Total synthesis of (-)-balanol, all stereoisomers, their N-tosyl analogues, and fully protected ophiocordin: An easy route to hexahydroazepine cores from garner aldehydes

Article abstract of DOI:10.1002/chem.200701991

Total syntheses of (-)-balanol and all of its stereoisomers starting from easily available Garner aldehydes are described. Diastereoselective Grignard reactions on Garner aldehydes and ring-closing metatheses are the key steps for the construction of hexahydroazepine subunits. The benzophenone subunits were constructed through coupling of suitably functionalized aromatic aldehyde and bromo components. The synthetic route constitutes a convenient and scalable reaction sequence to generate all of the stereoisomers of balanol. The methodology is explored further for the synthesis of N-tosyl analogues of balanol and of fully protected ophiocordin.

Full text of DOI:10.1002/chem.200701991

FULL PAPER
DOI: 10.1002/chem.200701991
Total Synthesis of (ꢀ)-Balanol, All Stereoisomers, Their N-Tosyl Analogues,
and Fully Protected Ophiocordin: An Easy Route to
Cores from Garner Aldehydes
A
Ajay Kumar Srivastava and Gautam Panda*[a]
Abstract: Total syntheses of (ꢀ)-bal-
anol and all of its stereoisomers start-
ing from easily available Garner alde-
hydes are described. Diastereoselective
Grignard reactions on Garner alde-
hydes and ring-closing metatheses are
the key steps for the construction of
hexahydroazepine subunits. The benzo-
phenone subunits were constructed
through coupling of suitably functional-
ized aromatic aldehyde and bromo
components. The synthetic route con-
stitutes a convenient and scalable reac-
tion sequence to generate all of the ste-
reoisomers of balanol. The methodolo-
gy is explored further for the synthesis
of N-tosyl analogues of balanol and of
fully protected ophiocordin.
Keywords: balanol · metathesis ·
natural products · Protein kinase C
inhibitors · total synthesis
Introduction
Protein kinase C (PKC) is a
Ca2+- and phospholipid-depen-
dent enzyme that phosphory-
lates serine and threonine resi-
dues in a wide variety of cellu-
lar proteins.[1] PKC mediates
the regulation of cardiac
muscle function by a variety of
neurotransmitters, hormones,
and extracellular signaling
molecules.[2] As PKC plays an
important role in signal transduction, cell proliferation, cell
differentiation, and gene expression,[3] the discovery of spe-
cific inhibitors of PKC would provide potential chemothera-
peutic agents[4–7] encompassing a wide spectrum of diseases:
cancer, disorders of the central nervous and cardiovascular
systems, diabetes, asthma, rheumatoid arthritis, and HIV in-
fection. Some PKC inhibitors are currently in clinical trials
for various types of cancer.[8–10]
collected from Pinus palustris needle litter in 1993, and later
by Ohshima et al. from Fusarium merismoids in 1994,[12] in-
hibits almost all PKC isoforms in the 4–5 nanomolar range.
Ophiocordin (3),[14,15] a regioisomer of (ꢀ)-balanol (1a), was
isolated from Cordyceps ophioglossoides in 1977 and serves
as an antibiotic with antifungal activity. While several efforts
to achieve selectivity among PKC isoforms have been un-
dertaken,[16–35] there is still a constant need for more selec-
tive and potent PKC inhibitors.
In our endeavors to develop some novel anticancer agents
we have recently reported various benzannulated heterocy-
cles synthesized from naturally abundant amino acids.[36] In
continuation of our program for nonbenzannulated hetero-
cycles, we became interested in achieving the synthesis of
two azepane-containing natural products (ꢀ)-balanol and
ophiocordin as well as their analogues.
Balanol (1a), an unusual metabolite isolated by Kulan-
thaivel et al.[11–13] from the fungus Verticillium balanoides
[a]A. K. Srivastava, Dr. G. Panda
Medicinal and Process Chemistry Division
Central Drug Research Institute, Lucknow, UP, 226001 (India)
Fax : (+91)522-2623-938
E-mail: gautam_panda@cdri.res.in
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
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4675

tional group transformations.
Similarly, the disconnection of
the ester and amide linkages of
ophiocordin
3
would also
afford the hexahydroazepine
subunit 6a and acid 4.
The highly congested tetra-
ortho-substituted
benzophe-
none fragments 4 and 5 should
be preparable by coupling of
The isolation and structure elucidation of balanol (1a)
was immediately followed by six total syntheses of the com-
pound.[37–46] Key to Nicolaouꢁs groupꢁs asymmetric synthesis
of balanol was chiral allylation of a substituted serinal with
Brownꢁs reagent (Ipc)2B-allyl.[39] An anionic homo-Fries re-
arrangement strategy to the benzophenone subunit and con-
struction of the azepane unit from 3-hydroxylysine was the
key step for 1a from Lampeꢁs and Hughesꢁ group.[38] Tan-
nerꢁs group used regio- and stereoselective opening of chiral
epoxides and aziridines for the synthesis of 1a.[42] Ring ex-
pansion of piperidin-4-ones into azepane ring systems and
further modification to give 1a has also been reported.[41]
A
radical cyclization approach to the hexahydroazepine ring
and a biomimetic route to the benzophenone fragment of
1a have been described by Naitoꢁs group.[46] Apart from
these, syntheses of the 3-amino-hex-
ahydro-azepin-4-ol ring of balanol
and suitable analogues have also
been reported, because of its potent
PKC inhibitory properties.[47–63] Here
we report for the first time total syn-
theses of all stereoisomers of bal-
anol, along with their N-tosyl ana-
logues 2a–d and also of fully pro-
tected ophiocordin, that follow a dif-
ferent conceptual design rooted in a
Scheme 1. Retrosynthetic analysis.
flexible and diversity-oriented ap-
proach based on ring-closing metathesis (RCM)[48,51] and
diastereoselective nucleophilic addition steps on Garner al-
dehydes.[64]
aldehyde 14 with bromo derivative 15 followed by MnO2
oxidation and functional group interconversions, while frag-
ments 8 and 8a should be preparable in good yields from p-
hydroxybenzoic acid. The hexahydroazepine and aromatic
domains can be coupled by Mukaiyama esterification and
amidation procedures to generate fully protected precursors
for target compounds. Finally total synthesis of 1a–d, 2a–d,
and 3 should be accomplished through global deprotection
of their fully protected precursors.
Results and Discussion
Retrosynthetic analysis and strategy: Retrosynthesis
(Scheme 1) illustrates disconnection of the ester and amide
linkages of 1a–d and 2a–d to afford the substituted hexahy-
droazepine units 6a–d and 7a–d, which can be easily ac-
cessed from their tetrahydroazepine precursors 9a–d and
10a–d, respectively (Scheme 1, bottom). These should in
turn be obtainable through RCM[65] of the pendant vinyl
groups of 11a–d and 12a–d, respectively. We envisioned
that the divinyl derivatives 11a–d and 12a–d should be
easily accessible from Garner aldehydes 13a–b by diastereo-
selective nucleophilic addition followed by expedient func-
Synthesis of the divinyl derivatives 11a–d and 12a–d: Our
synthesis started with the preparation of diastereomerically
pure alcohol precursors 16a–d (Scheme 2). Addition of vi-
nylmagnesium bromide to freshly prepared[64] (R)-Garner al-
dehyde (13a) at ꢀ788C delivered a mixture of syn-16a and
anti-16b allylic alcohols in 1:6 diastereomeric ratio.[66] The
two diastereomers were separated by flash chromatography.
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Natural Products
FULL PAPER
Similarly, addition of vinylmagnesium bromide to (S)-
Garner aldehyde (13b) furnished syn-16c and anti-16d. To
enhance the yields of syn alcohols the major anti alcohols
16b and 16d were converted into their corresponding syn al-
cohols 16a and 16c, respectively, by a Mitsunobu ap-
proach.[67] Other methods to acquire syn alcohols as the
major products by addition of vinyllithium[68] (generated in
situ from tetravinyltin and methyllithium) and zinc bromide
on Garner aldehyde were not suitable for scaling-up purpos-
es, due to the lower stabilities of the reagents. Diastereo-
merically pure allylic alcohols 16a–d were converted into
their corresponding MOM ethers 17a–d by treatment with
MOM chloride in quantitative yields. Selective removal of
the isopropylidene groups of 17a–d with catalytic amounts
of PTSA in methanol secured 18a–d, respectively. Further
tosylation of the resulting alcohols, followed by replacement
of tosyloxy groups with allylamine at 658C in a sealed tube,
furnished amines, which were protected as benzyl carba-
mates to afford the divinyl derivatives 11a–d (Scheme 2).
Similarly, alcohols 16a–d were converted into their corre-
sponding benzyl ether derivatives 19a–d by treatment with
NaH and benzyl bromide in THF at 08C (Scheme 3). Open-
ing of the isopropylidene rings of 19a–d furnished alcohols
20a–d, respectively, which were further tosylated. The tosyl-
Scheme 3. Synthesis of divinyl derivatives 12a–d. a) BnBr, NaH, THF,
08C!RT; b) PTSA, MeOH, 08C!RT, c) i) TsCl, Et3N, CH2Cl2, 08C,
ii) allylamine, MeOH, 658C, d) TsCl, Et3N, CH2Cl2, 08C.
catalyst delivered the tetrahydroazepines 9a–d and 10a–d,
respectively, in quantitative yields (Scheme 4). Reduction of
the double bonds in 9a–d by hydrogenation at atmospheric
pressure in THF furnished the hexahydroazepine cores 21a–
d. Simultaneous removal of MOM and Boc with 50% TFA
in CH2Cl2 afforded the amino alcohols, which were further
coupled with p-benzyloxybenzoyl chloride in Et3N/CH2Cl2
to provide their corresponding amido alcohols 22a–d.
Similarly, to achieve the synthesis of amido alcohols
24a–d, tetrahydroazepines 10a–d were converted into 23a–d
through simultaneous Boc removal and double bond reduc-
tion followed by debenzylation with 10% Pd/C in methanol
and HCl under pressure (Scheme 5). Amines 23a–d were
further coupled with p-benzyl-
A
sealed tube to afford amine derivatives, which were further
converted into their corresponding divinyl sulfonamides
12a–d through tosyl protection of their amino functionali-
ties.
Synthesis of amido alcohols 22a–d and 24a–d: Ring-closing
metatheses of the diastereomerically pure divinyl derivatives
11a–d and 12a–d in the presence of Grubbsꢁ first-generation
oxybenzoyl chloride after re-
generation of amine with trie-
thylamine in CH2Cl2 at 08C to
provide amido alcohols 24a–d
in good yields.
Synthesis of the benzophenone
fragments 4 and 5: The benzo-
phenone fragments of balanol
and ophiocordin were synthe-
sized by a modification of the
procedure
of
Hollinshead
et al.[69] In the reported proce-
dure, m-hydroxybenzaldehyde
was converted into aldehyde
29 (Scheme 6) in five steps
with the use of dibromotetra-
fluoroethane as a brominating
agent in one of the intermedi-
ate steps. To reduce the
number of steps and to avoid
the use of dibromotetrafluoro-
ethane, MOM-protected alde-
Scheme 2. Synthesis of divinyl derivatives 11a–d. a) Vinylmagnesium bromide, THF, ꢀ788C; b) MOMCl,
DIPEA, CH2Cl2, 08C!RT; c) PTSA, MeOH, 08C!RT; d) i) TsCl, Et3N, CH2Cl2, 08C, ii) allylamine, MeOH,
658C; e) CbzCl, Et3N, THF, 08C; f) i) p-nitrobenzoic acid, DEAD, PPh3, THF; ii) K2CO3, MeOH, RT.
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4677

G. Panda and A. K. Srivastava
the fully protected balanol de-
rivatives 30a–d and 31a–d, re-
spectively.
MOM removal in cat HCl/
MeOH (Scheme 7), followed
by debenzylation and purifica-
tion of 30a–d by Nicolaouꢁs
procedure allowed the total
syntheses of (ꢀ)-balanol (1a)
and its other stereosiomers
1b–d. The spectral data and
optical purity[46] of (ꢀ)-balanol
1a were in accordance with
the reported properties. Fully
protected 31a was converted
into N-tosyl balanol 2a
(Scheme 8) by simultaneous
removal of MOM and benzyl
groups under conditions simi-
lar to those described above.
Similarly, the syntheses of N-
tosylbalanols 2b–d could also
be achieved from the advanced
precursors 31b–d.
Scheme 4. Synthesis of amido alcohols 22a–d. a) Grubbsꢁ catalyst (1st gen), CH2Cl2, 458C, b) H2/Pd-C, THF,
RT, c) i) TFA, CH2Cl2, RT, 4 h s, ii) p-benzyloxybenzoyl chloride, CH2Cl2, Et3N.
Synthesis of fully protected
ophiocordin (3): To achieve
the synthesis of ophiocordin
(3), hexahydroazepine 21a was
converted into 32 by selective
removal of MOM with trime-
thylsilyl bromide, and this was
further esterified with p-benzy-
loxybenzoic acid to deliver 33
by Mukaiyama esterifications
(Scheme 9).[70] Boc removal in
TFA/CH2Cl2 furnished amino
ester 34. Several initial at-
tempts at amide coupling
(DCC, DIC, HBTU, TBTU) of
amine 34 with acid 4 to ach-
Scheme 5. Synthesis of amido alcohols 24a–d. a) Grubbs catalyst (1st gen.), CH2Cl2, 458C; b) H2/10% Pd-C,
MeOH/HCl; c) p-benzyloxybenzoyl chloride, CH2Cl2, Et3N, 0 8C.
hyde 14, which can easily be synthesized in three steps from
m-hydroxybenzaldehyde,[69] was used. Coupling of 14 with
the anion generated from bromo derivative 15 provided al-
cohol 25, which was oxidized to the ketone 26 with MnO2.
The ketal of 26 was unmasked with catalytic amounts of
PTSA in acetone/water 9:1 to provide aldehyde 27, which
was oxidized to the acid 4 required for the synthesis of
ophiocordin 3. Acid 4 was again esterified with benzyl bro-
mide and K2CO3 to furnish 28. Selective hydrolysis of the
tert-butyl ester component by thermolysis[38] in quinoline at
1958C delivered acid 5, required for the synthesis of 1a–d
and 2a–d.
ieve 35 were unsuccessful, which might be due to steric hin-
drance.
Finally, coupled product 35 was isolated by Mukaiyama
amidation,[71] albeit in poor yield and with recovery of un-
reacted amine 34. Ophiocordin 3 may be achieved through
final deprotection of fully protected ophiocordin 35.
Conclusion
In summary, total syntheses of naturally occurring (ꢀ)-
(R,R)-balanol and its stereoisomers from the easily available
(R)- and (S)-Garner aldehydes have been accomplished for
the first time, with overall yields of 9–13% in a stereoselec-
tive and regioselective diversity-oriented approach. The at-
tractiveness of the approach lies in its useful nucleophilic
Coupling of fragments and generation of balanol and ana-
logues: The acid 5 was further coupled with amido alcohols
22a–d and 24a–d by Mukaiyama esterification[70] to provide
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Natural Products
FULL PAPER
Scheme 6. Synthesis of acids 4 and 5. a) nBuLi, THF, ꢀ788C; b) MnO2,
CH2Cl2; c) PTSA, acetone/water 9:1, reflux; d) NaH2PO4, H2O2, NaClO2,
acetonitrile, e) benzyl bromide, K2CO3, acetone, f) quinoline, 1958C.
