Reinvestigation on total synthesis of kaitocephalin and its isomers

Article abstract of DOI:10.1016/j.tet.2010.12.068

Aldol reaction of 2,5-disubstituted pyrrolidine 3b with (R)-Garner aldehyde followed by Sharpless asymmetric dihydroxylation and other four reactions afforded mesylate 8a, which was introduced by an amide group via three ordinary transformations to provid

Full text of DOI:10.1016/j.tet.2010.12.068

Tetrahedron 67 (2011) 1673e1680
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reinvestigation on total synthesis of kaitocephalin and its isomers
,
Shouyun Yu a, Shaolin Zhu a, Xianhua Pan b, Jiade Yang a, Dawei Ma a
*
a State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
b Department of Chemistry, Fudan University, Shanghai 200433, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Aldol reaction of 2,5-disubstituted pyrrolidine 3b with (R)-Garner aldehyde followed by Sharpless
asymmetric dihydroxylation and other four reactions afforded mesylate 8a, which was introduced by an
amide group via three ordinary transformations to provide amide 9a. Careful deprotection with AlCl3/
Me2S and subsequent HPLC purification furnished kaitocephalin.
Received 8 November 2010
Received in revised form 23 December 2010
Accepted 24 December 2010
Available online 8 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric synthesis
Natural product
Amino acid
Aldol reaction
Oxazolidine
1. Introduction
Eupenicillium shearii.1a Biological evaluation of this compound
indicated that it has strong antagonistic ability toward AMPA and
In 1997, Shin-ya and co-workers isolated a novel pyrrolidine-
based amino acid, kaitocephalin, from the filamentous fungus
KA receptors, two subtypes of glutamate receptors that play a role
of utmost importance in many physiological processes, such as
neural plasticity, memory, and learning.1a Through intensive
studies using chemical transformation and NMR technology its
stereochemistry was initially assigned as 2S,3S,4R,7R,9S (as in-
dicated in structure 2, Fig. 1).1b About 1 year later the configura-
tion of this natural product was revised as 2R,3S,4R,7R,9S on the
basis of synthetic studies.2a The interesting biological activity of
this amino acid, together with its unique structural feature, had
immediately attracted synthetic studies, even before its structure
was not fully established. To date three groups have achieved its
total synthesis.2e4
Based on the initially proposed structure of kaitocephalin, we
started our synthetic investigations. As outlined in Scheme 1, we
planned to elaborate its right part via an aldol reaction of 2,5-di-
substituted pyrrolidine 3 with (R)-Garner aldehyde, and introduce
the left amino acid moiety through Sharpless asymmetric dihy-
droxylation and subsequent azidation (Scheme 1). It is noteworthy
that in our previous synthesis the final step gave a mixture of two
isomers (see studies described later), which was mistakenly
assigned as the natural kaitocephalin.5
Cl
O
HO
NH
CO2H
2
3
Cl
NH2
HO2C
9
N
H
7
HO
CO2H
kaitocephalin (1)
(revised structure)
Cl
Cl
O
HO
NH
CO2H
NH2
HO2C
9
2
3
N
H
7
HO
CO2H
2-epimer of kaitocephalin (2)
(proposed structure)
After the correct stereochemistry of kaitocephalin was estab-
lished,2a we found that our designed synthetic protocol for its
isomer 2, indeed, was more suitable for assembling kaitocephalin
itself. During the synthetic studies toward 2, we found that the
aldol reaction of 3a with (R)-Garner aldehyde provided oxazolidine
4 exclusively,5a in which the stereochemistry at C-3 was opposite to
Fig. 1. Structures of kaitocephalin and its 2-epimer.
* Corresponding author. E-mail address: madw@mail.sioc.ac.cn (D. Ma).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.068

1674
S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
Cl
Cl
LiHMDS then
CO Me
CO2Me
N
Boc
2
O
Boc
(S)-Garner
N
HO
aldehyde
THF, -78 oC-rt
N
N
+
NH
3b
CO2H
O
O
O
NH2
HO2C
MeO C
HO
2
2
N
H
O
5
3
(55% yield)
6 (27% yield)
HO
CO2H
kaitocephalin (1)
1. AD-mix-β, t-BuOH/H2O
2. TBSOTf, 2,6-lutidine, -78 oC-rt
3. MsCl, TEA, DMAP, DCM, -78 oC-rt
Boc
CO2Me Boc
R'
R
N
CO Me
Boc
N
2
2
N
TBSO
OHC
N
3
O
1. TBAF, HOAc, THF
N
O
O
2. Jones oxidation
then CH2N2, THF
O
O
5
O
CO2R
N
O
CO2Me
CO2Bn Boc
7a: R = OMs, R' = H (26% yield)
3a: R = Bn
Boc
2
N
7b: R = H, R' = OMs (39% yield)
N
3b: R = Me
N
3
OHC
O
O
O
O
4
R'
R
CO2Me
NHBoc
1. NaN3, DMF
MeO2C
2. Pd/C, MeOH, H2
N
Cl
3. HATU, ArCO2H, DIEA
CH2Cl2
O
O
CO2Me
HO
aldol reaction
O
NH
CO2H
3
8a: R = OMs, R' = H (40% yield)
Cl
Cl
NH2
8b: R = H, R' = OMs (29% yield)
HO2C
N
H
2
Sharpless asymmetric
dihydroxylation
HO
CO2H
Ar =
OBn
O
2-epimer of kaitocephalin (2)
Ar
Cl
NH
CO2Me
Scheme 1.
NHBoc
MeO2C
1. AlCl3, Me2S
9
N
2. aq. KOH, EtOH, 70 o
C
O
CO2Me
O
9a
: 9S-isomer, 39% yield
the target molecule 2. An oxidation/reduction operation was then
selected to invert the configuration of this position. If the stereo-
chemistry of C-3 in 4 could be introduced by (R)-Garner aldehyde
part during the aldol reaction, we would be able to obtain oxazo-
lidine 5, in which the stereochemistry at the 2 and 3 positions are
identical with kaitocephalin 1, by reacting the 2,5-disubstituted
pyrrolidine 3b with less expensive (S)-Garner aldehyde.
9b
: 9R-isomer, 50% yield
Cl
O
HO
NH
CO2H
NH2
Cl
HO2C
9
N
H
HO
CO2H
1
: 9S-isomer, 27% yield
Cl
Cl
2. Results and discussion
+
O
HO
With the idea in mind, we conducted the condensation of
a lithium salt of 3b with (S)-Garner aldehyde at ꢀ78 ꢁC (Scheme 2).
After the reaction mixture was warmed to room temperature, the
desired oxazolidine 5 was isolated in 55% yield, together with al-
cohol 6 in 27% yield. The formation of 6 indicated that the diaster-
eoselectivity in this case was not as good as the aldol reaction of 3
with (R)-Garner aldehyde,5a indicating that the stereochemistry of
the 2,5-disubstituted pyrrolidine also played a role in the asym-
metric induction.
NH
CO2H
NH2
HO2C
9
N
H
HO
CO2H
10: 9R-isomer, 31% yield
Scheme 2.
