A new example of a steroid-amino acid hybrid: Construction of constrained nine membered d-ring steroids

Article abstract of DOI:10.1039/b616155c

A new archetype of steroid-amino acid hybrids containing a nine membered d-ring with hetero atoms has been synthesized for the first time from estrone and amino acids by using Yamaguchi coupling reactions. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b616155c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A new example of a steroid–amino acid hybrid: construction of constrained
nine membered D-ring steroids†‡
Shagufta and Gautam Panda*
Received 6th November 2006, Accepted 10th November 2006
First published as an Advance Article on the web 4th December 2006
DOI: 10.1039/b616155c
A new archetype of steroid–amino acid hybrids containing a nine membered D-ring with hetero atoms
has been synthesized for the first time from estrone and amino acids by using Yamaguchi coupling
reactions.
onto the D-ring of steroid 2 (Fig. 1). The projected molecule 1,
Introduction
having a constrained nine membered D-ring with hetero atoms
Nature remains the unending source for biologically important
on the steroidal framework, provides a highly efficient access to
natural products of molecular diversity and complexity. These
novel molecular hybrids. To the best of our knowledge, only one
naturally occurring molecules, which are essentially derived from
example of a nine membered D-ring on a steroid using Heck
coupling is reported.10 Intramolecular macrolactonization on a
steroidal framework to furnish a nine membered D-ring has not
been reported so far.
particular or combined biosynthetic pathways, possess novel
physical, chemical and biological properties.1 The human quest to
acquire novel molecules with interesting properties has generated
an idea of architecting an inexhaustible reservoir of novel synthetic
endeavours by rationally combining two or more different classes
of natural products.2 During the past two decades, the design
and synthesis of such molecular structures have received much
attention and these have been referred to as ‘hybrid molecules’.
Hybrids or conjugates between hydrophobic steroids and hy-
drophilic amino acids or peptides, i.e. peptidyl steroids, have been
reported to play important roles to enhance oral antiarrhythmic
activity, to promote delivering prodrugs to specific target tissues
and to achieve ‘permissive action’.3–5 Several peptidyl steroids such
as polymastiamide A, a tyrosine conjugated steroid analog iso-
lated from the Norwegian marine sponge Polymastia boletiformis
exhibiting antimicrobial activity and bufetoxin, a 3-arginyl derived
steroid product isolated from the Chinese hoptoad have been
reported.6 Moreover, cholyl glycine or cholyl taurine which exists
in the bile of animals and contains a glycyl or a taurinyl group at
the 17-position of the steroid, has led to the development of several
steroid–amino acid conjugates for estrogen dependent biological
activity,7 14C-cholyl-glycine breath test,8 and as antidepressant
agents.9 To date, it is mainly peptidyl steroids of the androstane
and estrone series comprising amino acids or peptides attached
with the unchanged nucleus of steroids through an amide or
ester bond, that have been synthesized and examined. There is
no reported example of a chiral amino acid incorporated D-ring
modified peptidyl steroid.
Fig. 1 Structures of projected molecule 1 and estrone 2.
Retrosynthetic analysis revealed that projected molecule 1 could
be accessed from 3 which could be obtained from building blocks
seco-estrone aldehyde 4 and amino acid 5 through utilization of
reductive amination and macrolactonization (Scheme 1).
Scheme 1 Retrosynthetic analysis of target molecule.
The synthesis of seco-estrone aldehyde 4 was accomplished
from readily available estrone 2 (Scheme 2). Alkylation of estrone
2 with benzyl bromide–K2CO3 followed by base and an iodine
mediated haloform reaction gave marrianolic acid benzyl ether
6 (75%).11 LAH reduction of 6 led to diol 7 (35%). The overall
yield of 7 from 2 was very poor (26%). It was therefore decided to
develop an alternative strategy for large scale access to 7. Towards
this objective, estriol 8 was initially synthesized from 2 following
literature procedures.12 The phenolic hydroxy of 8 was benzylated
to give 9 (95%). The vicinal hydroxyl groups of estriol 3-benzyl
ether 9 were subjected to periodate cleavage (NaIO4) to deliver the
dialdehyde 10 which was subjected to LAH reduction to furnish
7 with 62% overall yield. Further, the C16 hydroxyl group of
diol 7 was selectively protected as TBDMS derivative 11 (67%)
by treatment of alcohol 7 with 1 : 1 equivalents of TBDMSCl
Results and discussion
Here we describe the design and synthesis of a new archetype
of ‘steroid–amino acid hybrid’ 1 with amino acids incorporated
Medicinal and Process Chemistry Division, Central Drug Research In-
stitute, Chattar Manzil Palace, Lucknow 226001, UP, India. E-mail:
gautam.panda@gmail.com
† CDRI Communication number 6739.
‡ Electronic supplementary information (ESI) available: 1H and 13C NMR
spectra of compounds 3–17 and 1H-1H COSY, HSQC and HMBC spectra
of 3b. See DOI: 10.1039/b616155c
360 | Org. Biomol. Chem., 2007, 5, 360–366
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Scheme 2 Synthesis of key intermediate D-seco estrone aldehyde 4.
Reagents and conditions: a) LAH, THF, 0–5 ◦C, 1 h, 35%; b) benzyl
bromide, K2CO3, acetone, reflux, 8 h, 95%; c) NaIO4, methanol–H2O (4 :
1), 0 ◦C, 24 h; d) LAH, THF, 0–5 ◦C, 1 h, 81% (two steps); e) TBDMSCl,
imidazole, DCM, 0 ◦C–rt, 6 h, 67%; f) TPAP, NMO, MS 4 A, DCM, rt,
˚
1 h, 82%.
Scheme
3
Synthesis of 3a–c. Reagents and conditions: a) TEA,
and imidazole. TPAP mediated oxidation of the primary hydroxyl
group in 11 led to the key aldehyde 4 in 82% yield. The aldehyde
4 was prepared on a large scale for the execution of reductive
amination with chiral amino acid ester.
methanol–THF (4 : 1), reflux–rt, 12 h; b) NaBH4, methanol, 0–5 ◦C,
1 h, 14a = 80%, 14b = 78% and 14c = 73% for two steps; c) MeI,
K2CO3, acetone, rt, 24 h, 15a = 97%, 15b = 95% and 15c = 93%; d)
AcOH–H2O–THF (3 : 1 : 1), 60 ◦C, 2 h, 16a = 66%, 16b = 63% and 16c =
70%; e) 1 N NaOH, dioxane, 60 ◦C, 1 h, 17a = 70%, 17b = 67% and 17c =
72%; f) 2,4,6-Cl3C6H2COCl, Et3N, THF, rt, then DMAP, PhMe, reflux,
3a = 53%, 3b = 63% and 3c = 42%.
