (15H, m), 1.08–1.03 (1H, m),
1.02–0.98 (1H, m), 0.99–0.87 (24H, m); 13C NMR (125 MHz, DMSO-
d6) dC: 172.8, 171.4, 171.2, 170.8, 168.6, 77.4, 60.0, 51.8, 48.3, 47.2,
41.2, 40.8, 40.2, 39.7, 36.6, 31.2, 30.4, 30.1, 29.0, 28.8, 26.1, 24.5, 22.0,
20.7, 23.1, 19.6,19.0,18.7,18.3,16.2,14.2,13.8,12.5; m/z (EI) 674.4451
(C34H61N5O7Na [MþNa]þ requires 674.4469).
4.19. 1-[N-[N-[N-[(2R,3R,4S,6S)-(2,4,6-Trimethyl)-3-[(2S)-2-
[[tert-butyloxycarbonyl]amino]-1-oxopropoxy]dodecanoyl]-
glycyl]-L-valyl]-L-leucyl]-L-alanine-tert-butyl ester (4a)
Precursor 4a was prepared according to the procedure described
for the synthesis of 3, 86 mg (0.2 mmol) of 18a and 124 mg
(0.3 mmol) of tetrapeptide
(78%) of 4a as a viscous clear oil. [
L
-Gly-Val-Lue-Ala-OtBu afforded 135 mg
25
a]
ꢀ32 (c 0.48, CH2Cl2); 1H NMR
D
(500 MHz, CDCl3) dH: 7.52 (1H, br s), 7.37 (1H, br s), 7.14 (1H, br s),
6.99 (1H, br s), 5.49 (1H, br s), 5.07 (1H, d, J 6.4), 4.65–4.60 (1H, m),
4.45–4.38 (2H, m), 4.26 (1H, br s), 4.11 (1H, m), 3.90 (1H, d, J 10.5),
2.72–2.67 (1H, m), 2.11–2.07 (1H, m), 1.89–1.85 (1H, m), 1.70–1.62
(1H, m),1.58–1.50 (3H, m),1.44 (9H, s), 1.42 (9H, s), 1.35 (3H, d, J 7.3),
1.33 (3H, d, J 7.2), 1.23 (11H, br s), 1.12 (3H, d, J 6.9), 1.02–0.97 (1H,
m), 0.92–0.85 (18H, m, 6ꢂMe), 0.82 (3H, d, J 7.0); 13C NMR
(125 MHz, CDCl3) dC: 174.3, 171.7 (2ꢂC), 171.5, 171.0, 169.3, 155.5,
81.6 (2ꢂC), 77.9, 60.3, 58.9, 51.6, 48.7, 43.5, 43.4, 41.3, 41.1, 36.7, 31.9,
31.4, 29.6, 29.5, 28.4 (3ꢂC), 28.3, 27.9 (3ꢂC), 26.7, 24.7, 22.8, 22.6
(2ꢂC), 22.1, 20.0, 19.1, 18.1, 18.0, 14.5, 14.0, 13.7; m/z (EI) 848.5714
(C43H79N5O10Na [MþNa]þ requires 848.5725).
Acknowledgements
We acknowledge financial support from the Hong Kong Re-
search Grants Council (Project: PolyU 5015/03P) and financial
support from the Shenzhen Bureau of Science, Technology, and
Information (Shenzhen Key Laboratory Advancement Scheme).
Z.S.X. would like to thank the support from Shenzhen foundation
for R&D of Sciences and Technologies.
Supplementary data
4.20. 1-[N-[N-[N-[(2R,3R,4S,6R)-(2,4,6-Trimethyl)-3-[(2S)-2-
[[tert-butyloxycarbonyl]amino]-1-oxopropoxy]dodecanoyl]-
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.01.082.
glycyl]-L-valyl]-L-leucyl]-L-alanine-tert-butyl ester (4b)
References and notes
Precursor 4b was prepared according to the procedure de-
scribed for the synthesis of 3, 86 mg (0.2 mmol) of 18b and 124 mg
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(0.3 mmol) of tetrapeptide
(75%) of 4b as a viscous clear oil. [
L
-Gly-Val-Lue-Ala-OtBu afforded 135 mg
25
a
]
ꢀ33 (c, 0.48, CH2Cl2); 1H
D
NMR (500 MHz, CDCl3) dH: 7.68 (1H, br s), 7.52 (1H, br s), 7.27 (1H,
br s), 7.12 (1H, br s), 5.55 (1H, d, J 7.6), 5.05 (1H, dd, J 7.5, 3.3), 4.66
(1H, br s), 4.48–4.41 (2H, m), 4.29–4.25 (1H, m), 4.20–4.16 (1H, m),
3.91–3.85 (1H, m), 2.74 (1H, br s), 2.18–2.14 (1H, m), 2.08–2.03 (1H,
m), 1.88–1.83 (1H, m), 1.70–1.60 (2H, m), 1.56–1.51 (1H, m), 1.45
(9H, s), 1.41 (9H, s), 1.36 (3H, d, J 7.2), 1.32 (3H, d, J 7.2), 1.22 (11H,
br s), 1.15 (3H, d, J 6.7),1.10–1.04 (1H, m), 0.90–0.84 (18H, m, 6ꢂMe),
0.78 (3H, d, J 6.5); 13C NMR (125 MHz, CDCl3) dC: 174.2, 172.5, 171.7,
171.6, 171.0, 169.3, 155.4, 81.5, 79.6, 79.2, 58.7, 51.6, 49.6, 48.7, 43.3,
42.2, 41.3, 41.1, 37.8, 31.9, 31.7, 29.8, 29.7, 28.4 (3ꢂC), 28.3, 28.0
(3ꢂC), 26.9, 24.7, 23.5, 22.89, 22.6, 22.2, 19.2, 19.1, 18.2, 18.0, 14.7,
14.0, 13.0; m/z (EI) 848.5718 (C43H79N5O10Na [MþNa]þ requires
848.5725).

2702
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