Sharpless asymmetric dihydroxylation6 of 5 was carried out with
AD-mix-b in tert-butanol and water. The resultant inseparable di-
cleaved and the liberated primary alcohols were further oxidized
and therefore diacids were obtained, which were treated with
diazomethane to furnish triesters 8. Transformation of 8 into the
corresponding azides via a SN2 reaction with sodium azide followed
by hydrogenation produced amines, which were condensed with
3,5-dichloro-4-benzoxybenzoic acid mediated by HATU to produce
amides 9. Treatment of 9 with AlCl3/Me2S3a,7 to remove the benzyl
ether, methyl ester, and Boc-protecting groups, and subsequent
hydrolysis with KOH to open the oxazolidinone ring, gave rise to
kaitocephalin 1 and its 9-epimer 10, after HPLC purification. It is
notable that deprotection of 9 by sequential base- and acid-cata-
lyzed hydrolysis provided a complex mixture.
astereomer mixture was treated with TBSOTf to selectively protect
the primary alcohol, followed by exposure onto MsCl and triethyl-
amine, to afford separable mesylates 7a and 7b. The stereochemistry
of newly created stereogenic centers in 7a and 7b was established by
converting them to known kaitocephalin and its 9-epimer 10 as
described later. To our surprise, after these transformations the de-
sired isomer 7a was isolated as a minor component. Since asym-
metric dihydroxylation of the terminal olefins with AD-mix-b often
provides the diol with R-configuration as the major isomer,6 we as-
sumed that the present stereochemistry outcome was mainly con-
trolled by substrate but not the ligand.
After obtaining natural kaitocephalin via a new protocol, we
decided to reinvestigate our previous synthesis, and hoped to use
the newly established HPLC isolation method to purify the mixture
obtained in our previous study.5a As outlined in Scheme 3,
After the silyl protecting group in esters 7 was removed with
TBAF, the resultant alcohols were converted into the corresponding
acids via Jones oxidation. In this case the acetonide moiety was

S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
1675
condensation of 3a with (R)-Garner aldehyde produced alcohol 11.
OMs
1. MsCl, Et3N, DMAP, CH2Cl2
2. TBAF, HOAc
CO2Me
NHBoc
Treatment of 11 with TsOH in methanol followed by selective pro-
tection of the liberated primary hydroxyl group with TBSCl afforded
an alcohol, which was subjected to stereochemistry inversion via
the oxidation/reduction strategy to deliver alcohol 12 with 70%
overall yield. Cleavage of the silyl ether in 12 and subsequent pro-
tection with acetic anhydride produced triester 13, which was
O
14a
N
3. PtO2, H2
4. Jones oxidation then CH2N2
76%
OMe
OAc
AcO
MeO2C
15
Z
Y
CO2Me
treated with AD-mix-b and then protected with TPSCl to provide
a separable mixture of 14a and 14b.
O
NHBoc
3 eq. Mg, MeOH, 35-40 oC
80%
N
OMe
OH
O
O
CO Bn
Boc
O
2
LiHMDS then (R)-Garner aldehyde
16a: Y = H, Z = OMs
N
3a
THF, -78 o
81%
C
16b: Y = OMs, Z = H
N
O
MeO2C
HO
11
Ar
1. NaN3, DMF
NH
CO2Me
NHBoc
1. Pd/C, H2
2. 2 N HCl
3. NaOH
2. Pd/C, MeOH, H2
O
1. CSA, MeOH
2. TBSCl, Et3N
3. Swern oxidation
4. NaBH4, MeOH
70%
CO2Bn
3. HATU, ArCO2H
DIEA, CH2Cl2
4. Jones oxidation
52%
N
1. TBAF, HOAc
NHBoc
OMe
CO2H
O
N
2. Ac2O, Et3N
93%
O
OTBS
HO
MeO2C
17a: 9S-isomer
17b: 9R-isomer
12
Cl
O
CO2Bn
β,
1. AD-mix- t-BuOH/H2O, rt
HO
NHBoc
NH
CO2H
NH2
N
2. TPSCl, DMAP, Et3N
92%
Cl
OAc
MeO2C
AcO
13
HO2C
9
N
H
CO2H
HO
Z
Y
2: 9S-isomer (2-epi-kaitocephalin), 22% yield
CO2Bn
NHBoc
18
: 9R-isomer, (2-epi-9-epi-kaitocephalin), 23% yield
N
OTPS
OAc
AcO
Cl
MeO2C
14a
: Y = H, Z = OH
14b
Ar =
OBn
: Y = OH, Z = H
Scheme 3.
Cl
Scheme 4.
Mesylation of 14a followed by desilylation gave rise to a primary
alcohol, which was hydrogenated, oxidized with Jones reagent, and
then exposed to diazomethane, providing mesylate 15 in 76% overall
yield (Scheme 4). Treatment of 15 with magnesium powder in
methanol gave a mixture of 16a and 16b, indicating that during the
oxazolidinone ring formation partial racemization at the 9-position
occurred. This phenomenon has unfortunately not been noticed in
our previous study,5a mainly because this mixture is inseparable via
column chromatography and two sets of proton NMR signals were
misunderstood as the signals displayed by two rotamers. In the
present case we were able to obtain the single isomer via HPLC
purification and found that there is only one set of proton NMR
signals for each isomer. Starting from isomer 14b, we could obtain
the 9-epimer of 15, which reacted with magnesium powder in
methanol to provide 16a and 16b in about 1/1 ratio. This result gave
additional evidence for the undesired partial racemization in oxa-
zolidinone ring formation step.
The mixture of 16a and 16b was reacted with sodium azide, fol-
lowed by Pd/C catalyzed hydrogenation to provide a primary amine.
Condensation of this amine with 3,5-dichloro-4-benzoxybenzoic
acid under the action of HATU produced an amide, which was sub-
jected to Jones oxidation to give acids 17 as a mixture of 9S- and 9R-
isomers. After hydrogenolysis of 17 to remove the benzyl protecting
group, HCl treatment and subsequent NaOH mediated hydrolysis
delivered a diastereomeric mixture. This mixture was separated with
HPLC to afford 2 (22% yield) and 18 (23% yield). 1H NMR data of these
two products were in agreement with those reported for 2-epi- and
2-epi-9-epi-kaitocephalin.2a Thus, we concluded that our previous
mixture5 might mainly contain 2-epi- and 2-epi-9-epi-kaitocephalin.
Interestingly, two cyclization products 19a and 19b, were isolated in
good combined yield when hydrolysis of two ester groups in 17 was
carried out before cleavage of the Boc-protecting group with HCl and
subsequent KOH-catalyzed hydrolysis (Scheme 5). These results
indicated that the reaction sequence for deprotection steps was
essential for complete deprotection.
O
Ar
NH
CO2Me
NHBoc
1. Pd/C, H2
2. KOH
O
N
3. HCl
OMe
CO2H
O
4. KOH
O
17a
: 9S-isomer
17b
: 9R-isomer
Cl
Cl
O
HO
NH
CO2H
OH
HO2C
N
CO2H
N
H
O
19a
: 9S-isomer, 42% yield
19b
: 9R-isomer, 44% yield
Scheme 5.