Reductive amination of 4 with amino acid methyl ester
hydrochloride13 12a–c in the presence of NaBH3CN and acetic
acid was performed to afford amine 14a (30%), 14b (34%) and 14c
(31%). Yield of the amine 14a–c was improved (80%, 78% and 73%
respectively) by performing the reaction in two steps through initial
formation of imine 13a–c followed by reduction with NaBH4. It
was decided to convert the secondary amine to a tertiary one to
avoid unnecessary reactions in the next steps. Treatment of amine
14a–c with MeI–K2CO3 in acetone furnished the fully protected
product 15a (97%), 15b (95%) and 15c (93%). Upon exposure to
AcOH–H2O–THF (3 : 1 : 1) at 50–60 ◦C, deprotection of TBDMS
ether occurred to afford the alcohol 16a (66%), 16b (63%) and 16c
(70%).
Additionally, the acid functionality of 17a–c can be further
coupled with other amino acids to elaborate macrocyclic steroid–
amino acid hybrids for interesting biological functions. Efforts in
this direction are in progress.
Experimental
General
Finally the methyl ester of 16a–c was hydrolyzed in the presence
of 1 N NaOH–dioxane to furnish the hydroxy acid 17a (70%),
17b (67%) and 17c (72%). The hydroxy acid was then subjected to
macrolactonization using the Yamaguchi method14 to furnish the
corresponding lactone 3a (53%), 3b (63%) and 3c (42%) which can
afford the target molecule 1 on deprotection of a benzyl group,
Scheme 3. The structure of steroid–amino acid hybrid 3a–c was
All the reactions were monitored by thin layer chromatography
over silica gel coated TLC plates. The spots on TLC were visualized
by warming ceric sulfate (2% CeSO4 in 2 N H2SO4) sprayed plates
on a hot plate or in an oven at about 100 ◦C. Silica gel 60–120
mesh was used for column chromatography. Melting points were
recorded on an electrically heated apparatus and are uncorrected.
IR spectra were recorded on a Perkin Elmer 881 or FT IR 820/PC
instrument and values are expressed in cm−1. Electron impact mass
spectra were recorded on a JEOL (Japan)/D-300 instrument and
FAM mass spectra were recorded on a JEOL SX 102/DA-6000
mass spectrometer using Argon/Xenon (6 KV, 10 MA) as the FAB
gas. 1H and 13C NMR spectra were recorded on a Bruker Avance
DPX 200 MHz instrument using TMS as an internal reference.
Chemical shift values are expressed in d ppm. Specific rotation
was determined with a Rudolph Autopol IIIrd polarimeter at
28 ◦C. Elementary analysis was carried out on a Carlo ERBA-1108
analyzer. Commercially available grades of organic solvents of
adequate purity were used in many reactions. Acetone was refluxed
with KMnO4 for 4 h, after that it was distilled and stored in a
bottle containing dried K2CO3. Benzene was refluxed with freshly
1
1
secured from incisive analysis of H, 13C NMR, H-1H COSY,
HSQC and HMBC spectra.
In conclusion, we have demonstrated a new prototype of
steroid–amino acid hybrid 1 from easily available estrone 2 and
amino acids i.e. alanine, phenyl alanine and isoleucine through
a series of simple and efficient steps involving NaIO4 cleavage of
estriol, reductive amination and Yamaguchi coupling reactions.
A simple and convenient approach to access chiral amino acid
incorporated D-ring modified steroid–amino acid hybrids (pep-
tidyl steroids) is described. In the process, we have synthesized
several important molecules such as diol, D-seco estrone aldehyde
and and D-seco estrone amino acid conjugates which can be used
as advanced intermediates for accessing new steroid derivatives.
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˚
2.09 (m, 2H), 1.95–1.91 (m, 9H), 0.81 {s, 9H, –C(CH3)3}, 0.56
(s, 3H, C-18-H3), 0.04 {s, 6H, –Si(CH3)2–}. 13C NMR (50 MHz,
CDCl3): d 157.1 (C-3), 138.1 (C-5), 137.7, 133.4 (C-10), 128.9,
128.2, 127.8, 127.1 (C-1), 114.9 (C-4), 112.9 (C-2), 70.9 (C-17),
70.3 (–O–CH2–C6H5), 65.8 (C-16), 44.0, 42.3, 41.0, 38.9 (C-13),
35.8, 31.0, 30.8 (C-6), 27.8 (C-12), 27.1(C-11), 26.5 {–C(CH3)3},
19.1{–C(CH3)3}, 16.3 (C-18), −4.9 {Si(CH3)2–}. MASS (FAB):
m/z (%): 495 (40, [M+ + H]), 363 (70, [M+–OH,-TBDMS]). Anal.
Calcd for (C31H46O3Si): C, 75.25; H, 9.37%. Found: C, 75.42; H,
9.64%.
cut and dried sodium metal pieces pressed in 3 A sieves for 4–6 h.
It was distilled and stored in a dry bottle. Tetrahydrofuran was
dried initially over calcium sulfate and then refluxed over lithium
aluminium hydride. Peroxide was removed by passage through a
column of alumina and distilled and stored over molecular sieves
˚
3 A.
Experimental procedure
Diol 7. To a stirred solution of estriol 3-benzyl ether 9 (2.62 g,
6.93 mmol) in methanol (40 ml) at 0 ◦C was added a solution of
NaIO4 (2.22 g, 10.40 mmol) in water (10 ml). After stirring at 0 ◦C
for 24 h, the methanol was evaporated in vacuo at low temperature.
The aqueous solution was extracted with CH2Cl2 twice. The
combined organic layer was washed with water, brine, dried over
Na2SO4 and concentrated under vacuum to yield dialdehyde 10
(3.0 g) as a yellow viscous oil which was used as such for the next
step.
Aldehyde 4. To a solution of 11 (1 g, 2.02 mmol) in CH2Cl2
˚
(25 ml) were added molecular sieves (4 A) followed by NMMO
(0.41 g, 3.04 mmol). After stirring the mixture for 10 min, TPAP
(0.07 g, 0.20 mmol) was added and it was stirred at rt for 2 h. After
completion (monitored by TLC), the reaction mixture was diluted
with CH2Cl2 and was washed with sodium sulfite, brine, saturated
CuSO4 solution, dried over Na2SO4 and concentrated in vacuo.
The residue was chromatographed over silica gel and elution with
10% ethyl acetate in hexane (Rf = 0.6) furnished 4 (0.82 g, 82%)
as white solid, mp 80 ◦C. IR (KBr): 3417, 2945, 1724, 1598, 1359,
1093, 837, 771 cm−1. 1H NMR (200 MHz, CDCl3): d 9.37 (s, 1H,
C-17-H), 7.36–7.29 (m, 5H, –O–CH2–C6H5), 7.16 (d, 1H, J = 8.6,
C-1-H), 6.71 (dd, 1H, J1 = 8.6, J2 = 2.4, C-2-H), 6.67 (d, 1H,
J = 2.4, C-4-H), 4.98 (s, 2H, –O–CH2–C6H5), 3.61–3.39 (m, 2H,
C-16-H2), 2.72–2.88 (m, 2H, C-6-H2), 2.35–2.22 (m, 2H), 2.15–
2.02 (m, 1H), 1.71–1.15 (m, 8H), 1.00 (s, 3H, C-18-H3), 0.85 {s,
9H, –C(CH3)3}, 0.00 {s, 6H, –Si(CH3)2–}. 13C NMR (50 MHz,
CDCl3): d 207.0 (C-17), 157.3 (C-3), 138.2 (C-5), 137.6, 132.5
(C-10), 128.9, 128.3, 127.8, 126.8 (C-1), 114.9 (C-4), 113.0 (C-2),
70.3 (–O–CH2–C6H5), 63.4 (C-16), 51.1 (C-13), 43.6, 41.0, 40.6,
34.1, 33.0, 30.7 (C-6), 27.4 (C-12), 26.4 {–C(CH3)3}, 25.8 (C-11),
18.7{–C(CH3)3}, 13.4 (C-18), −4.8 {Si(CH3)2–}. MASS (FAB):
m/z (%): 492 (60, [M+]), 491 (80, [M+–H]). Anal. Calcd for
(C31H44O3Si): C, 75.56; H, 9.00%. Found: C, 75.76; H, 9.29%.