Scheme 8. Synthesis of N-tosyl-balanol. a) Acid 5, 2-chloro-1-methylpyri-
dinium iodide, DMAP, Et3N, CH2Cl2, RT; b) i) HCl/MeOH, RT; ii) H2,
Pd/C, THF/water/acetic acid 4:1:1.
Scheme 9. Synthesis of fully protected ophiocordin derivative 35. a) Tri-
methylsilyl bromide, CH2Cl2, 08C!RT; b) p-benzyloxybenzoic acid, 2-
chloro-1-methylpyridinium iodide, DMAP, Et3N, CH2Cl2, RT; c) TFA/
CH2Cl2; d) acid 4, 2-chloro-1-methylpyridinium iodide, DMAP, Et3N,
CH2Cl2, RT.
addition with high diastereoselectivity, the displacement re-
action for access to the divinyl derivatives, and the rutheni-
um-catalyzed olefin metathesis for the construction of the
azepine rings. This easily executed sequence gave access to
the key hexahydroazepine building block units 21a–d and
Scheme 7. Synthesis of 1a–d. a) Acid 5, 2-chloro-1-methylpyridinium
iodide, DMAP, Et3N, CH2Cl2, RT; b) i) HCl/MeOH, RT; ii) H2, Pd/C,
THF/water/acetic acid 4:1:1.
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4679

G. Panda and A. K. Srivastava
and concentrated in vacuo. The residue was chromatographed over silica
22a–d, which are well suited for the preparation of several
balanol analogues for accessing more selective PKC inhibi-
tors. The synthetic route can also be further exploited for
the synthesis of other isosteres of balanols.
gel with ethyl acetate in hexane (15%) as eluent to furnish 16a (2.70 g,
92%) as a white solid. Rf =0.4 (ethyl acetate in hexane, 20%); [a]D25
=
+47.9 (c=1.25 in CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
5.89–5.82 (m, 1H; -CH=CH2), 5.85 (d, J=18 Hz, 1H; -CH=CH2), 5.30 (d,
J=12 Hz, 1H; -CH=CH2), 4.28 (pseudo t, 1H; CH-OH), 4.19 (brm, 1H;
4-H), 4.07–3.90 (m, 2H; 5-H), 1.60 (s, 3H; CH3), 1.57 (s, 9H; OC(CH3)3),
N
1.46 ppm (s, 3H; CH3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=
154.9 (C=O), 137.9 (-CH=CH2), 117.9 (CH=CH2), 96.5 (C-2), 81.2 (-CH-
Experimental Section
OH), 74.3 (C
A
E
(CH3); IR (neat): n˜ =3450, 2981, 2363, 1697 (-NH-C=O), 1382,
1260 cmꢀ1; MS (FAB): m/z (%): 258 (80) [M+H]+, 202 (100) [MꢀtBu]+,
184 (65) [MꢀtBuꢀH2O]+; elemental analysis (%) calcd for C13H23NO4:
C 60.68, H 9.01, N 5.44; found: C 60.64, H 8.81, N 5.29.
General remarks: Melting points were determined on a COMPLAB
melting point apparatus and are uncorrected. IR spectra were recorded
on a Perkin–Elmer RXI FT-IR spectrometer. 1H NMR and 13C NMR
1
spectra were recorded on Bruker DPX 200 (operating at 200 MHz for H
and 50 MHz for 13C) or DPX 300 (operating at 300 MHz for 1H and
75 MHz for 13C) spectrometers in CDCl3 and CD3OD as solvents. Tetra-
methylsilane (0.00 ppm) served as an internal standard in 1H NMR, and
CDCl3 (77.0 ppm) in 13C NMR. All spectra were recorded at 258C. Cou-
pling constants (J values) are given in Hz. Chemical shifts are expressed
in parts per million (ppm). Mass spectra were recorded by electron spray
ionization (ESI) or fast atom bombardment spectrometry (FAB-MS) on
a JEOL SX 102 spectrometer with argon/xenon as the FAB gas. Glycerol
or m-nitrobenzyl alcohol was used as matrix. Elemental analyses were
done on Varian EL-III CHN analyzer (Germany). Reactions were moni-
tored on silica gel TLC plates (coated with TLC-grade silica gel, obtained
from Merck). Detecting agents used (for TLC) were iodine vapors and/
or spraying with an aqueous solution of vanillin in 10% sulfuric acid fol-
lowed by heating at 1508C. Column chromatography was performed over
silica gel (60–120 mesh) procured from Qualigens (India) with freshly
distilled solvents. Anhydrous tetrahydrofuran used in Mitsunobu reac-
tions was obtained from Spectrochem and heated at reflux over sodium/
benzophenone prior to use.
A
acid
tert-butyl ester (16d): This compound was prepared as described for 16b
from (S)-Garner aldehyde (13b). Yield=74.3%; Rf =0.4 (ethyl acetate in
hexane, 20%); [a]2D5 =ꢀ32.3 (c=2.1 in methanol); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=5.91–5.68 (m, 1H; -CH=CH2), 5.41–5.13 (m, 2H;
-CH=CH2), 4.39 (brs, 1H; CH-OH), 4.22 (brs, 1H; 4-H), 4.16–3.81 (m,
2H; 5-H), 1.55 (s, 3H; CH3), 1.50 (s, 9H; OC(CH3)3), 1.48 ppm (s, 3H;
N
CH3); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=155.4, 137.1, 116.6,
94.9, 81.5, 74.6, 65.0, 62.4, 28.7, 26.6, 24.8 ppm; IR (neat): n˜ =3456, 2981,
2345, 1689 (-NH-C=O), 1376, 1280 cmꢀ1; MS (ESI): m/z (%): 257 (100)
[M]+, 202 (50) [MꢀtBu]+, 184 (25) [MꢀtBuꢀH2O]+; elemental analysis
(%) calcd for C13H23NO4: C 60.68, H 9.01, N 5.44; found: C 60.49, H
8.82, N 5.45.
AHCTREUNG
from 16d. Yield=63%; Rf =0.4 (ethyl acetate in hexane, 20%); [a]D25
=
ꢀ54.3 (c=2.1 in methanol); 1H NMR (300 MHz, CDCl3, 258C, TMS):
d=5.88–5.81 (m, 1H; -CH=CH2), 5.41–5.31 (m, 1H; -CH=CH2), 5.22 (d,
J=10.2 Hz, 1H; -CH=CH2), 4.29 (brs, 1H; CH-OH), 4.18 (s, 1H; 4-H),
A
acid
tert-butyl ester (16b): Freshly prepared vinylmagnesium bromide (1m so-
lution in THF, 175 mL) was added dropwise at ꢀ788C to a cooled solu-
tion of (R)-Garner aldehyde (13a, 10 g, 38.9 mmol) in anhydrous THF
(325 mL). The reaction mixture was stirred for 2 h at the same tempera-
ture and was then allowed to warm to room temperature before careful
addition of saturated ammonium chloride solution in water. The solution
was extracted with ether (500 mL”2). The combined organic extracts
were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo.
The residue was chromatographed on silica gel with ethyl acetate in
hexane (15%) as eluent to furnish a mixture of 16a and 16b 1:6 as a col-
orless oil (10.6 g, 94.6%). [a]2D5 =+27.6 (c=1.47, chloroform). Pure 16b
was further obtained by flash chromatography on silica gel (8.5 g,
75.8%). [a]2D5 =+54.6 (c=1.47, chloroform); Rf =0.4 (ethyl acetate in
hexane, 20%); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=5.87–5.82
(m, 1H; -CH=CH2), 5.38 (d, J=18 Hz, 1H; -CH=CH2), 5.23 (d, J=
12 Hz, 1H; -CH=CH2), 4.29–4.18 (brm, 1H; CH-OH), 4.07–4.02 (m, 1H;
4.07–3.56 (m, 2H; 5-H), 1.56 (s, 3H; CH3), 1.51 (s, 9H; OC(CH3)3),
G
1.46 ppm (s, 3H; CH3); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=
155.3, 137.9, 118.1, 94.8, 81.4, 76.0, 65.6, 62.1, 59.7, 28.7, 27.4, 26.7 ppm;
IR (neat): n˜ =3467, 2981, 2363, 1691 (-NH-C=O), 1379, 1280 cmꢀ1; MS
(FAB): m/z (%): 280 (100) [M+Na]+, 202 (35) [MꢀtBu]+, 184 (50)
[MꢀtBuꢀH2O]+; elemental analysis (%) calcd for C13H23NO4: C 60.68,
H 9.01, N 5.44; found: C 60.51, H 8.89, N 5.26.
General Procedure for MOM protection: DIPEA (1.35 mL, 7.78 mmol)
was added at 08C to a cooled solution of the alcohol (1.0 g, 3.89 mmol)
in dry CH2Cl2 (15 mL), followed by MOM chloride (0.44 mL,
5.84 mmol). The reaction mixture was stirred at the same temperature
for 4 h. After completion of the reaction, solvent was evaporated, and
the residue was diluted with ethyl acetate. The organic layer was washed
with water and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was chromatographed over silica gel with ethyl ace-
tate in hexane (5%) as eluent to furnish the protected alcohol.
4-H), 3.99–3.90 (m, 2H; 5-H), 1.57 (s, 3H; CH3), 1.51 (s, 9H; OC(CH3)3},
G
1.45 ppm (s, 3H; CH3); 13C NMR (50 MHz, CDCl3+CCl4, 258C, TMS):
d=154.9, 137.9, 117.8, 94.7, 81.1, 75.6, 65.0, 62.3, 28.7, 27.4, 24.7 ppm; IR
A
acid tert-butyl ester (17a): Yield=84%; Rf =0.62 (ethyl acetate in
hexane, 10%); [a]2D5 =+72.4 (c=0.915 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=5.77–5.71 (m, 1H; -CH=CH2), 5.31–5.22 (m, 2H;
-CH=CH2), 4.71 (d, J=6.6 Hz, 1H; -CH2-O-CH3), 4.56 (d, J=6.6 Hz,
1H; -CH2-O-CH3), 4.39–4.28 (brm, 1H; 4-H), 4.08 (dd, J=8.4,1.2 Hz,
1H; -CH-OMOM), 4.01–3.87 (m, 2H; 5-H), 3.35 (s, 3H; OCH3), 1.51 (s,
(neat): n˜ =3449, 2982, 2363, 1696 (-NH-C=O), 1389, 1287 cmꢀ1
; MS
(FAB): m/z (%): 258 (60) [M+H]+, 202 (100) [MꢀtBu]+, 184 (50)
[MꢀtBuꢀH2O]+; elemental analysis (%) calcd for C13H23NO4: C 60.68,
H 9.01, N 5.44; found: C 60.57, H 8.89, N 5.34.
A
acid
3H; CH3), 1.49 (s, 3H; CH3), 1.48 ppm (s, 9H; OC
(50 MHz, CDCl3, 258C, TMS): d=151.2 (C=O), 134.3 (-CH=CH2), 117.9
(-CH=CH2), 93 (O-CH2-O), 78.7 (CH-OMOM), 62.7 (C(CH3)3), 58.9 (C-
4), 57.9 (O-CH3), 54.6 (C-5), 28.4 (C(CH3)3), 27.1 (CH3), 25.6 ppm
A
tert-butyl ester (16a): Diethyl azodicarboxylate (5.4 g, 0.031 mol) was
added dropwise at 08C to a stirred solution of alcohol 16b (4.0 g,
0.015 mol), triphenylphosphine (8.34 g, 0.031 mol), and 4-nitrobenzoic
acid (5.2 g, 0.031 mol) in anhydrous THF (100 mL). The reaction mixture
was stirred at 08C for 15 min and then for 1 h at room temperature. The
reaction mixture was concentrated and chromatographed over silica gel
to afford the nitrobenzoate as a syrup. Solid K2CO3 (3.1 g, 0.022 mol) was
added to a solution of the nitrobenzoate (4.5 g, 0.011 mol) in methanol
(50 mL) and the reaction mixture was stirred for 30 min at room temper-
ature. After completion of the reaction, solid was filtered off, and the fil-
trate was concentrated in vacuo. The residue was diluted with ethyl ace-
tate, washed with water followed by brine, dried over anhydrous Na2SO4,
AHCTREUNG
AHCTREUNG
(CH3); IR (neat): n˜ =3861, 3821, 2932, 2362, 1700, 1386, 1169, 1098,
1033 cmꢀ1; MS (ESI): m/z (%): 301.9 (89) [M]+, 245.9 (100) [MꢀtBu]+,
202.1 (12) [MꢀtBoc]+; elemental analysis (%) calcd for C15H27NO5: C
59.78, H 9.03, N 4.65; found: C 59.68, H 8.93, N 4.56.
(1S,4R)-4-(1-Methoxymethoxyallyl)-2,2-dimethyloxazolidine-3-carboxylic
acid tert-butyl ester (17b): Yield=81%; Rf =0.64 (ethyl acetate in
hexane, 10%); [a]2D5 =+61.4 (c=0.376 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=5.76–5.68 (m, 1H; -CH=CH2), 5.35–5.22 (m, 2H;
4680
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4675 – 4688

Natural Products
FULL PAPER
-CH=CH2), 4.63 (d, J=6.6 Hz, 1H; -CH2-O-CH3), 4.56 (d, J=6.6 Hz,
1H; -CH2-O-CH3), 4.41–4.26 (brm, 1H; -CH-OMOM), 4.09–3.76 (m,
3H; 4-H and 5-H), 3.37 (s, 3H; OCH3), 1.61 (s, 3H; CH3), 1.51 (s, 3H;
65.5, 64.0, 60.6, 28.8, 27.3, 25.4 ppm; IR (neat): n˜ =3984, 3876, 3712, 3537,
2979, 1838, 1699, 1384, 1170, 1084 cmꢀ1; MS (FAB): m/z (%): 348 (27)
[M+H]+, 292 (65) [MꢀtBu]+, 248 (100) [MꢀtBoc]+; elemental analysis
(%) calcd for C20H29NO4: C 69.14, H 8.41, N 4.03; found: C 68.87, H
8.04, N 3.96.
CH3), 1.45 ppm (s, 9H; OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C,
A
TMS): d=152.7, 135.9, 120.5, 94.1, 85.5, 80.2, 70.2, 64.7, 60.2, 55.9, 28.6,
27.7, 26.6 ppm; IR (neat): n˜ =3860, 3821, 2912, 2361, 1710, 1386, 1169,
1068, 1033 cmꢀ1; MS (ESI): m/z (%): 301.9 (89) [M]+, 245.9 (100)
[MꢀtBu]+, 202.1 (12) [MꢀtBoc]+; elemental analysis (%) calcd for
C15H27NO5: C 59.78, H 9.03, N 4.65; found: C 59.71, H 8.90, N 4.51.