1676
S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
3. Conclusions
adding brine. The solution was partitioned between EtOAc and
water. The organic layer was washed with brine and dried over
Na2SO4. After the solution was concentrated, the residue was
chromatographed (eluting with 1/6 to 1/2 EtOAc/hexanes) to afford
In conclusion, we have demonstrated that synthesis of kaito-
cephalin and its stereoisomers could be achieved starting from
a 2,5-disubstituted pyrrolidine and the Garner aldehydes. The key
steps include the aldol reaction of these two partners and Sharpless
asymmetric dihydroxylation. Due to poor diastereoselectivity in
7b (556 mg, 60%) and 7a (357 mg, 40%) as white foams. Compound
24
7a: [
a
]
ꢀ38.3 (c 0.99, CHCl3); IR (film) 2956, 2860, 1767,
D
1705 cmꢀ1
;
1H NMR (300 MHz, CDCl3)
d
5.03 and 4.91 (due to
these two steps, overall yield was only 0.32% (for 15 steps from
pyroglutamic acid). Further investigations to solve this problem are
required to make this route more useful.
L
-
rotamers, both d, J¼9.3 and 7.5 Hz,1H), 4.87e474 (m,1H), 4.26e4.18
(m,1H), 4.13e3.78 (m, 5H) 3.80 (s, 3H), 3.17e3.04 (m, 3H), 2.63e2.57
(m, 1H), 2.45e2.38 (m, 1H), 2.06e1.86 (m, 3H), 1.61e1.50 (m, 15H),
0.89 (s, 9H), 0.09 (s, 6H); MS (ESI) m/z 673.3 (MþNa)þ; HRMS m/z
calcd for C28H50N2O11SSiNa (MþNa)þ 673.2797, found 673.2798.
4. Experimental
Compound 7b: [
a
]
24 ꢀ26.7 (c 0.9, CHCl3); IR (film) 2938, 2860,1766,
D
4.1. Aldol reaction of 3a with (S)-Garner aldehyde
1702, 1391 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
4.90 and 4.37 (due to
rotamers, both d, J¼9.3 and 10.8 Hz, 1H), 4.86e4.75 (m, 1H),
4.30e4.23 (m, 1H), 4.12e3.93 (m, 3H), 3.91e3.68 (m, 2H), 3.81 and
3.79 (due to rotamers, both s, 3H), 3.18e3.13 (m, 3H), 2.65e2.57 (m,
1H), 2.56e2.39 (m, 1H), 1.94e1.82 (m, 2H), 1.80e1.71 (m, 2H),
1.57e1.48 (m, 15H), 0.95 (s, 9H), 0.06 (m, 6H); MS (ESI) m/z 673.3
(MþNa)þ; HRMS m/z calcd for C28H50N2O11SSiNa (MþNa)þ
673.2797, found 673.2806.
To a solution of 3a (2.29 g, 10.1 mmol) in 10 mL THF was added
a solution of LiHMDS (1.0 M in THF, 12.0 mL) at ꢀ78 ꢁC. The re-
sultant solution was stirred for 1 h at the same temperature and
then warmed to ꢀ30 ꢁC during 1 h. The solution was cooled to
ꢀ78 ꢁC again before a solution of (S)-Garner aldehyde (2.99 g,
13.0 mmol) in 50 mL THF was added dropwise. The reaction mix-
ture was stirred for 2 h at ꢀ78 ꢁC and then warmed to room tem-
perature during 2 h. The reaction was quenched by adding 50 mL
1 M HCl and extracted with EtOAc. The combined organic layers
were washed with brine and dried over Na2SO4. Concentration and
column flash chromatography (eluting with 1/30 to 1/10 EtOAc/
hexanes) gave 5 (2.36 g, 55%) and 6 (1.24 g, 27%) as colorless oils.
4.3. Synthesis of triesters 8
To a solution of 7a (1.05 g, 1.61 mol) in 25 mL THF were added
TBAF (1.0 M in THF, 3.2 mL) and CH3CO2H (179 mg, 2.93 mmol) at
room temperature. The resultant solutionwas stirred for 5 h at room
temperature and then concentrated. Flash chromatography of the
residue eluting with 1/1 to 2/1 EtOAc/hexanes afforded the corre-
sponding alcohol (745 mg, 86%) as white foam.
To the solution of the above alcohol (524 mg, 0.98 mmol) in
30 mL acetone was added 3.6 mL freshly prepared Jones reagent
(about 2.7 M) at 0 ꢁC. After the reaction mixture was stirred for 1 h
at 0 ꢁC, and 0.5 h at room temperature, the reaction was quenched
by adding 3.6 mL i-PrOH at 0 ꢁC. The stirring was continued for 1 h
before the mixture was filtered. The filtration cake was dissolved in
brine and extracted with CHCl3. The combined organic layers were
dried over Na2SO4 and concentrated. The residue was dissolved in
20 mL THF and treated with a solution of CH2N2 in ether until the
reaction mixture turned yellow. The stirring was continued until the
color disappeared. Concentration and flash chromatography (elut-
Compound 5: [
a
]
26 ꢀ21.7 (c 0.95, CHCl3); IR (film) 3078, 2980,1770,
D
1702, 1643, 1458 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
5.84e5.71 (m,
1H), 5.14e5.05 (m, 2H), 4.87 and 4.69 (due to rotamers, both d,
J¼7.5 and 3.9 Hz, 1H), 4.30e3.83 (m, 4H), 3.97 and 3.79 (due to
rotamers, both s, 3H), 2.65e2.57 (m, 1H), 2.55e2.30 (m, 1H),
2.27e2.13 (m, 2H), 1.72e1.55 (m, 2H), 1.52e1.50 (m, 15H); MS (ESI)
m/z 425.2 (MþH)þ, 447.3 (MþNa)þ; HRMS m/z calcd for
24
C21H35N2O7 (MþH)þ 425.2282, found 425.2281. Compound 6: [
a]
D
ꢀ5.4 (c 1.1, CHCl3); IR (film) 3413, 2981, 2957,1753,1716,1693,1642,
1506 cmꢀ1
; d 5.77e5.67 (m, 1H),
1H NMR (300 MHz, CDCl3)
5.10e5.04 (m, 2H), 4.63 (d, J¼9.3 Hz, 1H), 4.11e4.05 (m, 1H), 3.99
(dd, J¼4.5, 11.7 Hz, 1H), 3.72 (s, 6H), 3.72e3.63 (m, 2H), 2.45e2.40
(m, 1H), 2.39e2.32 (m, 1H), 2.30e2.24 (m, 1H), 2.15e1.98 (m, 2H),
1.76e1.70 (m,1H),1.47 (s, 3H),1.39 (s, 9H),1.32 (s, 3H); MS (ESI) m/z
479.2 (MþNa)þ; HRMS m/z calcd for C22H36N2O8Na (MþNa)þ
479.2364, found 479.2366.
ing with 1/4 to 1/1 EtOAc/hexanes) gave 8a (248 mg, 46%) as white
25
foam. [
a]
ꢀ12.3 (c 0.93, CHCl3); IR (film) 3365, 2986, 1762, 1717,
D
1521 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
5.25 (d, J¼6.6 Hz, 1H), 5.15
4.2. Synthesis of mesylates 7
(dd, J¼6.0, 6.6 Hz, 1H), 4.84 (dd, J¼6.9, 16.8 Hz, 1H), 4.58e4.43 (m,
1H), 4.10e3.97 (m, 1H), 3.86 (s, 3H), 3.86 (s, 3H), 3.79 (s, 3H), 3.17 (s,
3H), 2.52e2.37 (m, 2H), 2.30e2.16 (m, 2H), 2.09e2.01 (m, 1H),
1.90e1.78 (m, 1H), 1.44 (s, 9H); MS (ESI) m/z 570.4 (MþNH4)þ, 575.3
(MþNa)þ; HRMS m/z calcd for C21H32N2O13SNa (MþNa)þ 575.1517,
found 575.1506.