Dialdehyde 10 (3.0 g) in THF (5 ml) was added dropwise to a
stirred solution of LAH (0.45 g, 11.97 mmol) in 40 ml of THF
at 0 ◦C. The resulting solution was stirred at rt for 1 h. After
completion (monitored by TLC), the reaction was quenched with
ethyl acetate followed by water at 0 ◦C. The aqueous layer was
extracted twice with ethyl acetate. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4 and concentrated
under vacuum. The residue was chromatographed over silica gel
and elution with 40% ethyl acetate in hexane (Rf = 0.5) furnished
◦
diol 7 (2.12 g, 81%) as white solid, mp 135 C. IR (KBr): 3336,
2920, 1606, 1255, 1035, 740 cm−1. H NMR (200 MHz, CDCl3):
1
d 7.44–7.20 (m, 6H, –O–CH2–C6H5 and C-1-H), 6.78 (dd, 1H,
J1 = 8.6, J2 = 2.4, C-2-H), 6.70 (d, 1H, J = 2.4, C-4-H), 5.02
(s, 2H, –O–CH2–C6H5), 4.00–3.85 (m, 1H, C-16-H), 3.67 (d, 1H,
J = 11.7, C-17-H), 3.61–3.46 (m, 1H, C-16-H), 3.09 (d, 1H, J =
11.7, C-17-H), 2.85–2.83 (m, 2H, C-6-H2), 2.33–2.26 (m, 2H),
2.01–1.95 (m, 2H), 1.75–1.28 (m, 7H), 0.69 (s, 3H, C-18-H3). 13
C
Amine 14a. To a solution of alanine methyl ester hydrochloride
12a (0.16 g, 1.13 mmol) in methanol (12 ml) was added triethyl
amine (0.21 ml, 1.50 mmol). After stirring the mixture for 5 min, a
solution of aldehyde 4 (0.37 g, 0.75 mmol) in THF (3 ml) was added
and the reaction mixture was refluxed for 2 h. After stirring at rt
overnight, the solvent was removed and the residue was dissolved
in ethyl acetate. The undissolved material was filtered off and the
filtrate was concentrated to afford the crude imine 13a (0.4 g).
To a solution of crude imine 13a (0.4 g) in methanol (15 ml),
N◦aBH4 (0.04 gm, 1.04 mmol) was added in a small portion at
0 C. After 15 min, the solvent was removed under vacuum and
the residue was passed through silica gel and elution with 10%
ethyl acetate in hexane (Rf = 0.4) furnished 14a (0.35 g, 80%) as a
white solid, mp 72 ◦C, [a]D20 +17 (c 2, MeOH). IR (KBr): 3570, 2935,
1737, 1598, 1463, 1251, 1093, 840, 775 cm−1. 1H NMR (200 MHz,
CDCl3): d 7.39–7.02 (m, 6H, –O–CH2–C6H5 and C-1-H), 6.61 (dd,
1H, J1 = 8.6, J2 = 2.4, C-2-H), 6.58 (d, 1H, J = 2.4, C-4-H), 4.94
(s, 2H, –O–CH2–C6H5), 3.65 (s, 3H, –CO2CH3), 3.63–3.39 (m,
2H, C-16-H2), 3.26–3.06 (m, 1H, –CH–CH3), 2.80–2.62 (m, 2H,
C-6-H2), 2.29 (s, 2H, C-17-H2), 2.28–2.01 (m, 3H), 1.65–1.47 (m,
4H), 1.40–1.09 (m, 4H), 1.22 (d, 3H, J = 7, –CH–CH3), 0.84 {s,
9H, –C(CH3)3}, 0.72 (s, 3H, C-18-H3), 0.00 {s, 6H, –Si(CH3)2–}.
13C NMR (50 MHz, CDCl3): d 177.1 (–CO2CH3), 157.1 (C-3),
138.4 (C-5), 137.9, 133.5 (C-10), 128.9, 128.2, 127.8, 126.9 (C-
NMR (50 MHz, CDCl3): d 157.1 (C-3), 138.2 (C-5), 137.7, 133.4
(C-10), 128.9, 128.2, 127.9, 127.0 (C-1), 114.8 (C-4), 112.9 (C-2),
70.5 (C-17), 70.4 (–O–CH2–C6H5), 64.3 (C-16), 43.9, 42.2, 41.2,
38.9 (C-13), 35.7, 31.0, 30.3 (C-6), 27.8 (C-12), 27.0 (C-11), 16.4
(C-18). MASS (FAB): m/z (%): 380 (100, [M+]), 363 (40, [M+–
OH)]). Anal. Calcd for (C25H32O3): C, 78.91; H, 8.48%. Found: C,
79.17; H, 8.60%.
TBDMS derivative 11. To a solution of diol 7 (2 g, 5.26 mmol)
in CH2Cl2 (20 ml) at 0 ◦C was added imidazole (0.36 g, 5.26 mmol)
followed by TBDMSCl (0.79 g, 5.26 mmol). The mixture was
stirred at rt overnight. The reaction was quenched with H2O and
diluted with CH2Cl2. The aqueous layer was extracted with CH2Cl2
twice. The combined organic layers were dried over Na2SO4 and
concentrated under vacuum. The residue was chromatographed
over silica gel and elution with 10% ethyl acetate in hexane (Rf =
0.5) furnished 11 (1.75 g, 67%) as a white solid, mp 77 ◦C with
recovery of starting material 7 (0.592 g, 30%). IR (KBr): 3473,
1
2927, 1500, 1463, 1253, 1046, 836 cm−1. H NMR (200 MHz,
CDCl3): d 7.28–7.22 (m, 5H, –O–CH2–C6H5), 7.12 (d, 1H, J =
8.6, C-1-H), 6.69 (dd, 1H, J1 = 8.6, J2 = 2.4, C-2-H), 6.59 (d, 1H,
J = 2.4, C-4-H), 4.97 (s, 2H, –O–CH2–C6H5), 3.85–3.69 (m, 1H, C-
16-H), 3.55 (d, 1H, J = 12, C-17-H), 3.43–3.32 (m, 1H, C-16-H),
2.95 (d, 1H, J = 12, C-17-H), 2.73–2.72 (m, 2H, C-6-H2), 2.32–
362 | Org. Biomol. Chem., 2007, 5, 360–366
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1), 114.8 (C-4), 112.8 (C-2), 70.3 (–O–CH2–C6H5), 64.8 (C-16),
58.4 (C-17), 57.8 (–CH–CH3), 52.0 (–CO2CH3), 43.9, 42.4, 42.1,
37.9 (C-13), 36.9, 32.8, 31.0 (C-6), 28.0 (C-12), 26.9 (C-11), 26.5
{–C(CH3)3}, 19.4 {–C(CH3)3}, 18.9 (–CH–CH3), 18.1 (C-18),
−4.7 {Si(CH3)2–}. MASS (FAB): m/z (%): 580 (100, M+). Anal.
