Total synthesis of emericellamides A and B

Article abstract of DOI:10.1016/j.tetasy.2013.07.012

A concise total synthesis of emericellamides A and B, two cyclic depsipeptides exhibiting antibacterial and cytotoxic activities, is reported. A Paterson anti-aldol reaction and a hydroxy directed 1,3-anti reduction were applied for construction of the po

Full text of DOI:10.1016/j.tetasy.2013.07.012

Tetrahedron: Asymmetry 24 (2013) 1042–1051
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Total synthesis of emericellamides A and B
⇑
Tapan Kumar Pradhan, Karla Mahender Reddy, Subhash Ghosh
CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 June 2013
Accepted 12 July 2013
A concise total synthesis of emericellamides A and B, two cyclic depsipeptides exhibiting antibacterial
and cytotoxic activities, is reported. A Paterson anti-aldol reaction and a hydroxy directed 1,3-anti
reduction were applied for construction of the polypropionate unit with the required stereochemistry
in emericellamides A and B. An FDPP mediated macrolactamization was used to construct the macrocycle
of emericellamides A and B.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
emericellamides A and B have antibacterial activity against meth-
icillin-resistant Staphylococcus aureus with MIC values of 3.8 and
Although the marine environment is a rich source of secondary
metabolites with interesting structures and functions, natural
product chemists continue to develop new techniques to harvest
novel molecules. The co-culture technique (culturing two different
microbial strains in the same culture vessel) is one such method by
which one can produce new natural products or increase the pro-
duction of known natural products through induction.1 In 2007
Fenical et al. isolated two new depsipeptides, emericellamides A
and B, by using this co-culture technique.2a Subsequently they
have also isolated four new cyclic depsipeptides, named emericel-
lamide C–F2b (Fig. 1). Initial biological studies revealed that
6
l
M, respectively. They are also cytotoxic against the HCT-116
human colon carcinoma cell line with IC50 values of 23 and
100 M, respectively. With the help of detailed NMR studies, the
l
structures of emericellamides A and B were established. Marfey’s
method,3 J-based configurational analysis, and a modified Mosher
method4 were used to establish the absolute stereochemistry of
1 and 2.
Due to their interesting structure and biological activities, they
have attracted the attention of synthetic organic chemists, for their
total synthesis. As a result three total syntheses of emericellamide
A and two total syntheses of emericellamide B have appeared in
the literature.5 The first total synthesis of emericellamide A was re-
ported by us,5a which involved Evans alkylation, Sharpless asym-
metric epoxidation, and Me2CuLi mediated epoxide opening
reactions to construct the polypropionate unit with the requisite
stereochemistry and FDPP mediated macrolactamization between
Gly and Val for construction of the macrocycle. Li et al. reported
the total synthesis of emericellamides A and B via macrolactamiza-
tion between the two alanine residues.5b The decanoic acid moie-
ties of emericellamides A and B with the requisite stereotetrad
were synthesized through Evans alkylation and crotylboration
reactions. Ma et al. achieved the total synthesis of emericellamide
A by applying Evans alkylation, Evans asymmetric aldol, and FDPP
meditated macrolactamization reactions.5c Yadav et al. reported on
the total synthesis of emericellamide B, where a desymmetrization
methodology was applied for the synthesis of the decanoic acid.5d
Herein we report the total synthesis of emericellamides A and B by
using a Paterson anti-aldol reaction followed by a hydroxy directed
stereoselective ketone reduction and FDPP mediated (Scheme 1)
macrolactamization as the key steps.
R1
O
R2
R3
H
N
H
N
n
O
O
O
O
O
NH
H
N
N
H
Me
Me
O
emericellamide A 1: n=0, R1 = R2 = R3 = Me
emericellamide B 2: n=1, R1 = R2 = R3 = Me
emericellamide C 3: n=0, R1 = Me, R2 = R3 = H
emericellamide D 4: n=0, R1 = R3 = H, R2 = Me
emericellamide E 5: n=1, R1 = Me, R2 = R3 = H
emericellamide F 6: n=1, R1 = R3 = H, R2 = Me
Figure 1. Structures of emericellamide A–F.
In our previous synthesis of emericellamide A,5a the macrolact-
onization was unsuccessful and the synthesis was accomplished
through macrolactamization at the Gly-Val site. With this earlier
⇑
Corresponding author. Tel.: +91 4027191604.
E-mail address: subhash@iict.res.in (S. Ghosh).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.07.012

T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
1043
Me
Me
Me
HOOC
NH2
Me
O
Me
Me
H
N
H
N
H
N
n
n
O
O
O
O
O
O
O
7: n=0
8: n=1
O
O
NH
O
NH
H
N
H
N
N
H
Me
N
H
Me
Me
O
Me
O
emericellamide A 1: n=0
emericellamide B 2: n=1
O
O
Me
Me
Me
Me
O
H
N
H
OH
N
BocHN
N
H
n
+
O
O
O
O
O
9: n = 0
10: n = 1
11
Me
Me
Me
CbzHN
Me
R
n
OH
OHC
OTIPS
12: R = CH2OTBS; n=0
13: R = CH2OTBS; n=1
Me
Me
15
+
PMBO
OTIPS
Me Me
O
14
OH
PMBO
16
O
Me
Me
Me
Me
Me
O
Me
Me
O
O
OH
17
PMBO
PMP
O
OH
18
19
Scheme 1. Retrosynthetic analysis.
observation in mind, we decided to adopt a similar macrolactami-
zation strategy for the synthesis of the target molecules. However,
we planned to synthesize the polypropionate unit via a Paterson
anti aldol reaction and hydroxy directed 1,3-anti-reduction as the
key steps. Thus retrosynthetically emericellamides A and B could
be obtained via macrolactamization of compounds 7 and 8, respec-
tively. Compounds 7 and 8 could be obtained from compounds 9
and 10 through peptide chain elongation with 11. Compounds 9
and 10 could be obtained from the secondary alcohol 12 and 13
via acylation with CbzAlaOH followed by TBS deprotection, oxida-
cally pure 1,3-anti diol compound 20 in 90% yield. The acid
catalyzed deprotection of TIPS provided a triol compound, which
upon oxidative cleavage followed by Wittig reaction with the ylide
Ph3P@CH–(CH2)3CH3 and reduction of the resulting alkene, fur-
nished the PMB deprotected 1,3-diol compound 21 in 65% yield
over four steps. Selective protection of the primary hydroxyl group
as a TBS ether afforded (Scheme 2) secondary alcohol 12 in 95%
yield.
For the synthesis of the polypropionate unit 13 of emericella-
mide B, we started from the known aldehyde 19,10 which upon
reaction with the E-enolate generated from ketone 16 provided al-
dol product 18 in 90% yield as shown in Scheme 3. The hydroxy di-
rected 1,3-anti reduction of the keto group of aldol product 18
under Evans conditions furnished the 1,3-anti diol compound 22
in 90% yield (de >95%). Oxidative rearrangement of the PMB group
was performed with DDQ11 to give the p-methoxybenzylidene pro-
tected compound 17 in 80% yield. Compound 24 was synthesized
from 23 via a two step Barton–McCombie deoxygenation reac-
tion.12 Alcohol 17 was converted into xanthate 23, which upon
treatment with Bu3SnH and AIBN provided the deoxygenated com-
pound 24 in 63% over two steps. Deprotection of the p-methoxy-
benzylidene group under hydrogenation conditions provided diol
25, whose selective protection of the primary hydroxyl group with
TBSCl and imidazole in THF provided fragment 13 in 81% over two
steps.
t
tion, and amide bond formation with BuOGlyNH2. The secondary
alcohol 12 could be obtained from the b-hydroxy ketone 14, via hy-
droxyl directed 1,3-anti reduction followed by functional group
manipulation. The b-hydroxy ketone 14 could be obtained by
means of a Paterson aldol reaction between aldehyde 15 and ke-
tone 16. The secondary alcohol 13 required for the synthesis of
emericellamide B could be obtained via deoxygenation of the free
hydroxyl group of 17, which might be obtained via hydroxy direc-
ted reduction of ketone 18, which in turn could be obtained via a
Paterson aldol reaction between 19 and 16.
2. Results and discussion
Our synthesis started with the addition of the enolate generated
from the known ketone 166 to the known aldehyde 157 under
8
The completion of the synthesis of emericellamide A is depicted
in Scheme 4. Acylation of the secondary alcohol 12 with CbzAlaOH
under DCC and DMAP conditions afforded the acylated compound
Paterson conditions to provide b-hydroxy ketone 14 in 94% (de
>95%). The b-hydroxy ketone 14 was subjected to a hydroxy direc-
ted 1,3-anti reduction with Me4NHB(OAc)39 to give diastereomeri-

1044
T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
Me
Me
PMBO
Me
Me
O
Me
Me
16
O
ii
PMBO
OTIPS
PMBO
OTIPS
H
OTIPS
Me
i
OH
OH
15
O
OH
20
14
Me
Me
Me
iii
iv
HO
TBSO
OH
OH
12
21
Scheme 2. Synthesis of fragment 12. Reagents and conditions: (i) c-hex2BCl, Et3N, Et2O, ꢁ78 to 0 °C, overnight, 94%; (ii) Me4NHB(OAc)3, acetone:AcOH (1:1), ꢁ20 °C, 4 h, 90%;
(iii) (a) CSA, MeOH:CH2Cl2(1:1), rt, 1 h; (b) NaIO4, THF:H2O (2:1), 0 °C, 30 min; (c) Ph3P@CH–(CH2)3–CH3, NaHMDS, THF, ꢁ78 °C, 30 min; (d) H2/Pd–C, MeOH, 2 h, 65% over
four steps; (iv) TBSCl, imidazole, THF, 0 °C, 95%.
Me
Me
Me
Me
Me
Me
Me
i
ii
PMBO
PMBO
Me
16
5
19
O
O
OH
OH
OH
18
22
Me
Me
S
Me
Me
Me
iii
iv
v
O
O
O
S
O
O
OH
Me
17
23
PMP
PMP
Me
Me
Me
Me
Me
Me
vi
vii
13
HO
O
O
25
OH
24
PMP
Scheme 3. Synthesis of fragment 13. Reagents and conditions: (i) 16, c-hex2BCl, Et3N, Et2O, ꢁ78 to 0 °C, overnight, 90%; (ii) Me4NHB(OAc)3, acetone:AcOH (1:1), ꢁ20 °C, 30 h,
90%; (iii) DDQ, 4 Å, MS, CH2Cl2, 0 °C, 30 min, 80%; (iv) NaHMDS, CS2, MeI, THF, ꢁ78 °C, 85%; (v) Bu3SnH, AIBN, 120 °C, 30 min, 75%; (vi) H2/Pd–C, MeOH, 2 h, 90%; (vii) TBSCl,
imidazole, THF, 8 h, 96%.