A
acid
tert-butyl ester (19c): Yield=79%; Rf =0.6 (ethyl acetate in hexane,
10%); [a]2D5 =ꢀ53.4 (c=1.714 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.34 (s, 5H; ArH), 5.89–5.78 (m, 1H; -CH=CH2), 5.33–
5.26 (m, 2H; -CH=CH2), 4.63 (d, J=11.6 Hz, 1H; -CH2-Ph), 4.33 (d, J=
11.6 Hz, 1H; -CH2-Ph), 4.16–3.98 (m, 2H; 4-H, -CHOBn), 3.92–3.88 (m,
A
acid tert-butyl ester (17c): Yield=82%; Rf =0.6 (ethyl acetate in hexane,
10%) [a]2D5 =ꢀ77.4 (c=0.715 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.74–5.67 (m, 1H; -CH=CH2), 5.31–5.22 (m, 2H; -CH=
CH2), 4.71 (d, J=6.6 Hz, 1H; -CH2-O-CH3), 4.56 (d, J=6.6 Hz, 1H;
-CH2-O-CH3), 4.39–4.28 (brm, 1H; 4-H), 4.08 (dd, J=8.4, 1.2 Hz, 1H;
-CH-OMOM), 4.01–3.87 (m, 2H; 5-H), 3.35 (s, 3H; O-CH3), 1.51 (s, 3H;
2H; 5-H), 1.51 (s, 3H; -CH3), 1.46 (s, 9H; -OC(CH3)3), 1.43 ppm (s, 3H;
T
-CH3); 13C NMR (50 MHz, CDCl3): d=152.9 (C=O), 138.8 (-CH=CH2),
136.8, 128.8, 128.3, 119.7, 118.9 (-CH=CH2), 94.6 (C-2), 81.7, 80.6, 71.2
(C
A
(neat): n˜ =3981, 3876, 3612, 3537, 2979, 1830, 1702, 1384, 1170,
1084 cmꢀ1
;
MS (ESI): m/z (%): 360.3 (29) [M+Na]+, 292.3 (45)
CH3), 1.49 (s, 3H; CH3), 1.46 ppm (s, 9H; OC
(CH3)3); 13C NMR
N
[MꢀtBu]+, 248.3 (100) [MꢀtBoc]+; elemental analysis (%) calcd for
(75 MHz, CDCl3, 258C, TMS): d=151.1, 134.3, 127.4, 117.8, 93.0, 88.1,
78.6, 72.1, 63.1, 58.6, 54.4, 27.0, 27.5 ppm; IR (neat): n˜ =3851, 3821, 2942,
2262, 1732, 1380, 1098, 1033 cmꢀ1; MS (ESI): m/z (%): 301.9 (89) [M]+,
245.9 (100) [MꢀtBu]+, 202.1 (12) [MꢀtBoc]+; elemental analysis (%)
calcd for C15H27NO5: C 59.78, H 9.03, N 4.65; found: C 59.69, H 8.89, N
4.60.
C20H29NO4: C 69.14, H 8.41, N 4.03; found: C 69.00, H 8.24, N 3.79.
A
acid
tert-butyl ester (19d): Yield=78.5%; Rf =0.54 (ethyl acetate in hexane,
8%); [a]2D5 =ꢀ49.8 (c=2.025 in CHCl3); 1H NMR (200 MHz, CDCl3,
258C, TMS): d=7.32 (s, 5H; ArH), 5.89–5.78 (m, 2H; -CH=CH2), 5.32–
5.23 (m, 1H; -CH=CH2), 4.61 (d, J=11.6 Hz, 1H; -CH2-Ph), 4.35 (d, J=
11.6 Hz, 1H; -CH2-Ph), 4.15–4.02 (m, 2H; 4-H, -CHOBn), 3.90 (brs, 2H;
5-H), 1.59 (s, 3H; -CH3), 1.49 (s, 3H; -CH3), 1.46 ppm (s, 9H; -OC-
A
ic acid tert-butyl ester (17d): Yield=83.4%; Rf =0.6 (ethyl acetate in
hexane, 10%); [a]2D5 =ꢀ66.4 (c=0.776 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=5.75–5.70 (m, 1H), 5.30–5.24 (m, 2H), 4.68 (d,
J=6.6 Hz, 1H), 4.53 (d, J=6.6 Hz, 1H), 4.38–4.35 (brm, 1H), 4.13–3.88
(m, 3H), 3.34 (s, 3H; OCH3), 1.55 (s, 3H; -CH3), 1.48 (s, 3H; -CH3),
A
128.7, 128.3, 119.6, 118.8, 94.6, 81.6, 80.4, 71.2, 65.6, 64.7, 60.6, 30.1, 28.8,
27.3 ppm; IR (neat): n˜ =3967, 3871, 3712, 3537, 2979, 1838, 1699, 1374,
1170, 1084 cmꢀ1; MS (FAB): m/z (%): 348 (29) [M+H]+, 292 (45)
[MꢀtBu]+, 248 (51) [MꢀtBoc]+, 234 (85) [MꢀBn+Na]+, 91 (100)
[PhCH2]+; elemental analysis (%) calcd for C20H29NO4: C 69.14, H 8.41,
N 4.03; found: C 68.94, H 8.24, N 3.94.
1.44 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS):
A
d=151.1, 134.3, 117.9, 92.6, 78.8, 64.9, 62.7, 58.8, 54.4, 50.9, 27.0,
25.6 ppm; IR (neat): n˜ =3900, 3811, 2932, 2342, 1700, 1356, 1160, 1098,
1033 cmꢀ1; MS (ESI): m/z (%): 301.6 (79) [M]+, 245.6 (100) [MꢀtBu]+,
202.1 (32) [MꢀtBoc]+; elemental analysis (%) calcd for C15H27NO5: C
59.78, H 9.03, N 4.65; found: C 59.73, H 8.93, N 4.59.
General Procedure for acetonide deprotection: A catalytic amount of
PTSA (100 mg) was added to
a solution of an acetonide (0.9 g,
2.99 mmol) in methanol (10 mL) and the reaction mixture was stirred at
room temperature for 3 h. Methanol was removed at low temperature,
the residue was dissolved in ether, and the organic layer was washed with
NaHCO3 (5%) followed by brine, dried over Na2SO4, and concentrated
in vacuo. The residue was chromatographed on silica gel with ethyl ace-
tate in hexane (40%) as eluent to furnish the deprotected product.
General Procedure for benzyl protection: Washed NaH (1.86 g,
7.78 mmol) was added at 08C to a cooled solution of the alcohol (1.0 g,
3.89 mmol) in dry THF (15 mL), followed by benzyl bromide (800 mg,
4.67 mmol). The reaction mixture was stirred at room temperature for
5 h. After completion of the reaction, methanol was added dropwise to
neutralize excess NaH, and solvent was evaporated. The residue was di-
luted with ethyl acetate, washed with water followed by brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue was chroma-
tographed over silica gel to furnish the protected product.
A
tert-butyl ester (18a): Yield=87%; Rf =0.33 (ethyl acetate in hexane,
30%); [a]2D5 =+82.8 (c=0.433 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.83–5.71 (m, 1H; -CH=CH2), 5.37–5.23 (m, 3H; -CH=
CH2, NH), 4.61 (dd, J=23.7, 6.6 Hz, 2H; OCH2OCH3), 4.28 (pseudo t,
J=5.4 Hz, 1H; CH-OMOM), 3.91 (dd, J=11.7, 4.2 Hz, 1H; 1-H), 3.64
(d, J=9.6 Hz, 2H; CH2OH), 3.39 (s, 3H; OCH3), 2.79 (brs, 1H; OH),
A
tert-butyl ester (19a): Yield=78%; Rf =0.5 (ethyl acetate in hexane,
6%); [a]2D5 =+59.4 (c=0.711 in CHCl3); 1H NMR (200 MHz, CDCl3,
258C, TMS): d=7.32 (s, 5H; ArH), 5.96–5.61 (m, 1H; -CH=CH2), 5.32–
5.24 (m, 2H; -CH=CH2), 4.62 (d, J=11.6 Hz, 1H; -CH2-Ph), 4.36 (d, J=
11.6 Hz, 1H; -CH2-Ph), 4.11–4.03 (m, 2H; 4-H, -CHOBn), 3.90 (brs, 2H;
5-H), 1.59 (s, 3H; -CH3), 1.51 (s, 3H; -CH3), 1.46 ppm (s, 9H; -OC-
1.45 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS):
G
d=154.5 (C=O), 133.6, 117.7, 94.8, 93.3, 78.2, 77.5, 60.7, 54.4, 53.4,
27.1 ppm; IR (neat): n˜ =3446, 2977, 2363, 1634 cmꢀ1; MS (FAB): m/z
(%): 261 (43) [M+H]+, 261 (100) [M]+, 205 (80) [MꢀtBu]+, 162 (65)
[MꢀtBoc]+; elemental analysis (%) calcd for C12H23NO5: C 55.16, H
8.87, N 5.36; found: C 55.10, H 8.78, N 5.29.
ACHTREUNG
ACHTREUNG
(neat): n˜ =3984, 3876, 3712, 3537, 2979, 1838, 1699, 1384, 1170,
1084 cmꢀ1; MS (FAB): m/z (%): 348 (29) [M+H]+, 292 (45) [MꢀtBu]+,
248 (51) [MꢀtBoc]+, 234 (85) [MꢀBn+Na]+, 91 (100) [PhCH2]+; ele-
mental analysis (%) calcd for C20H29NO4: C 69.14, H 8.41, N 4.03; found:
C 68.97, H 8.34, N 3.99.
A
tert-butyl ester (18b): Yield=84%; Rf =0.31 (ethyl acetate in hexane,
30%), [a]2D5 =+89.8 (c=0.476 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.83–5.72 (m, 1H; -CH=CH2), 5.37–5.28 (m, 3H; -CH=
CH2, NH), 4.61 (dd, J=23.7, 6.6 Hz, 2H; OCH2OCH3), 4.30 (pseudo t,
J=5.4 Hz, 1H; CH-OMOM), 3.91 (dd, J=11.7, 4.2 Hz, 1H; 1-H), 3.64
(d, J=9.6 Hz, 2H; CH2OH), 3.39 (s, 3H; OCH3), 2.80 (brs, 1H; OH),
A
acid
tert-butyl ester (19b): Yield=76.8%; Rf =0.51 (ethyl acetate in hexane,
6%); [a]2D5 =+46.4 (c=0.738 in CHCl3); 1H NMR (200 MHz, CDCl3,
258C, TMS): d=7.27 (s, 5H; ArH), 5.91–5.67 (m, 1H; -CH=CH2), 5.30–
5.21 (m, 2H; -CH=CH2), 4.59 (d, J=11.6 Hz, 1H; -CH2-Ph), 4.33 (d, J=
11.6 Hz, 1H; -CH2-Ph), 4.11–3.89 (m, 4H; 4-H, 5-H, -CHOBn), 1.51 (s,
1.45 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=154.8, 133.2, 117.7, 93.4, 78.3, 77.7, 60.8, 54.5, 53.4, 28.3, 27.0 ppm; MS
(ESI): m/z (%): 284.1 (48) [M+Na]+, 261.9 (100) [M]+, 205.9 (86)
[MꢀtBu]+, 162.0 (68) [MꢀtBoc]+; elemental analysis (%) calcd for
C12H23NO5: C 55.16, H 8.87, N 5.36; found: C 55.10, H 8.78, N 5.29.
3H; -(CH3)2), 1.46 (s, 9H; -(CH3)2), 1.43 ppm (s, 3H; -OC(CH3)3);
A
13C NMR (50 MHz, CDCl3+CCl4): d=152.7 (C=O), 138.7 (-CH=CH2),
136.9, 135.5, 128.7, 120.6, 119.4 (-CH=CH2), 94.1, 81.6, 80.0, 79.4, 71.2,
ACHTREUNG
Chem. Eur. J. 2008, 14, 4675 – 4688
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4681

G. Panda and A. K. Srivastava
30%); [a]2D5 =ꢀ59.7 (c=0.438 in CHCl3); 1H NMR (200 MHz, CDCl3,
258C, TMS): d=5.87–5.69 (m, 1H; -CH=CH2), 5.39–5.29 (m, 3H; -CH=
CH2, NH), 4.61 (dd, J=23.7, 6.6 Hz, 2H; OCH2OCH3), 4.29 (pseudo t,
J=5.4 Hz, 1H; CH-OMOM), 3.93 (d, J=8.88 Hz, 1H; 1-H), 3.68 (d, J=
7.42 Hz, 2H; CH2OH), 3.40 (s, 3H; OCH3), 2.90 (brs, 1H; OH),
sis (%) calcd for C17H25NO4: C 66.43, H 8.20, N 4.56; found: C 66.34, H
8.12, N 4.44.
General Procedure for the preparation of divinyl derivatives 11a–d: The
starting compound (250 mg, 0.96 mmol) was taken up in dry CH2Cl2
(15 mL) and the mixture was cooled to 08C. Triethylamine (0.2 mL,
1.44 mmol) was added, followed by tosyl chloride (220 mg, 1.15 mmol),
and the reaction mixture was stirred at 08C for 4 h. After completion of
the reaction, solvent was evaporated and the residue was dissolved in
ether. The organic layer was washed with water, followed by brine, and
dried on Na2SO4. Column chromatography over silica gel gave the tosy-
lated product (350 g, 88%), which was stirred in a glass pressure bomb
with allylamine (5 mL) in methanol (5 mL) at 658C for 6 h. The reaction
mixture was concentrated, and the residue was dissolved in THF. Trie-
thylamine (1.0 mL) was added at 08C, followed by benzyl chloroformate
(170 mg, 0.99 mmol). The reaction mixture was stirred for 3 h. After com-
pletion of the reaction it was diluted with ethyl acetate and organic layer
was washed with water, followed by brine, dried over anhydrous Na2SO4,
and concentrated in vacuo. The residue was chromatographed over silica
gel with ethyl acetate in hexane (25%) as eluent to furnish the pure di-
vinyl product.
1.45 ppm (s, 9H; OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS):
A
d=155.8, 134.7, 119.0, 94.5, 79.6, 78.7, 61.9, 55.7, 54.6, 28.3 ppm; MS
(ESI): m/z (%): 284.1 (43) [M+Na]+, 261.9 (100) [M]+, 205.9 (82)
[MꢀtBu]+, 162.0 (79) [MꢀtBoc]+; elemental analysis (%) calcd for
C12H23NO5: C 55.16, H 8.87, N 5.36; found: C 55.10, H 8.78, N 5.29.
A
tert-butyl ester (18d): Yield=89%; Rf =0.31 (ethyl acetate in hexane,
30%); [a]2D5 =ꢀ65.4 (c=0.384 in CHCl3); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=5.84–5.73 (m, 1H; -CH=CH2), 5.38–5.30 (m, 3H; -CH=
CH2, NH), 4.61 (dd, J=23.7, 6.6 Hz, 2H; OCH2OCH3), 4.28 (pseudo t,
J=5.4 Hz, 1H; CH-OMOM), 3.94 (d, J=10.7 Hz, 1H; 1-H), 3.79–3.64
(m, 2H; CH2OH), 3.39 (s, 3H; OCH3), 2.76 (brs, 1H; OH), 1.45 ppm (s,
9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=154.6,
N
133.4, 117.8, 93.3, 78.3, 77.6, 60.8, 54.5, 53.3, 27.1 ppm; MS (ESI): m/z
(%): 284.1 (43) [M+Na]+, 261.9 (100) [M]+, 205.9 (82) [MꢀtBu]+, 162.0
(79) [MꢀtBoc]+; elemental analysis (%) calcd for C12H23NO5: C 55.16, H
8.87, N 5.36; found: C 55.10, H 8.78, N 5.29.