Calcd for (C35H53NO4Si): C, 72.49; H, 9.21; N, 2.42%. Found: C,
72.71; H, 9.39; N, 2.51%.
N-Methyl amine derivative 15a. A mixture of 14a (0.2 g,
0.35 mmol), anhydrous K2CO3 (0.24 g, 1.72 mmol), methyl iodide
(0.04 ml, 0.69 mmol) and dry acetone (15 ml) was stirred at room
temperature for 24 h. K2CO3 was filtered off and the acetone was
removed in vacuo. The residue was diluted with water and extracted
with ethyl acetate. The organic layer was washed with water, brine,
dried over anhydrous Na2SO4 and concentrated under vacuum.
The residue was chromatographed over silica gel and elution with
5% ethyl acetate in hexane (Rf = 0.45) furnished 15a (0.20 g, 97%)
as a white semi solid, [a]2D0 +39.5 (c 2, MeOH). IR (KBr): 3460,
Amine 14b. As described for 14a, phenylalanine methyl ester
hydrochloride 12b (0.20 g, 0.91 mmol) in methanol (15 ml), triethyl
amine (0.17 ml, 1.22 mmol), aldehyde 4 (0.3 g, 0.61 mmol) in THF
(3 ml) furnished imine 13b (0.33 g).
1
2932, 1735, 1609, 1500, 1461, 1248, 1091, 772 cm−1. H NMR
(200 MHz, CDCl3): d 7.30–7.17 (m, 5H, –O–CH2–C6H5), 7.05 (d,
1H, J = 8.6, C-1-H), 6.69 (dd, 1H, J1 = 8.6, J2 = 2.4, C-2-H),
6.57 (d, 1H, J = 2.4, C-4-H), 4.93 (s, 2H, –O–CH2–C6H5), 3.60
(s, 3H, –CO2CH3), 3.59–3.18 (m, 3H, C-16-H2 and –CH–CH3),
2.81–2.67 (m, 2H, C-6-H2), 2.55 (d, 1H, J = 11.8, C-17-H), 2.31 (s,
3H, –N–CH3), 2.29 (d, 1H, J = 11.8, C-17-H), 2.29–1.99 (m, 3H),
1.81–1.26 (m, 8H), 1.21 (d, 3H, J = 7.1, –CH–CH3), 0.84 {s, 9H,
–C(CH3)3}, 0.77 (s, 3H, C-18-H3), 0.01 {s, 6H, –Si(CH3)2–}. 13C
NMR (50 MHz, CDCl3): d 174.7 (–CO2CH3), 157.1 (C-3), 138.3
(C-5), 137.7, 133.5 (C-10), 128.9, 128.2, 127.8, 127.0 (C-1), 114.8
(C-4), 112.8 (C-2), 70.3 (–O–CH2–C6H5), 67.8 (C-17), 64.8 (C-16),
64.0 (–CH–CH3), 51.4 (–CO2CH3), 44.6, 44.1, 42.2, 40.7 (–N–
CH3), 40.2 (C-13), 37.9, 33.2, 31.0 (C-6), 28.0 (C-12), 26.9 (C-11),
26.5 {–C(CH3)3}, 18.9 {–C(CH3)3}, 16.7 (–CH–CH3), 16.0 (C-18),
−4.6 {Si(CH3)2–}. MASS (FAB): m/z (%): 594 (100, M+). Anal.
Calcd for (C36H55NO4Si): C, 72.80; H, 9.33; N, 2.36%. Found: C,
72.96; H, 9.49; N, 2.45%.
13b (0.33 g, 0.505 mmol) in methanol (15 ml), NaBH4 (0.03 g,
0.76 mmol) furnished 14b (0.31 g, 78%) as a viscous oil, Rf =
0.45 (10% ethyl acetate in hexane), [a]2D0 +27 (c 2, MeOH). IR
1
(Neat): 3427, 2931, 1737, 1598, 1355, 1091, 839, 773 cm−1. H
NMR (200 MHz, CDCl3): d 7.33–7.11 (m, 11H, –O–CH2–C6H5,
–CH–CH2–C6H5 and C-1-H), 6.58 (dd, 1H, J1 = 8.6, J2 = 2.4, C-
2-H), 6.65 (d, 1H, J = 2.4, C-4-H), 4.94 (s, 2H, –O–CH2–C6H5),
3.56 (s, 3H, –CO2CH3), 3.46–3.34 (m, 3H, C-16-H2 and –CH–
CH2–C6H5), 2.85 (d, 2H, J = 6.8, –CH–CH2–C6H5), 2.83–2.77 (m,
2H, C-6-H2), 2.44–2.34 (m, 2H, C-17-H2), 2.26–2.09 (m, 3H), 2.02
(bs, 1H, –NH–), 1.59–1.19 (m, 8H), 0.84 {s, 9H, –C–(CH3)3}, 0.68
(s, 3H, C-18-H3), 0.00 {s, 6H, –Si(CH3)2–}. 13C NMR (50 MHz,
CDCl3): d 175.8 (–CO2CH3), 157.1 (C-3), 138.4 (C-5), 138.0, 137.7,
133.5 (C-10), 129.7, 128.9, 128.7, 128.2, 127.8, 127.0 (C-1), 114.8
(C-4), 112.8 (C-2), 70.3 (–O–CH2–C6H5), 64.7 (C-16), 64.5 (–CH–
CH2–C6H5), 58.5 (C-17), 51.9 (–CO2CH3), 44.0, 42.4, 42.2, 40.4
(–CH–CH2–C6H5), 38.2 (C-13), 36.8, 32.9, 31.0 (C-6), 28.0 (C-12),
26.9 (C-11), 26.4 {–C(CH3)3}, 18.8 {–C(CH3)3}, 18.1 (C-18), −4.6
{Si(CH3)2–}. MASS (FAB): m/z (%): 656 (100, M+ + H). Anal.
Calcd for (C41H57NO4Si): C, 75.07; H, 8.76; N, 2.14%. Found: C,
75.18; H, 8.88; N, 2.05%.