To a solution of 5 (2.11 g, 4.97 mmol) in 25 mL t-BuOH, and 25 mL
water was added AD-mix-b
(7.21 g) at 0 ꢁC. The resultant solution
was stirred for 1 h at the same temperature and then overnight at
room temperature. After the solution was cooled to 0 ꢁC, 50 mL half-
saturated Na2SO3 solution was added and the solution was stirred
for 1 h at room temperature. The organic layer was separated and
the aqueous layer was extracted with EtOAc (50 mLꢂ5). The com-
bined organic layers were washed with brine and dried over Na2SO4.
Concentration and column flash chromatography (eluting with
EtOAc/hexanes) give a diol (1.66 g, 73%) as white foam.
To the solution of the above diol in 30 mL CH2Cl2 were succes-
sively added 2,6-lutidine (0.58 mL, 5.0 mmol) and TBSOTf (0.91 mL,
4.0 mL) at ꢀ78 ꢁC. The reaction mixture was warmed to room
temperature overnight. Concentration and column flash chroma-
tography (eluting with 1/4 to 1/2 EtOAc/hexanes) give the silyl ether
(1.87 g, 90%) as white foam.
Following the same procedure from 7a to 8a, 8b was obtained
from 7b in 29% yield. [
a
]
;
26 ꢀ41.7 (c 1.2, CHCl3); IR (film) 3367, 2938,
D
1807, 1718, 1522 cmꢀ1
1H NMR (300 MHz, CDCl3)
d 5.29 (d,
J¼8.1 Hz, 1H), 5.16 (d, J¼10.5 Hz, 1H), 4.86 (d, J¼9.0 Hz, 1H),
4.56e4.51 (m, 1H), 4.11e4.06 (m, 1H), 3.85 (s, 3H), 3.80 (s, 3H) 3.79
(s, 3H), 3.16 (s, 3H), 2.50e2.40 (m,1H), 2.30e2.22 (m, 2H), 2.16e1.99
(m, 2H), 1.84e1.73 (m, 1H), 1.43 (s, 9H); MS (ESI) m/z 575.1
(MþNa)þ; HRMS m/z calcd for C21H32N2O13SNa (MþNa)þ 575.1517,
found 575.1529.
4.4. Preparation of amides 9
To a solution of the above silyl ether (783 mg, 1.37 mmol), tri-
ethylamine (1.2 mL, 8.4 mmol), DMAP (30 mg, 0.25 mmol) in 10 mL
CH2Cl2 was added MsCl (0.42 mL, 5.4 mmol) at ꢀ78 ꢁC. The reaction
mixture was warmed to ꢀ10 ꢁC during 2.5 h and then quenched by
To a solution of 8a (70 mg, 0.13 mmol) in 3 mL DMF was added
NaN3 (25 mg, 0.38 mmol). The reaction mixture was stirred at room
temperature for 36 h. The mixture was partitioned between brine
and EtOAc, and aqueous phase was extracted with EtOAc. The

S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
1677
combined organic phase was washed with brine and dried over
Na2SO4. Concentration and flash chromatography (eluting with 1/6
to 1/2 EtOAc/hexanes) gave the corresponding azide (37 mg, 65%)
as white foam.
To a solution of the above azide (32 mg, 0.071 mmol) in 1.5 mL
MeOH was added 4 mg of 10% Pd/C. The resultant mixture was
stirred under hydrogen at ordinary pressure for 0.5 h. After the
catalyst was filtered off, the filtrate was concentrated and the res-
idue was dissolved in 1.5 mL CH2Cl2. To this solution were added
HATU (41 mg, 0.11 mmol), 4-(benzyloxy)-3,5-dichlorobenzoic acid
(32 mg, 0.11 mmol), and DIEA (0.025 mL, 0.14 mmol) at 0 ꢁC. The
mixture was stirred at room temperature overnight. After the so-
lution was concentrated, flash chromatography of the residue
resultant solution was stirred for 1 h at the same temperature and
then warmed to ꢀ30 ꢁC slowly. The solution was cooled to ꢀ78 ꢁC
again before a solution of (S)-Garner aldehyde (1.96 g, 8.55 mmol,
1.2 equiv) in 80 mL THF was added in a dropwise manner. After the
addition the reaction mixture was stirred for 1 h at the same
temperature. To this solution was added 7 mL saturated NH4Cl at
ꢀ78 ꢁC to quench the reaction. The mixture was extracted with
ethyl acetate and the combined organic layers were washed with
brine and dried over anhydrous Na2SO4. Concentration and flash
chromatography (eluting with 1/11 to 1/9 EtOAc/hexanes) gave 11
25
(3.07 g, 81%) as colorless oil. [
(300 MHz, CDCl3)
a
]
þ23.6 (c 0.62, CHCl3); 1H NMR
D
d
7.38e7.30 (m, 5H), 5.80e5.54 (m, 1H),
5.30e5.26 (m, 0.5H), 5.17 (s, 1H), 5.06e4.98 (m, 2H), 4.94e4.88 (m,
1H), 4.65e4.61 (m, 0.5H), 4.43e4.38 (m, 0.5H), 4.31e4.27 (m, 1H),
4.19e4.15 (m, 1H), 4.09e4.07 (m, 0.5H), 4.04e3.92 (m, 0.5H),
3.89e3.84 (m, 1H), 3.79e3.69 (m, 2H), 3.41 (s, 1.5H), 2.80e2.76 (m,
0.5H), 2.57e2.53 (m, 1H), 2.50e2.40 (m, 0.5H), 2.18e2.11 (m, 2H),
2.01e1.94 (m,1H), 1.83e1.76 (m,1H),1.60 (s, 3H),1.49 and 1.43 (due
to rotamers, both s, 3H),1.47 and 1.44 (due to rotamers, both s, 9H);
MS (ESI) m/z 555.2 (MþNa)þ.
(eluting with 1/6 to 1/2 EtOAc/hexanes) afforded 9a (32 mg, 60%
25
yield) as white foam. [
a
]
D
ꢀ52.8 (c 0.65, CHCl3); IR (film) 3348,
2956, 1747, 1592, 1537 cmꢀ1 1H NMR (300 MHz, CDCl3)
; d 7.18 (d,
J¼7.5 Hz, 1H), 7.84 (s, 2H), 7.57e7.54 (m, 2H), 7.44e7.34 (m, 3H),
5.27 (d, J¼8.7 Hz, 1H), 5.08 (s, 2H), 4.85 (d, J¼9.3 Hz, 1H), 3.97e3.92
(m, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.78 (s, 3H), 2.49e2.34 (m, 2H),
2.30e2.25 (m, 2H), 2.08e1.91 (m, 1H), 1.91e1.78 (m, 1H), 1.44 (s,
9H); MS (ESI) m/z 752.4 (MþH)þ, 774.3 (MþNa)þ; HRMS m/z calcd
for C34H40N3O12Cl2 (MþH)þ 752.1984, found 752.1974.
4.7. Synthesis of alcohol 12
Following the same procedure from 8a to 9a, 9b was obtained
26
from 8b in 50% yield. Compound 9b: [
a
]
ꢀ45.8 (c 1.3, CHCl3); IR
To a solution of 11 (2.53 g, 4.75 mmol) in 50 mL methanol was
added CSA (1.16 g, 5 mmol) at 0 ꢁC. After stirring at 0 ꢁC for 7 h, 8 mL
saturated NaHCO3 was added to quench the reaction. The solution
was concentrated and the residue was extracted with ethyl acetate.