A
enyl)-carbamic acid benzyl ester (11a): Overall yield=59%; Rf =0.4
(ethyl acetate in hexane, 20%); [a]2D5 =+9.2 (c=0.426 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.34 (s, 5H; ArH), 5.82–
5.66 (m, 2H), 5.31–5.12 (m, 4H), 5.15 (s, 2H), 4.67–4.52 (m, 2H), 4.21–
4.05 (m, 2H), 3.91–3.88 (m, 1H), 3.79–3.71 (m, 1H), 3.39 (s, 3H; OCH3),
A
butyl ester (20a): Yield=81%; Rf =0.4 (ethyl acetate in hexane, 40%);
[a]2D5 =+44.6 (c=0.967 in CHCl3); 1H NMR (CDCl3, 200 MHz, 258C,
TMS): d=7.32 (s, 5H; ArH), 5.92–5.74 (m, 1H; -CH=CH2), 5.41–5.34
(m, 2H; -CH=CH2), 5.27 (s, 1H; NH), 4.64 (d, 1H; J=11.8 Hz, -CH2Ph),
4.33 (d, J=11.8 Hz, 1H; -CH2Ph), 4.07 (brs, 1H; 1-H), 3.94 (d, J=
10.05 Hz, 1H; 2-H), 3.67–3.61 (m, 2H; CH2OH), 1.42 ppm (s, 9H; -OC-
3.35–3.26 (m, 2H), 1.44 ppm (s, 9H; OC
(CH3)3); 13C NMR (50 MHz,
G
CDCl3, 258C, TMS): d=155.8 (C=O), 154.3 (C=O), 135.4, 133.7, 132.2,
127.2, 126.9, 126.6, 117.4, 115.6, 94.9, 93.3, 77.7, 77.1, 66.25, 65.9, 54.4,
51.6, 48.1, 44.4, 28.4 ppm; IR (neat): n˜ =3447, 2932, 2362, 1704, 1640,
1464, 1243 cmꢀ1; MS (ESI): m/z (%): 457.1 (53) [M+Na]+, 434.9 (50)
[M]+, 378.8 (42) [MꢀtBu]+, 335.2 (100) [MꢀtBoc]+; elemental analysis
(%) calcd for C23H34N2O6: C 63.57, H 7.89, N 6.45; found: C 63.55, H
7.68, N 6.25.
A
128.5, 127.8, 119.2, 82.0, 79.5, 71.1, 61.9, 54.5, 28.3 ppm; IR (neat): n˜ =
3963, 3857, 3697, 1813, 1706, 1512, 1371, 1170, 1056, 771 cmꢀ1; MS
(FAB): m/z (%): 330 (52) [M+Na]+, 252 (98) [MꢀtBu]+, 208 (82)
[MꢀtBoc]+, 91 (100) [PhCH2]+; elemental analysis (%) calcd for
C17H25NO4: C 66.43, H 8.20, N 4.56; found: C 66.32, H 8.04, N 4.36.
A
A
enyl)-carbamic acid benzyl ester (11b): Overall yield=58%; Rf =0.4
(ethyl acetate in hexane, 20%); [a]2D5 =+11.2 (c=0.413 in CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.36 (s, 5H; ArH), 5.86–
5.74 (m, 2H), 5.30–5.11 (m, 4H), 5.16 (s, 2H), 4.69–4.55 (m, 2H), 4.21–
4.27 (m, 2H), 4.12–3.81 (m, 1H), 3.79–3.73 (m, 1H), 3.38 (s, 3H; OCH3),
butyl ester (20b): Yield=86.5%; Rf =0.4 (ethyl acetate in hexane, 40%);
[a]2D5 =+54.8 (c=0.967 in CHCl3); 1H NMR (CDCl3, 200 MHz, 258C,
TMS): d=7.73–7.25 (m, 5H; ArH), 5.90–5.72 (m, 1H; -CH=CH2), 5.45–
5.18 (m, 2H; -CH=CH2), 4.60 (d, J=11.6 Hz, 1H; -CH2-Ph), 4.33 (d, J=
11.6 Hz, 1H; -CH2-Ph), 4.10 (brs, 1H), 3.97 (d, J=10 Hz, 1H; 2-H),3.61
3.35–3.26 (m, 2H), 1.40 ppm (s, 9H; OC(CH3)3); MS (ESI): m/z (%):
A
(brs, 2H; -CH2OH), 1.42 ppm (s, 9H; -OC
457.1 (100) [M+Na]+, 434.9 (50) [M]+, 378.8 (40) [MꢀtBu]+, 335.2 (20)
[MꢀtBoc]+; elemental analysis (%) calcd for C23H34N2O6: C 63.57, H
7.89, N 6.45; found: C 63.48, H 7.79, N 6.47.
CDCl3+CCl4, 258C, TMS): d=156.03 (C=O), 138.11, 135.75, 128.88,
128.21, 128.13, 127.27, 119.47, 82.29, 79.73, 71.53, 71.01, 62.22, 55.02,
28.81 cmꢀ1; MS (FAB): m/z (%): 308 (52) [M+H]+, 252 (85) [MꢀtBu]+,
208 (60) [MꢀtBoc]+, 91 (100) [PhCH2]+; elemental analysis (%) calcd
for C17H25NO4: C 66.43, H 8.20, N 4.56; found: C 66.39, H 8.11, N 4.31.
A
enyl)-carbamic acid benzyl ester (11c): Overall yield=63%; Rf =0.4
(ethyl acetate in hexane, 20%); [a]2D5 =ꢀ10.7 (c=0.236 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.38 (s, 5H; ArH), 5.78–
5.70 (m, 2H), 5.36–5.08 (m, 4H), 5.14 (s, 2H), 4.67–4.51 (m, 2H), 4.21–
4.04 (m, 2H), 3.94–3.79 (m, 1H), 3.78–3.74 (m, 1H), 3.39 (s, 3H; OCH3),
A
butyl ester (20c): Yield=84%; Rf =0.4 (ethyl acetate in hexane, 40%);
[a]2D5 =ꢀ49.3 (c=0.967 in CHCl3); 1H NMR (CDCl3, 200 MHz, 258C,
TMS): d=7.37–7.26 (m, 5H; ArH), 5.89–5.77 (m, 1H), 5.41–5.27 (m,
3H), 4.64 (d, J=11.2 Hz, 2H), 4.33 (d, J=11.2 Hz, 1H), 4.07 (s, 1H),
3.94 (d, J=8.6 Hz, 1H), 3.67–3.62 (m, 2H), 1.42 ppm (s, 9H; -OC-
3.35–3.26 (m, 2H), 1.44 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz,
N
CDCl3, 258C, TMS): d=155.9, 154.6, 135.4, 133.5, 132.1, 127.1, 126.4,
117.4, 116.0, 115.5, 93.5, 77.8, 77.4, 66.2, 66.0, 54.4, 51.5, 51.2, 48.6, 48.1,
44.3, 43.5, 27.1 ppm; MS (ESI): m/z (%): 457.1 (53) [M+Na]+, 378.8 (60)
[MꢀtBu]+, 335.2 (100) [MꢀtBoc]+; elemental analysis (%) calcd for
C23H34N2O6: C 63.57, H 7.89, N 6.45; found: C 63.42, H 7.73, N 6.35.
A
128.5, 127.8, 119.2, 82.0, 79.5, 71.0, 61.9, 54.4, 28.3 ppm; MS (FAB): m/z
(%): 330 (52) [M+Na]+, 252 (98) [MꢀtBu]+, 208 (82) [MꢀtBoc]+, 91
(100) [PhCH2]+; elemental analysis (%) calcd for C17H25NO4: C 66.43, H
8.20, N 4.56; found: C 66.22, H 8.14, N 4.39.
A
enyl)-carbamic acid benzyl ester (11d): Overall yield=60%; Rf =0.41
(ethyl acetate in hexane, 20%); [a]2D5 =ꢀ13.7 (c=0.209 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.33 (s, 5H; ArH), 5.78–
5.70 (m, 2H), 5.36–5.08 (m, 4H), 5.14 (s, 2H), 4.67–4.51 (m, 2H), 4.20–
4.07 (m, 2H), 3.95–3.88 (m, 1H), 3.79–3.74 (m, 1H), 3.39 (s, 3H; OCH3),
A
butyl ester (20d): Yield=88%; Rf =0.4 (ethyl acetate in hexane, 40%);
[a]2D5 =ꢀ51.8 (c=0.953 in CHCl3); 1H NMR (CDCl3, 300 MHz, 258C,
TMS): d=7.37–7.33 (m, 5H), 5.91–5.79 (m, 1H), 5.43–5.32 (m, 2H), 4.67
(d, J=11.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.12 (s, 1H), 4.00–3.96
3.35–3.26 (m, 2H), 1.40 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz,
T
(brm, 1H), 3.73–3.64 (m, 2H), 1.45 ppm (s, 9H; -OC
CDCl3, 258C, TMS): d=155.6, 154.6, 135.4, 133.4, 133.3, 132.1, 127.1,
126.6, 126.4, 117.9, 117.4, 115.5, 93.3, 77.9, 77.1, 65.9, 54.4, 51.6, 48.1, 44.3,
28.4, 27.0 ppm; MS (ESI): m/z (%): 457.1 (40) [M+Na]+, 434.9 (40) [M]+
, 378.8 (80) [MꢀtBu]+, 335.2 (100) [MꢀtBoc]+; elemental analysis (%)
(75 MHz, CDCl3): d=154.5 (C=O), 133.6, 135.0, 128.5, 127.9, 119.2,
82.2,79.1, 71.2, 62.1, 54.4, 28.3 ppm; MS (ESI): m/z (%): 330.1 (52)
[M+Na]+, 252.1 (80) [MꢀtBu]+, 208 (100) [MꢀtBoc]+; elemental analy-
4682
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4675 – 4688

Natural Products
FULL PAPER
calcd for C23H34N2O6: C 63.57, H 7.89, N 6.45; found: C 63.39, H 7.81, N
6.37.
ACHTREUNG
Genaral Procedure for the preparation of divinyl derivatives 12a–d: The
starting compound was taken up in dry CH2Cl2 and cooled at 08C. Tri-
ethylamine was added, followed by tosyl chloride. The reaction mixture
was stirred at the same temperature for 3 h. After completion of the re-
action, solvent was evaporated, and the residue was dissolved in ether.
The organic layer was washed with water, followed by brine, and dried
on anhydrous Na2SO4. Column chromatography over silica gel gave the
tosylated product, which was heated in a steel bomb with allylamine and
methanol at 658C for 10–12 h. The reaction mixture was concentrated,
and the residue was dissolved in CH2Cl2. Triethylamine was added at
08C, followed by TsCl. The reaction mixture was stirred for 3 h. After
completion of the reaction the mixture was diluted with ethyl acetate,
and the organic layer was washed with water, followed by brine, and
dried over sodium sulfate. Chromatography over silica gel gave the divin-
yl product.
OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=156.2, 143.6,
G
138.6, 137.5, 135.4, 132.9, 130.1, 128.7, 128.0, 127.6, 119.9, 119.2, 81.3,
79.7, 71.3, 52.4, 51.0, 46.2, 28.8, 21.9 ppm; MS (ESI): m/z (%): 523.1 (100)
[M+Na]+, 445.1 (40) [MꢀtBu]+, 401.1 (50) [MꢀtBoc]+; elemental analy-
sis (%) calcd for C27H36N2O5S: C 64.77, H 7.25, N 5.60; found: C 64.62,
H 7.19, N 5.54.
General Procedure for RCM: Grubbsꢁ catalyst (5 mol%) was added to a
solution of the starting compound at reflux in dry CH2Cl2, and the reac-
tion mixture was stirred overnight. After completion of the reaction, sol-
vent was removed and the residue was chromatographed over silica gel
to furnish the tetrahydroazepine core.
A
3-enyl)-carbamic acid tert-butyl ester (12a): Overall yield=65%; Rf =0.4
(ethyl acetate in hexane, 15%); m.p. 1058C; [a]2D5 =+6.3 (c=1.850 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.69 (d, J=8.1 Hz,
2H; ArH), 7.37–7.23 (m, 7H; ArH), 5.89–5.70 (m, 1H; 5-H), 5.67–5.48
(m, 1H; 8-H), 5.38–5.29 (m, 2H; 6-H), 5.19–5.11 (m, 2H; 9-H), 5.00 (d,
J=7.08 Hz, 1H; NH), 4.63 (d, J=11.97 Hz, 1H; -CH2Ph), 4.34 (d, J=
12.0 Hz, 1H; -CH2Ph), 4.03 (pseudo t, 1H), 3.92–3.83 (m, 3H), 3.52 (dd,
J1 =10.47 Hz, J2 =14.6 Hz, 1H), 3.15 (dd, J1 =4.68 Hz, J2 =14.6 Hz, 1H),
(3R,4R)-3-tert-Butoxycarbonylamino-4-methoxymethoxy-2,3,4,7-tetrahy-
dro-azepine-1-carboxylic acid benzyl ester (9a): Yield=76%; Rf =0.4
(ethyl acetate in hexane, 30%); [a]2D5 =ꢀ40.5 (c=2.1 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.35 (s, 5H; ArH), 5.98–
5.89 (m, 1H), 5.82–5.72 (m, 1H), 5.15 (s, 2H), 4.65–4.54 (m, 2H), 4.35 (d,
J=12.6 Hz, 1H), 4.20 (dd, J=17.0, 3.6 Hz, 2H), 3.91–3.65 (m, 3H), 3.32
(s, 3H; OCH3), 1.43 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3,
H
2.44 (s, 3H; CH3), 1.45 ppm {s, 9H; -OC
(CH3)3); 13C NMR (50 MHz,
G
258C, TMS): d=154.5, 149.3 (C=O), 129.6, 127.2, 126.7, 126.5, 94.9, 93.9,
78.14, 73.6, 66.1, 54.2, 52.0, 50.2, 47.9, 45.3, 28.42 ppm; IR (neat): n˜ =
3860, 3445, 2932, 2362, 1700, 1636, 1387, 1167, 1099, 1033 cmꢀ1; MS
(ESI): m/z (%): 429.1 (100) [M+Na]+, 407.0 (10) [M]+, 373.1 (12)
[MꢀtBu+Na]+, 307.1 (13) [MꢀtBoc]+; elemental analysis (%) calcd for
C21H30N2O6: C 62.05, H 7.44, N 6.89; found: C 61.97, H 7.44, N 6.78.
CDCl3, 258C, TMS): d=159 (C=O), 143, 139, 137, 135, 131, 130, 129, 127,
127.7, 120.1, 118.5, 81.3, 78, 71, 51, 50, 46, 30, 27.7, 21.8 ppm; IR (neat):
n˜ =3953.1, 3906.5, 3755.2, 3375.0, 2980.3, 2932.4, 2369.0, 1690.7, 1597.5,
1534.4, 1352.8, 1159.5, 1091.4, 1046.1, 988.7, 921.8, 808.5, 759.0, 704.0,
661.8, 550.5 cmꢀ1; MS (FAB): m/z (%): 501 (15) [M+H]+, 445 (30)
[MꢀtBu]+, 401 (100) [MꢀtBoc]+; elemental analysis (%) calcd for
C27H36N2O5S: C 64.77, H 7.25, N 5.60; found: C 64.52, H 7.20, N 5.44.