Me
Me
Me
Me
Me
Me
Me
TBSO
TBSO
HO
i
ii
OH
O
O
O
O
12
26
CbzHN
Me
CbzHN
Me
27
Me
Me
Me
H
N
H
N
O
O
iii
iv
O
O
O
O
O
O
O
O
O
O
H
N
9
BocHN
N
N
H
Me
H
CbzHN
Me
O
Me
28
v
1
Scheme 4. Synthesis of emericellamide A. Reagents and conditions: (i) Cbz-Ala-OH, DCC, DMAP (cat), 0 °C to rt, 5 h, 75%; (ii) CSA (cat), MeOH:CH2Cl2, (1:1), 0 °C, 0.5 h, 85%;
(iii) (a) SO3:Py, DMSO:CH2Cl2 (2:1.8), 0 °C, 1 h (b) NaH2PO4ꢀ2H2O, NaClO2, 2-methyl-2-butene, tBuOH, 0 °C to rt, 1 h; (c) EDCI, HOBt, NH2Gly-OtBu, 0 °C to rt, 1 h, 81% over two
steps; (iv) (a) H2, Pd/C, EtOAc, 1 N, HCl, 10 min; (b) Boc-Val-Leu-Ala-OH, EDCI, HOBt, CH2Cl2, DIPEA, 0 °C, 1 h, 75%; (v) (a) TFA:CH2Cl2 (1:1), 0 °C, 1 h; (b) FDPP, DIPEA, CH3CN,
10ꢁ3 M, 0 °C to rt, 72 h, 75% over two steps.

T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
1045
26, which upon TBS deprotection provided primary alcohol 27 in
63% over two steps. Parikh–Doering oxidation13 of the primary
alcohol 27 followed by further oxidation of the aldehyde under
Pinnick conditions14 provided an acid, which upon coupling with
the H2NGlyOtBu under EDCI conditions furnished compound 9 in
81% over two steps. The Cbz-deprotection of compound 9 provided
an amine, which upon coupling with the BocVal-Leu-Ala-OH fur-
nished cyclization precursor 28 in 75% over two steps. Deprotec-
tion of Boc and tertiarybutyl groups was achieved with TFA to
give a seco-amino acid, which upon macrolactamization with penta
fluorophenyl diphenylphosphinate15 (FDPP) at high dilution in
CH3CN afforded emericellamide A 1, whose analytical data were
in good agreement with the literature.2a
After completion of the synthesis of emericellamide A, we
turned our attention toward the synthesis of emericellamide B by
following a similar synthetic strategy. Accordingly, secondary alco-
hol 13 was subjected to acylation with the CbzAlaOH under DCC/
DMAP (cat) conditions. However, we found that the acylation reac-
tion was unsuccessful under DCC/DMAP (cat) conditions. Heating
the reaction mixture further or increasing the amount of DMAP
(stoichiometric) led to the formation of a product with extensive
racemization at Ala center. By using other reagents and conditions,
the acylation was unsuccessful (Scheme 5).
This unsuccessful acylation may be explained by the steric
crowding around the secondary hydroxyl group. Thus, we felt
that by keeping the sterically less hindered group at the C1 po-
sition, it might allow the acylation of the hydroxyl group.
Accordingly we decided to keep –CH@CH2 in place of –CH2–
OTBS, so that steric crowding would be much less and the –
C@CH2 unit could be converted into the acid at the required
stage. Thus the p-methoxybenzylidene acetal of 24 was opened
with DIBAL-H to give the primary alcohol 30, which was sub-
jected to Ley oxidation16 followed by Wittig reaction of the
resulting aldehyde with the ylide Ph3P@CH2 in ether gave ole-
finic compound 31 which upon treatment with DDQ furnished
secondary alcohol 32 in 70% over four steps (Scheme 6). Acyla-
tion of the secondary alcohol proceeded smoothly with good
yield and diastereomeric excess (80%, de >95%). Dihydroxylation
of the olefinic moiety provided the 1,2-diol compound, which
upon oxidative cleavage with NaIO4 followed by Pinnick oxida-
tion of the resulting aldehyde furnished an acid, which upon
coupling with H2NGlyOtBu provided compound 10. Deprotection
of Cbz from compound 10, followed by peptide chain elongation
furnished cyclization precursor 34, which on treatment with TFA
followed by macrolactamization of the resulting seco-amino acid
provided emericellamide B 2 in 80% over two steps.
Me
Me
Me
Me
Me
Me
i orXii or iii
iv or v
TBSO
TBSO
13
29
O
29
O
O
O
CbzHN
Me
CbzHN
Me
Scheme 5. Acylation of 13 with CbzAlaOH. Reagents and conditions: (i) CbzAlaOH, DCC, DMAP (cat), CH2Cl2, 0 °C to rt; (ii) EDCI, HOBt, CH2Cl2, 0 °C to rt; (iii) EDCI, DMAP (cat),
CH2Cl2, 0 °C to rt; (iv) CbzAlaOH, DCC, DMAP (1 equiv), CH2Cl2, 0 °C to rt; (v) CbzAlaOH, DCC, DMAP (cat), CH2Cl2, reflux.
Me
Me
Me
Me
Me
Me
Me
ii
i
24
HO
Me
30
OPMB
31
OPMB
Me
Me
Me
Me
v
iv
iii
O
O
33
32
OH
Me
CbzHN
O
Me
O
Me
Me
H
N
O
O
Me
Me
Me
H
N
O
O
O
vi
O
O
H
N
O
O
O
BocHN
N
H
N
H
Me
10
O
Me
34
CbzHN
Me
vii
emericellamide B 2
Scheme 6. Synthesis of emericellamide B: (i) DIBAL-H, CH2Cl2, ꢁ78 to 0 °C, 30 min, 97%; (ii) TPAP, NMO, CH2Cl2, 4 Å MS, rt, 10 min; (b) Ph3P@CH2, tBuOK, Et2O, 0 °C, 80%; (iii)
DDQ, CHCl3:H2O (20:1), 0 °C, 30 min, 92%; (iv) Cbz-Ala-OH, DCC, DMAP (cat), CH2Cl2, 0 °C to rt, 1 h, 80%; (v) (a) OsO4, NMO, methane sulfonamide, 0 °C to rt, 4 h, (b) NaIO4,
t
THF:H2O (1:1), 0 °C to rt, 30 min (c) NaH2PO4ꢀ2H2O, NaClO2, 1 h, H2O, 2-methyl-2-butene, BuOH; (d) EDCI, HOBt, NH2Gly-OtBu; 0 °C to rt, 1 h, 70%; (vi) (a) H2, Pd/C, EtOAc,
1 M HCl, 10 min; (b) BocVal-Leu-Ala-OH, EDCI, HOBt, CH2Cl2, DIPEA,1 h, 75%; (vii) (a) TFA:CH2Cl2 (1:1), 0 °C, 1 h; (b) FDPP, DIPEA, CH3CN, 10ꢁ3 M, 0 °C to rt, 72 h, 80% over two
steps.

1046
T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
room temperature for 3 h. The organic layer was extracted with
3. Conclusion
ethyl acetate (2 ꢂ 20 mL). The combined organic extracts were
washed sequentially with water (2 ꢂ 5 mL), brine (2 ꢂ 5 mL) and
dried over anhydrous Na2SO4. The organic solution was concen-
trated in vacuo and chromatographed on silica gel (60–120 mesh,
10% EtOAc/hexane) to afford 20 (630 mg, 90%) as a colorless oil.
In conclusion we have reported on the total synthesis of emer-
icellamides A and B from compounds 15 (15 steps, 15% overall
yield) and 19 (18 steps 9.9% overall yield) respectively. The key fea-
tures of the synthetic sequence include a diastereoselective Pater-
son anti-aldol reaction, hydroxy directed stereoselective
reductions of a b-hydroxyl ketone and FDPP mediated macrolacta-
mization. The total synthesis of other members of the emericella-
mide and analogues of emericellamide A–F is currently in
progress, and will be reported in due course.
Rf = 0.1 (SiO2, 15% EtOAc/hexane); ½a D25
¼ þ15:6 (c 1.08, CHCl3);
ꢃ
IR (Neat): mmax = 3442, 2936, 2924, 2864, 1613, 1513, 1461, 1363,
1300, 1247, 1173, 1093, 1040, 996, 921, 882, 813 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d = 7.26 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz,
2H), 4.47 (ABq, J = 11.5 Hz, 2H), 3.94 (dd, J = 9.4, 2.0 Hz, 1H),
3.87–3.77 (m, 4H), 3.76–3.68 (m, 2H), 3.59 (dd, J = 9.0, 4.4 Hz,
1H), 3.51 (t, J = 9.0 Hz, 1H), 1.99 (m, 1H), 1.83 (m, 1H), 1.73–1.47
(m, 2H), 1.18–1.02 (m, 21H), 0.97 (d, J = 7.2 Hz, 3H), 0.78 (t,
J = 7.0 Hz, 3H) ppm. 13C NMR (50 MHz, CDCl3): d = 159.5, 129.9,
129.5, 114.0, 76.6, 75.9, 75.1, 73.3, 65.7, 55.4, 35.9, 35.6, 18.1,
13.2, 12.1, 9.4 ppm. MS (ESI): m/z = 477 [M+Na]+. HRMS (ESI): calcd
for C25H46O5NaSi [M+Na]+ 477.3012, found 477.3007.
4. Experimental
4.1. General
1H NMR and 13C NMR spectra were recorded on Bruker
300 MHz (Avance) and Varian Unity 500 MHz (Innova) spectrome-
ters at ambient temperature in CDCl3 solvent by using TMS as an
internal standard. Chemical shifts are reported in ppm with respect
to TMS. FTIR spectra were recorded on Alpha (Bruker) infrared
spectrophotometer. A Horiba Sepa 300 polarimeter was used to re-
cord the optical rotations. All the reactions were carried out under
inert atmosphere in flame dried glass apparatus. Freshly distilled
anhydrous solvents were used to carry out the reactions. All chem-
icals from Aldrich were used as such. Column chromatography was
carried out on silica gel (60–120 mesh) packed in glass columns.
4.1.3. (2S,3R,4S)-2,4-Dimethyldecane-1,3-diol 21
A solution of compound 20 (600 mg, 1.32 mmol) in CH2Cl2/
MeOH (1:1, 5 mL) was treated with CSA (camphor sulfonic acid)
(613 mg, 2.64 mmol) at 0 °C. After being stirred for 30 min at the
same temperature, the reaction mixture was quenched with a sat-
urated aqueous NaHCO3 solution (60 mL) and extracted with
EtOAc (2 ꢂ 30 mL). The combined extracts were washed with
water (20 mL), brine (20 mL), dried (Na2SO4), and concentrated in
vacuo.
