Concise asymmetric synthesis of (R)-(+)-tanikolide

Article abstract of DOI:10.1016/j.tetasy.2007.09.012

A highly stereoselective total synthesis of (R)-(+)-tanikolide, a δ-lactonic marine natural product, was accomplished in seven steps from easily available starting materials with a 51% overall yield. An asymmetric synthesis of an α-hydroxy aldehyde having

Full text of DOI:10.1016/j.tetasy.2007.09.012

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 18 (2007) 2185–2189
Concise asymmetric synthesis of (R)-(+)-tanikolide
Chenxia Zhang, Naoya Hosoda and Masatoshi Asami*
Department of Advanced Materials Chemistry, Graduate School of Engineering, Yokohama National University,
Yokohama 240-8501, Japan
Received 5 July 2007; accepted 7 September 2007
Abstract—A highly stereoselective total synthesis of (R)-(+)-tanikolide, a d-lactonic marine natural product, was accomplished in seven
steps from easily available starting materials with a 51% overall yield. An asymmetric synthesis of an a-hydroxy aldehyde having a
stereogenic quaternary center, by the use of (S)-2-(anilinomethyl)pyrrolidine as a chiral auxiliary, was employed in a key step.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
of the aliphatic side-chain is different, and a methyl
substituent at the C-2 position of the d-lactone 2 is lacking
in 1 (Fig. 1). Furthermore, they show different biological
activities, that is, 1 exhibits antifungal activity against
Candida albicans and strong toxicity against brine shrimp
(LD50 of 3.6 lg mLꢀ1) and snail (LD50 of 9.0 lg mLꢀ1),
whereas (ꢀ)-malyngolide 2 shows antimicrobial activity
against Streptococcus pyogenes, Staphylococcus, Pseudo-
monas, and Mycobacterium smegmatis, but no activity to
C. albicans.
(+)-Tanikolide 1 is a d-lactonic natural product, isolated
from the lipid extract of a blue-green algae, cyano-
bacterium Lyngbya majuscula collected at Tanikeli Island,
Madagascar, by Gerwick et al. in 1999 (Fig. 1).1 A charac-
teristic feature of the structure of (+)-tanikolide 1 is the
chiral quaternary carbon center with a hydroxymethyl
group and a long-alkyl side-chain. The structure of (+)-
tanikolide 1 was determined by the spectroscopic analysis
and its absolute configuration was determined to be (R)
1
by the H NMR analysis of its amide derivative1 and also
Several enantioselective syntheses of (+)-tanikolide 1 have
already been reported.2–11 Baeyer–Villiger oxidation of
chiral cyclopentanone derivatives,2,3,11 ring-closing meta-
thesis of open-chain compounds,4,6 or oxidative cleavage
of a carbon–carbon double bond to form a lactone7 or
lactol8 have been employed for the construction of
d-lactone framework. Only one group has reported a more
direct method, namely, the preparation and lactonization
of chiral d-hydroxy carboxylic acid,5 although the overall
yield was not so high due to a rather long sequence. Herein
we report a versatile method for a highly stereoselective
synthesis of d-hydroxy carboxylic acid having chiral
tertiary alcohol moiety and the synthesis of (+)-tanikolide
1, applying the asymmetric synthesis of an a-hydroxy
aldehyde using a chiral aminal (Scheme 1).13
by enantioselective total synthesis.2–11
R1
R2
R3
)-(+)-tanikolide 1; R1=H, R2=
2R,5S)-(−)-malyngolide 2; R1=CH3, R2=CH2OH, R3=
O
O
(R
n
-C11H23, R3=CH2OH
-C9H19
(
n
Figure 1. Structure of (+)-tanikolide and (ꢀ)-malyngolide.
Although (+)-tanikolide 1 was isolated from the same
marine source, cyanobacterium Lyngbya majuscula
Gomont, as (ꢀ)-malyngolide 212 and their structures have
a similarity with each other, the absolute configuration of
the stereogenic quaternary center is opposite, the length
2. Results and discussion
As (+)-tanikolide 1 has an (R)-configuration, (R)-4-hydr-
oxy-4-hydroxymethylhexadecanoic acid 7 is an appropriate
precursor for the lactonization. Considering the
*
Corresponding author. Tel./fax: +81 45 339 3968; e-mail: m-asami@
ynu.ac.jp
0957-4166/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.09.012

2186
C. Zhang et al. / Tetrahedron: Asymmetry 18 (2007) 2185–2189
reagents with 3 without magnesium chloride.13b Next,
4,4,4-trimethoxybutylmagnesium bromide (2.5 equiv) was
added to a THF solution of 4a at ꢀ78 ꢁC and the reaction
mixture was gradually warmed up to room temperature.