N-Methyl amine derivative 15b. As described for 15a, amine
14b (0.22 g, 0.34 mmol), K2CO3 (0.23 g, 1.68 mmol), methyl iodide
(0.04 ml, 0.67 mmol) in acetone (15 ml) furnished 15b (0.21 g, 95%)
as a white semi-solid, Rf = 0.5 (5% ethyl acetate in hexane), [a]D20
+12.5 (c 2, MeOH). IR (KBr): 3375, 2935, 1738, 1598, 1352, 1245,
1089, 771 cm−1. 1H NMR (200 MHz, CDCl3): d 7.32–7.08 (m, 11H,
–O–CH2–C6H5, –CH–CH2–C6H5 and C-1-H), 6.68 (dd, 1H, J1 =
8.6, J2 = 2.4, C-2-H), 6.61 (d, 1H, J = 2.4, C-4-H), 4.93 (s, 2H, –O–
CH2–C6H5), 3.58 (s, 3H, –CO2CH3), 3.48–3.23 (m, 3H, C-16-H2
and –CH–CH2–C6H5), 2.97–2.71 (m, 2H, –CH–CH2–C6H5), 2.69–
2.52 (m, 2H, C-6-H2), 2.38–2.24 (m, 5H, C-17-H2 and –N–CH3),
2.09–1.14 (m, 11H), 0.83 {s, 9H, –C–(CH3)3}, 0.63 (s, 3H, C-18-
H3), 0.00 {s, 6H, –Si(CH3)2–}. 13C NMR (50 MHz, CDCl3): d 173.3
(–CO2CH3), 157.1 (C-3), 139.3 (C-5), 138.3, 137.8, 133.6 (C-10),
129.9, 128.9, 128.6, 128.2, 127.8, 127.0 (C-1), 126.7, 114.7 (C-4),
112.8 (C-2), 71.0 (–CH–CH2–C6H5), 70.3 (–O–CH2–C6H5), 68.2
(C-17), 64.7 (C-16), 51.4 (–CO2CH3), 43.7, 43.5, 42.3, 40.5 (–N–
CH3), 40.4 (C-13), 37.4, 36.5 (–CH–CH2–C6H5), 33.2, 31.0 (C-6),
27.9 (C-12), 26.9 (C-11), 26.5 {–C(CH3)3}, 18.9 {–C(CH3)3}, 17.0
(C-18), −4.6 {Si(CH3)2–}. MASS (FAB): m/z (%): 670 (100, M+
+ H). Anal. Calcd for (C42H59NO4Si): C, 75.29; H, 8.88; N, 2.09%.
Found: C, 75.45; H, 9.15; N, 2.19%.
Amine 14c. As described for 14a, isoleucine methyl ester
hydrochloride 12c (0.17 g, 0.91 mmol) in methanol (15 ml), triethyl
amine (0.17 ml, 1.22 mmol), aldehyde 4 (0.3 g, 0.61 mmol) in THF
(3 ml) furnished imine 13c (0.35 g).
13c (0.35 g, 0.57 mmol) in methanol (15 ml), NaBH4 (0.03 g,
0.85 mmol) furnished 14c (0.28 g, 73%) as a viscous oil, Rf =
0.5 (10% ethyl acetate in hexane), [a]2D0 +19.5 (c 2, MeOH). IR
(Neat): 3447, 2930, 1733, 1609, 1500, 1463, 1382, 1252, 1091,
837, 759 cm−1. 1H NMR (200 MHz, CDCl3): d 7.36–7.21 (m, 5H,
–O–CH2–C6H5), 7.19–7.03 (d, 1H, J = 8.6, C-1-H), 6.65 (dd, 1H,
J1 = 8.6, J2 = 2.4, C-2-H), 6.62 (d, 1H, J = 2.4, C-4-H), 4.92 (s,
2H, –O–CH2–C6H5), 3.63 (s, 3H, –CO2CH3), 3.52–3.35 (m, 2H,
C-16-H2), 3.52–3.35 {m, 1H, –CH–CH–(CH3)–CH2–CH3}, 2.80–
2.68 (m, 2H, C-6-H2), 2.35–1.89 (m, 5H), 1.62–1.14 (m, 15H),
0.83 {bs, 12H, –C(CH3)3}, 0.69 (s, 3H, C-18-H3), 0.00 {s, 6H,
–Si(CH3)2–}. 13C NMR (50 MHz, CDCl3): d 176.5 (–CO2CH3),
157.1 (C-3), 139.2 (C-5), 138.4, 133.6 (C-10), 128.9, 128.2, 127.8,
126.9 (C-1), 114.9 (C-4), 112.8 (C-2), 70.3 (–O–CH2–C6H5),
67.9 {–CH–CH–(CH3)–CH2–CH3}, 64.8 (C-16), 59.0 (C-17), 51.6
(–CO2CH3), 44.0, 42.4, 42.2, 39.0 {–CH–CH–(CH3)–CH2–CH3},
38.2 (C-13), 37.0, 33.0, 31.1 (C-6), 28.1 (C-12), 26.9 (C-11),
26.5 {–C(CH3)3}, 26.2 {–CH–CH–(CH3)–CH2–CH3}, 18.8
{–C(CH3)3}, 18.3 (C-18), 16.2 {–CH–CH–(CH3)–CH2–CH3},
12.0 {–CH–CH–(CH3)–CH2–CH3}, −4.6 {Si(CH3)2–}. MASS
(FAB): m/z (%): 621 (100, M+). Anal. Calcd for (C38H59NO4Si):
C, 73.38; H, 9.56; N, 2.25%. Found: C, 73.45; H, 9.25; N, 2.12%.
N-Methyl amine derivative 15c. As described for 15a, amine
14c (0.2 g, 0.32 mmol), K2CO3 (0.22 g, 1.61 mmol), methyl iodide
(0.04 ml, 0.64 mmol) in acetone (15 ml) furnished 15c (0.19 g,
93%) as a viscous oil, Rf = 0.55 (5% ethyl acetate in hexane), [a]D20
+12 (c 2, MeOH). IR (Neat): 3438, 2931, 2361, 1731, 1461, 1378,
1
1249, 1093, 772 cm−1. H NMR (300 MHz, CDCl3): d 7.36–7.23
(m, 5H, –O–CH2–C6H5), 7.13 (d, 1H, J = 8.7, C-1-H), 6.70 (dd,
1H, J1 = 8.7, J2 = 2.5, C-2-H), 6.62 (d, 1H, J = 2.4, C-4-H), 4.95
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(s, 2H, –O–CH2–C6H5), 3.62 (s, 3H, –CO2CH3), 3.55–3.42 (m, 2H,
C-16-H2), 2.81–2.75 {m, 3H, –CH–CH–(CH3)–CH2–CH3 and C-
6-H2}, 2.36–2.34 (m, 2H, C-17-H2), 2.27 (s, 3H, –N–CH3), 2.26–
2.14 (m, 2H), 1.97–1.10 (m, 3H), 1.84–1.60 (m, 3H), 1.34–1.22
(m, 4H), 0.97–0.90 (m, 1H), 0.84 (bs, 12H, –C(CH3)3), 0.77–0.73
(m, 6H, C-18-H3), 0.72–0.66 (m, 1H), 0.00 {s, 6H, –Si(CH3)2–}.