The crude product was then dissolved in THF:H2O (1:1, 10 mL)
and cooled to 0 °C, after which NaIO4 (700 mg, 3.3 mmol) was
added and stirred at room temperature for 2 h. The reaction was
diluted with water and the aqueous layer was extracted with
EtOAc (2 ꢂ 20 mL). The combined organic layers were washed with
H2O (20 mL), brine (20 mL), dried (Na2SO4), filtered, and concen-
trated in vacuo. The crude aldehyde was used for the next step.
At first, NaHMDS (7.9 mL, 7.92 mmol) was added to a suspen-
sion of [Ph3P–CH2–(CH2)3–CH3]+Brꢁ (5 g, 13.2 mmol) in dry THF
(20 mL) at ꢁ78 °C. The mixture was then stirred at the same tem-
perature for 30 min. The resulting ylide was added to a solution of
aldehyde in THF (10 mL) at 0 °C. After 0.5 h, the reaction mixture
was quenched with a saturated aqueous NH4Cl solution (10 mL).
The organic layer was separated, washed with brine (25 mL), dried
(Na2SO4), and concentrated in vacuo.
4.1.1. (2S,4S,5R)-5-Hydroxy-1-(4-methoxybenzyloxy)-2,4-dimet
hyl-6 (triisopropylsilyloxy)hexan-3-one 14
To a cooled solution of chlorodicyclohexylborane (5.91 mL,
5.91 mmol) in dry ether (12 mL) at ꢁ78 °C were added dropwise
triethylamine (1 mL, 7.09 mmol) followed by ketone 16 (930 mg,
3.94 mmol) in ether (5 mL). The milky mixture was stirred at 0 °C
for 2.5 h. The solution was again cooled to ꢁ78 °C before the slow
addition of aldehyde 15 (1.27 g, 5.91 mmol) and the resulting solu-
tion was stirred for 2 h at the same temperature. The mixture was
kept at ꢁ25 °C overnight and then stirred at 0 °C for 30 min. The
reaction mixture was quenched successively with MeOH (11 mL),
pH 7 buffer (11 mL), H2O2 (50%) (11 mL), and stirred for 30 min
at room temperature. The organic layer was extracted with ethyl
acetate (2 ꢂ 50 mL). The combined organic extracts were washed
sequentially with water (10 mL), brine (10 mL), and dried over
anhydrous Na2SO4. The organic solution was concentrated in vacuo
and chromatographed on silica gel (60–120 mesh, 5% EtOAc/hex-
ane) to afford 14 (1.67 g, 94%) as a colorless oil. Rf = 0.4 (SiO2,
The crude product was dissolved in MeOH (10 mL), after which
Pd/C (10%) (300 mg) was added and subjected to hydrogenation
under atmospheric pressure using H2-filled balloon. After 2 h, the
reaction mixture was filtered through a short pad of Celite and
the filter cake was washed with EtOAc. The filtrate and washings
were combined and concentrated in vacuo and subjected to col-
umn chromatography on silica gel (60–120 mesh, 15% EtOAc/hex-
ane) to afford 21 (200 mg, 70%) as a colorless liquid; Rf = 0.5 (SiO2,
10% EtOAc in hexane); ½a D25
¼ þ19:75 (c 2.05 CHCl3). IR (Neat):
ꢃ
m
max = 3497, 2936, 2864, 1709, 1613, 1512, 1460, 1370, 1297,
1245, 1173, 1096, 1036, 1003, 919, 880, 808 cmꢁ1 1H NMR
.
(300 MHz, CDCl3): d = 7.19 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz,
2H), 4.40 (dd, J = 15.9, 11.5 Hz, 2H), 3.79 (s, 3H), 3.78–3.55 (m,
4H), 3.42 (m, 1H), 3.10–2.89 (m, 2H), 1.12–0.94 (m, 27H) ppm.
13C NMR (50 MHz, CDCl3): d = 159.1, 141.6, 130.1, 129.1, 113.7,
74.1, 72.9, 71.9, 65.2, 55.2, 47.4, 46.8, 17.9, 13.1, 12.9, 11.9 ppm.
MS (ESI): m/z = 475 [M+Na]+. HRMS (ESI): calcd for C25H44O5NaSi
[M+Na]+ 475.2855, found 475.2858.
30% EtOAc/hexane).
m
½
a 3D0
ꢃ
¼ þ14:6 (c 4.91, CHCl3). IR (Neat):
max = 3355, 2959, 2925, 2855, 1460 cmꢁ1
.
1H NMR (300 MHz,
CDCl3): d = 3.70 (dd, J = 10.5, 3.7 Hz, 1H), 3.59 (dd, J = 10.5, 8.3 Hz,
1H), 3.44 (dd, J = 9.1, 3.0 Hz, 1H), 2.99–2.52 (br s, 2H), 1.82 (m,
1H), 1.59 (m, 1H), 1.40–1.21 (m, 10H), 0.93–0.84 (m, 6H), 0.80 (d,
J = 6.8 Hz, 3H) ppm. 13C NMR (100 MHz, CDCl3): d = 79.6, 68.2,
37.1, 34.9, 33.9, 31.8, 29.4, 27.3, 22.5, 13.9, 13.4, 12.1 ppm. MS
(ESI): m/z = 226 [M+Na]+. HRMS (ESI): calcd for C12H26O2
[M+Na]+ 226.1964; found 226.1960.
4.1.2. (2R,3R,4S,5S)-6-(4-Methoxybenzyloxy)-3,5-dimethyl-1-(tri
isopropylsilyloxy) hexane-2,4-diol 20
Compound 14 (697 mg, 1.54 mmol) was taken in a (1:1) mix-
ture of AcOH and acetone (3 mL each) and cooled to ꢁ20 °C. Next,
Me4NHB(OAc)3 (1.21 g, 4.62 mmol) was added very quickly to the
reaction mixture and it was stirred at the same temperature for
5 h. After completion of the reaction, it was quenched with a satu-
rated solution of sodium potassium tartrate (5 mL) and stirred at
4.1.4. (2S,3R,4S)-1-(tert-Butyldimethylsilyloxy)-2,4-dimethyldec
an-3-ol 12
To a stirred solution of 21 (190 mg, 0.94 mmol) in dry THF
(5 mL) was added imidazole (200 mg, 2.82 mmol) at 0 °C. After
10 min TBSCl (213 mg, 1.42 mmol) was added to it. After stirring

T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
1047
for 8 h the reaction was quenched with saturated NH4Cl at 0 °C.
The reaction mixture was extracted with EtOAc (60 mL) and the
combined organic extracts were washed with water (10 mL), brine
(10 mL), dried (Na2SO4), and concentrated in vacuo. It was then
subjected to column chromatography on silica gel (60–120 mesh,
10% EtOAc/hexane) to yield pure compound 12 (285 mg, 96%) as
z = 403 [M+Na]+; HRMS (ESI): calcd for C23H40O4Na [M+Na]+
403.2824, found 403.2821.
4.1.7. (2S,3S,4S)-2-((4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,3-
dioxan-4-yl)-4-methyldecan-3-ol 17
The 1,3-anti-diol compound 22 (1.7 g, 4.47 mmol) was taken in
dry CH2Cl2 (15 mL) and 4 Å MS (2.2 g, 1.3 equiv with respect to
weight) were added. The mixture was stirred for 1 h at room tem-
perature. Next, DDQ (1.52 g, 6.71 mmol) was added to the reaction
mixture at 0 °C and kept at the same temperature for 30 min. After
complete consumption of the starting material, the reaction mix-
ture was quenched with a saturated aqueous NaHCO3 solution
(10 mL) and extracted with EtOAc (100 mL). The organic extracts
were washed with water (2 ꢂ 10 mL), brine (10 mL), dried (Na2-
SO4), and filtered. After evaporation of the solvents under vacuum
the crude mass was subjected to chromatographic purification sil-
ica gel (60–120 mesh 5–6% EtOAc/hexane) to afford pure com-
pound 17 (1.35 g, 80%) as a colorless liquid; Rf = 0.40 (SiO2, 20%
a colorless oil; Rf = 0.3 (SiO2, 15% EtOAc/hexane). ½a D30
¼ þ22:4 (c
ꢃ
2.75, CHCl3). IR (Neat):
mmax = 2957, 2927, 2856, 1743, 1464,
1385, 1254, 1077 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 3.75 (dd,
.
J = 9.8, 3.7 Hz, 1H), 3.58 (dd, J = 9.8, 8.3 Hz, 1H), 3.38 (dd, J = 8.3,
3.0 Hz, 1H), 1.77 (m, 1H), 1.49 (m, 1H), 1.38–1.19 (m, 10H), 0.93–
0.89 (m, 12H), 0.86 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 7.5 Hz, 3H),
0.10–0.06 (m, 6H) ppm. 13C NMR (75 MHz, CDCl3): d = 79.4, 69.3,
37.3, 35.3, 34.1, 31.8, 29.5, 27.4, 25.8, 22.6, 18.1, 14.0, 13.3, 12.4,
ꢁ5.7 ppm. MS (ESI): m/z = 317 [M+H]+. HRMS (ESI): calcd for C18-
H41O2Si [M+H]+ 317.2875, found 317.2878.
4.1.5. (2S,4S,5S,6S)-5-Hydroxy-1-(4-methoxybenzyloxy)-2,4,6-tri
methyl dodecan-3-one 18
EtOAc/hexane).
max = 3532, 2958, 2926, 2854, 1516, 1461, 1388, 1250, 1169,
1112, 1077, 1032 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.30 (d,
½
a 2D4
ꢃ
¼ þ28:4 (c 2.28, CHCl3). IR (Neat):
m
To a cooled solution of chlorodicyclohexylborane (19.06 mL,
19.0 mmol) in dry ether (50 mL) at ꢁ78 °C were added dropwise
triethylamine (3.17 mL, 22.8 mmol) followed by ketone 16 (3 g,
12.7 mmol) in ether (10 mL). The milky mixture was stirred at
0 °C for 2.5 h. The solution was again cooled to ꢁ78 °C before the
slow addition of aldehyde 19 (2.7 g, 19.0 mmol) and the resulting
solution was stirred for 2 h at the same temperature. The mixture
was then kept at ꢁ25 °C overnight after which it was stirred at 0 °C
for 30 min. The reaction mixture was quenched successively with
MeOH (38 mL), pH 7 buffer (38 mL), H2O2 (50%) (38 mL) and then
stirred for 30 min at room temperature. The organic layer was ex-
tracted with ethyl acetate (2 ꢂ 100 mL). The combined extracts
were washed sequentially with water (2 ꢂ 15 mL), brine (10 mL)
and dried over anhydrous Na2SO4. The organic solution was con-
centrated in vacuo and chromatographed (SiO2 10% EtOAc/hexane)
to afford 18 (4.7 g, 98%) as a colorless oil; Rf = 0.2 (SiO2, 15% EtOAc/
.