Simultaneous mild acidic hydrolysis of the aminal moiety
and orthoester moiety of the resulting crude hydroxyl
aminal 5a afforded chiral a-hydroxy aldehyde 6a, methyl
(R)-4-formyl-4-hydroxyhexadecanoate, in 82% yield from
4a after purification by silica-gel column chromatography.
Chiral diol ester 8, methyl (R)-4-hydroxy-4-hydroxy-
methylhexadecanoate, was then obtained in 97% yield by
reduction of 6a with sodium borohydride in ethanol at
room temperature. The enantiomeric excess (ee) of 8 was
determined to be more than 99% by chiral HPLC analysis
of the corresponding tert-butyldiphenylsilyl (TBDPS)
ether (R)-9, methyl (R)-5-t-butyldiphenylsiloxymethyl-5-
hydroxyhexadecanoate.
N
N
R2MgBr
R1MgBr
O
N
O
N
H
Ph
H
Ph
R1
OMe
4
3
CHO
H+
N
R2
R1
R1
N
OH
HO
H
Ph
R2
5
6
78-100% ee
Scheme 1. Asymmetric synthesis of a-hydroxy aldehyde.
stereochemical course of the reaction of keto aminal 4 and
the Grignard reagent,13 the desired a-hydroxy aldehyde 6a
is obtained by the reaction of keto aminal 4a and 4,4,4-
trimethoxybutylmagnesium bromide whose alkyl group
can be easily converted into the 3-methoxycarbonylpropyl
group (Scheme 2).
As chiral diol ester 8 was obtained, intramolecular transe-
sterification was examined under various reaction condi-
tions. However, starting material 8 was recovered when
the reaction was carried out in refluxing toluene. A side
reaction, probably dehydration, took place in the reaction
using TsOH in refluxing toluene, or in CH2Cl2 at room
temperature, and (+)-tanikolide 1 was not obtained. Under
basic conditions (6 equiv NaH in THF, rt, 1 h), the starting
materials was recovered. Chiral diol ester 8 was then
hydrolyzed to examine the lactonization reaction. (R)-4-
2-Methoxycarbonylaminal 3 was prepared by mixing
(S)-2-(anilinomethyl)pyrrolidine and methyl 2-hydroxy-2-
methoxyacetate in refluxing benzene with removal of water
azeotropically for 1 h. Although aminal 3 was used without
purification in the previous reports,13 3 was isolated in 98%
yield after removal of the solvent from the reaction mixture
followed by silica-gel column chromatography. The reac-
tion of 3 with undecylmagnesium bromide was then exam-
ined in THF at ꢀ78 ꢁC in the presence of magnesium
chloride to give keto aminal 4a in 57%. The yield was
increased to 79% by carrying out the reaction using
2.7 equiv of undecylmagnesium bromide at ꢀ100 ꢁC in
the absence of magnesium chloride with little formation
of the corresponding tertiary alcohol, although the forma-
tion of tertiary alcohol sometimes decreased the yield of
keto aminal in the reaction of small alkyl Grignard
Hydroxy-4-hydroxymethylhexadecanoic acid
7
was
obtained in 96% yield by treatment of chiral diol ester 8
with NaOH in MeOH–H2O at room temperature
for 5 h. The lactonization reaction using Mukaiyama
reagent,14 2-chloro-1-methylpyridinium iodide, as a dehy-
23
drating reagent afforded (+)-tanikolide 1, ½aꢁD ¼ þ2:85
25
ðc 0:65; CHCl3Þ (natural:1 ½aꢁD ¼ þ2:3 ðc 0:65; CHCl3Þ;
25
synthetic:2 ½aꢁD ¼ þ2:9 ðc 0:65; CHCl3Þ); mp 47.5–48.5 ꢁC
(synthetic:2 mp 38–40 ꢁC), in high yield (87%) under milder
reaction conditions compared with the reported method.5
The corresponding e-lactone was not obtained without
the protection of the primary hydroxy group. The synthetic
route is summarized in Scheme 3. The enantiomeric excess
CH2OH
(CH2)3COOH
OH
O
OH
n-C11H23
O
n-C11H23
(+)-Tanikolide 1
7
N
CHO
OMe
OMe
OMe
O
N
(CH2)3COOMe
OH
BrMg
Ph
n-C11H23
H
Ph
n-C11H23
4a
6a
N
Ph
+
O
N
N
H
OH
n-C11H23MgBr
N
H
H
OMe
MeO COOMe
3
Scheme 2. Retrosynthetic analysis of (+)-tanikolide 1.