The combined organic layers were washed with brine and dried
over Na2SO4. Concentration followed by flash chromatography
(eluting with 2/1 EtOAc/hexanes) gave a diol (1.94 g, 83%) as white
foam.
To a solution of the above diol (1.44 g, 2.92 mmol) in 14 mL
methylene chloridewere added triethylamine (1.42 mL,10.23 mmol)
and DMAP (72 mg, 0.58 mmol). The resultant solution was cooled to
ꢀ20 ꢁC before a solution of TBSCl (529 g, 3.51 mmol) in 5 mL
methylene chloride was added. The reaction mixture was warmed to
0 ꢁC and then stirred for 5 h at this temperature. After the solution
was washed with 1 N KHSO4, saturated NaHCO3 and brine, it was
dried over Na2SO4. Concentration followed by flash chromatography
(eluting with 1/2 to 1/1 EtOAc/hexanes) gave the corresponding
alcohol (1.67 g, 94%) as white foam.
To a solution of oxalic chloride (1.8 mL, 19 mmol) in 25 mL
methylene chloride was added dropwise a mixture of DMSO (2.4 mL,
32 mmol) and 3 mL methylene chloride at ꢀ78 ꢁC for 15 min. After
the resultant solution was stirred for 5 min, a solution of above al-
cohol (6.06 g, 10 mmol) in 25 mL methylene chloride was added
dropwise. After the addition the solution was allowed to warm to
ꢀ50 to 40 ꢁC, and then the stirring was continued for 1 h. To this
solutionwas added 5 mL triethylamine before it was warmed to 0 ꢁC.
After 20 mL saturated NaHCO3 was added, the organic layer was
separated and the aqueous layer was extracted with ether. The
combined organic layers were washed with brine, dried over anhy-
drous Na2SO4. Concentration and column flash chromatography
(eluting with 1/5 to 1/4 EtOAc/hexanes) gave a ketone (5.75 g, 95%)
as white foam.
A mixture of the above ketone (1.43 g, 2.36 mmol) in 50 mL dry
ether was cooled to ꢀ50 ꢁC before NaBH4 (536 mg, 14.18 mmol) and
6 mL anhydrous methanol was added, respectively. The reaction
mixture was allowed to warm to 10 ꢁC and then the stirring was
continued for 1 h. To this solution 50 mL saturated NH4Cl was added
to quench the reaction. The organic layer was separated and the
aqueous layer was extracted with ethyl acetate. The combined or-
ganic layers were washed with brine, dried over anhydrous Na2SO4.
Concentration and column flash chromatography (eluting with 1/15
D
(film) 3346, 2959,1750,1666,1592 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d
8.13 (d, J¼8.4 Hz, 1H), 7.94 (s, 2H), 7.55 (dd, J¼1.8, 7.8 Hz, 2H),
7.43e7.36 (m, 3H), 5.21 (d, J¼8.7 Hz, 1H), 5.08 (s, 2H), 5.07e5.01 (m,
1H), 4.95 (d, J¼9.9 Hz, 1H), 4.49 (t, J¼8.7 Hz, 1H), 4.13e4.03 (m, 1H),
3.88 (s, 3H), 3.80 (s, 3H), 3.72 (s, 3H), 2.46e2.40 (m, 1H), 2.34e2.19
(m, 3H), 1.98e1.81 (m, 2H), 1.42 (s, 9H); MS (ESI) m/z 774.3
(MþNa)þ; HRMS m/z calcd for C34H39N3O12Cl2Na (MþNa)þ
774.1803, found 774.1817.
4.5. Kaitocephalin and its 9-epimer
To a solution of 9a (17 mg, 22.6 mmol) in Me2S (0.5 mL) was
added AlCl3 (85 mg, 0.65 mmol) at room temperature. The reaction
mixture was stirred at room temperature for 36 h, quenched with
H2O, and concentrated under reduced pressure. The residue was
purified by Dowex 50 Wꢂ2 (elution with 1 N NH4OH) to give the
crude product. To a solution of this crude product in 0.5 mL EtOH
was added 0.5 mL 1 M KOH. The resultant mixture was stirred at
70 ꢁC for 9 h. The solutionwas cooled to room temperature and then
0.5 mL 1 M HCl was added to quench the reaction. After the mixture
was concentrated, the residue was purified by Dowex 50 Wꢂ2
(elution with 1 N NH4OH), and then HPLC (Sensyu Pak, PEGASIL-
ODS
4
4.6ꢂ250 mm, elution with 4% MeOH/20 mM diethylamine/
CO2 buffer pH 7, 1 mL/min) to give kaitocephalin 1 (2.95 mg, 27% for
two steps) as white foam. [
(500 MHz, D2O)
25
a
]
D
ꢀ31.4 (c 0.11, H2O); 1H NMR
d
7.80 (s, 2H), 4.58 (s, 1H), 4.51 (dd, J¼6.4, 5.9 Hz,
1H), 4.33 (s, 1H), 3.89e3.85 (m, 1H), 2.62e2.57 (m, 1H), 2.48e2.44
(m,1H), 2.30e2.25 (m,1H), 2.23e2.16 (m, 2H),1.82e1.76 (m,1H); 13C
NMR (125 MHz, D2O)
d 177.6, 174.3, 170.8, 168.5, 162.1, 127.6, 124.1,
117.7, 76.3, 70.7, 59.2, 55.6, 53.5, 35.2, 32.1, 29.7; MS (ESI) m/z 494.1
(MþH)þ, 492.1 (MꢀH)ꢀ.
Following the same procedure from 9a to kaitocephalin, 9-epi-
mer of kaitocephalin 10 was obtained from 9b in 31% yield. Com-
pound 10: [
a
]
23 ꢀ11.6 (c 0.09, H2O); 1H NMR (500 MHz, D2O)
d 7.81
D
(s, 2H), 4.58 (s, 1H), 4.50 (dd, J¼3.7, 9.6 Hz, 1H), 4.33 (s, 1H),
3.82e3.77 (m,1H), 2.50e2.44 (m, 2H), 2.40e2.32 (m, 2H), 2.20e2.16
(m, 1H), 1.81e1.75 (m, 1H); MS (ESI) m/z 494.1 (MþH)þ.
4.6. Aldol reaction of 3b with (R)-Garner aldehyde
To a solution of 3b (2.16 g, 7.11 mmol) in 18 mL THF was added
a solution of LiHMDS (1 M in THF, 8.5 mL, 1.2 equiv) at ꢀ78 ꢁC. The
to 1/10 EtOAc/hexanes) gave 12 (1.22 g, 85%) and its 3R-isomer
25
alcohol (143 mg, 10%) as white foam. Compound 12: [
a
]
ꢀ27.1
D

1678
S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
(c 1.50, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.35e7.31 (m, 5H), 6.55
(due to rotamers, both s, 1H), 5.21e5.96 (m, 2H), 4.83 (d, J¼10.2 Hz,
1H), 4.64e4.54 (m, 1H), 4.16e4.06 (m, 3H), 3.81e3.67 (m, 1H),
3.60e3.42 (m, 3H), 3.29 (s, 3H), 2.64e2.54 (m, 1H), 2.26e2.17 (m,
2H), 2.05e1.98 (m, 1H), 2.06 (s, 3H), 2.00 (s, 3H), 1.89e1.84 (m, 2H),
1.46 (s, 9H), 1.06 (s, 9H); MS (ESI) m/z 871.4 (MþNa)þ; HRMS m/z
calcd for C45H60N2O12SiNa (MþNa)þ 871.3808, found 871.3826.