J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 2H), 5.42 (s, 1H), 4.08 (dd,
J = 10.9, 4.3 Hz, 1H), 3.82 (dd, J = 10.0, 2.0 Hz, 1H), 3.78 (s, 3H),
3.48 (t, J = 11.0 Hz, 1H), 3.24 (dd, J = 6.7, 5.5 Hz, 1H), 2.30 (m,
1H), 2.09 (m, 1H), 1.97 (m, 1H), 1.71–1.51 (m, 2H), 1.40–1.20 (m,
8H), 1.07 (d, J = 7.1 Hz, 3H), 0.88 (d, J = 6.7 Hz, 3H), 0.88 (t,
J = 6.6 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H) ppm. 13C NMR (150 MHz,
CDCl3): d = 159.7, 130.6, 127.1, 113.4, 100.8, 82.9, 79.1, 73.0, 55.1,
36.3, 34.1, 31.8, 31.2, 30.1, 29.5, 26.9, 22.5, 16.2, 14.0,
11.7, 11.2 ppm. MS (ESI): m/z = 401 [M+Na]+; HRMS (ESI): calcd
for C23H38O4Na [M+Na]+ 401.2667, found 401.2671.
4.1.8. O-(2R,3S,4S)-2-((4S,5S)-2-(4-Methoxyphenyl)-5-methyl-1,
3-dioxan-4-yl)-4-methyldecan-3-yl (S)-methyl carbonodithio-
ate 23
Compound 17 (770 mg, 2.03 mmol) was taken in dry THF
(10 mL) and then cooled to ꢁ78 °C. Next, 1 M NaHMDS (20.3 mL,
20.3 mmol) was added dropwise to it and the reaction mixture
was kept at the same temperature for 30 min. Next, CS2 (2.4 mL,
40.6 mmol) was added to that solution and stirred for 30 min at
ꢁ78 °C after which MeI (3.7 mL, 60.9 mmol) was added to that
reaction mixture and after stirring for 5 min at the same tempera-
ture, quenched by saturated aqueous H2O (5 mL), extracted with
EtOAc (2 ꢂ 30 mL). The extracts were washed with water (5 mL),
brine (5 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
Purification by column chromatography on silica gel (60–120 mesh
5% EtOAc/hexane) furnished 23 (810 mg, 85%) as a colorless liquid;
hexane) = ꢁ0.7 (c 2.9, CHCl3). IR (Neat):
m
max = 2923, 2854, 1708,
1612, 1513, 1459, 1371, 1246, 1174, 1093, 1036, 958 cmꢁ1
.
1H
NMR (300 MHz, CDCl3): d = 7.12 (d, J = 8.7 Hz, 2H), 6.77 (d,
J = 8.7 Hz, 2H), 4.34 (dd, J = 16.6, 11.6 Hz, 2H), 3.74 (s, 3H), 3.56
(t, J = 8.7 Hz, 1H), 3.39 (dd, J = 6.9, 4.8 Hz, 1H), 3.31 (dd, J = 8.7,
4.8 Hz, 1H), 2.99 (ddq, J = 8.7, 4.8, 7.0 Hz, 1H), 2.82 (p, J = 7.0 Hz,
1H), 1.44 (m, 1H), 1.32–1.16 (m, 10H), 1.05 (d, J = 7.1 Hz, 3H),
0.98 (d, J = 7.0 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.85 (t, J = 6.7 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): d = 218, 159.1, 130.6, 129.7,
129.2, 113.7, 78.2, 72.9, 71.9, 55.2, 48.6, 45.5, 35.4, 31.8, 30.0,
29.6, 27.1, 22.6, 16.9, 14.0, 13.7 ppm. MS (ESI): m/z = 401
[M+Na]+; HRMS (ESI): calcd for C23H38O4Na [M+Na]+ 401.2667,
found 401.267.
Rf = 0.50 (SiO2, 10% EtOAc/hexane). ½a D25
¼ þ62:85 (c 2.97, CHCl3).
ꢃ
IR (Neat):
1044 cmꢁ1
mmax = 2926, 2854, 2362, 1516, 1461, 1391, 1224,
.
1H NMR (300 MHz, CDCl3): d = 7.39 (d, J = 8.6 Hz, 2H),
4.1.6. (2S,3S,4S,5S,6S)-1-(4-Methoxybenzyloxy)-2,4,6-trimethyl-
dodecane-3,5-diol 22
6.84 (d, J = 8.8 Hz, 2H), 5.99 (dd, J = 9.6, 2.5 Hz, 1H), 5.27 (s, 1H),
4.06 (dd, J = 11.2, 4.7 Hz, 1H), 3.76 (s, 3H), 3.42 (t, J = 11.2 Hz,
1H), 3.28 (dd, J = 10.0, 1.3 Hz, 1H), 2.50 (s, 3H), 2.16 (m, 1H), 2.01
(m, 1H), 1.84 (m, 1H), 1.35–1.11 (m, 10H), 0.94 (d, J = 7.1 Hz, 3H),
0.92 (d, J = 6.7 Hz, 3H), 0.86 (t, J = 6.9 Hz, 3H), 0.70 (d, J = 6.7 Hz,
3H) ppm. 13C NMR (75 MHz, CDCl3): d = 216.4, 159.7, 131.5,
127.5, 113.3, 100.8, 88.4, 81.4, 73.0, 55.2, 35.7, 35.0, 31.9, 30.1,
29.5, 27.3, 22.6, 18.9, 16.8, 14.1, 12.1, 9.6 ppm. MS (ESI): m/
z = 491[M+Na]+; HRMS (ESI): calcd for C25H40O4NaS2 [M+Na]+
491.2265, found 491.2256.
Compound 18 (3 g, 7.94 m mol) was reduced with
Me4NHB(OAc)3 under the same conditions as used earlier to give
compound 22 (2.7 g, 90%). Rf = 0.2 (SiO2, 20% EtOAc/hexane).
½
a 2D5
ꢃ
¼ ꢁ9:1 (c 2.5, CHCl3). IR (Neat):
m
max = 3442, 2957, 2924,
2855, 1513, 1460, 1247, 1078, 1038, 972, 820 cmꢁ1
.
1H NMR
(500 MHz, CDCl3): d = 7.17 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz,
2H), 4.41 (dd, J = 16.6, 11.4 Hz, 2H), 3.79 (dd, J = 9.3, 2.0 Hz, 1H),
3.77 (s, 3H), 3.52 (dd, J = 9.3, 4.0 Hz, 1H), 3.41 (t, J = 9.0 Hz, 1H),
3.11 (dd, J = 8.4, 4.3 Hz, 1H), 1.95 (m, 1H), 1.73 (m, 1H), 1.64 (m,
1H), 1.34–1.21 (m, 8H), 1.11–1.02 (m, 2H), 0.98 (d, J = 7.0 Hz,
3H), 0.86 (t, J = 7.0 Hz, 3H), 0.79 (d, J = 6.6 Hz, 3H), 0.72 (d,
J = 7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 159.3, 129.6,
129.3, 113.8, 80.6, 76.3, 76.2, 73.1, 55.1, 36.5, 35.8, 34.5, 32.3,
31.9, 29.7, 27.0, 22.7, 16.2, 14.1, 13.0, 10.7 ppm. MS (ESI): m/
4.1.9. (4R,5S)-2-(4-Methoxyphenyl)-5-methyl-4-((2S,4S)-4-meth
yl decan-2-yl)-1,3-dioxane 24
The methyl xanthate derivative 23 (504 mg, 1.07 mmol) was ta-
ken in neat Bu3SnH (3 mL, used as a reagent as well as solvent) and
a catalytic amount of AIBN (17.5 mg, 0.10 mmol) was added. The

1048
T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
mixture was heated at 120 °C for 30 min and after completion of
the reaction it was quenched with H2O (5 mL). The reaction mix-
ture was extracted with EtOAc (2 ꢂ 30 mL). The combined organic
extracts were washed with water (5 mL), brine (5 mL), dried (Na2-
SO4), filtered, and concentrated in vacuo. Purification by column
chromatography on silica gel (60–120 mesh 2% EtOAc/hexane)
afforded 24 (292 mg, 75%) as a colorless liquid; Rf = 0.60 (SiO2,
dried (Na2SO4), and concentrated in vacuo. It was then subjected
to column chromatography on silica gel (60–120 mesh, 10%
EtOAc/hexane) to yield pure compound 26 (146 mg, 75%) as a col-
orless oil; Rf = 0.3 (SiO2, 15% EtOAc/hexane). ½a D30
¼ ꢁ15:1 (c 2.55,
ꢃ
CHCl3). IR (Neat):
mmax = 3384, 2956, 2928, 2856, 1727, 1506,
1458, 1383, 1337, 1252, 1208, 1093, 1067 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d = 7.35–7.27 (m, 5H), 5.30 (d, J = 7.5 Hz, 1H),
5.07 (Abq, J = 12.3 Hz, 2H), 4.88 (dd, J = 9.0, 3.7 Hz, 1H), 4.32 (p,
J = 7.1 Hz, 1H), 3.52 (dd, J = 9.8, 3.7 Hz, 1H), 3.33 (dd, J = 9.8,
6.5 Hz, 1H), 1.90 (m, 1H), 1.74 (m, 1H), 1.43 (d, J = 7.5 Hz, 3H),
1.35–1.21 (m, 9H), 1.08 (m, 1H), 0.92 (d, J = 6.8 Hz, 3H), 0.90–
0.85 (m, 15H), 0.05 (s, 3H), 0.01 (s, 3H) ppm.13C NMR (125 MHz,
CDCl3): d = 172.5, 155.4, 136.3, 128.4, 127.9, 78.7, 66.6, 64.4, 49.7,
37.3, 33.9, 33.8, 31.7, 29.3, 26.9, 25.8, 22.5, 18.9, 18.2, 13.9, 13.9,
13.3, ꢁ5.6 ppm. MS (ESI): m/z = 544 [M+Na]+; HRMS (ESI): calcd
for C29H51NO5NaSi [M+Na]+ 544.3434; found 544.3440.
10% EtOAc/hexane).
m
½
a 2D5
ꢃ
¼ þ15:6 (c 0.4 CHCl3). IR (Neat):
max = 2945, 2927, 2850, 1457, 1068, 1037 cmꢁ1
.