C. Zhang et al. / Tetrahedron: Asymmetry 18 (2007) 2185–2189
2187
MeO
O
OMe
BrMg
OMe
N
HO OMe
(1.1 eq.)
OMe
N
O
N
n-C11H23MgBr(2.7 eq.)
(2.5 eq.)
THF, -78 °C~rt, 17 h
Ph
O
N
N
H
H
Ph
N
H
H
Ph
THF, -100 °C
n-C11H23
refl. 1 h
OMe
3
4a 79%
98%
O
H
OH
O
O
N
NaBH4
n-C11H23
dil. HCl(aq.)
THF, rt, 4 h
N
OMe
OMe
n-C11H23
n-C11H23
HO
H
Ph
EtOH, rt, 15 min
OH
OH
OMe
OMe
OMe
6a 82% (for 2 steps)
8
97%, >99% ee
5a
N
CH3
(1.2 eq.)
Cl
Et3N
OH
I
1) 4 M NaOH(aq.)
MeOH, rt, 5 h
O
(2.4 eq.)
O
n-C11H23
O
OH
n-C11H23
2) H3O+
OH
96%
CH2Cl2, rt, 30 min, 87%
OH
7
(+)-Tanikolide 1, >99% ee
Scheme 3. Synthesis of (+)-tanikolide 1.
of the resulting (+)-tanikolide 1 was confirmed to be more
than 99% by chiral HPLC analysis of the corresponding
were carried out on a Vario EL Elemental analyzer. TLC
analyses were done on silica-gel 60 F254-precoated alumi-
num backed sheets (E. Merck). Preparative TLC was
performed on silica-gel-coated plates (Wakogel B-5F,
20 cm · 20 cm). Wakogel C-200 and Silica gel 60 N (spher-
ical, neutral, 63–210 lm) were used for column
chromatography.
TBDPS ether (R)-10, (R)-6-tert-butyldiphenylsiloxymethyl-
29
6-undecyltetrahydropyran-2-one.8
½aꢁD ¼ ꢀ7:9 ðc 0:81;
CHCl3Þ. (Daicel Chiralcel OD–H (25 cm · 0.46 cm i.d.);
254 nm UV detector; eluent, hexane/2-PrOH = 100/1; flow
rate, 0.5 mL/min; tS, 14.9 min, tR, 18.1 min).15
4.2. (2R,5S)-2-Dodecanoyl-3-phenyl-1,3-diazabicyclo-
[3,3,0]-octane 4a
3. Conclusion
In conclusion, we achieved a concise asymmetric synthesis
of (R)-(+)-tanikolide 1, a d-lactonic marine natural prod-
uct, in high enantiomeric excess (>99% ee) with 51% over-
all yield. This method will be useful for the synthesis of
related compounds as all reagents are commercially avail-
able; all experiments can be carried out using easy opera-
tions, and the chiral auxiliary is recyclable.
An Et2O solution of undecylmagnesium bromide, prepared
from 1-bromoundecane (1.412 g, 6.0 mmol) and Mg turn-
ings (0.160 g, 6.6 mmol) in Et2O (12 mL) in the presence
of a small amount of iodine, was added dropwise through
a syringe to a stirred THF (10 mL) solution of 3 (0.246 g,
1.0 mmol) at ꢀ100 ꢁC. The reaction was monitored care-
fully by TLC and saturated aqueous NH4Cl was added
to the reaction mixture quickly after the disappearance of
3 by TLC (about 20 min after the end of the addition of
the Grignard reagent). The reaction mixture was then
warmed to room temperature and extracted with Et2O 4
times. The combined organic layer was washed with water
and brine, and dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, the crude
product was purified by silica-gel (spherical, neutral)
4. Experimental
4.1. General
All air-sensitive experiments were carried out under an
atmosphere of argon. Melting points were determined on
a SANWA TSUSHO SMP3 melting point apparatus and
are uncorrected. IR spectra were recorded on a HORIBA
FT-730 spectrometer. 1H and 13C NMR spectra were
recorded on JEOL JNM-EX-270 spectrometer or JEOL
JNM-AL-400 spectrometer in CDCl3 using tetramethylsil-
ane as an internal standard. Optical rotations were mea-
sured on a JASCO P-1000 automatic polarimeter. HPLC
analyses were carried out on JASCO instruments (pump,
PU-2080 plus; detector, UV-2075). Elemental analyses
column chromatography (CH2Cl2/Et2O = 30/1) to give
23
4a (0.293 g, 79%) as
a
pale yellow oil. ½aꢁD ¼
ꢀ29:3 ðc 1:0; CHCl3Þ; IR (neat): c 2953, 2925, 2853, 1716
(CO), 1600, 1505, 1367 cmꢀ1 1H NMR (270 MHz,
;