(3R,4S)-3-tert-Butoxycarbonylamino-4-methoxymethoxy-2,3,4,7-tetrahy-
dro-azepine-1-carboxylic acid benzyl ester (9b): Yield=78.4%; Rf =0.4
(ethyl acetate in hexane, 30%); [a]2D5 =ꢀ34.5 (c=2.3 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.38 (s, 5H; ArH), 5.93
(pseudo t, 1H), 5.79–5.77 (m, 1H), 5.15 (s, 2H), 4.71–4.58 (m, 2H), 4.36
(d, J=12.6 Hz, 1H), 4.22 (dd, J=17.0, 3.6 Hz, 2H), 3.86–3.69 (m, 3H),
(3R,4S)-(1-{[Allyl-(toluene-4-sulfonyl)-amino]-methyl}-2-benzyloxy-but-
3-enyl)-carbamic acid tert-butyl ester (12b): Overall yield=64%; Rf =0.4
(ethyl acetate in hexane, 15%); m.p. 1128C; [a]2D5 =+11.23 (c=0.824 in
CHCl3); 1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.66 (d, J=8.1 Hz,
2H; ArH), 7.32–7.24 (m, 7H; ArH), 5.89–5.68 (m, 1H; 5-H), 5.61–5.40
(m, 1H; 8-H), 5.37–5.26 (m, 2H; 6-H), 5.18–5.08 (m, 2H; 9-H), 4.95 (d,
J=6.2 Hz, 1H; NH), 4.61 (d, J=11.8 Hz, 1H; -CH2Ph), 4.34 (d, J=
11.8 Hz, 1H; -CH2Ph), 4.0 (pseudo t, J=4.5 Hz, 1H; 3-H), 3.82–3.76 (m,
3H), 3.51–3.39 (m, 1H), 3.18–3.08 (m, 1H), 2.43 (s, 3H; CH3), 1.42 ppm
3.35 (s, 3H; OCH3), 1.43 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz,
A
CDCl3, 258C, TMS): d=154.5, 135.3, 129.6, 127.2, 126.7, 125.6, 94.0, 78.2,
73.5, 66.1, 63.9, 54.2, 50.2, 47.9, 45.3, 30.6, 28.4, 27.0, 21.3 ppm; MS (ESI):
m/z (%): 429.1 (100) [M+Na]+, 407.0 (20) [M]+, 350.1 (10) [MꢀtBu]+,
307.1 (80) [MꢀtBoc]+; elemental analysis (%) calcd for C21H30N2O6: C
62.05, H 7.44, N 6.89; found: C 62.01, H 7.29, N 6.79.
(s, 9H; -OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=156
G
(C=O), 143, 138, 137, 135, 132, 130, 129, 128, 127.7, 120.1, 119, 81.3, 79,
71, 52, 51, 46, 30, 28, 21.9 ppm; IR (neat): n˜ =3377, 3315, 3247, 2812,
A
2374, 1596, 1350, 1163, 763, 663, 553 cmꢀ1
;
MS (FAB):
dro-azepine-1-carboxylic acid benzyl ester (9c): Yield=78%; Rf =0.41
(ethyl acetate in hexane, 30%); [a]2D5 =+48.5 (c=2.1 in CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.36 (s, 5H; ArH), 5.89
(brs, 1H), 5.72 (brs, 1H), 5.23 (s, 2H), 4.69–4.49 (m, 2H), 4.31 (brs, 1H),
4.08 (brs, 2H), 3.82–3.61 (m, 3H), 3.24 (s, 3H; OCH3), 1.35 ppm (s, 9H;
m/z (%): 501 (15) [M+H]+, 445 (30) [MꢀtBu]+, 401 (100) [MꢀtBoc]+;
elemental analysis (%) calcd for C27H36N2O5S: C 64.77, H 7.25, N 5.60;
found: C 64.68, H 7.18, N 5.53.
A
OC
(CH3)3); MS (ESI): m/z (%): 429.1 (100) [M+Na]+, 407.0 (10) [M]+,
N
enyl)-carbamic acid tert-butyl ester (12c): Overall yield=69%; Rf =0.41
(ethyl acetate in hexane, 15%); m.p. 1028C; [a]2D5 =ꢀ6.76 (c=0.700 in
CHCl3); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.68 (d, J=8.3 Hz,
2H; ArH), 7.39–7.28 (m, 7H; ArH), 5.86–5.71 (m, 1H; 5-H), 5.61–5.49
(m, 1H; 8-H), 5.38–5.29 (m, 2H; 6-H), 5.19–5.11 (m, 2H; 9-H), 5.00 (d,
J=8.67 Hz, 1H; NH), 4.62 (d, J=11.8 Hz, 1H; -CH2Ph), 4.36 (d, J=
11.8 Hz, 1H; -CH2Ph), 4.04 (pseudo t, J=4.6 Hz, 1H; 3-H), 3.92–3.80 (m,
3H), 3.51 (dd, J1 =10.5 Hz, J2 =14.5 Hz, 1H), 3.16 (dd, J1 =3.84 Hz, J2 =
373.1 (15) [MꢀtBu+Na]+, 307.1 (13) [MꢀtBoc]+; elemental analysis (%)
calcd for C21H30N2O6: C 62.05, H 7.44, N 6.89; found: C 61.89, H 7.19, N
6.75.
A
dro-azepine-1-carboxylic acid benzyl ester (9d): Yield=78.5%; Rf =0.41
(ethyl acetate in hexane, 30%); [a]2D5 =+39.5 (c=2.2 in CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.36 (s, 5H; ArH), 5.94–
5.92 (m, 1H), 5.79–5.74 (m, 1H), 5.16 (s, 2H), 4.67–4.58 (m, 2H), 4.39
(brs, 1H), 4.20 (d, J=8.6 Hz, 2H), 3.91–3.69 (m, 3H), 3.32 (s, 3H;
14.6 Hz, 1H), 2.44 (s, 3H; CH3), 1.42 ppm (s, 9H; -OC
(CH3)3); 13C NMR
N
(50 MHz, CDCl3, 258C, TMS): d=156.2 (C=O), 143.6, 138.6, 137.5, 135.4,
133, 130.1, 128.7, 128.0, 127.6, 119.9, 119.2, 81.3, 79.7, 74.4, 71.3, 52.4,
51.1, 46.2, 28.8, 21.9 ppm; IR (neat): n˜ =3960.1, 3907.0, 3859.8, 3372.9,
2369.4, 1595.9, 1352.0, 1159.3, 1091.9 cmꢀ1; MS (ESI): m/z (%): 523.1
(100) [M+Na]+, 445.1 (30) [MꢀtBu]+, 401.1 (50) [MꢀtBoc]+; elemental
analysis (%) calcd for C27H36N2O5S: C 64.77, H 7.25, N 5.60; found: C
64.71, H 7.20, N 5.52.
OCH3), 1.43 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C,
R
TMS): d=154.5, 136.4, 130.1, 129.6, 127.2, 126.7, 94.0, 78.2, 73.5, 66.3,
66.1, 54.3, 50.1, 47.9, 45.3, 28.4, 27.0 ppm; MS (ESI): m/z (%): 429.1 (100)
[M+Na]+, 407.0 (10) [M]+, 373.1 (35) [MꢀtBu+Na]+, 307.1 (13)
[MꢀtBoc]+; elemental analysis (%) calcd for C21H30N2O6: C 62.05, H
7.44, N 6.89; found: C 61.91, H 7.23, N 6.81.
Chem. Eur. J. 2008, 14, 4675 – 4688
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4683

G. Panda and A. K. Srivastava
A
53.9, 47.6, 47.2, 30.1, 28.8, 27.6, 20.6 ppm; IR (neat): n˜ =3861, 3754, 3445,
azepin-3-yl]-carbamic acid tert-butyl ester (10a): Yield=76%; Rf =0.4
(ethyl acetate in hexane, 25%); [a]2D5 =+7.14 (c=0.370 in CHCl3);
1H NMR (CDCl3, 300 MHz, 258C, TMS): d=7.63 (d, J=8.0 Hz, 2H;
ArH), 7.35–7.23 (m, 7H; ArH), 5.80–5.68 (m, 2H; 5-H, 6-H), 4.43 (dd,
J1 =12 Hz, J2 =22 Hz, 2H; -CH2Ph), 4.37 (brs, 1H), 4.29 (brs, 1H; 4-H),
3.76 (brs, 2H; 2-H, 7-H), 3.48–3.32 (m, 2H; 2’-H, 7’-H), 2.38 (s, 3H;
3021, 2364, 1702, 1217, 765 cmꢀ1
; MS (ESI): m/z (%): 431.2 (100)
[M+Na]+, 399.2 (20) [MꢀOCH3+Na]+, 375.2 (12) [MꢀtBu+Na]+, 309.2
(13) [MꢀtBoc]+; elemental analysis (%) calcd for C21H32N2O6: C 61.75,
H 7.90, N 6.86; found: C 61.64, H 7.88, N 6.82.
A
boxylic acid benzyl ester (21b): Yield=93%; Rf =0.41 (ethyl acetate in
hexane, 30%); [a]2D5 =+26.5 (c=0.269 in CHCl3); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=7.45 (s, 5H; ArH), 5.24–5.09 (m, 1H), 5.16 (s,
2H), 4.66 (dd, J=12.8, 6.4 Hz, 2H), 3.94–3.88 (m, 2H), 3.75–3.65 (m,
2H), 3.43 (s, 3H; OCH3), 3.33–3.24 (m, 2H), 2.07–1.66 (m, 4H),
CH3), 1.48 ppm (s, 9H; -OC
(CH3)3); 13C NMR (50 MHz, CDCl3): d=
156.1 (C=O), 143.9, 138.2, 136.1, 133.4, 130.2, 128.8, 128.1, 127.6, 80.1,
71.2, 51.9, 50.2, 48.4, 32.3, 30.1, 28.8, 27.1, 23.1, 21.9, 14.5 ppm; IR (neat):
n˜ =3980, 3950, 3711, 1838, 1716, 1500, 1365, 1163, 764, 673 cmꢀ1; MS
(FAB): m/z (%): 473 (15) [M+H]+, 417 (70) [MꢀtBu]+, 373 (90)
[MꢀtBoc]+, 91 (100) [PhCH2]+; elemental analysis (%) calcd for
C25H32N2O5S: C 63.54, H 6.82, N 5.93; found: C 63.51, H 6.73, N 5.85.
1.45 ppm (s, 9H; OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS):
N
d=156.5, 155.3, 137.2, 128.8, 128.2, 96.6, 96.3, 79.7, 67.6, 67.4, 56.3, 53.8,
47.6, 47.1, 30.0, 28.1, 27.7, 21.6 ppm; MS (ESI): m/z (%): 431.2 (100)
[M+Na]+, 399.2 (20) [MꢀOCH3+Na]+, 375.2 (12) [MꢀtBu+Na]+, 309.2
(13) [MꢀtBoc]+; elemental analysis (%) calcd for C21H32N2O6: C 61.75,
H 7.90, N 6.86; found: C 61.71, H 7.86, N 6.76.
A
azepin-3-yl]-carbamic acid tert-butyl ester (10b): Yield=79%; Rf =0.42
(ethyl acetate in hexane, 25%); [a]2D5 =+4.21 (c=0.190 in CHCl3);
1H NMR (200 MHz, CDCl3, 258C, TMS): d=7.64 (d, 2H; J=8.2 Hz,
ArH), 7.28–7.20 (m, 7H; ArH), 5.96–5.71 (m, 2H; 5-H, 6-H), 4.82 (d, J=
8 Hz, 1H; NH), 4.52 (dd, J1 =11.2 Hz, J2 =22.0 Hz, 2H; -CH2Ph), 4.39–
4.29 (m, 2H; 3-H, 4-H), 3.77 (m, 2H; 2-H, 7-H), 3.61–3.34 (m, 2H; 2’-H,
A
boxylic acid benzyl ester (21c): Yield=95%; Rf =0.41 (ethyl acetate in
hexane, 30%); [a]2D5 =ꢀ15.5 (c=0.396 in CHCl3); 1H NMR (200 MHz,
CDCl3, 258C, TMS): d=7.42–7.26 (m, 5H; ArH), 5.26–5.15 (m, 1H), 5.14
(s, 2H), 4.66 (dd, J=12.6, 6.6 Hz, 2H), 3.94–3.67 (m, 4H), 3.39 (s, 3H;
OCH3), 3.33–3.27 (m, 2H), 2.07–1.67 (m, 4H), 1.44 ppm (s, 9H; OC-
7’-H), 2.41 (s, 3H; CH3), 1.43 ppm (s, 9H; -OC
(CH3)3); 13C NMR
(50 MHz, CDCl3, 258C, TMS): d=155.8 (C=O), 143.5, 138.2, 136.5, 133.4,
130.1, 128.7, 128.1, 127.6, 96.6, 79.8, 71.1, 51.8, 50.2, 48.4, 28.8, 21.9 ppm;
IR (neat): n˜ =3980, 3950, 3711, 1838, 1716, 1500, 1365, 1163, 764,
673 cmꢀ1; MS (FAB): m/z (%): 473 (65) [M+H]+, 417 (70) [MꢀtBu]+,
373 (90) [MꢀtBoc]+, 91 (100) [PhCH2]+; elemental analysis (%) calcd
for C25H32N2O5S: C 63.54, H 6.82, N 5.93; found: C 63.45, H 6.78, N 5.79.
A
[MꢀOCH3+Na]+, 375.2 (50) [MꢀtBu+Na]+, 309.2 (13) [MꢀtBoc]+; ele-
mental analysis (%) calcd for C21H32N2O6: C 61.75, H 7.90, N 6.86;
found: C 61.71, H 7.79, N 6.80.
A
A
boxylic acid benzyl ester (21d): Yield=96%; Rf =0.42 (ethyl acetate in
hexane, 30%); [a]2D5 =ꢀ29.5 (c=0.278 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.48–7.29 (m, 5H; ArH), 5.28–5.12 (m, 1H), 5.17
(s, 2H), 4.65 (dd, J=12.6, 6.6 Hz, 2H), 3.92–3.90 (m, 2H), 3.76–3.66 (m,
2H), 3.43 (s, 3H; OCH3), 3.42–3.29 (m, 2H), 2.08–1.69 (m, 4H),
3-yl]-carbamic acid tert-butyl ester (10c): Yield=82%; Rf =0.4 (ethyl
acetate in hexane, 25%); [a]2D5 =ꢀ8.20 (c=0.256 in CHCl3); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.67 (d, J=8.2 Hz, 2H; ArH), 7.38–
7.28 (m, 7H; ArH), 5.85–5.73 (m, 2H; 5-H, 6-H), 4.91 (d, J=8.4 Hz, 1H;
NH), 4.56 (dd, J1 =11.7 Hz, J2 =25.0 Hz, 2H), 4.43 (s, 1H), 4.35 (brs,
1H), 3.79 (d, J=3.3 Hz, 2H), 3.56–3.42 (m, 2H), 2.43 (s, 3H; CH3),
1.44 ppm (s, 9H; OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS):
G
d=156.5, 155.3, 137.3, 128.8, 128.2, 96.3, 79.7, 67.5, 56.3, 53.8, 47.6, 47.2,
30.1, 28.7, 27.7, 20.6 ppm; MS (ESI): m/z (%): 431.2 (100) [M+Na]+,
399.2 (35) [MꢀOCH3+Na]+, 352.2 (55) [MꢀtBu]+, 309.2 (13)
[MꢀtBoc]+; elemental analysis (%) calcd for C21H32N2O6: C 61.75, H
7.90, N 6.86; found: C 61.71, H 7.82, N 6.79.
1.47 ppm (s, 9H; -OC
(CH3)3); 13C NMR (50 MHz, CDCl3, 258C, TMS):
d=156.1 (C=O), 143.9, 138.2, 136.1, 133.4, 130.2, 128.8, 128.1, 127.6, 80.1,
73.8, 73.1, 71.2, 51.9, 50.2, 48.4, 28.7, 21.9 ppm; MS (FAB): m/z (%): 473
(45) [M+Na]+, 417 (100) [MꢀtBu]+, 373 (90) [MꢀtBoc]+; elemental
analysis (%) calcd for C25H32N2O5S: C 63.54, H 6.82, N 5.93; found: C
63.481, H 6.81, N 5.89.