1H NMR
(300 MHz, CDCl3): d = 7.35 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz,
2H), 5.37 (s, 1H), 4.07 (dd, J = 11.1, 4.7 Hz, 1H), 3.79 (s, 3H), 3.44
(t, J = 11.1 Hz, 1H), 3.33 (dd, J = 9.9, 2.1 Hz, 1H), 2.03 (m, 1H),
1.87 (m, 1H), 1.61–1.42 (m, 2H), 1.38–1.16 (m, 10H), 1.07 (m,
1H), 0.94 (d, J = 6.6 Hz, 3H), 0.87 (d, J = 6.5 Hz, 3H), 0.86 (t,
J = 7.1 Hz, 3H), 0.76 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (75 MHz,
CDCl3): d = 159.7, 131.7, 127.2, 113.4, 100.9, 84.5, 73.3, 55.3, 40.8,
37.2, 31.9, 30.6, 30.5, 29.6, 29.6, 26.9, 22.6, 20.0, 14.1, 13.9,
12.0 ppm. MS (ESI): m/z = 385 [M+Na]+; HRMS (ESI): calcd for
C23H38O3Na [M+Na]+ 385.2265, found 385.2258.
4.1.13. (S)-((2S,3R,4S)-1-Hydroxy-2,4-dimethyldecan-3-yl)2-
(benzyloxycarbonylamino)propanoate 27
A
solution of compound 26 (135 mg, 0.25 mmol) in
4.1.10. (2S,3R,4S,6S)-2,4,6-Trimethyldodecane-1,3-diol 25
Compound 24 (270 mg, 0.745 mmol) was dissolved in MeOH
(5 mL), after which Pd/C (10% 170 mg) was added and subjected
to hydrogenation under atmospheric pressure using an H2-filled
balloon. After 2 h, the reaction mixture was filtered through a short
pad of celite and the filter cake was washed with EtOAc. The filtrate
and washings were combined and concentrated in vacuo and sub-
jected to column chromatography on silica gel (60–120 mesh 20%
EtOAc/hexane) to yield pure compound 25 (163 mg, 90%) as a col-
CH2Cl2/MeOH (1:1, 3 mL) was treated with CSA (60 mg,
0.25 mmol) at 0 °C. After being stirred for 30 min at the same tem-
perature, the reaction mixture was quenched with a saturated
aqueous NaHCO3 solution (1 mL), extracted with EtOAc
(2 ꢂ 10 mL), washed with water (2 mL), brine (2 mL), dried (Na2-
SO4), and concentrated in vacuo. The residue was purified by col-
umn chromatography using silica gel (60–120 mesh 25–30%
EtOAc/hexane) to give pure compound 27 (89 mg, 85%) as a color-
less oil; Rf = 0.3 (SiO2, 40% EtOAc/hexane). ½a D30
¼ ꢁ17:9 (c 0.39,
ꢃ
orless oil.Rf = 0.60 (SiO2, 45% EtOAc/hexane). ½a D25
ꢃ
¼ þ4:0 (c 0.7,
CHCl3). IR (KBr): mmax = 3512, 2957, 2928, 2857, 1465, 1386,
CHCl3). IR (Neat):
m
max = 3350, 2950, 2925, 2855, 1457 cmꢁ1
.
1H
1254, 1077, 837, 736 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.35–
.
NMR (300 MHz, CDCl3): d = 3.72 (dd, J = 10.7, 3.8 Hz, 1H), 3.64
(dd, J = 10.7, 7.8 Hz, 1H), 3.45 (dd, J = 9.1, 2.4 Hz, 1H), 3.09–2.48
(m, 2H), 1.85 (m, 1H), 1.75 (m, 1H), 1.48 (m, 1H), 1.32–1.14 (m,
11H), 1.05 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H), 0.85 (d, J = 6.4 Hz, 3H),
0.85 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3): d 79.7, 68.9, 41.4, 37.4, 37.0, 32.0, 31.9, 29.8,
29.6, 26.9, 22.6, 20.0, 14.0, 13.5, 12.7 ppm. MS (ESI): m/z = 267
[M+Na]+; HRMS (ESI): calcd for C15H32O3Na [M+Na]+ 267.4672,
found 267.469.
7.27 (m, 5H), 5.25 (d, J = 6.8 Hz, 1H), 5.08 (s, 2H), 4.88 (dd,
J = 10.5, 2.2 Hz, 1H), 4.33 (d, J = 7.0 Hz, 1H), 3.51 (dd, J = 11.8,
3.2 Hz, 1H), 3.41 (dd, J = 11.8, 3.0 Hz, 1H), 1.88–1.67 (m, 2H), 1.44
(d, J = 6.8 Hz, 3H), 1.35–1.81 (m, 10H), 0.99 (d, J = 6.8 Hz, 3H),
0.93–0.85 (m, 6H) ppm.13C NMR (75 MHz, CDCl3): d = 174.1,
155.7, 136.1, 128.5, 128.1, 128.0, 78.6, 66.9, 64.1, 49.9, 36.8, 34.1,
33.6, 31.7, 29.3, 27.0, 22.5, 18.4, 14.0, 13.9, 12.9 ppm. MS (ESI):
m/z = 430 [M+Na]+. HRMS (ESI): calcd for C23H37NO5Na [M+Na]+
430.2569, found 430.2574.
4.1.11. (2S,3R,4S,6S)-1-(tert-Butyldimethylsilyloxy)-2,4,6-trimet
hyldodecan-3-ol 13
4.1.14. (S)-((2R,3R,4S)-1-(2-tert-Butoxy-2-oxoethylamino)-2,4-
dimethyl-1-oxohexan-3-yl)2-(benzyloxycarbonylamino) prop-
anoate (9)
The TBS protection of compound 25 (150 mg, 0.614 mmol) was
performed to obtain compound 13 (209 mg, 0.58 mmol) by follow-
ing the same conditions as used above for the synthesis of 12.
To a solution of compound 27 (132 mg, 0.32 mmol) in anhy-
drous CH2Cl2 (1.8 mL) was added with stirring, DMSO (2 mL),
Et3N (0.2 mL, 1.62 mmol), and SO3–Py complex (258 mg,
1.62 mmol) portionwise at 0 °C under a nitrogen atmosphere. It
was then allowed to run for 1 h at room temperature, after which
the reaction was quenched with saturated aqueous NH4Cl (2 mL)
and extracted with EtOAc (2 ꢂ 30 mL). The combined organic ex-
tracts were washed with saturated aqueous NH4Cl (5 mL), water
(5 mL), brine (2 mL), dried (Na2SO4), and concentrated in vacuo.
The aldehyde thus obtained was purified by column chromatogra-
phy and used directly for the next reaction.
½
a 2D4
ꢃ
¼ þ14:6 (c 0.9, CHCl3). IR (Neat):
mmax = 2957, 2927, 2850,
1742, 1466, 1390, 1254, 1071 cmꢁ1 1H NMR (300 MHz, CDCl3):
.
d = 3.74 (dd, J = 9.8, 4.0 Hz, 1H), 3.59 (dd, J = 9.8, 8.2 Hz, 1H), 3.4
(dd, J = 8.6, 2.7 Hz, 1H), 1.8 (m, 1H), 1.71–1.46 (m, 3H), 1.44–1.20
(m, 9H), 1.13–1.0 (m, 2H), 1.03 (m, 1H), 0.91–0.85 (m, 15H), 0.84
(d, J = 2 Hz, 3H), 0.77 (d, J = 6.5 Hz, 3H), 0.08 (s, 6H) ppm. 13C
NMR (75 MHz, CDCl3): d 78.9, 69.5, 41.6, 37.4, 36.8, 32.3, 31.9,
29.8, 29.7, 26.9, 25.8, 22.7, 20.1, 18.1, 14.1, 13.3, 12.9, -5.58, -
5.6 ppm. MS (ESI): m/z = 381 [M+Na]+; HRMS (ESI): calcd for C21
H46O2NaSi [M+Na]+ 381.3089, found 381.3085.
t
To a solution of crude aldehyde in BuOH/2-methyl-2-butene
(2:1, 3 mL) at room temperature, NaClO2 (88 mg, 0.927 mmol)
and NaH2PO4ꢀ2H2O (144 mg, 0.927 mmol), dissolved in the mini-
mum amount of H2O, were added. After being stirred for 1 h at
room temperature it was quenched with 1 M HCl at 0 °C (up to
pH 1), the solvent was removed in a rotary evaporator and the res-
idue was extracted with ethyl acetate (2 ꢂ 50 mL). The combined
organic extracts were washed with brine (3 mL), dried (Na2SO4),
and concentrated in vacuo to afford the carboxylic acid as a color-
less liquid. The acid thus obtained was used directly for the peptide
coupling reaction.
4.1.12. (S)-((2S,3R,4S)-1-(tert-Butyldimethylsilyloxy)-2,4-dimeth
yldecan-3-yl)2-(benzyloxycarbonylamino)propanoate 26
To a solution of compound 12 (118 mg, 0.37 mmol) and Cbz-
Ala-OH (125 mg, 0.56 mmol) in anhydrous CH2Cl2 (0.5 mL) at
0 °C, DCC (231 mg, 1.12 mmol) followed by DMAP (7 mg,
0.05 mmol) were added. After stirring for 5 h at room temperature,
the reaction mixture was filtered through Celite. It was then con-
centrated in vacuo, diluted with EtOAc (40 mL), washed with satu-
rated aqueous ammonium chloride solution (4 mL), brine (2 mL),

T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
1049
To a solution of crude acid (136 mg, 0.32 mmol) in CH2Cl2
4.1.16. Emericellamide A 1
(5 mL) at 0 °C, HOBt (65 mg, 0.48 mmol), followed by EDCI
(92 mg, 0.48 mmol) were added and stirred for 10 min. Then at
the same temperature, compound NH2Gly-OtBu (59 mg,
0.45 mmol) was added followed by DIPEA (0.17 mL, 0.97 mmol).
The reaction was monitored via TLC and after completion of the
reaction it was quenched with saturated NH4Cl. Then the
crude mixture was extracted with EtOAc (50 mL), washed with
1 M HCl (4 mL), NaHCO3 (4 mL), H2O (2 mL), brine (2 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude mass
was subjected to column chromatography (SiO2, 25% EtOAc in
petroleum ether eluant) to provide 9 (155 mg, 90%, over three
To a stirred solution of 28 (78 mg, 0.099 mmol) in dry CH2Cl2
(4 mL) was added TFA (2 mL) at 0 °C and stirred for 1 h. After the
reaction mixture was diluted with CH2Cl2 and concentrated in va-
cuo, it was azeotroped 3 times with dry CH2Cl2 and this crude mass
was subjected to macrolactamization without further
characterization.