CDCl3): d 0.87 (t, J = 6.6 Hz, 3H), 1.08–1.62 (m, 18H),
1.64–2.20 (m, 4H), 2.30–2.62 (m, 2H), 2.82 (dt, J = 13.0,
4.9 Hz, 1H), 3.12 (dd, J = 7.9, 6.6 Hz, 1H), 3.21 (ddd,
J = 11.1, 6.1, 4.1 Hz, 1H), 3.77 (t, J = 7.9 Hz, 1H), 3.85–
3.97 (m, 1H), 4.43 (s, 1H), 6.46 (d, J = 8.6 Hz, 2H), 6.73

2188
C. Zhang et al. / Tetrahedron: Asymmetry 18 (2007) 2185–2189
(t, J = 7.3 Hz, 1H), 7.20 (t, J = 8.2 Hz, 2H); 13C NMR
(67.8 MHz, CDCl3): 14.2, 22.8, 23.4, 25.1, 29.2, 29.3,
29.4, 29.5, 29.7 (·2), 30.4, 32.0, 36.6, 53.2, 55.0, 62.8,
86.2, 112.4 (·2), 117.3, 129.2 (·2), 145.6, 209.7. Anal. Calcd
for C24H38N2O: C, 77.79; H, 10.34; N, 7.56. Found: C,
77.81; H, 10.50; N, 7.17.
(270 MHz, CDCl3): d 0.88 (t, J = 6.6 Hz, 3H), 1.17–1.38
(m, 18H), 1.40–1.72 (m, 6H), 1.95 (br s, 1H), 2.08 (br s,
1H), 2.35 (t, J = 6.9 Hz, 2H), 3.40–3.54 (m, 2H), 3.68 (s,
3H); 13C NMR (67.8 MHz, CDCl3): 14.2, 18.9, 22.7,
23.4, 29.4, 29.7 (·4), 30.3, 32.0, 34.2, 35.1, 35.9, 51.6,
67.9, 74.5, 174.1; Anal. Calcd for C18H36O4: C, 68.31; H,
11.47. Found: C, 68.05; H, 11.54.
4.3. Methyl (R)-4-formyl-4-hydroxyhexadecanoate 6a
4.5. Methyl (R)-5-tert-butyldiphenylsiloxymethyl-5-
hydroxyhexadecanoate 9
A THF solution of 4,4,4-trimethoxybutylmagnesium bro-
mide (6.4 mL, 3.0 mmol), prepared from 4,4,4-trimethoxy-
butylbromide (1.363 g, 6.0 mmol), and Mg turnings
(0.160 g, 6.6 mmol) in THF (12 mL) in the presence of a
small amount of iodine, was added dropwise through a
syringe to a stirred THF (4.8 mL) solution of 4a (0.445 g,
1.2 mmol) at ꢀ78 ꢁC and the reaction mixture was gradu-
ally warmed to room temperature over 17 h. The saturated
aqueous NH4Cl and water were added to the reaction mix-
ture. The aqueous layer was extracted with Et2O (3 times).
The combined organic layer was washed with water and
brine, and then dried over anhydrous Na2SO4. After
removal of the solvent under reduced pressure, crude 5a
was obtained as a yellow oil and was hydrolyzed without
purification.
To a solution of diol ester 8 (8.9 mg, 0.028 mmol) and
imidazole (9.5 mg, 0.140 mmol) in DMF (0.1 mL) was
added
a
solution of t-butyldiphenylsilyl chloride
(TBDPSCl) (38.5 mg, 0.140 mmol) in DMF (0.4 mL) at
0 ꢁC. After the reaction mixture was stirred at room tem-
perature for 41 h, water was added to the mixture. The
mixture was extracted with Et2O (4 times). The combined
organic layer was washed with brine and dried over anhy-
drous Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by preparative TLC (hex-
ane/AcOEt = 7/1) to afford methyl (R)-5-tert-butyldiphe-
nylsiloxymethyl-5-hydroxyhexadecanoate 9 (5.1 mg, 33%)
28
as a colorless oil. ½aꢁD ¼ ꢀ2:7 ðc 0:25; CHCl3Þ; IR (neat):
c 3452 (OH), 2927, 2855, 1742 (COOR), 1464, 1428,
Dilute hydrochloric acid (0.7%, 4.8 mL) was added to a
THF (8 mL) solution of the resulting crude hydroxyl ami-
nal 5a. The reaction mixture was stirred at room tempera-
ture for 4 h, and extracted with Et2O 4 times. The
combined organic layer was washed with water and brine,
and dried over anhydrous Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified
by silica-gel column chromatography (hexane/Et2O =
1113 cmꢀ1;1H NMR (270 MHz, CDCl3):
d 0.88 (t,
J = 6.6 Hz, 3H), 1.07 (s, 9H), 1.12–1.72 (m, 24H), 2.23–
2.38 (m, 3H), 3.42–3.52 (m, 2H), 3.65 (s, 3H), 7.33–7.52
(m, 6H), 7.59–7.72 (m, 4H); 13C NMR (67.8 MHz, CDCl3):
14.2, 19.1, 19.4, 22.8, 23.6, 27.0 (·3), 29.4, 29.7 (·4), 30.4,
32.0, 34.6, 35.5, 36.1, 51.5, 68.8, 74.2, 127.7 (·4), 129.7
(·2), 133.0 (·2), 135.5 (·4), 173.8.