General Procedure for preparation of amido alcohols 22a–d: The starting
compound was stirred with TFA (50%) at room temperature for 30 min.
The solvent was evaporated, and coevaporation was performed with dry
CH2Cl2 to remove excess TFA. The residue was dissolved in dry CH2Cl2,
and triethylamine was added at 08C, followed by p-benzyloxybenzoyl
chloride. The reaction mixture was stirred at room temperature for 1 h.
Solvent was evaporated, and the residue was dissolved in ethyl acetate.
The organic layer was washed with NaHCO3 (5%), followed by brine,
and dried over sodium sulfate. Chromatography over silica gel furnished
the amido alcohols.
A
azepin-3-yl]-carbamic acid tert-butyl ester (10d): Yield=75%; Rf =0.4
(ethyl acetate in hexane, 25%); [a]2D5 =ꢀ5.22 (c=0.134 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.61 (d, J=8 Hz, 2H;
ArH), 7.32–7.22 (m, 7H; ArH), 5.89–5.68 (m, 2H; 5-H, 6-H), 4.86 (d, J=
9.0 Hz, 1H; NH), 4.52 (dd, J1 =12.3 Hz, J2 =21 Hz, 2H; -CH2Ph), 4.37
(brs, 1H; 3-H), 4.30 (brs, 1H; 4-H), 3.76 (brs, 2H; 2-H, 7-H), 3.47–3.41
(m, 2H; 2’-H, 7’-H), 2.38 (s, 3H; CH3), 1.41 ppm (s, 9H; -OC(CH3)3);
13C NMR (50 MHz, CDCl3, 258C, TMS): d=143.9 (C=O), 138.1, 136.0,
133.45, 130.2, 128.8, 128.1, 127.56, 80.07, 71.2, 51.9, 50.2, 48.4, 30.1, 28.7,
21.9 ppm; MS (ESI): m/z (%): 496.2 (100) [M+Na]+, 417.1 (70)
[MꢀtBu]+, 373 (90) [MꢀtBoc]+; elemental analysis (%) calcd for
C25H32N2O5S: C 63.54, H 6.82, N 5.93; found: C 63.49, H 6.72, N 5.84.
(3R,4R)-3-(4-Benzyloxybenzoylamino)-4-hydroxyazepane-1-carboxylic
acid benzyl ester (22a): Yield=59%; Rf =0.3 (ethyl acetate in hexane,
50%); [a]2D5 =ꢀ82.85 (c=2.1 in methanol); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=8.18 (d, J=8.7 Hz, 1H), 7.80 (d, J=7.98 Hz, 2H; ArH),
7.47–7.31 (m, 10H; ArH), 7.01 (d, J=8.19 Hz, 2H; ArH), 5.31 (s, 1H),
5.27–5.19 (m, 2H), 5.15 (s, 2H), 4.45 (s, 1H), 4.22 (d, J=14.3 Hz, 1H),
4.04–3.94 (m, 2H), 3.19 (d, J=14.5 Hz, 1H), 3.10–3.04 (m, 1H), 2.05–
1.64 ppm (m, 4H); 13C NMR (50 MHz, CDCl3, 258C, TMS): d=156.4,
139.3 135.1, 128.0, 127.4, 127.3, 126.9, 126.5, 126.1, 113.4, 68.81, 66.5, 46.2,
30.6, 28.4, 28.1, 27.7, 21.4 ppm; IR (neat): n˜ =3906.5, 3867, 3820, 3440,
2924, 2857, 2363, 1636, 1427, 1380, 670 cmꢀ1; MS (FAB): m/z (%): 497.6
(100) [M+Na]+; elemental analysis (%) calcd for C28H30N2O5: C 70.87, H
6.37, N 5.90; found: C 70.85, H 6.34, N 5.82.
General Procedure for hydrogenation to prepare 21a–d: The starting
compound (500 mg) was taken up in THF (25 mL). Pd/C (10%, 25 mg)
was added, and the reaction mixture was stirred under hydrogen at room
temperature. The solution was filtered through Celite, and the filtrate
was concentrated and passed through a small silica column to furnish the
product.
(3R,4R)-3-tert-Butoxycarbonylamino-4-methoxymethoxy-azepane-1-car-
boxylic acid benzyl ester (21a): Yield=95%; Rf =0.42 (ethyl acetate in
hexane, 30%); [a]2D5 =+19.5 (c=0.496 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.44–7.30 (m, 5H; ArH), 5.26–5.11 (m, 1H), 5.17
(s, 2H), 4.65 (dd, J=12.6, 6.6 Hz, 2H), 3.94–3.88 (m, 2H), 3.75–3.67 (m,
2H), 3.43 (s, 3H; OCH3), 3.33–3.24 (m, 2H), 2.07–1.67 (m, 4H),
(3R,4S)-3-(4-Benzyloxybenzoylamino)-4-hydroxyazepane-1-carboxylic
acid benzyl ester (22b): Yield=70%; Rf =0.31 (ethyl acetate in hexane,
50%); [a]2D5 =ꢀ73.6 (c=0.85 in methanol); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.20–6.99 (m, 14H; ArH), 5.26–5.14 (m, 4H), 4.45 (s,
1H), 4.33–3.85 (m, 3H), 3.67–3.09 (m, 2H), 3.19 (d, J=14.5 Hz, 1H),
3.10–3.04 (m, 1H), 2.05–1.62 ppm (m, 4H); 13C NMR (75 MHz, CDCl3,
1.46 ppm (s, 9H; OC
d=156.5 (C=O), 155.4 (C=O), 137.4, 128.8, 128.3, 96.4, 79.8, 67.6, 56.3,
4684
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4675 – 4688

Natural Products
FULL PAPER
258C, TMS): d=157.1, 135.1, 131.1, 130.6, 128.0, 127.4, 127.3, 127.0,
126.5, 126.2, 120.9, 113.5, 72.5, 68.9, 66.5, 55.4, 46.1, 30.6, 28.4, 21.4, 20.5,
12.8 ppm; MS (ESI): m/z (%): 497.2 (100) [M+Na]+; elemental analysis
(%) calcd for C28H30N2O5: C 70.87, H 6.37, N 5.90; found: C 70.34, H
6.14, N 5.59.
(%) calcd for C27H30N2O5S: C 65.57, H 6.11, N 5.66; found: C 65.53, H
6.10, N 5.38.
A
benzamide (24c): Yield=75%; Rf =0.3 (ethyl acetate in hexane, 60%);
m.p. 1378C; [a]2D5 =ꢀ10.72 (c=0.25 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.97 (d, J=8.8 Hz, 2H; ArH), 7.70 (d, J=
8.8 Hz, 2H; ArH), 7.47–7.28 (m, 7H; ArH), 7.05 (d, J=8.8 Hz, 2H;
ArH), 5.14 (s, 2H; CH2Ph), 4.48 (s, 1H; NH), 4.10 (s, 1H; 3-H), 3.86–
3.67 (m, 3H; 4-H, 2-H,7-H), 2.97–2.89 (m, 2H; 2’-H, 7’-H), 2.46 (s, 3H;
CH3), 2.16–1.68 ppm (m, 4H; 5-H, 6-H); 13C NMR (75 MHz, CDCl3,
258C, TMS): d=168.4, 160.5, 142.8, 135.1, 133.4, 128.7, 128.2, 127.8,
127.3, 126.8, 126.1, 125.8, 124.4, 120.8, 113.5, 68.8, 51.99, 47.2, 46.3, 28.4,
27.2, 21.1, 20.2 ppm; IR (neat): n˜ =3906.7, 3756.1, 3399.8, 2926.0, 2370.1,
1735.2, 1603.8, 1345.0, 1252.9, 1154.2, 1091.8, 757.2, 659.9, 545.6 cmꢀ1; MS
(ESI): m/z (%): 517.3 (100) [M+Na]+, 495.2 (40) [M+H]+; elemental
analysis (%) calcd for C27H30N2O5S: C 65.57, H 6.11, N 5.66; found: C
65.52, H 6.05, N 5.52.
A
acid benzyl ester (22c): Yield=67%; Rf =0.32 (ethyl acetate in hexane,
50%); [a]2D5 =+79.6 (c=1.25 in methanol); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=8.20 (d, J=8.7 Hz, 1H), 7.80 (d, J=7.98 Hz, 2H; ArH),
7.47–7.31 (m, 10H; ArH), 7.01 (d, J=8.19 Hz, 2H; ArH), 5.30–5.12 (m,
4H), 4.43 (s, 1H), 4.17 (d, J=14.3 Hz, 1H), 4.01–3.92 (m, 2H), 3.19 (d,
J=14.5 Hz, 1H), 3.10–3.04 (m, 1H), 2.05–1.60 ppm (m, 4H); 13C NMR
(75 MHz, CDCl3, 258C, TMS): d=156.2, 135.0, 128.0, 127.4, 127.3, 126.9,
126.5, 126.1, 113.4, 72.3, 68.8, 66.3, 55.3, 46.1, 30.4, 28.4, 21.4, 19.1,
12.9 ppm; MS (ESI): m/z (%): 497.2 (100) [M+Na]+; elemental analysis
(%) calcd for C28H30N2O5: C 70.87, H 6.37, N 5.90; found: C 70.73, H
6.19, N 5.63.
A
A
acid benzyl ester (22d): Yield=65%; Rf =0.3 (ethyl acetate in hexane,
50%); [a]2D5 =+63.65 (c=1.25 in methanol); 1H NMR (300 MHz, CDCl3,
258C, TMS): d=7.81 (d, J=7.98 Hz, 2H), 7.44–7.28 (m, 10H; ArH), 7.01
(d, J=8.19 Hz, 2H; ArH), 5.30–5.12 (m, 4H), 4.45 (s, 1H), 4.20 (d, J=
14.3 Hz, 1H), 4.04–3.94 (m, 2H), 3.18 (d, J=14.5 Hz, 1H), 3.10–3.04 (m,
1H), 2.05–1.63 ppm (m, 4H); 13C NMR (75 MHz, CDCl3, 258C, TMS):
d=153.6, 138.4, 135.1, 128.0, 127.4, 127.3, 126.9, 126.4, 126.1, 113.4, 68.8,
66.2, 47.8, 46.1, 30.6, 28.4, 27.6, 21.4, 12.8 ppm; MS (ESI): m/z (%): 497.1
(100) [M+Na]+; elemental analysis (%) calcd for C28H30N2O5: C 70.87, H
6.37, N 5.90; found: C 70.80, H 6.27, N 5.69.
benzamide (24d): Yield=73%; Rf =0.31 (ethyl acetate in hexane, 60%);
m.p. 1418C; [a]2D5 =ꢀ3.72 (c=0.345 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.94 (d, J=8.8 Hz, 2H; ArH), 7.68 (d, J=
8.8 Hz, 2H; ArH), 7.48–7.31 (m, 7H; ArH), 7.02 (d, J=8.8 Hz, 2H;
ArH), 5.16 (s, 2H; CH2Ph), 4.46 (s, 1H; NH), 4.02 (s, 1H; 3-H), 3.88–
3.67 (m, 3H; 4-H, 2-H, 7-H), 2.96–2.90 (m, 2H; 2’-H, 7’-H), 2.43 (s, 3H;
CH3), 2.05–1.82 ppm (m, 4H; 5-H,6-H); IR (neat): n˜ =3906.7, 3756.1,
3399.8, 2926.0, 2370.1, 1735.2, 1603.8, 1345.0, 1252.9, 1154.2, 1091.8, 757.2,
659.9, 545.6 cmꢀ1; MS (ESI): m/z (%): 517.3 (100) [M+Na]+, 495.2 (40)
[M+H]+; elemental analysis (%) calcd for C27H30N2O5S: C 65.57, H 6.11,
N 5.66; found: C 65.47, H 6.01, N 5.54.
General Procedure for preparation of amido alcohols 24a–d: The starting
compound (200 mg, 0.424 mmol) was taken up in methanol and a catalyt-
ic amount of HCl was added, followed by Pd/C (10%, 5% w/w). The re-
action mixture was stirred under hydrogen in a Parr apparatus at 40 psi
pressure. The reaction mixture was filtered through Celite, and the fil-
trate was concentrated and dissolved in dry CH2Cl2 (10 mL). Triethyla-
mine (0.5 mL) was added at 08C, followed by p-benzyloxybenzoyl chlo-
ride (170 mg, 0.70 mmol). The reaction mixture was stirred at room tem-
perature for 1 h. Solvent was evaporated, and the residue was dissolved
in ethyl acetate. The organic layer was washed with NaHCO3 (5%), fol-
lowed by brine, and dried over sodium sulfate. Chromatography over
silica gel furnished the amido alcohol.
3,5-Dibenzyloxy-4-[(2-[1,3]dioxan-2-yl-6-methoxymethoxy-phenyl)-hy-
droxy-methyl]-benzoic acid tert-butyl ester (25): n-BuLi (4.5 mL, 1.0m so-
lution in hexane) was added dropwise at ꢀ788C under nitrogen to a solu-
tion of bromo compound 15 (2 g, 4.27 mmol) in dry THF. The solution
was stirred for 5 min, and then
3.97 mmol) in THF was added dropwise. The reaction mixture was stirred
at the same temperature for 1 h and then at room temperature for 4 h.
The reaction was quenched with sat. NH4Cl solution. The organic layer
was separated, and the aq. layer was extracted with ethyl acetate. The
combined organic layer was washed with brine and dried over anhydrous
Na2SO4. Chromatography over silica gel afforded alcohol 25 (2.1 g, 79%)
as a sticky solid. Rf =0.3 (ethyl acetate in hexane, 50%); 1H NMR
(300 MHz, CDCl3, 258C, TMS): d=7.45 (d, J=8.7 Hz, 1H; ArH), 7.44–
7.21 (m, 12H; ArH), 7.01 (d, J=8.7 Hz. 1H; ArH), 6.69 (d, J=8.7 Hz,
1H; ArH), 6.06 (s, 1H), 5.33 (d, J=8.9 Hz, 1H), 5.11 (s, 4H), 4.80 (s,
2H), 4.16–4.11 (m, 2H), 3.87 (t, J=15 Hz, 1H), 3.68 (t, J=15 Hz, 1H),
(3R,4R)-4-Benzyloxy-N-[4-hydroxy-1-(toluene-4-sulfonyl)-azepan-3-yl]-
benzamide (24a): Yield=73%; Rf =0.3 (ethyl acetate in hexane, 60%);
m.p. 1478C; [a]2D5 =+11.65 (c=0.156 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.97 (d, J=8.8 Hz, 2H; ArH), 7.70 (d, J=
8.8 Hz, 2H; ArH), 7.51–7.32 (m, 7H; ArH), 7.05 (d, J=8.8 Hz, 2H;
ArH), 5.15 (s, 2H; -CH2Ph), 4.90 (brs, 1H; NH), 4.49 (s, 1H; 3-H), 3.89–
3.71 (m, 3H; 2-H, 7-H, 4-H), 2.96–2.88 (m, 2H; 2’-H, 7’-H), 2.46 (s, 3H;
CH3), 2.06–1.95 (m, 6-H), 1.86–1.83 (m, 1H; 5-H), 1.65–1.51 ppm (m,
1H; 5’-H); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=168.4, 160.56,
142.78, 135.13, 133.46, 128.69, 128.24, 127.36, 126.84, 126.16, 125.87,
124.46, 113.52, 68.83, 52.01, 47.29, 46.40, 27.24, 21.17, 20.22 ppm; IR
(neat): n˜ =3907, 3855, 3804, 3756, 3453, 2933, 2370, 1602, 1347, 1249,
1153, 1092, 756, 660 cmꢀ1; MS (ESI): m/z (%): 517.3 (35) [M+Na]+,
495.2 (100) [M+H]+; elemental analysis (%) calcd for C27H30N2O5S: C
65.57, H 6.11, N 5.66; found: C 65.37, H 6.04, N 5.64.