To a stirred solution of the above crude mass in dry CH3CN
(100 mL, 10ꢁ3 M) were added FDPP (114 mg, 0.29 mmol) followed
by DIPEA (0.03 mL, 0.19 mmol) at 0 °C. Then it was stirred for 72 h
at room temperature. The solvent was concentrated in a rotary
evaporator to give a crude mass as a white solid. The crude mass
was dissolved in a minimum amount of methanol and then poured
in large excess dry ether to precipitate out the product. The precip-
itate was filtered, washed with CH3CN, dried to give emericella-
steps) as
¼ ꢁ4:0 (c 2.75 CHCl3). IR (Neat):
2361, 1726, 1630, 1384, 1217, 1156 cmꢁ1
a
colorless oil; Rf = 0.3 (SiO2, 40% EtOAc/hexane).
max = 3317, 2925, 2657,
1H NMR (300 MHz,
½
a 3D0
ꢃ
m
.
CDCl3): d = 7.42–7.30 (m, 5H), 6.11 (t, J = 5.2 Hz, 1H), 5.70 (d,
J = 7.5 Hz, 1H), 5.15–5.05 (m, 3H), 4.42 (dd, J = 15.1, 7.5 Hz, 1H),
3.94 (dd, J = 18.1, 5.2 Hz, 1H), 3.78 (dd, J = 18.1, 5.2 Hz, 1H), 2.85
(dt, J = 15.1, 6.8 Hz, 1H), 1.83–1.61 (m, 3H), 1.52–1.39 (m, 12H),
1.35–1.19 (m, 8H), 1.31 (d, J = 7.5 Hz, 3H), 0.91–0.81 (m, 6H)
ppm. 13C NMR (75 MHz, CDCl3): d = 175.8, 171.9, 169.3, 155.7,
136.4, 128.3, 127.9, 127.8, 82.1, 78.4, 66.5, 49.7, 43.3, 41.8, 34.1,
33.4, 31.6, 29.2, 27.8, 26.8, 22.5, 18.2, 14.5, 13.9, 13.2 ppm. MS
(ESI): m/z = 557 [M+Na]+. HRMS (ESI): calcd for C29H46N2O7Na
[M+Na]+ 557.3202, found 557.3197.
mide A 1 (45.5 mg, 75%) as a white solid. ½a D30
¼ ꢁ43:0 (c 0.2,
ꢃ
MeOH) {literature2a
m
½
a 3D0
ꢃ
¼ ꢁ43:0 (c 0.23, MeOH)}. IR (Neat):
max = 3401, 3317, 3067, 2962, 2929, 2858, 1755, 1635, 1549,
1458, 1380, 1326, 1285, 1239, 1169, 1064 cmꢁ1 1H NMR
.
(500 MHz, DMSO-d6): d = 8.10 (d, J = 8.2 Hz, 1H), 8.02 (d,
J = 3.3 Hz, 1H) 7.98 (d, J = 8.2 Hz, 1H), 7.47 (dd, J = 5.5, 2.7 Hz,
1H), 7.39 (d, J = 6.6 Hz, 1H), 4.92 (dd, J = 10.2, 2.0 Hz, 1H), 4.31
(dd, J = 17.0, 5.5 Hz, 1H), 4.10–4.01 (m, 3H), 3.98 (dd, J = 8.2,
8.2 Hz, 1H), 3.62 (dd, J = 17.0, 2.7 Hz, 1H), 2.86 (dq, J = 10.0,
7.1 Hz, 1H), 1.89 (m, 1H), 1.67 (m, 1H), 1.60–1.53 (m, 3H), 1.24
(d, J = 7.1 Hz, 3H) 1.22 (d, J = 7.1 Hz, 3H), 1.28–1.16 (m, 8H), 1.10
(m,1H), 1.02 (m,1H), 0.90 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.0 Hz,
3H), 0.88 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 7.0 Hz, 3H), 0.84 (t,
J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 6.0 Hz, 3H)
ppm. 13C NMR (150 MHz, DMSO-d6): d = 172.9, 171.4, 171.3,
171.2, 170.8, 168.7, 76.6, 60.1, 51.7, 48.2, 47.3, 42.5, 41.0, 40.8,
33.5, 33.25, 31.2, 30.2, 28.9, 26.6, 24.5, 23.2, 22.1, 20.7, 19.1,
18.8, 18.3, 16.3, 14.3, 14.0, 12.9 ppm. MS (ESI): m/z = 632
[M+Na]+; HRMS (ESI): calcd for C31H55N5O7Na [M+Na]+ 632.3999;
found 632.3996.
4.1.15. (6S,9S,12S,15S)-((2R,3R,4S)-1-(2-tert-Butoxy-2-oxoethyl
amino)-2,4-dimethyl-1-oxohexan-3-yl)-9-isobutyl-6-isopropyl-
2,2,12,15-tetramethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetra-
azahexadecan-16-oate 28
Compound 9 (134 mg, 0.25 mmol) was dissolved in EtOAc
(5 mL), after which 1 M HCl (0.5 mL), and Pd/C (10%) (100 mg)
were added and subjected to hydrogenation under atmospheric
pressure using H2-filled balloon. After 10 min, the reaction mixture
was filtered through a short pad of Celite and the filter cake was
washed with EtOAc. The filtrate and washings were combined
and concentrated in vacuo to give a crude amine salt, which was
used in the next step for peptide coupling. To a stirred solution
of BocVal-Leu-Ala-OH (301 mg, 0.75 mmol) in dry CH2Cl2:DMF
(1:1) (5 mL) at 0 °C, HOBt (152 mg, 1.12 mmol), followed by EDCI
(214 mg, 1.12 mmol) were added and stirred for 10 min. At the
same temperature the amine prepared above was added to the
reaction mixture followed by DIPEA (0.4 mL, 2.2 mmol). The reac-
tion was monitored via TLC and after completion of the reaction,
it was quenched with saturated NH4Cl. The crude mixture was
then extracted with EtOAc (50 mL), washed with 1 M HCl (4 mL),
NaHCO3 (4 mL), H2O (5 mL), brine (2 mL), dried (Na2SO4), filtered,
and concentrated in vacuo. The crude mixture was subjected to
column chromatography (SiO2, 60% EtOAc /hexane) to yield 28
(147 mg, 75%) as a colorless liquid; Rf = 0.3 (SiO2, 80% EtOAc/hex-
1H NMR data of natural emericellamide A: (500 MHz, DMSO-
d6): d = 8.08 (d, J = 8.0 Hz, 1H), 8.01 (d, J = 3.5 Hz, 1H) 7.93 (d,
J = 8.5 Hz, 1H), 7.50 (dd, J = 5.5, 2.5 Hz, 1H), 7.39 (d, J = 7.5 Hz,
1H), 4.92 (dd, J = 10.0, 2.0 Hz, 1H), 4.30 (dd, J = 17.5, 5.5 Hz, 1H),
4.01 (m, 1H), 4.07 (m, 1H), 4.05 (m, 1H), 3.97 (dd, J = 8.5, 8.5 Hz,
1H), 3.61 (dd, J = 17.5, 2.5 Hz, 1H), 2.85 (dq, J = 10.0, 7.0 Hz, 1H),
1.88 (m, 1H), 1.66 (m, 1H), 1.55 (m, 3H), 1.24 (d, J = 7.5 Hz, 3H)
1.21 (d, J = 7.5 Hz, 3H), 1.22–1.10 (m, 10H), 0.90 (d, J = 7.0 Hz,
3H), 0.89 (d, J = 6.5 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 0.87 (d,
J = 7.0 Hz, 3H), 0.84 (t, J = 7.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.80
(d, J = 6.5 Hz, 3H) ppm. 13C NMR data of natural emericellamide
A (125 MHz, DMSO-d6): d = 172.6, 171.1, 171.0, 170.9, 170.5,
168.4, 76.3, 59.8, 51.5, 47.9, 47.0, 42.1, 39.1, 40.8, 33.2, 32.9,
30.9, 29.9, 28.6, 26.3, 24.2, 22.9, 21.8, 20.4, 18.7, 18.5, 18.0, 16.0,
14.0, 13.7, 12.7 ppm. MS (ESI): m/z = 632 [M+Na]+; HRMS (ESI):
calcd for C31H55N5O7Na [M+Na]+ 632.3999; found 632.3996.
ane). ½a 3D0
ꢃ
¼ ꢁ33:4 (c 3.05, CHCl3). IR (Neat):
mmax = 3280, 3079,
2961, 2928, 2857, 1742, 1638, 1544, 1456, 1369, 1216,
4.1.17. (2S,3R,4S,6S)-3-(4-Methoxybenzyloxy)-2,4,6-trimethyl
dodecan-1-ol 30
1162 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.08 (d, J = 7.9 Hz, 1H),
.
7.02 (d, J = 7.8 Hz, 1H), 6.70 (t, J = 5.2 Hz, 1H), 6.42 (d, J = 6.9 Hz,
1H), 5.09 (dd, J = 9.0, 3.0 Hz, 1H), 4.98 (d, J = 5.4 Hz, 1H), 4.60 (m,
1H), 4.46 (m, 1H), 4.35 (m, 1H), 4.01 (dd, J = 18.0, 6.9 Hz, 1H),
3.87 (dd, J = 18.0, 6.0 Hz, 1H), 3.81 (t, J = 5.7 Hz, 1H), 2.73 (m,
1H), 2.16 (m, 1H), 2.02 (m, 1H), 1.77–1.62 (m, 12H), 1.49–1.37
(m, 21H), 1.31 (d, J = 6.8 Hz, 3H), 1.01–0.83 (m, 21H) ppm. 13C
NMR (75 MHz, CDCl3): d = 173.9, 172.1, 171.1, 171.7, 171.4,
169.4, 156.2, 81.6, 80.1, 78.6, 60.6, 52.0, 48.7, 48.0, 43.1, 41.7,
40.9, 33.9, 33.5, 31.7, 30.6, 29.2, 28.2, 27.9, 27.0, 24.7, 22.9, 22.5,
21.7, 19.1, 18.2, 18.1, 17.8, 14.1, 13.9, 12.9 ppm. MS (ESI): m/
z = 806 [M+Na]+. HRMS (ESI): calcd for C40H73N5O10Na [M+Na]+
806.5255, found 806.5250.
To a solution of 24 (364 mg, 1.0 mmol) in dry CH2Cl2 (3 mL) at
ꢁ78 °C, a solution of DIBAL-H (2.8 mL, 1.4 M in toluene, 4 mmol)
was added dropwise and stirred at that temperature for 30 min.