(d, J¼9.6 Hz, 1H), 5.65e5.59 (m, 1H), 5.28 (d, J¼11.4 Hz, 1H), 5.18(d,
J¼12.6 Hz, 1H), 5.01e4.94 (m, 2H), 4.81 (d, J¼10.5 Hz, 1H), 4.38 (d,
J¼9.9 Hz, 1H), 3.99e3.95 (m, 1H), 3.84e3.81 (m, 1H), 3.78 (s, 3H),
3.46e3.56 (m, 2H), 2.55e2.50 (m, 1H), 2.30e2.24 (m, 2H), 2.04e1.91
(m, 2H), 1.68e1.65 (m, 1H), 1.41 (s, 9H), 0.84 (s, 9H), 0.03 (s, 6H); MS
(ESI) m/z 629.3 (MþNa)þ; HRMS m/z calcd for C31H50N2O8SiNa
(MþNa)þ 629.3229, found 629.3234.
4.10. Synthesis of mesylate 15
4.8. Conversion of 12 to triester 13
To a mixture of 14a (2.22 g, 2.61 mmol), triethylamine (3.3 mL,
23.6 mmol), DMAP (96 mg, 0.8 mmol), and 16 mL anhydrous
methylene chloride were added MsCl (0.81 mL, 10.5 mmol) at
ꢀ78 ꢁC. The reaction mixture was warmed to 0 ꢁC in 1 h. After it
was stirred for 1 h at the same temperature, the solution was par-
titioned between ethyl acetate and water. The organic layer was
washed with 1 N KHSO4, saturated NaHCO3, and brine. The solution
was dried over anhydrous Na2SO4. Concentration and flash chro-
matography (eluting with 1/3 to 1/2 EtOAc/hexanes) gave the
corresponding mesylate (2.40 g, 99% yield) as white foam. After this
mesylate was dissolved in 68 mL THF, a solution of TBAF (1 M in
THF, 6.8 mL) and acetic acid (315 mg, 5.2 mmol) were added. The
resultant solution was stirred for 1 h at room temperature before it
was concentrated. Column flash chromatography (eluting with 1/1
EtOAc/hexanes) gave the corresponding alcohol (1.66 g, 92% yield)
as white foam.
To a solution of the above alcohol (1.6 g, 2.32 mmol) in 140 mL
ethyl acetate, 160 mg PtO2 was added. The resultant mixture was
stirred under hydrogen atmosphere at ordinary pressure until the
starting material disappeared monitored by TLC. The mixture was
filtered and the filtrate was dissolved in 70 mL acetone. To this
solution was added 7.7 mL freshly prepared Jones reagent at 0 ꢁC.
After the resultant solution was stirred for 40 min at room tem-
perature, 3 mL i-PrOH was added to quench the reaction. After the
stirring was continued for 20 min, the mixture was partitioned
between brine and chloroform. The organic layer was separated
and the aqueous layer was extracted with chloroform. The com-
bined organic layers were dried over anhydrous Na2SO4, and
concentrated. The residue was dissolved in 40 mL THF and treated
with a solution of CH2N2 in ether until the reaction mixture turned
yellow. The stirring was continued until the color disappeared.
Concentration and flash chromatography (eluting with 1/2 to 2/3
A solution of 12 (2.83 g, 4.67 mmol) in 10 mL THF was cooled to
0 ꢁC before a solution of TBAF (1 M in THF, 9.3 mL) and acetic acid
(504 mg, 8.40 mmol) were added. The reaction solution was stir-
red at room temperature for 1 h and then concentrated. The res-
idue was allowed to pass a short column of silica gel to afford
a diol. This diol was dissolved in 25 mL methylene chloride. To this
solution were added triethylamine (4.6 mL, 32.7 mmol), DMAP
(240 mg, 2 mmol), and acetic anhydride (2.2 mL, 20 mmol) at 0 ꢁC.
The resultant mixture was stirred at room temperature overnight.
Concentration and column flash chromatography (eluting with 1/
26
15 to 1/9 EtOAc/hexanes) gave the trimester 13 (2.50 g, 93%). [a]
D
þ44.61 (c 0.55, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.37e7.34 (m,
5H), 5.82e5.74 (m, 1H), 5.69 (s, 1H), 5.22e5.09 (m, 2H), 5.07e5.01
(m, 2H), 4.86e4.82 (m, 1H), 4.60e4.55 (m, 1H), 4.16e4.00 (m, 2H),
3.97e3.91 and 3.88e3.78 (m, 1H), 3.66 and 3.38 and 3.34 (due to
rotamers, both s, 3H), 2.72e2.67 (m, 1H), 2.52e2.46 (m, 1H),
2.24e2.14(m, 2H), 2.11 and 2.08 (due to rotamers, both s, 3H), 2.01
and 1.99 (due to rotamers, both s, 3H), 1.79e1.73 (m, 1H),
1.70e1.58 (m, 1H), 1.45 (s, 9H); MS (ESI) m/z 599.2 (MþNa)þ;
HRMS m/z calcd for C29H40N2O10Na (MþNa)þ 599.2575, found
599.2568.
4.9. Preparation of alcohols 14
A solution of AD-mix-b (2.06 g) in 7.4 mL t-BuOH and 7.4 mL
water was stirred at room temperature for 10 min. The mixture was
cooled to 0 ꢁC and the olefin 13 (850 mg, 1.47 mmol) was added. The
mixture was stirred for 16 h at 0 ꢁC, and 16 h at room temperature.
After the solution was cooled to 0 ꢁC,1.91 g of Na2SO3 was added and
the solution was stirred for 1 h at room temperature to quench the
reaction. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were
washed with brine, dried over anhydrous Na2SO4, and concentrated
to give the crude diol.
EtOAc/hexanes) gave diester 15 (1.23 g, 83% yield) as white foam.
23
Compound 15: [
CDCl3)
a
]
þ56.6 (c 0.50, CHCl3); 1H NMR (300 MHz,
D
d
5.80 and 5.71 (due to rotamers, both s, 1H), 5.11 and 5.04
(due to rotamers, both dd, J¼3.0,10.2 Hz,1H), 4.85 and 4.84 (due to
rotamers, both d, J¼10.2 Hz, 1H), 4.57e4.53 (m, 1H), 4.16e4.00 (m,
3H), 3.82 (s, 3H), 3.79 and 3.75 (due to rotamers, both s, 3H), 3.68
and 3.62 (due to rotamers, both s, 3H), 3.21 (s, 3H), 2.63e2.33 (m,
2H), 2.24e2.18 (m, 2H), 2.11e2.02 (m, 1H), 2.11 (s, 3H), 2.02 (s, 3H),
1.90e1.84 (m,1H),1.46 (s, 9H); MS (ESI) m/z 663.1 (MþNa)þ; HRMS
m/z calcd for C25H40N2O15SNa (MþNa)þ 663.2042, found
663.2039.