2.98 (s, 3H; OCH3), 2.21–2.09 (m, 1H), 1.58 (s, 9H; OC(CH3)3),
1.33 ppm (d, J=14 Hz, 1H); MS (ESI): m/z (%): 665 (59) [M+Na]+,
566.9 (100) [MꢀCO2tBu+Na]+; elemental analysis (%) calcd for
C38H42O9: C 71.01, H 6.59; found: C 70.71, H 6.54.
3,5-Dibenzyloxy-4-(2-[1,3]dioxan-2-yl-6-methoxymethoxy-benzoyl)-ben-
zoic acid tert-butyl ester (26): Alcohol 2 (1.5 g) was taken up in dry
CH2Cl2 (50 mL). MnO2 (1.5 g) was added to it in one portion, and the re-
action mixture was stirred for 6 h at room temperature. The solid was fil-
tered through Celite, and the filtrate was concentrated. The residue was
chromatographed over silica gel to furnish the oxidized product 26 (1.4 g)
as a sticky solid. Yield=93.6%; Rf =0.4 (ethyl acetate in hexane, 45%);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.50 (d, J=9.0 Hz, 1H;
ArH), 7.39 (t, J=8.1 Hz, 1H; ArH), 7.30–7.15 (m, 12H; ArH), 7.00 (d,
J=9.0 Hz, 1H; ArH), 5.64 (s, 1H), 5.06 (s, 4H), 4.70 (s, 2H), 4.16–4.11
(m, 2H), 3.80 (t, J=9.0 Hz, 2H), 2.94 (s, 3H; OCH3), 2.21–2.17 (m, 1H),
A
benzamide (24b): Yield=71%; Rf =0.3 (ethyl acetate in hexane, 60%);
m.p. 1428C; [a]2D5 =+3.65 (c=0.245 in CHCl3); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.92 (d, J=8.8 Hz, 2H; ArH), 7.69 (d, J=
8.8 Hz, 2H; ArH), 7.47–7.26 (m, 7H; ArH), 7.05 (d, J=8.8 Hz, 2H;
ArH), 5.12 (s, 2H; CH2Ph), 4.45 (s, 1H; NH), 4.00 (s, 1H; 3-H), 3.88–
3.67 (m, 3H; 4-H, 2-H,7-H), 2.96–2.88 (m, 2H; 2’-H, 7’-H), 2.46 (s, 3H;
CH3), 2.06–1.66 ppm (m, 4H; 5-H, 6-H); 13C NMR (50 MHz, CDCl3,
258C, TMS): d=169.8, 161.8, 144.1, 136.3, 134.5, 130.0, 129.5, 129.2,
128.6, 128.1, 127.5, 127.1, 127.0, 125.6, 114.7, 70.1, 53.1, 48.5, 47.4, 29.7,
28.4, 27.7, 22.3, 21.6, 14.1 ppm; IR (neat): n˜ =3906.7, 3756.1, 3399.8,
2926.0, 2370.1, 1735.2, 1603.8, 1345.0, 1252.9, 1154.2, 1091.8, 757.2, 659.9,
545.6 cmꢀ1; MS (FAB): m/z (%): 495 (100) [M+H]+; elemental analysis
1.58 (s, 9H; OC
(CH3)3), 1.33 ppm (d, J=14 Hz, 1H); 13C NMR (50 MHz,
CDCl3, 258C, TMS): d=165.1, 157.5, 154.2, 139.2, 136.7, 133.8, 131.2,
128.8, 128.1, 128.5, 121.3, 115.6, 106.7, 99.9, 94.6, 83.1, 70.8, 67.7, 56.4,
28.5 ppm; IR (neat): n˜ =3954, 3906, 3754, 3428, 2820, 2370, 1595, 1351,
1111 cmꢀ1
[M+H]+; elemental analysis (%) calcd for C38H40O9: C 71.23, H 6.29;
found: C 71.03, H 6.12.
Chem. Eur. J. 2008, 14, 4675 – 4688
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4685

G. Panda and A. K. Srivastava
3,5-Dibenzyloxy-4-(2-formyl-6-methoxymethoxybenzoyl)-benzoic
acid
hexane, 45%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (3:1 rotameric
mixture) d=7.64 (d, J=8.7 Hz, 2H; ArH), 7.49–6.81 (m, 30H; ArH),
6.82 (d, J=8.7 Hz, 2H; ArH), 5.31 (d, J=7.9 Hz, 1H), 5.19–4.69 (m,
12H), 3.98 (pseudo t, 1H), 3.71–3.21 (m, 3H), 3.18–3.03 (m, 2H), 3.02 (s,
3H; OCH3), 2.23–1.64 ppm (m, 4H); IR (neat): n˜ =3864, 3447, 2922,
2358, 1638, 1461, 1380, 1256, 764, 670 cmꢀ1; MS (ESI): m/z (%): 1091.2
(20) [M+Na]+, 1089.2 (100) [M]+, 1089.2 (100) [M]+; elemental analysis
(%) calcd for C66H60N2O13: C 72.78, H 5.55, N 2.57; found: C 72.71, H
5.52, N 2.49.
tert-butyl ester (27): Compound 26 (1.2 g, 1.87 mmol) was taken up in
acetone/water (25 mL, 9:1 v/v). A catalytic amount of PTSA was added
to it, and the reaction mixture was heated at reflux for 30 min. The sol-
vent was evaporated and the residue was diluted with ethyl acetate. The
organic layer was washed with water, followed by brine, and dried over
anhydrous Na2SO4. Chromatography over silica gel furnished 27
(900 mg) as a white solid. Yield=86%; Rf =0.5 (ethyl acetate in hexane,
45%); m.p.: 658C. 1H NMR (300 MHz, CDCl3, 258C, TMS): d=9.90 (s,
1H; CHO), 7.56–7.10 (m, 15H; ArH), 5.08 (s, 4H), 4.79 (s, 2H), 3.01 (s,
A
3H; OCH3), 1.60 ppm (s, 9H; OC(CH3)3); IR (neat): n˜ =3954, 3854,
R
carbonyl-6-methoxymethoxy-benzoyl)-benzoyloxy]-azepane-1-carboxylic
acid benzyl ester (30b): Yield=86%; Rf =0.4 (ethyl acetate in hexane,
45%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (3:1 rotameric mix-
ture)[3] d=8.18 (m, 1H), 7.64 (d, J=8.7 Hz, 2H; ArH), 7.46–7.07 (m,
32H; ArH), 6.82 (d, J=8.7 Hz, 2H; ArH), 5.31 (d, J=7.9 Hz, 1H), 5.20–
4.76 (m, 12H), 4.18 (brs, 1H), 3.81–3.34 (m, 3H), 3.18–2.98 (m, 2H), 3.08
(s, 3H; OCH3), 2.16–1.60 ppm (m, 4H); MS (FAB): m/z (%): 1090.2 (45)
[M+H]+, 1089.2 (100) [M]+; elemental analysis (%) calcd for
C66H60N2O13: C 72.78, H 5.55, N 2.57; found: C 72.69, H 5.48, N 2.52.
3777, 3408, 2966, 2368, 1595, 1351, 1161, 1104 cmꢀ1; MS (ESI): m/z (%):
605.1 (100) [M+Na]+, 582.9 (40) [M+H]+; elemental analysis (%) calcd
for C35H34O8: C 72.15, H 5.88; found: C 71.65, H 5.38.
3,5-Dibenzyloxy-4-(2-carboxy-6-methoxymethoxy-benzoyl)-benzoic acid
tert-butyl ester (4): A solution of aldehyde 27 (700 mg, 1.2 mmol) and
NaH2PO4 (50 mg, 0.42 mmol) in acetonitrile/water (16 mL, 6:1 v/v) was
cooled to 08C. H2O2 (0.3 mL, 30% solution in water) was added, fol-
lowed by sodium chlorite (0.44 g). The mixture was stirred for 1 h and
the solvent was removed in vacuo. The residue was dissolved in ethyl ace-
tate, and the organic layer was washed with water, followed by brine, and
dried over Na2SO4. Chromatography over silica gel furnished acid 4
(650 mg, 86%) as a sticky solid. Rf =0.4 (methanol in chloroform, 5%);
1H NMR (300 MHz, CDCl3, 258C, TMS): d=8.31 (s, 1H; ArH), 7.44–
7.09 (m, 15H; ArH), 5.07 (dd, J1 =6.7, J2 =35 Hz, 2H), 4.95 (s, 4H), 3.22
A
carbonyl-6-methoxymethoxy-benzoyl)-benzoyloxy]-azepane-1-carboxylic
acid benzyl ester (30c): Yield=82%; Rf =0.41 (ethyl acetate in hexane,
45%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (3:1 rotameric mixture)
d=7.63 (d, J=8.7 Hz, 2H; ArH), 7.58–6.92 (m, 30H; ArH), 6.85–6.77
(m, 2H; ArH), 5.31 (d, J=7.9 Hz, 1H), 5.19–4.61 (m, 12H), 4.00 (pseu-
do t, 1H), 3.86–3.21 (m, 3H), 3.18–3.03 (m, 2H), 3.02 (s, 3H; OCH3),
2.34–1.64 ppm (m, 4H); MS (FAB): m/z (%): 1090.1 (70) [M+H]+,
1089.2 (100) [M]+; elemental analysis (%) calcd for C66H60N2O13: C
72.78, H 5.55, N 2.57; found: C 72.73, H 5.51, N 2.51.
(s, 3H; OCH3), 1.59 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3,
N
258C, TMS): d=163.2, 157.1, 134.8, 133.6, 129.6, 127.7, 127.1, 127, 126.8,
126.6, 126.2, 126.1, 117.7, 116.6, 105.4, 103.6, 93.1, 92.6, 80.7, 69.5, 54.6,
26.8, 24.1, 21.7, 12.7 ppm; IR (neat): n˜ =3906, 3858, 3806, 3755, 3652,
3425, 2976, 2368, 1675, 1593, 1354, 111.9 cmꢀ1; MS (FAB): m/z (%): 621.1
(100) [M+Na]+, 598.9 (70) [M+H]+, 542.9 (40) [MꢀtBu]+; elemental
analysis (%) calcd for C35H34O9: C 70.22, H 5.72; found: C 70.02, H 5.51.
A
carbonyl-6-methoxymethoxy-benzoyl)-benzoyloxy]-azepane-1-carboxylic
acid benzyl ester (30d): Yield=84%; Rf =0.4 (ethyl acetate in hexane,
45%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (3:2 rotameric mixture)
d=7.64 (d, J=8.7 Hz, 2H; ArH), 7.39–6.07 (m, 30H; ArH), 6.89 (brs,
2H; ArH), 5.38 (d, J=7.9 Hz, 1H), 5.16–4.74 (m, 12H), 4.02 (pseudo t,
1H), 3.81–3.41 (m, 3H), 3.21–3.03 (m, 2H), 3.02 (s, 3H; OCH3), 2.15–
1.63 ppm (m, 4H; 5,6-H); MS (FAB): m/z (%): 1090.2 (65) [M+H]+,
1089.2 (100) [M]+; elemental analysis (%) calcd for C66H60N2O13: C
72.78, H 5.55, N 2.57; found: C 72.74, H 5.49, N 2.47.
Benzyl ester 28: Solid K2CO3 (580 mg, 4.2 mmol) was added to a solution
of compound 4 (500 mg, 0.84 mmol) in dry acetone (15 mL), followed by
benzyl bromide (157 mg, 0.9 mmol). The reaction mixture was heated at
reflux at 708C for 1 h, the solid was filtered off, and the filtrate was con-
centrated in vacuo. Chromatography over silica gel furnished compound
28 (540 mg, 94%) as a sticky solid. Rf =0.6 (ethyl acetate in hexane,
25%); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=7.39–7.11 (m, 20H;
ArH), 5.16 (s, 2H), 4.96 (s, 4H), 4.80 (s, 2H), 3.15 (s, 3H; OCH3),
A
1.61 ppm (s, 9H; OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS):
R
40%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (mix of rotamers 3:2)
d=7.83 (d, J=8.8 Hz, 2H; ArH), 7.69 (d, J=8.8 Hz, 2H; ArH), 7.46–
7.04 (m, 27H; ArH), 6.91 (d, J=8.8 Hz, 2H; ArH), 5.32 (d, J=8.3 Hz,
1H), 5.10 (s, 2H; CH2OCH3), 4.99 (s, 2H; CH2Ph), 4.96 (s, 2H; CH2Ph),
4.81–4.80 (m, 1H), 4.76 (s, 2H; OCH2Ph), 3.98–3.91 (m, 1H), 3.73 (dd,
J1 =3.99 Hz, J2 =14.7 Hz, 1H), 3.15 (dd, J1 =3.3 Hz, J2 =14.7 Hz, 1H),
3.05 (s, 3H; CH2OCH3), 2.97–2.91 (m, 1H), 2.43 (s, 3H; CH3), 2.32–2.29
(m, 1H), 2.22–2.04 (m, 2H), 1.98–1.83 ppm (m, 2H); IR (neat): n˜ =
3931.0, 3906.0, 3857.8, 3756.1, 3425.7, 2371.3, 1597.3, 1350.2, 1158.0,
d=189.9, 165.4, 163.5, 157.10, 153.3, 134.9, 134.6, 133.8, 132.7, 130.3,
128.6, 126.9, 126.6, 126.4, 126.0, 121.8, 117.1, 105.7, 93.3, 80.4, 69.6, 65.6,
54.5, 30.6, 28.4, 28.0, 26.8, 21.4, 12.7 ppm; IR (neat): n˜ =3956, 3906, 3757,
3425, 2816, 2371, 1595, 1351 cmꢀ1; MS (FAB): m/z (%): 711.2 (100)
[M+Na]+, 688.9 (89) [M+H]+, 632.9 (20) [MꢀtBu]+; elemental analysis
(%) calcd for C42H40O9: C 73.24, H 5.85; found: C 73.06, H 5.62.
Acid 5: A solution of compound 28 (500 mg) in dry quinoline (5 mL) was
heated at 1958C under nitrogen for 1 h. The reaction mixture was diluted
with ether. The organic layer was washed with HCl (2n), followed by
brine, and dried over anhydrous Na2SO4. Chromatography over silica gel
furnished acid 2 (250 mg, 54%) as a sticky brown solid. Rf =0.3 (5%
methanol in chloroform); 1H NMR (300 MHz, CDCl3, 258C, TMS): d=
12.05 (s, 1H; CO2H), 7.39–7.08 (m, 20H; ArH), 5.13 (d, J=5.1 Hz, 1H),
4.95 (s, 4H), 4.78 (d, J=5.1 Hz, 1H), 4.58 (s, 2H), 3.60 ppm (s, 3H;
OCH3); MS (ESI): m/z (%): 655.1 (100) [M+Na]+, 632.8 (39) [M]+,
599.0 (9) [MꢀOCH3]+, 576.8 (10) [MꢀtBu]+; elemental analysis (%)
calcd for C38H32O9: C 72.14, H 5.10; found: C 72.02, H 4.98.