13C NMR (75 MHz, CDCl3): d 172.8 (–CO2CH3), 156.7 (C-3),
137.9 (C-5), 137.6, 133.1 (C-10), 128.5, 127.8, 127.4, 126.5 (C-1),
114.4 (C-4), 112.8 (C-2), 74.0 {–CH–CH–(CH3)–CH2–CH3}, 69.9
(–O–CH2–C6H5), 67.4 (C-17), 64.4 (C-16), 50.5 (–CO2CH3), 44.1,
43.6, 41.8, 40.2 40.2 (C-13), 39.0 (–N–CH3), 37.7, 34.5 {–CH–CH–
(CH3)–CH2–CH3}, 32.8, 30.6 (C-6), 29.6, 27.6 (C-12), 26.5 (C-11),
26.0 {–C(CH3)3}, 25.1 {–CH–CH–(CH3)–CH2–CH3}, 18.4
{–C(CH3)3}, 16.4 {–CH–CH–(CH3)–CH2–CH3}, 16.1 (C-18),
11.3 {–CH–CH–(CH3)–CH2–CH3}, −5.1 {Si(CH3)2–}. MASS
m/z (%): 556 (100, M+ + H). Anal. Calcd for (C36H45NO4): C,
77.80; H, 8.16; N, 2.52%. Found: C, 77.99; H, 8.37; N, 2.77%.
Alcohol 16c. As described for 16a, 15c (0.15 g, 0.24 mmol)
in AcOH–H2O–THF (3 : 1 : 1) furnished 16c (0.1 g, 70%) as
a transparent viscous liquid, Rf = 0.55 (30% ethyl acetate in
hexane), [a]2D0 +35 (c 0.8, MeOH). IR (Neat): 3989, 2927, 1734,
1
1611, 1490, 1459, 1228, 1021, 768 cm−1. H NMR (300 MHz,
CDCl3): d 7.43–7.19 (m, 6H, –O–CH2–C6H5 and C-1-H), 6.79 (dd,
1H, J1 = 8.7, J2 = 2.5, C-2-H), 6.71 (d, 1H, J = 2.5, C-4-H), 5.03
(s, 2H, –O–CH2–C6H5), 3.70 (s, 3H, –CO2CH3), 3.45–3.39 (m,
2H, C-16-H2), 2.91–2.83 {m, 3H, {–CH–CH–(CH3)–CH2–CH3
and C-6-H2}, 2.48–2.39 (m, 2H, C-17-H2), 2.35 (s, 3H, –N–CH3),
2.71–2.27 (m, 2H), 2.03–1.67 (m, 9H), 1.45–1.32 (m, 2H),
0.95–0.8 (m, 11H, C-18-H3). 13C NMR (50 MHz, CDCl3): d 172.7
(–CO2CH3), 156.2 (C-3), 138.1 (C-5), 137.2, 133.5 (C-10), 128.4,
127.6, 127.5, 126.4 (C-1), 114.7 (C-4), 112.2 (C-2), 74.2 {–CH–
CH–(CH3)–CH2–CH3}, 70.0 (–O–CH2–C6H5), 67.0 (C-17), 64.2
(C-16), 50.2 (–CO2CH3), 44.5, 43.2, 41.7, 40.5 (C-13), 39.5 (–N–
CH3), 37.5, 34.5 {–CH–CH–(CH3)–CH2–CH3}, 32.2, 30.5 (C-6),
27.5 (C-12), 26.2 (C-11), 25.5 {–CH–CH–(CH3)–CH2–CH3},
16.5 {–CH–CH–(CH3)–CH2CH3}, 16.2 (C-18), 11.2 {–CH–CH–
(CH3)–CH2–CH3}. MASS (FAB): m/z (%): 507 (100, M+).
(FAB): m/z (%): 636 (100, M+
+ H). Anal. Calcd for
(C39H61NO4Si): C, 73.65; H, 9.67; N, 2.20%. Found: C, 73.99;
H, 9.79; N, 2.30%.
Alcohol 16a. Compound 15a (0.15 g, 0.25 mmol) was heated
at 60 ◦C in acetic acid (3 ml), water (1 ml), THF (1 ml) (3 : 1 :
1) for 2 h. The solvent was removed under vacuum. The residue
was chromatographed over silica gel and elution with 30% ethyl
acetate in hexane (Rf = 0.45) furnished 16a (0.08 g, 66%) as a
white semi-solid, [a]2D0 +36.5 (c 2, MeOH). IR (KBr): 3400, 2927,
Hydroxy acid 17a. To a solution of 16a (0.1 g, 0.21 mmol) in
dioxane (5 ml) was added 1 N NaOH (0.1 ml) and the resulting
solution was heated at 70 ◦C for 2 h. The reaction mixture
was cooled and acidified with 1 N HCl. The resulting solution
was extracted with ethyl acetate and dried over Na2SO4 and
concentrated in vacuo. The residue was chromatographed over
silica gel and elution with 10% methanol in chloroform (Rf = 0.5)
furnished 17a (0.07 g, 70%) as a light yellow foam, [a]2D0 +52 (c
2, MeOH). IR (KBr): 3442, 2925, 1707, 1596, 1500, 1352, 1028,
800, 582 cm−1. 1H NMR (200 MHz, CDCl3): d 7.42–7.29 (m, 5H,
–O–CH2–C6H5), 7.13 (d, 1H, J = 8.6, C-1-H), 6.75 (dd, 1H, J1 =
8.6, J2 = 2.4, C-2-H), 6.67 (d, 1H, J = 2.4, C-4-H), 4.99 (s, 2H,
–O–CH2–C6H5), 3.91–3.84 (m, 2H, C-16-H2), 3.63–3.53 (m, 1H,
–CH–CH3), 3.03–2.95 (m, 2H, C-6-H2), 2.86 (s, 3H, –N–CH3),
2.82–2.69 (m, 2H, C-17-H2), 2.30–2.25 (m, 2H), 2.04–1.73 (m,
4H), 1.49 (d, 3H, J = 7, –CH–CH3), 1.48–1.25 (m, 5H), 0.94 (s,
3H, C-18-H3). 13C NMR (50 MHz, CDCl3): d 171.5 (–CO2H),
157.2 (C-3), 138.0 (C-5), 137.6, 132.3 (C-10), 128.9, 128.2, 127.8,
126.9 (C-1), 114.8 (C-4), 113.0 (C-2), 70.3 (–O–CH2–C6H5), 66.5
(C-17), 65.3 (C-16), 62.9 (–CH–CH3), 43.3, 42.9, 41.1 (–N–CH3),
38.6 (C-13), 37.8, 32.5, 30.8 (C-6), 27.5 (C-12), 27.0 (C-11), 18.8
(–CH–CH3), 12.1 (C-18). MASS (FAB): m/z (%): 466 (100, M+).
Anal. Calcd for (C29H39NO4): C, 74.81; H, 8.44; N, 3.01%. Found:
C, 74.99; H, 8.72; N, 3.11%.