The reaction was then quenched by the slow addition of a few
drops dry MeOH followed by saturated aqueous potassium–so-
dium tartrate solution. The reaction mixture was stirred (ꢄ2 h) un-
til two clear layers became separated. The aqueous layer was
extracted with EtOAc (30 mL) and washed with brine (5 mL), dried
(Na2SO4), and concentrated in vacuo. Purification by column chro-
matography on silica gel (60–120 mesh 10% EtOAc/hexane) to af-
ford pure compound 30 (355 mg, 97%) as a colorless liquid;
Rf = 0.20 (SiO2, 20% EtOAc/hexane). ½a D24
¼ þ1:9 (c 0.53, CHCl3). IR
ꢃ

1050
T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
(Neat):
m
max = 3459, 2956, 2923, 2855, 1513, 1461, 1248, 1068,
.
31.4, 29.8, 29.6, 26.8, 22.6, 20.1, 16.6, 14.1, 13.1 ppm. MS (ESI):
1037 cmꢁ1
1H NMR (500 MHz, CDCl3): d = 7.27 (d, J = 8.7 Hz, 2H),
m/z = 263 [M+Na]+; calcd for C16H32ONa [M+Na]+ 263.2453, found
6.87 (d, J = 8.5 Hz, 2H), 4.58 (d, J = 10.7 Hz, 1H), 4.49 (d,
J = 10.7 Hz, 1H), 3.80 (s, 3H), 3.67–3.58 (m, 2H), 3.24 (dd, J = 7.6,
3.2 Hz, 1H), 1.91 (m, 1H), 1.83 (m, 1H), 1.68–1.48 (m, 2H), 1.44
(p, J = 6.7 Hz, 1H), 1.36–1.18 (m, 9H), 1.16–1.01 (m, 2H), 0.94 (d,
J = 6.0 Hz, 3H), 0.93 (d, J = 6.1 Hz, 3H), 0.90–0.85 (m, 6H) ppm.
13C NMR (75 MHz, CDCl3): d = 159.3, 130.6, 129.4, 113.8, 87.8,
74.8, 66.7, 55.2, 42.3, 37.7, 36.6, 33.2, 31.9, 30.1, 29.7, 26.8, 22.7,
20.4, 15.5, 14.8, 14.1 ppm. MS (ESI): m/z = 387 [M+Na]+; HRMS
(ESI): calcd for C23H40O3Na [M+Na]+ = 387.2875, found 387.2891.
263.2456.
4.1.20. (S)-((3S,4R,5S,7S)-3,5,7-Trimethyltridec-1-en-4-yl)2-(ben
zyloxy carbonylamino)propanoate 33
Acylation of 32 (50 mg, 0.20 m mol) was carried out with CbzA-
laOH to give 33 (62 mg, 80%) by using the same procedure as used
for the preparation of 26 from 12. ½a D30
¼ þ2:8 (c 1.0, CHCl3). IR
ꢃ
(Neat):
mmax = 2925, 2855, 1740, 1708, 1695, 1648, 1546, 1531,
1515, 1462, 1395 cmꢁ1 1H NMR (300 MHz, CDCl3): d = 7.39–7.29
.
(m, 5H), 5.62 (m, 1H), 5.31 (d, J = 7.9 Hz, 1H), 5.08 (dd, J = 14.2,
12.4 Hz, 2H), 4.98 (dd, J = 17.1, 1.7 Hz, 1H), 4.95 (dd, J = 10.0,
1.2 Hz, 1H), 4.75 (dd, J = 8.0, 3.9 Hz, 1H), 4.37–4.25 (m, 2H), 2.44
(m, 1H), 1.87 (m, 1H), 1.72–1.46 (m, 3H), 1.42 (d, J = 7.1 Hz, 3H),
1.36–1.14 (m, 10H), 0.99 (d, J = 6.8 Hz, 3H), 0.92–0.81 (m, 9H)
ppm. 13C NMR (75 MHz, CDCl3): d = 172.4, 155.4, 140.1, 139.8,
136.3, 128.5, 128.1, 128.0, 115.5, 79.9, 66.7, 49.8, 41.2, 40.4, 36.6,
31.8, 31.0, 29.6, 29.4, 26.7, 22.6, 20.1, 19.1, 17.0, 14.1 ppm. MS
(ESI): m/z = 468 [M+Na]+; HRMS (ESI): calcd for C27H43NO4Na
[M+Na]+ 468.3089, found 468.3073.
4.1.18. 1-Methoxy-4-(((3S,4R,5S,7S)-3,5,7-Trimethyltridec-1-en-
4-yloxy) methyl) benzene 31
Solid TPAP (tetra propyl ammoniumperruthenate) (14 mg,
5 mol %) was added in one portion to alcohol 30 (295 mg,
0.81 mmol), NMO (284 mg, 2.43 mmol), and activated 4 Å MS
(100 mg) in CH2Cl2 (4 mL) at room temperature under a nitrogen
atmosphere. After being stirred for 10 min, the reaction mixture
was filtered through a small bed of Celite and the filter cake was
washed with EtOAc (20 mL). The combined organic layers were
then washed sequentially with water (5 mL), brine (5 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude aldehyde
without purification and characterization was taken forward for
the next reaction.
4.1.21. (S)-((2R,3R,4S,6S)-1-(2-tert-Butoxy-2-oxoethylamino)-
2,4,6-trimethyl-1-oxododecan-3-yl)2-(benzyloxycarbonyl
amino)propanoate 10
Potassium tert-butoxide (727 mg, 6.48 mmol) was added to a
suspension of methyltriphenylphosphonium iodide (3.27 g,
8.1 mmol) in dry ether (20 mL) at 0 °C. The mixture was then stir-
red at room temperature for 30 min. The resulting methylenetri-
phenylphosphorane was added to a solution of aldehyde in ether
(5 mL) at 0 °C. After 0.5 h, the reaction mixture was quenched with
saturated aqueous NH4Cl solution (5 mL). The organic layer was
separated, washed with brine (5 mL), dried (Na2SO4), and concen-
trated in vacuo. Purification by column chromatography on silica
gel (60–120 mesh 5% EtOAc/hexane) afforded pure compound 31
(233 mg, 80%) as colorless liquid; Rf = 0.60 (SiO2, 5% EtOAc/hex-
To a stirred solution of the olefinic compound 33 (50 mg,
0.128 mmol) in dioxane:water (1:1, 2 mL), OsO4 (catalytic), NMO
(10.9 mg, 0.09 mmol) and methanesulfonamide (5 mg, 0.07 mmol)
were added at 0 °C. The temperature of the reaction mixture was
raised to room temperature and stirred for 4 h. After removing
the solvent in vacuo, the residue was extracted with EtOAc
(10 mL), washed with saturated aqueous Na2SO3 (5 mL), water
(5 mL), brine (5 mL), dried (Na2SO4), filtered, and concentrated in
vacuo. Purification by column chromatography (SiO2, 30–40%
EtOAc in hexane eluant) afforded a pure compound as a gummy
liquid, which was used directly for the next step without any
characterization.
ane). ½a 2D5
ꢃ
¼ þ2:2 (c 1.58, CHCl3). IR (Neat):
m
max = 2956, 2923,
2854, 1513, 1460, 1247, 1070, 1093, 819 cmꢁ1
.
1H NMR
The diol compound was treated with NaIO4 (18 mg, 0.22 mmol)
in THF:H2O (1:1) at 0 °C for 30 min. After completion of the reac-
tion it was quenched with NaHCO3 (5 mL) and extracted with
EtOAc (20 mL), washed with saturated aqueous water (5 mL), brine
(5 mL), dried (Na2SO4), filtered, and concentrated in vacuo.
(500 MHz, CDCl3): d = 7.27 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.3 Hz,
1H), 5.76 (ddd, J = 17.6, 10.3, 7.9 Hz, 1H), 5.09–4.93 (m, 2H), 4.53
(d, J = 10.7 Hz, 1H), 4.43 (d, J = 10.7 Hz, 1H), 3.79 (s, 3H), 3.03 (dd,
J = 6.3, 4.3 Hz, 1H), 2.48 (q, J = 7.6 Hz, 1H), 1.78 (m, 1H), 1.49 (m,
1H), 1.39 (p, J = 6.8 Hz, 1H), 1.34–1.15 (m, 11H), 1.02 (d,
J = 6.8 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.88 (t, J = 6.8 Hz, 3H), 0.84
(d, J = 7.0 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3): d = 158.9,
142.0, 131.4, 129.1, 114.0, 113.6, 86.4, 74.3, 55.2, 41.9, 41.0, 36.4,
32.9, 31.9, 29.9, 29.7, 26.7, 22.6, 20.3, 17.5, 14.9, 14.1 ppm. MS
(ESI): m/z = 383 [M+Na]+; HRMS (ESI): calcd for C24H40O2Na
[M+Na]+ 383.2926, found 383.2935.
t
To a solution of the crude aldehyde in BuOH/2-methyl-2-bu-
tene (2:1, 3 mL) at room temperature, NaClO2 (20 mg, 0.22 mmol)
and NaH2PO4.2H2O (34 mg, 0.22 mmol), dissolved in the minimum
amount of H2O, were added. After being stirred for 1 h at room
temperature, the reaction mixture was quenched with 1 M HCl at
0 °C (up to pH 1), the solvent was removed on a rotary evaporator,
and the residue was extracted with ethyl acetate (2 ꢂ 50 mL). The
combined organic extracts washed with brine (3 mL), dried
(Na2SO4), and concentrated in vacuo afforded a crude acid. The acid
thus obtained was directly used for the peptide coupling reaction.
To a solution of crude acid (0.07 mmol) in CH2Cl2 (5 mL) at 0 °C,
HOBt (15 mg, 0.11 mmol), followed by EDCI (21 mg, 0.11 mmol)
were added and stirred for 10 min. At the same temperature, com-
pound NH2Gly-OtBu (70 mg, 0.53 mmol) was added followed by
DIPEA (0.01 mL, 0.22 mmol). The reaction was monitored by TLC
and after completion of the reaction, it was quenched with satu-
rated NH4Cl, and extracted with EtOAc (1 ꢂ 50 mL), washed with
1 M HCl (4 mL), NaHCO3 (4 mL), H2O (2 mL), brine (2 mL), dried
(Na2SO4), filtered, and concentrated in vacuo. The crude mixture
was subjected to column chromatography on silica gel
(60–120 mesh 25% EtOAc/hexane) to give 10 (46 mg, 70%);
4.1.19. (3S,4R,5S,7S)-3,5,7-Trimethyltridec-1-en-4-ol 32
To a solution of 31 (100 mg, 0.27 mmol) in CHCl3:H2O (20:1,
5 mL) was added DDQ (92 mg, 0.401 mmol) at 0 °C. The reaction
was continued for 30 min and quenched with saturated NaHCO3
solution (5 mL), after which it was extracted with CH2Cl2
(50 mL), washed with brine (2 mL), and dried over anhydrous
Na2SO4. The organic extract was then concentrated in vacuo and
purified by column chromatography on silica gel (100–200 mesh
2% EtOAc/hexane) to give pure compound 32 (61 mg, 92%);
Rf = 0.30 (SiO2, 5% EtOAc /hexane). ½a D24
¼ þ4:7 (c 0.83, CHCl3). IR
ꢃ
(Neat):
mmax = 3453, 2923, 2854, 1729, 1657, 1515, 1281, 1127,
.