The above diol was dissolved in 15 mL methylene chloride and
then triethylamine (1.0 mL, 7.35 mmol) and DMAP (36 mg,
0.29 mmol) were added. To this stirring solution was added drop-
wise a solution of TBDPSCl (485 mg, 1.76 mmol) in 3 mL methylene
chloride at ꢀ78 ꢁC. The reaction mixture was warmed to room
temperature overnight before it was partitioned between ethyl
acetate and saturated NH4Cl. The organic layer was separated,
washed with saturated NaHCO3, water, and brine, dried over an-
hydrous Na2SO4. Concentration and column flash chromatography
(eluting with 1/4 to 1/2 EtOAc/hexanes) gave the silyl ether 14a
(766 mg, 61%) and 14b (384 mg, 31%) as white foam. Compound
4.11. Conversion of the mesylate 15 to 16
To a solution of 15 (480 mg, 0.75 mmol) in 15 mL methanol was
added Mg (54 mg, 2.25 mmol, 3 equiv). The resultant mixture was
heated at 35e40 ꢁC for 2 h and then to it was added 1 N HCl to
adjust pH¼6e7. The solution was partitioned between ethyl acetate
and water. The organic layer was dried over anhydrous Na2SO4 and
concentrated. The residue was chromatographed eluting with 50/
50/1 petroleum ether/ethyl acetate/methanol to afford 16 (314 mg,
80%) as a mixture of 9R and 9S isomer (about 1/1 ratio). Pure 16b
could be obtained by HPLC purification (Grace Vydac cat:
238DE1022, C18 Monomeric, 120A. elution with MeCN/H2O¼30/70,
2 mL/min, 0e5 min 16b, 5e40 min 16a and 16b). Compound 16b:
14a: [
a
]
27 þ36.7 (c 0.80, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.64 (d,
D
J¼6.9 Hz, 4H), 7.46e7.36 (m, 6H), 7.26e7.20 (m, 5H), 5.82 and 5.69
(due to rotamers, both s, 1H), 5.19e5.04 (m, 2H), 4.84 (d, J¼9.9 Hz,
1H), 4.65e4.54 (m, 1H), 4.18e4.00 (m, 3H), 3.71e3.35 (m, 3H), 3.64
and 3.31 (due to rotamers, both s, 3H), 2.68e2.41 (m, 2H), 2.18e1.94
(m, 3H), 2.08 (s, 3H), 2.01 (s, 3H),1.77e1.65 (m, 2H),1.46 (s, 9H),1.06
(s, 9H); MS (ESI) m/z 871.3 (MþNa)þ; HRMS m/z calcd for
C45H60N2O12SiNa (MþNa)þ 871.3808, found 871.3836. Compound
14b: [
a
]
27 þ24.2 (c 0.45, CHCl3); 1H NMR (300 MHz, CDCl3)
d7.65 (d,
D
J¼4.5 Hz, 4H), 7.46e7.36 (m, 6H), 7.26e7.205 (m, 5H), 5.80 and 5.67

S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
1679
26
[
a]
ꢀ28.4 (c 0.48, CHCl3); 1H NMR (300 MHz, CDCl3)
d
5.19 (dd,
pH¼7.0 and then concentrated. The residue was purified by Dowex
50 Wꢂ2 (elution with 1 N NH4OH) and then HPLC (Agilent, ZOR-
D
J¼1.8, 10.8 Hz, 1H), 4.98 (d, J¼9.9 Hz, 1H), 4.91 (d, J¼2.4 Hz, 1H),
4.13e4.07 (m, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.71e3.66 (m, 2H), 3.25
(s, 3H), 2.34e2.20 (m, 4H), 2.03 (ddd, J¼3.9, 10.8, 14.7 Hz, 1H),
BAX SB-C18
4
9.4ꢂ250 mm, elution with 5% MeOH/20 mM dieth-
ylamine/CO2 pH¼7 buffer, 2 mL/min) to give 18 (3.2 mg) and 2
1.77e1.67 (m, 2H), 1.44 (s, 9H); MS (ESI) m/z 547.2 (MþNa)þ. Data
(3.1 mg) as white foam. Compound 2: [
NMR (500 MHz, D2O)
a
]
24 ꢀ23.0 (c 0.05, H2O); 1H
D
22
for mixture of 16a and 16b: [
a]
ꢀ12.5 (c 0.22, CHCl3); 1H NMR
d
7.62 (s, 2H), 4.36 (dd, J¼5.0, 8.5 Hz, 1H), 4.30
D
(300 MHz, CDCl3)
d
5.19 and 5.16 (both dd, J¼1.5, 10.5 , 6.0, 7.2 Hz,
(d, J¼2.5 Hz, 1H), 3.79 (d, J¼2.5 Hz, 1H), 3.61e3.53 (m, 1H),
2.34e2.27 (m, 2H), 2.13e2.08 (m, 2H), 2.05e2.02 (m, 1H), 1.58e1.52
(m, 1H); MS (ESI) m/z 494.2 (MþH)þ, 516.1 (MþNa)þ; HRMS m/z
calcd for C18H20Cl2N3O9 (MꢀH)ꢀ 492.0582, found 492.0577. Com-
1H), 4.97e4.94 (m, 1H), 4.91 and 4.87 (both d, J¼2.7 , 1.8 Hz, 1H),
4.16e4.02 (m, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.72e3.64 (m, 2H), 3.26
and 3.19 (both s, 3H) 2.43e2.20 (m, 4H), 2.08e1.99 (m, 1H),
1.77e1.67 (m, 2H), 1.44 (s, 9H); MS (ESI) m/z 547.2 (MþNa)þ; HRMS
m/z calcd for C20H32N2O12SNa (MþNa)þ 547.1568, found 547.1572.
pound 18: [
a
]
24 ꢀ12.6 (c 0.09, H2O); 1H NMR (500 MHz, D2O)
d 7.71
D
(s, 2H), 4.40 (dd, J¼5.0, 8.0 Hz, 1H), 4.34 (d, J¼4.5 Hz, 1H), 3.87 (d,
J¼4.5 Hz, 1H), 3.68e3.60 (m, 1H), 2.40 (dd, J¼6.5, 12.0 Hz, 1H),
2.30e2.18 (m, 4H), 1.69e1.65 (m, 1H); MS (ESI) m/z 494.2 (MþH)þ,
516.3 (MþNa)þ; HRMS m/z calcd for C18H20Cl2N3O9 (MꢀH)ꢀ
492.0582, found 492.0574 (MꢀH)ꢀ.
4.12. Preparation of the acids 17
A mixture of 16a and 16b (157 mg, 0.3 mmol), sodium azide
(65 mg, 1.0 mmol), and 4 mL DMF was stirred at room tempera-
ture for 7 h. The solvent was removed in vacuo and the residue
was chromatographed to give the azides (116 mg, 82%) as white
foam.
4.14. Synthesis of 19
A mixture of 17 (15 mg, 0.02 mmol), 2 mg of 10% Pd/C, and
1.0 mL anhydrous methanol was stirred under hydrogen atmo-
sphere (1 atm) for 15 min. After Pd/C was filtered off, the filtrate
was concentrated. The residue was dissolved in 0.64 mL THF and
0.64 mL 1% KOH. The resultant solution was stirred at room tem-
perature for 1.5 h and then concentrated to remove solvents. The
residue was dissolved in 2 mL 2 N HCl, and stirred at room tem-
perature for 3 h and then at 50 ꢁC for 1 h. The solution was cooled to
room temperature and concentrated to 1 mL. The residue was pu-
rified by Dowex 50 Wꢂ2 (elution with 1 N NH4OH) to afford an acid
as light yellow foam.