1
1732, 1598, 1353, 1236, 1037, 744 cm−1. H NMR (200 MHz,
CDCl3): d 7.40–7.26 (m, 5H, –O–CH2–C6H5), 7.14 (d, 1H, J =
8.6, C-1-H), 6.72 (dd, 1H, J1 = 8.6, J2 = 2.4, C-2-H), 6.64 (d,
1H, J = 2.4, C-4-H), 5.00 (s, 2H, –O–CH2–C6H5), 3.70 (s, 3H,
–CO2CH3), 3.69–3.35 (m, 3H, C-16-H2 and –CH–CH3), 2.90–2.71
(m, 2H, C-6-H2), 2.31 (s, 3H, –N–CH3), 2.30–2.11 (m, 2H, C-17-
H2), 2.07–2.03 (m, 2H), 1.75–1.62 (m, 4H), 1.49–1.21 (m, 5H),
1.21 (d, 3H, J = 7.1, –CH–CH3), 0.82 (s, 3H, C-18-H3). 13C NMR
(50 MHz, CDCl3): d 174.3 (–CO2CH3), 157.1 (C-3), 138.2 (C-5),
137.7, 133.2 (C-10), 128.9, 128.2, 127.8, 127.0 (C-1), 114.7 (C-4),
112.9 (C-2), 70.3 (–O–CH2–C6H5), 67.3 (C-17), 64.1 (C-16), 63.7
(–CH–CH3), 51.6 (–CO2CH3), 43.9, 43.5, 42.7, 39.7 (–N–CH3),
39.3 (C-13), 38.3, 33.0, 31.0 (C-6), 27.8 (C-12), 27.4 (C-11), 18.3
(–CH–CH3), 15.4 (C-18). MASS (FAB): m/z (%): 480 (100, M+).
Anal. Calcd for (C30H41NO4): C, 75.12; H, 8.62; N, 2.92%. Found:
C, 75.38; H, 8.76; N, 3.15%.
Alcohol 16b. As described for 16a, 15b (0.17 g, 0.25 mmol) in
AcOH–H2O–THF (3 : 1 : 1) furnished 16b (0.09 g, 63%) as a white
semi-solid, Rf = 0.5 (30% ethyl acetate in hexane), [a]2D0 +16.5 (c 2,
MeOH). IR (KBr): 3980, 2925, 1730, 1606, 1498, 1454, 1222, 1029,
763 cm−1. 1H NMR (200 MHz, CDCl3): d 7.44–7.14 (m, 11H, –O–
CH2–C6H5, –CH–CH2–C6H5 and C-1-H), 6.78 (dd, 1H, J1 = 8.6,
J2 = 2.4, C-2-H), 6.64 (d, 1H, J = 2.4, C-4-H), 5.01 (s, 2H, –O–
CH2–C6H5), 3.65 (s, 3H, –CO2CH3), 3.57–3.44 (m, 3H, C-16-H2
and –CH–CH2–C6H5), 3.05–2.85 (m, 2H, –CH–CH2–C6H5), 2.81–
2.65 (m, 2H, C-6-H2), 2.55–2.25 (m, 5H, C-17-H2 and –N–CH3),
2.19–1.12 (m, 11H), 0.72 (s, 3H, C-18-H3). 13C NMR (50 MHz,
CDCl3): d 173.2 (–CO2CH3), 157.1 (C-3), 139.0 (C-5), 138.2, 137.7,
133.4 (C-10), 129.9, 128.9, 128.6, 128.2, 127.8, 127.0 (C-1), 126.7,
114.7 (C-4), 112.9 (C-2), 70.9 (–CH–CH2–C6H5), 70.3 (–O–CH2–
C6H5), 67.9 (C-17), 64.1 (C-16), 51.5 (–CO2CH3), 43.6, 43.2, 42.5,
40.2 (–N–CH3), 40.0 (C-13), 37.6, 36.4 (–CH–CH2–C6H5), 33.1,
31.0 (C-6), 27.8 (C-12), 27.1 (C-11), 17.9 (C-18). MASS (FAB):
Hydroxy acid 17b. As described for 17a, 16b (0.10 g,
0.18 mmol) in dioxane (5 ml), 1 N NaOH (0.1 ml) furnished 17b
(0.07 g, 67%) as a light yellow foam, Rf = 0.55 (10% methanol
in chloroform), [a]2D0 +49 (c 2, MeOH). IR (KBr): 3445, 2923,
1709, 1593, 1506, 1354, 1026, 801, 584 cm−1. 1H NMR (200 MHz,
CDCl3): d 7.41–7.12 (m, 10H, –O–CH2–C6H5, –CH–CH2–C6H5)
7.03 (d, 1H, J = 8.6, C-1-H), 6.67 (dd, 1H, J1 = 8.6, J2 = 2.4,
C-2-H), 6.57 (d, 1H, J = 2.4, C-4-H), 5.01 (s, 2H, –O–CH2–C6H5),
3.95–3.42 (m, 1H, –CH–CH2–C6H5), 3.75–3.61 (m, 2H, C-16-H2),
3.43–2.29 (m, 2H, –CH–CH2–C6H5), 2.98–3.18 (m, 2H, C-6-H2),
2.91 (s, 3H, –N–CH3), 2.74–2.67 (m, 2H, C-17-H2), 2.18–1.13 (m,
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11H), 0.75 (s, 3H, C-18-H3). 13C NMR (75 MHz, CDCl3): d 171.4
(–CO2H), 156.8 (C-3), 137.9 (C-5), 137.6, 137.0, 132.2 (C-10),
129.5, 128.7, 128.5, 127.8, 127.4, 126.8 (C-1), 126.5, 114.4 (C-4),
112.6 (C-2), 71.9 (–CH–CH2–C6H5), 69.9 (–O–CH2–C6H5), 66.2
(C-17), 62.7 (C-16), 42.9, 42.7, 42.3, 41.3 (N–CH3), 38.8 (C-13),
37.4, 33.6 (–CH–CH2–C6H5), 32.1, 30.4 (C-6), 27.1 (C-12), 26.5
(C-11), 17.8 (C-18). MASS (FAB): m/z (%): 542 (100, M+ + H).
Anal. Calcd for (C35H43NO4): C, 77.60; H, 8.00; N, 2.59%. Found:
C, 77.86; H, 8.26; N, 2.78%.
yellow oil, Rf = 0.5 (10% ethyl acetate in hexane), [a]2D0 +15.5 (c
1
2, MeOH). H NMR (300 MHz, CDCl3): d 7.45–7.20 (m, 11H,
–O–CH2–C6H5, –CH–CH2–C6H5 and C-1-H), 6.79 (dd, 1H, J1 =
8.6, J2 = 2.4, C-2-H), 6.72 (d, 1H, J = 2.4, C-4-H), 5.04 (s, 2H,
–O–CH2–C6H5), 4.53–4.50 (m, 1H, C-16-H), 4.19–4.05 (m, 1H,
C-16-H), 3.66–3.64 (m, 1H, –CH–CH2–C6H5), 3.07–2.91 (m, 2H,
–CH–CH2–C6H5), 2.87–2.86 (m, 2H, C-6-H2), 2.66 (s, 3H, –N–
CH3), 2.39–2.27 (m, 2H, C-17-H2), 2.05–1.81 (m, 4H), 1.68–1.27
(m, 7H), 0.68 (s, 3H, C-18-H3). 13C NMR (50 MHz, CDCl3): d
173.9 (–CO–), 156.8 (C-3), 138.9 (C-5), 137.9, 137.3, 133.2 (C-10),
129.3, 128.5, 128.4, 127.8, 127.4, 126.2(C-1), 126.1, 114.4 (C-4),
112.4 (C-2), 71.8(–CH–CH2–C6H5), 69.9 (–O–CH2–C6H5), 67.1
(C-16), 61.1 (C-17), 46.2 (–N–CH3), 43.1, 42.4, 41.1, 40.4 (C-13),
37.3, 30.4 (C-6), 29.7, 28.6 (–CH–CH2–C6H5), 27.6 (C-12), 26.0
(C-11), 17.9 (C-18). MASS (FAB): m/z (%): 524 (100, M+ + H).