1074 cmꢁ1
1H NMR (500 MHz, CDCl3): d = 5.73 (m, 1H), 5.18–
5.08 (m, 2H), 3.17 (dd, J = 8.1, 2.6 Hz, 1H), 2.28 (m, 1H), 1.74 (m,
1H), 1.48 (br s, 1H), 1.43 (m, 1H), 1.38–1.18 (m, 10H), 1.05 (m,
1H), 0.98 (d, J = 6.9 Hz, 3H), 0.90–0.84 (m, 9H) ppm. 13C NMR
(75 MHz, CDCl3): d = 141.6, 116.3, 76.4, 42.4, 41.8, 36.8, 31.9,
Rf = 0.5 (SiO2, 50% EtOAc /hexane). ½a D25
¼ ꢁ7:1 (c 1.2 CHCl3). IR
ꢃ
(Neat):
mmax = 3330, 2925, 2855, 1728, 1660, 1530, 1457, 1372,
1338, 1219, 1158, 1062 cmꢁ1
.
1H NMR (500 MHz, CDCl3):

T. K. Pradhan et al. / Tetrahedron: Asymmetry 24 (2013) 1042–1051
1051
d = 7.34–7.31 (m, 5H), 6.04 (t, J = 5.0 Hz, 1H), 5.64 (d, J = 8.0 Hz,
1H), 5.07 (d, J = 5.3 Hz, 1H), 5.04 (dd, J = 8.5, 3.5 Hz, 1H), 4.38 (m,
1H), 3.90 (dd, J = 18.4, 5.2 Hz, 1H), 3.75 (dd, J = 18.4, 4.8 Hz, 1H),
2.55 (m, 1H), 1.87 (m, 1H), 1.76–1.40 (m, 11H), 1.42 (d, J = 7.5 Hz,
3H), 1.34–1.17 (m, 10H), 1.13 (d, J = 7.2 Hz, 3H), 0.93 (m, 1H),
0.88 (t, J = 7.0 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.7 Hz,
3H) ppm. 13C NMR (125 MHz, CDCl3): d 173.5, 171.9, 169.4,
155.7, 136.4, 128.5, 128.1, 128.0, 82.3, 77.9, 66.6, 49.8, 43.5, 41.9,
41.1, 36.6, 31.9, 31.2, 29.6, 29.4, 27.9, 26.7, 22.6, 20.0, 18.5, 14.5,
14.1, 13.7 ppm. MS (ESI): m/z = 599 [M+Na]+; HRMS (ESI): calcd
for C32H52N2O7Na [M+Na]+ 599.3672, found 599.3662.
3H), 0.82 (d, J = 6.0 Hz, 3H), 0.79 (m, 1H), 0.79 (d, J = 6.5 Hz, 3H)
ppm. 13C NMR (150 MHz, DMSO-d6): d = 172.9, 171.3, 171.2,
171.0, 170.7, 168.7, 75.7, 59.9, 51.6, 48.1, 47.2, 40.9, 40.7, 40.1,
39.6, 36.8, 31.3, 30.1, 30.0, 28.9, 28.6, 26.1, 24.5, 23.2, 22.0, 20.6,
19.4, 18.9, 18.7, 18.3, 16.3, 14.3, 13.9, 13.6 ppm. MS (ESI): m/
z = 674 [M+Na]+; HRMS (ESI): calcd for C34H61N5O7Na [M+Na]+
674.4468, found 674.4466. 1H NMR data of natural emericellamide
B
(500 MHz, DMSO-d6): d = 8.53 (d, J = 8.0 Hz, 1H), 8.51 (d,
J = 8.5 Hz, 1H) 8.07 (d, J = 3.5 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.35
(dd, J = 5.5, 2.5 Hz, 1H), 4.92 (dd, J = 10.0, 2.0 Hz, 1H), 4.25 (dd,
J = 17.5, 5.5 Hz, 1H), 4.05 (m, 1H), 4.03 (m, 1H),, 3.97 (dd, 8.5,
7.5 Hz, 1H),3.96 (m, 1H),, 3.60 (dd, J = 17.5, 2.5 Hz, 1H), 2.85 (dq,
J = 10.0, 7.0 Hz, 1H), 1.92 (m, 1H), 1.81 (m, 1H), 1.53–1.55 (m,
4H), 1.24 (d, J = 7.5 Hz, 3H), 1.20 (d, J = 7.5 Hz, 3H), 1.24–1.01 (m,
11H), 0.90 (d, J = 7.0 Hz, 3H), 0.86 (d, J = 6.5 Hz, 3H), 0.86 (d,
J = 7.0 Hz, 3H), 0.86 (d, J = 7.0 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H), 0.82
(d, J = 6.0 Hz, 3H), 0.82 (d, J = 7.0 Hz, 3H), 0.79 (m, 1H), 0.79 (d,
J = 6.5 Hz, 3H) ppm. 13C NMR data of natural emericellamide B
(75 MHz, DMSO-d6): d = 172.7, 171.3, 171.3, 171.2, 171.0, 168.6,
75.7, 60.3, 51.7, 48.2, 47.0, 41.1, 40.7, 40.0, 39.6, 36.8, 31.3, 30.1,
30.1, 29.0, 28.7, 26.1, 24.4, 23.2, 22.0, 20.7, 19.4, 19.0, 18.8, 18.4,
16.3, 14.2, 13.9, 13.5 ppm.
4.1.22. (6S,9S,12S,15S)-((2R,3R,4S,6S)-1-(2-tert-Butoxy-2-oxoe
thylamino)-2,4,6-trimethyl-1-oxododecan-3-yl) 9-isobutyl-6-
isopropyl-2,2,12,15-tetramethyl-4,7,10,13-tetraoxo-3-oxa-
5,8,11,14-tetraazahexadecan-16-oate 34
Compound 10 (35 mg, 0.067 m mol) was coupled with the tri-
peptide 11 to give 34 (41 mg, 75%) under the same conditions as
used for the preparation of compound 28; ½a D25
¼ ꢁ26:7 (c 0.45,
ꢃ
CHCl3). IR (Neat):
mmax = 3620, 3281, 2925, 2856, 1741, 1635,
1531, 1460, 1367, 1163, 700 cmꢁ1 1H NMR (500 MHz, CDCl3):
.
d = 7.07 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 7.9 Hz, 1H), 6.67 (t,
J = 5.4 Hz, 1H), 6.45 (d, J = 6.1 Hz, 1H), 5.06 (dd, J = 9.3, 2.5 Hz,
1H), 5.00 (d, J = 5.8 Hz, 1H), 4.59 (p, J = 7.3 Hz, 1H), 4.46 (p,
J = 7.2 Hz, 1H), 4.36 (m, 1H), 4.00 (dd, J = 18.0, 5.2 Hz, 1H), 3.91–
3.74 (m, 2H), 2.70 (m, 1H), 2.12 (m, 1H), 1.87 (dq, J = 2.4, 7.1 Hz,
1H), 1.77–1.50 (m, 6H), 1.44 (s, 9H), 1.43 (s, 9H), 1.40 (d,
J = 7.3 Hz, 3H), 1.37 (d, 7.2 Hz, 3H), 1.31–1.17 (m, 10H), 1.31 (d,
J = 6.9 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.4 Hz, 6H),
0.91 (d, J = 6.3 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.86 (t, J = 7.1 Hz,
3H), 0.82 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (75 MHz, CDCl3):
d = 179.4, 174.1, 173.3, 171.7, 171.6, 171.0, 169.7, 81.8, 81.0, 78.1,
54.1, 52.7, 49.1, 48.0, 43.2, 41.8, 41.2, 40.5, 36.6, 31.9, 31.0, 29.6,
29.4, 28.2, 28.0, 26.6, 24.9, 24.8, 23.0, 22.8, 22.6, 21.8, 21.6, 20.0,
17.7, 17.4, 14.2, 14.0, 13.4 ppm. MS (ESI): m/z = 848 [M+Na]+;
HRMS (ESI): calcd for C43H79N5O10Na [M+Na]+ 848.3672, found
848.3668.
Acknowledgments
K.M.R. thanks CSIR, New Delhi for research fellowships. S. G is
thankful to Council of Scientific and Industrial Research for funding
under ORIGIN programme of the 12th five year plan.
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~
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Compound 34 (25 mg, 0.03 mmol) was cyclized under similar
conditions as used for the cyclization of 28 to give emericellamide
B
2
(15 mg, 80%).
¼ ꢁ34:0 (c 0.76, MeOH). IR (Neat):
½
a 3D0
ꢃ
¼ ꢁ34:1 (c 0.12, MeOH), literature2a
½
a 3D0
ꢃ
mmax = 3653, 3622, 3388,
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3364, 3286, 2922, 2852, 1730, 1650, 1536, 1462, 1375, 1282,
1126, 1076 cmꢁ1 1H NMR (600 MHz, DMSO-d6): d = 8.04 (br s,
.
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1H), 7.90 (d, J = 8.9 Hz, 1H), 7.70 (br s, 1H), 7.53 (br s, 1H), 7.37
(d, J = 7.8 Hz, 1H), 4.90 (d, J = 10.0 Hz, 1H), 4.31 (dd, J = 17.3,
5.5 Hz, 1H), 4.09–3.96 (m, 4H), 3.62 (dd, J = 17.3, 3.0 Hz, 1H), 2.88
(dq, J = 10.0, 6.8 Hz, 1H), 1.86 (m, 1H), 1.81 (m, 1H), 1.62–1.50
(m, 4H), 1.24 (d, J = 7.5 Hz, 3H), 1.20 (d, J = 7.0 Hz, 3H), 1.20–1.06
(m, 10H), 1.03 (m, 1H), 0.91–0.89 (m, 6H), 0.88 (d, J = 7.1 Hz, 3H),
0.86 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.0 Hz, 3H), 0.83 (d, J = 6.2 Hz,
16. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666.