1110.3, 1016.0, 753.5, 695.8 cmꢀ1
; MS (ESI): m/z (%): 1090.2 (60)
[M+H]+, 1089.2 (100) [M]+; elemental analysis (%) calcd for
C65H60N2O13S: C 70.38, H 5.45, N 2.53; found: C 70.32, H 5.39, N 2.48.
A
40%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (mix of rotamers) d=
7.81 (d, J=8.8 Hz, 2H; ArH), 7.67 (d, J=8.25 Hz, 2H; ArH), 7.38–7.02
(m, 27H; ArH), 6.89 (d, J=8.8 Hz, 2H; ArH), 5.29 (brs, 1H), 5.08 (s,
2H; CH2OCH3), 4.97 (s, 2H; CH2Ph), 4.90 (s, 2H; CH2Ph), 4.81–4.78 (m,
1H), 4.74 (s, 2H; OCH2Ph), 3.97–3.90 (m, 1H), 3.71 (dd, J1 =4.18 Hz,
J2 =14.6 Hz, 1H), 3.14 (dd, J1 =3.14 Hz, J2 =14.7 Hz, 1H), 3.06 (s, 3H;
CH2OCH3), 2.97–2.90 (m, 1H), 2.43 (s, 3H; CH3), 2.34–2.25 (m, 1H),
2.22–2.09 (m, 2H), 1.98–1.87 ppm (m, 2H); IR (neat): n˜ =3931.0, 3906.0,
3857.8, 3756.1, 3425.7, 2371.3, 1597.3, 1350.2, 1158.0, 1110.3, 1016.0, 753.5,
695.8 cmꢀ1; MS (ESI): m/z (%): 1090.2 (60) [M+H]+, 1089.2 (100) [M]+;
elemental analysis (%) calcd for C65H60N2O13S: C 70.38, H 5.45, N 2.53;
found: C 70.31, H 5.41, N 2.45.
General Procedure for Mukaiyama esterification: Amido alcohol
(1 mmol), acid
5 (1 mmol), and 2-chloro-1-methylpyridinium iodide
(1.3 mmol) were taken up in dry CH2Cl2 (10 mL). Et3N (1.5 mmol) was
added, and the reaction mixture was stirred at room temperature. A cata-
lytic amount of DMAP was added after 30 min, and the mixture was
stirred for 1 h. The solvent was removed, and the residue was chromato-
graphed over silica gel to furnish the coupled product.
A
(3S,4S) derivative 31c: Yield=93%; Rf =0.31 (ethyl acetate in hexane,
N
4686
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 4675 – 4688

Natural Products
FULL PAPER
(m, 27H; ArH), 6.89 (d, J=8.8 Hz, 2H; ArH), 5.31 (brs, 1H), 5.10 (s,
2H; CH2OCH3), 4.98 (s, 2H; CH2Ph), 4.90 (s, 2H; CH2Ph), 4.81–4.78 (m,
1H), 4.76 (s, 2H; OCH2Ph), 3.98–3.89 (m, 1H), 3.72 (dd, J1 =4.17 Hz,
J2 =14.8 Hz, 1H), 3.14 (dd, J1 =3.36 Hz, J2 =14.5 Hz, 1H), 3.06 (s, 3H;
CH2OCH3), 2.97–2.90 (m, 1H), 2.43 (s, 3H; CH3), 2.34–2.25 (m, 1H),
2.22–2.09 (m, 2H), 1.98–1.87 ppm (m, 2H); IR (neat): n˜ =3931.0, 3906.0,
3857.8, 3756.1, 3425.7, 2371.3, 1597.3, 1350.2, 1158.0, 1110.3, 1016.0, 753.5,
695.8 cmꢀ1; MS (ESI): m/z (%): 1109.0 (100) [M+Na]+; elemental analy-
sis (%) calcd for C65H60N2O13S: C 70.38, H 5.45, N 2.53; found: C 70.30,
H 5.31, N 2.51.
3827.8, 3751.1, 3421.7, 2371.3, 1697.3, 1351.2, 1058.0, 1016.0, 753.5,
695.8 cmꢀ1; MS (ESI): m/z (%): 727.2 (100) [M+Na]+; elemental analysis
(%) calcd for C35H32N2O12S: C 59.65, H 4.58, N 3.98; found: C 59.59, H
4.51, N 3.78.
A
acid benzyl ester (32): Compound 21a (70 mg, 0.172 mmol) was taken up
in dry CH2Cl2 (10 mL), trimethylsilyl bromide (0.034 mL, 0.258 mmol)
was added at 08C, and the reaction mixture was stirred at room tempera-
ture for 4 h. The solvent was removed, and the residue was dissolved in
diethyl ether. The organic layer was washed with aqueous NaHCO3, fol-
lowed by brine, and the organic layer was dried on anh. Na2SO4 and
evaporated in vacuo. The residue was passed through a small silica pad
and was used for the next step without further purification. Crude yield:
75%; Rf =0.4 (ethyl acetate in hexane, 35%), Crude MS (ESI): m/z (%):
387.2 (100) [M+Na]+; elemental analysis (%) calcd for C19H28N2O5: C
62.62, H 7.74, N 7.69; found: C 62.58, H 7.67, N 7.59.
A
40%); 1H NMR (300 MHz, CDCl3, 258C, TMS): (mix of rotamers 3:2)
d=7.83 (d, J=8.8 Hz, 2H; ArH), 7.69 (d, J=8.8 Hz, 2H; ArH), 7.40–
7.09 (m, 27H; ArH), 6.92 (d, J=8.8 Hz, 2H; ArH), 5.31 (d, J=8.3 Hz,
1H), 5.09 (s, 2H; CH2OCH3), 4.98 (s, 2H; CH2Ph), 4.91 (s, 2H; CH2Ph),
4.81–4.80 (m, 1H), 4.76 (s, 2H; OCH2Ph), 3.98–3.92 (m, 1H), 3.73 (dd,
J1 =3.99 Hz, J2 =14.7 Hz, 1H), 3.15 (dd, J1 =3.3 Hz, J2 =14.7 Hz, 1H),
3.07 (s, 3H; CH2OCH3), 2.97–2.91 (m, 1H), 2.45 (s, 3H; CH3), 2.32–2.29
(m, 1H), 2.22–2.04 (m, 2H), 1.98–1.83 ppm (m, 2H); IR (neat): n˜ =
3931.0, 3906.0, 3857.8, 3756.1, 3425.7, 2371.3, 1597.3, 1350.2, 1158.0,
A
pane-1-carboxylic acid benzyl ester (33): Compound 32 (50 mg,
0.137 mmol), p-benzyloxy-benzoic acid (36.2 mg, 0.164 mmol), and 2-
chloro-1-methylpyridinium iodide (52.5 mg, 0.206 mmol) were taken up
in dry CH2Cl2 (5 mL). Triethylamine (0.04 mL, 0.274 mmol) was added,
and the reaction mixture was stirred for one hour. After completion of
the reaction, solvent was evaporated, and the residue was chromato-
graphed to furnish the pure product 33 as a sticky solid. Yield=75 mg
(95%); Rf =0.6 (ethyl acetate in hexane, 40%); 1H NMR (300 MHz,
CDCl3, 258C, TMS): d=7.97 (d, J=8.7 Hz, 2H; ArH), 7.93–7.31 (m,
10H; ArH), 6.97 (d, J=8.7 Hz, 2H; ArH), 5.28–5.08 (m, 4H), 4.16 (brs,
1H), 3.68–3.50 (brm, 4H), 2.18 (brs, 1H), 1.98–1.61 (brm, 4H), 1.40 ppm
1110.3, 1016.0, 753.5, 695.8 cmꢀ1
; MS (ESI): m/z (%): 1090.2 (60)
[M+H]+, 1089.2 (100) [M]+; elemental analysis (%) calcd for
C65H60N2O13S: C 70.38, H 5.45, N 2.53; found: C 70.29, H 5.35, N 2.46.
General procedure for deprotection: A catalytic amount of HCl was
added to a solution of a fully protected balanol derivative in methanol.
The reaction mixture was heated to 508C and stirred at same tempera-
ture for 3 h. The solvent was evaporated, and the residue was debenzylat-
ed by Nicolaouꢁs procedure[39] to afford the balanol derivative.
(s, 9H; -OC
(CH3)3); 13C NMR (75 MHz, CDCl3, 258C, TMS): d=164.3,
R
(3R,4R)-Balanol (1a): [a]D25 =ꢀ107 (c=0.252 in methanol); 1H NMR
153.7, 138.5, 130.4, 127.4, 127.2, 126.9, 126.6, 126.4, 126.1, 113.3, 78.4,
68.8, 66.3, 66.1, 45.8, 28.4, 27.0 ppm; IR (neat): n˜ =3766, 3452, 3221, 1736,
1692, 1112, 760 cmꢀ1; MS (ESI): m/z (%): 597.1 (100) [M+Na]+, 575.2
(75) [M+H]+, 418 (60) [MꢀtBu]+, 475.2 (45) [MꢀtBoc]+; elemental
analysis (%) calcd for C33H38N2O7: C 68.97, H 6.67, N 4.87; found: C
68.91, H 6.59, N 4.74.
(300 MHz, CD3OD, 258C, TMS): d=7.60 (d, J=8.7 Hz, 2H; ArH), 7.25
(d, J=7.8 Hz, 1H; ArH), 7.17 (t, J=7.8 Hz, 1H; ArH), 6.92 (s, 2H;
ArH), 6.80 (d, J=7.8 Hz, 1H; ArH), 6.76 (d, J=8.7 Hz, 2H; ArH), 5.29
(m, 1H; 4-H), 4.32 (brm, 1H; 3-H), 3.42–2.98 (brm, 4H; 2,7-H), 1.84–
2.12 ppm (brm, 4H; 5,6-H); MS (ESI): m/z (%): 551.6 (100) [M+H]+; el-
emental analysis (%) calcd for C28H26N2O10: C 61.09, H 4.76, N 5.09;
found: C 60.99, H 4.72, N 5.01.
Fully protected ophiocordin (35): Compound 33 (25 mg, 0.05 mmol) was
taken up in dry CH2Cl2. TFA in CH2Cl2 (5%) was added, and the reac-
tion mixture was stirred at room temperature for 2 h. After consumption
of all of the starting material, solvent was evaporated. Co-evaporation
was performed twice with CH2Cl2 to remove the excess TFA. The residue
was dried and again dissolved in CH2Cl2. Acid 4 (30 mg, 0.05 mmol) and
2-chloro-1-methylpyridinium iodide (27 mg, 0.105 mmol) were added, fol-
lowed by tri-n-butylamine (0.035 mL, 0.150 mmol), and the reaction mix-
ture was stirred at room temperature. A catalytic amount of DMAP was
added after 30 min, and the system was stirred for 1 h. The solvent was
removed, and the residue was chromatographed over silica gel to furnish
the coupled product 35 (7 mg, 35%). Some starting material 34 was re-
covered (15 mg). (3:1.5 rotameric mixture); 1H NMR (600 MHz, CDCl3,
258C, TMS): d=8.02 (d, J=12 Hz, 2H; ArH), 7.49–7.00 (m, 43H; ArH),
5.16–4.92 (m, 10H), 4.22 (brs, 2H), 3.78–3.6 (m, 4H), 3.31 (s, 3H), 3.29
(s, 3H), 2.43–2.31 (m, 1H), 2.21–1.8 (m, 4H), 1.55 ppm (s, 9H); MS
(ESI): m/z (%): 1077.2 (10) [M+Na]+, 1055.1 (100) [M+H]+, 999.1 (15)
[MꢀtBu]+; elemental analysis (%) calcd for C63H62N2O13: C 71.71, H
5.92, N 2.65; found: C 71.65, H 5.87, N 2.60.
(3R,4S)-Balanol (1b): [a]D25 =ꢀ64 (c=0.252 in methanol); 1H NMR
(3S,4S)-Balanol (1c): [a]D25 =+97.8 (c=0.331 in methanol); 1H NMR
(300 MHz, CD3OD, 258C, TMS): d=7.60 (d, J=8.7 Hz, 2H; ArH), 7.25
(d, J=7.8 Hz, 1H; ArH), 7.17 (t, J=7.8 Hz, 1H; ArH), 6.92 (s, 2H), 6.80
(d, J=7.8 Hz, 1H; ArH), 6.76 (d, J=8.7 Hz, 2H; ArH), 5.19 (m, 1H; 4-
H), 4.35 (brm, 1H; 3-H), 3.47–3.03 (brm, 4H; 2,7-H), 2.12–1.74 (brm,
4H; 5,6-H); MS (ESI): m/z (%): 551.5 (100) [M+H]+; elemental analysis
(%) calcd for C28H26N2O10: C 61.09, H 4.76, N 5.09; found: C 60.91, H
4.67, N 5.00.
(3S,4R)-Balanol (1d): [a]D25 =+54 (c=0.321 in methanol); 1H NMR
(300 MHz, CD3OD, 258C, TMS): d=7.60 (d, J=8.7 Hz, 2H; ArH), 7.25
(d, J=7.8 Hz, 1H; ArH), 7.17 (t, J=7.8 Hz, 1H; ArH), 6.92 (s, 2H), 6.80
(d, J=7.8 Hz, 1H; ArH), 6.76 (d, J=8.7 Hz, 2H; ArH), 5.51 (m, 1H; 4-
H), 4.51 (brm, 1H; 3-H), 3.32–3.07 (brm, 4H; 2,7-H), 2.12–1.78 ppm
(brm, 4H; 5,6-H); MS (ESI): m/z (%): 551.6 (100) [M+H]+; elemental
analysis (%) calcd for C28H26N2O10: C 61.09, H 4.76, N 5.09; found: C
60.94, H 4.70, N 4.91.
Acknowledgements
N-Tosyl-(R,R)-balanol (2a): Yield=89%; Rf =0.3 (MeOH in CHCl3,
60%); [a]2D5 =ꢀ48.3 (c=0.121 in methanol); 1H NMR (300 MHz,
CD3OD, 258C, TMS): d=7.76 (t, J=7.9 Hz, 3H; ArH), 7.66 (d, J=
8.6 Hz, 1H; ArH), 7.43 (t, J=7.32 Hz, 2H; ArH), 7.22 (t, J=8.5 Hz, 2H;
ArH), 6.94 (d, J=7.8 Hz, 1H; ArH), 6.93 (s, 2H; ArH), 6.80 (d, J=
8.7 Hz, 2H; ArH), 5.38 (d, J=9.3 Hz, 1H; 4-H), 4.51 (brm, 1H; 3-H),
3.56 (brs, 2H; 2,7-H), 3.42 (brs, 2H; 2,7-H), 2.44 (s, 3H; CH3), 2.37–2.21
(brm, 2H; 5,6-H), 1.93–1.87 ppm (brm, 2H; 5,6-H); IR (neat): n˜ =
This research project was supported by the Department of Science and
Technology (SR/S1/OC-23/2005) New Delhi, India. A.K.S. thanks the
CSIR for providing a fellowship (NET-SRF). The authors thank Mr.
Sandip Kumar Chakraborty and Sanjit Kumar Das for the preparation of
starting materials used in this synthesis. This is CDRI communication
number 7473.
Chem. Eur. J. 2008, 14, 4675 – 4688
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: December 18, 2007
Published online: April 9, 2008
4688
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