To a solution of the above azides (116 mg, 0.25 mmol) in 5 mL
methanol was added 12 mg of 10% Pd/C. The resultant mixture was
stirred under hydrogen atmosphere at ordinary pressure until the
starting material disappeared monitored by TLC. After catalyst was
filtered off, the filtrate was concentrated and the residue was dis-
solved in 2.5 mL CH2Cl2. Tothis solutionwere added HATU (145 mg,
0.38 mmol), 4-(benzyloxy)-3,5-dichlorobenzoic acid (82 mg,
0.28 mmol), and DIEA (0.09 mL, 0.50 mmol) at 0 ꢁC. The mixture
was stirred at room temperature overnight before it was concen-
trated. Flash chromatography of the residue (eluting with 1/6 to 1/2
EtOAc/hexanes) afforded amide (136 mg, 75%) as white foam.
The above amide (136 mg, 0.19 mmol) was dissolved in 2 mL
acetone. To this solution was added 0.2 mL freshly prepared Jones
reagent at 0 ꢁC. After the resultant solution was stirred for 40 min at
room temperature, 0.5 mL i-PrOH was added to quench the re-
action. After the stirring was continued for 20 min, the mixture was
partitioned between brine and ethyl acetate. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate.
The combined organic layers were dried over MgSO4 and concen-
trated. The residue was chromatographed eluting with 50/5/1 ethyl
acetate/methanol/HOAc to afford a mixture of acids 17a and 17b
After 0.5 mL 1 N KOH in MeOH solution was added to the above
product, the resultant mixture was stirred at 65 ꢁC for 10 h. The
cooled solution was neutralized to pH¼7.0 and then concentrated.
The residue was purified by Dowex 50 Wꢂ2 (elution with 1 N
NH4OH) and HPLC (Sensyu Pak, PEGASIL-ODS
elution with 2% MeOH/20 mM diethylamine/CO2 buffer pH 7,1 mL/
4
4.6ꢂ250 mm,
min) to give 19a (7.2 mg, 42% for four steps) and 19b (7.5 mg, 44%
for four steps) as white foam. Compound 19a: [
a
]
29 þ12.4 (c 0.72,
D
H2O); 1H NMR (500 MHz, D2O)
d
7.85 (s, 2H), 4.44 (s, 1H), 4.32 (s,
1H), 4.03 (d, J¼7.4 Hz, 1H), 4.01 (s, 1H), 2.73 (d, J¼12.0 Hz, 1H),
2.52e2.50 (m, 1H), 2.26e2.22 (m, 1H), 2.11e2.05 (m, 1H), 1.80 (dd,
1H, J¼11.7, 20.2 Hz), 1.65e1.55 (m, 1H); 13C NMR (100 MHz, D2O)
(115 mg, 85%) as white foam. 1H NMR (300 MHz, CDCl3)
d 8.15 (br s,
1H), 7.94 and 7.86 (s, 2H), 7.58e7.48 (m, 2H), 7.42e7.34 (m, 3H),
5.80 (br s, 1H), 5.28 (s, 1H), 5.06 (s, 2H), 4.99e4.86 (m, 1H),
4.46e4.18 (m,1H), 4.15e3.92 (m,1H), 3.81 and 3.78 (s, 3H), 3.72 and
3.69 (s, 3H), 2.26e2.05 (m, 5H), 1.81e1.54 (m, 1H), 1.38 (s, 9H); MS
(ESI) m/z 738.2 (MþH)þ, 760.1 (MþNa)þ.
d
181.2, 180.1, 178.1, 170.2, 161.0, 158.6, 130.3, 125.6, 125.5, 75.2,
73.3, 60.9, 58.3, 57.1, 41.6, 39.1, 31.9; MS (ESI) m/z 517.8 (MꢀH)ꢀ;
HRMS m/z calcd for C19H18Cl2N3O10 (MꢀH)ꢀ 518.0375, found
29
518.0380. Compound 19b: [
a
]
þ3.67 (c 0.52, H2O); 1H NMR
D
(500 MHz, D2O)
d
7.89 (s, 2H), 4.38 (d, J¼12.2 Hz, 1H), 4.35 (d,
Following the same procedure, pure 17b could be obtained from
J¼3.3 Hz, 1H), 4.08e4.03 (m, 1H), 3.99 (d, J¼3.4 Hz, 1H), 2.54 (dd,
J¼6.7, 11.0 Hz, 1H), 2.44 (dt, J¼5.3, 14.6 Hz, 1H), 2.28e2.22 (m, 1H),
1.80 (dd, J¼1.5, 20.1 Hz, 1H), 1.62e1.59 (m, 1H); 13C NMR (100 MHz,
16b. Compound 17b: [
CDCl3)
a
]
23 ꢀ35.7 (c 0.97, CHCl3); 1H NMR (300 MHz,
D
d
8.98 (br s, 1H), 8.21 (br s, 1H), 7.94 (s, 2H), 7.54 (d, J¼6.6 Hz,
2H), 7.40e7.38 (m, 3H), 5.95 (br s, 1H), 5.24 (s, 1H), 5.06 (s, 2H),
4.98e4.96 (m, 1H), 4.41e4.27 (m, 1H), 4.03 (t, J¼6.6 Hz, 1H), 3.82 (s,
3H), 3.70 (s, 3H), 2.30e2.17 (m, 5H), 1.83e1.67 (m, 1H), 1.38 (s, 9H);
MS (ESI) m/z 738.2 (MþH)þ, 736.3 (MꢀH)ꢀ; HRMS m/z calcd for
C33H37N3O12Cl2Na (MþNa)þ 760.1646, found 760.1660.
D2O)
d 182.0, 180.2, 177.8, 170.4, 161.1, 158.2, 130.4, 125.6, 125.5,
76.0, 73.1, 60.6, 58.3, 57.4, 40.4, 38.4, 30.7; MS (ESI) m/z 517.8
(MꢀH)ꢀ; HRMS m/z calcd for C19H18Cl2N3O10 (MꢀH)ꢀ 518.0375,
found 518.0381.
Acknowledgements
4.13. 2-epi-Aitocephalin 2 and 2-epi-9-epi-kaitocephalin 18
The authors are grateful to Chinese Academy of Sciences for fi-
nancial support, and Professors Xiyan Lu and Lixin Dai for helpful
discussions.
A mixture of 17a and 17b (17 mg, 0.023 mmol), 2 mg of 10% Pd/
C, and 1.2 mL anhydrous methanol was stirred under hydrogen
atmosphere (1 atm) for 15 min. After Pd/C was filtered off, the fil-
trate was concentrated. The residue was dissolved in 1.2 mL 2 N
HCl. The resultant solution was stirred at room temperature for 3 h
and then at 50 ꢁC for 1 h. To the cooled solution were added 1.1 mL
MeOH, 1.1 mL THF, and 144 mg NaOH. The resultant mixture was
stirred at 50 ꢁC for 18 h. The cooled solution was neutralized to
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.12.068.

1680
S. Yu et al. / Tetrahedron 67 (2011) 1673e1680
4. Vasawani, R. G.; Chamberlin, R. J. Org. Chem. 2008, 73, 1661.
References and notes
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