Anal. Calcd for (C35H41NO3): C, 80.27; H, 7.89; N, 2.67%. Found:
C, 80.48; H, 7.99; N, 2.86%.
Hydroxy acid 17c. As described for 17a, 16c (0.1 g, 0.19 mmol)
in dioxane (5 ml), 1 N NaOH (0.1 ml) furnished 17c (0.07 g, 72%) as
a light yellow viscous oil, Rf = 0.6 (10% methanol in chloroform),
[a]2D0 +28 (c 2, MeOH). IR (Neat): 3438, 2929, 1708, 1587, 1509,
1358, 1029, 805, 589 cm−1. 1H NMR (200 MHz, CDCl3): d 7.38–
7.11 (m, 6H, –O–CH2–C6H5, and C-1-H), 6.77–6.69 (m, 2H, C-
2-H and C-4-H), 4.99 (s, 2H, –O–CH2–C6H5), 3.77–3.73 (m, 2H,
C-16-H2), 2.80–2.73 {m, 3H, –CH–CH–(CH3)–CH2–CH3 and C-
6-H2}, 2.38–2.26 (m, 2H, C-17-H2), 2.23 (s, 3H, –N–CH3), 2.16–
1.39 (m, 13H), 1.00–0.89 (m, 8H), 0.59 (s, 3H, C-18-H3). 13C NMR
(50 MHz, CDCl3): d 171.5 (–CO2H), 157.2 (C-3), 138.1 (C-5),
137.9, 132.5 (C-10), 128.9, 128.2, 127.8, 126.9 (C-1), 114.9 (C-4),
112.9 (C-2), 73.5 {–CH–CH–(CH3)–CH2–CH3}, 70.2 (–O–CH2–
C6H5), 66.9 (C-17), 62.4 (C-16), 44.6, 43.3, 42.4, 42.0 (C-13), 38.4
(–N–CH3), 36.4, 34.9 {–CH–CH–(CH3)–CH2–CH3}, 32.6, 30.7
(C-6), 27.5 (C-12), 26.6 (C-11), 25.9 {–CH–CH–(CH3)–CH2–
CH3}, 16.9 {–CH–CH–(CH3)–CH2–CH3}, 14.6 (C-18), 12.4
{–CH–CH–(CH3)–CH2–CH3}. MASS (FAB): m/z (%): 507
(100, M+).
Lactone 3c. As described for 3a, 17c (20 mg, 0.04 mmol)
in THF (1 ml), triethyl amine (0.05 ml, 0.39 mmol), 2,4,6-
trichlorobenzoyl chloride (0.04 ml, 0.24 mmol), DMAP (60 mg,
0.47 mmol) in toluene (30 ml) furnished 3c (8 mg, 42%) as a light
1
yellow oil, Rf = 0.45 (10% ethyl acetate in hexane). H NMR
(300 MHz, CDCl3): d 7.43–7.30 (m, 5H, –O–CH2–C6H5), 7.19 (d,
1H, J = 8.7, C-1-H), 6.77 (dd, 1H, J1 = 8.7, J2 = 2.7, C-2-H), 6.71
(d, 1H, J = 2.7, C-4-H), 5.02 (s, 2H, –O–CH2–C6H5), 4.40–4.21 (m,
1H, C-16-H), 4.21–4.16 (m, 1H, C-16-H), 3.15–3.19 (m, 1H, –CH–
CH–(CH3)–CH2–CH3}, 2.86–2.85 (m, 2H, C-6-H2), 2.80–2.75 (m,
1H), 2.31–2.23 (m, 4H, –N–CH3), 1.95–1.75 (m, 5H), 1.73–1.07
(m, 7H), 0.94–0.68 (m, 8H), 0.68 (s, 3H, C-18-H3). MASS (FAB):
m/z (%): 490 (100, M+ + H).
Lactone 3a. A stirred solution of hydroxy acid 17a (20 mg,
0.04 mmol) in THF (1 ml) at RT under N2 was treated with triethyl
amine (0.06 ml, 0.43 mmol) followed by 2,4,6-trichlorobenzoyl
chloride (0.04 ml, 0.26 mmol) and it was stirred overnight. The
solution was diluted with toluene (5 ml) and added dropwise over
4 h to a refluxing solution of DMAP (60 mg, 0.51 mmol) in toluene
(30 ml) under N2. The reaction was further stirred for 2 h at reflux,
and allowed to cool to room temperature. It was diluted with
ethyl acetate and washed with a saturated solution of NaHCO3.
The layers were separated and the water layer was extracted with
ethyl acetate. The combined organic extracts were washed with
0.1 M aq. HCl, brine, dried over Na2SO4 and concentrated under
vacuum. The residue was chromatographed over silica gel and
elution with 10% ethyl acetate in hexane (Rf = 0.4) furnished 3a
(10 mg, 53%) as a light yellow oil. 1H NMR (300 MHz, CDCl3): d
7.43–7.31 (m, 5H, –O–CH2–C6H5), 7.21 (d, 1H, J = 8.6, C-1-H),
6.78 (dd, 1H, J1 = 8.6, J2 = 2.4, C-2-H), 6.71 (d, 1H, J = 2.4,
C-4-H), 5.03 (s, 2H, –O–CH2–C6H5), 4.79–4.71 (m, 1H, C-16-H),
3.98–3.81 (m, 1H, C-16-H), 3.62–3.60 (m, 1H, –CH–CH3), 2.88–
2.78 (m, 2H, C-6-H2), 2.55 (s, 3H, –N–CH3), 2.48–2.20 (m, 2H,
C-17-H2), 2.00–1.97 (m, 2H), 1.84–1.73 (m, 3H), 1.43–1.30 (m,
3H), 1.16 (d, 3H, J = 6.6, –CH–CH3), 0.88–0.81 (m, 3H), 0.61
(s, 3H, C-18-H3). MASS (FAB): m/z (%): 448 (100, M+ + H).
Exact Mass (ESI-MS) calculated for C29H37NO3 [M]+ : 447.27735,
found: 447.27740.
Acknowledgements
Financial support of this work by DST (SR/FTP/CSA-05/2002)
and MOH, New Delhi and a fellowship to Shagufta by CSIR are
gratefully acknowledged. Dr Raja Roy is sincerely thanked for
recording 1H-1H COSY, HSQC and HMBC spectra.
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