3/1) to afford a-hydroxy aldehyde 6a (0.309 g) in 82%
The ee of (R)-9 was more than 99% by HPLC analysis
24
overall yield from 4a as
a
yellow oil. ½aꢁD ¼
using
a
chiral column (Daicel Chiralcel OD–H
þ5:9 ðc 1:0; CHCl3Þ; IR (neat): c 3500 (OH), 2924, 2854,
25 cm · 0.46 cm i.d.; 254 nm UV detector; eluent, hexane/
2-PrOH = 99.75/0.25; flow rate, 1.0 mL/min; tS, 20.0 min,
tR, 24.6 min).16
1734 (COOR), 1718 (CHO), 1457, 1437, 1174 cmꢀ1; H
1
NMR (270 MHz, CDCl3): d 0.88 (t, J = 6.6 Hz, 3H),
1.02–1.54 (m, 19H), 1.61–1.78 (m, 5H), 2.27–2.38 (m,
2H), 3.28 (s, 1H), 3.66 (s, 3H), 9.50 (s, 1H); 13C NMR
(67.8 MHz, CDCl3): 14.2, 18.6, 22.7, 23.0, 29.3, 29.4,
29.5, 29.6 (·2), 29.9, 31.9, 33.9, 35.3, 36.2, 51.6, 80.3,
173.4, 204.1; Anal. Calcd for C18H34O4: C, 68.75; H,
10.90. Found: C, 68.91; H, 10.87.
4.6. (R)-4-Hydroxy-4-hydroxymethylhexadecanoic acid 7
NaOH (4 M solution in H2O, 1 mL) was added to a stirred
solution of diol ester 8 (0.236 g, 0.75 mmol) in methanol
(4 mL). The reaction mixture was stirred for 5 h at room
temperature. Dilute hydrochloric acid (about 0.7%) was
added to the reaction mixture until the solution became
pH 2. The mixture was then extracted with Et2O (4 times).
The combined organic layer was washed with water and
brine, and dried over anhydrous MgSO4. After removal
of the solvent under reduced pressure, (R)-4-
hydroxy-4-hydroxymethylhexadecanoic acid 7 (0.217 g,
4.4. Methyl (R)-4-hydroxy-4-hydroxymethylhexadeca-
noate 8
A small amount of sodium borohydride (ca. 0.011 g) was
added to a stirred solution of a-hydroxy aldehyde 6a
(0.278 g, 0.884 mmol) in ethanol (5 ml) at room tempera-
ture. The reaction mixture was stirred for 15 min at the
same temperature. Water was added to stop the reaction,
and the mixture was extracted with Et2O 4 times. The com-
bined organic layer was washed with dilute hydrochloric
acid (about 0.7%), water and brine, and dried over anhy-
drous Na2SO4. After removal of the solvent under
reduced pressure, the crude product was purified by
silica-gel column chromatography (hexane/Et2O = 1/10)
96%) was obtained in an almost pure form as a white solid.
27
mp 76.1–76.4 ꢁC; ½aꢁD ¼ ꢀ0:8 ðc 1:0; CHCl3Þ; IR (KBr): c
3474 (OH), 3180, 2953, 2918, 2849, 1731 (CO), 1466,
1212, 1200, 1170, 1046 cmꢀ1; 1H NMR (270 MHz, CDCl3):
d 0.88 (t, J = 6.4 Hz, 3H), 0.98–1.79 (m, 24H), 2.38 (t,
J = 6.6 Hz, 2H), 3.37–3.60 (m, 2H), 4.43 (br s, 2H); 13C
NMR (67.8 MHz, CDCl3): 14.2, 18.7, 22.8, 23.4, 29.4,
29.7 (·4), 30.3, 32.0, 34.0, 34.8, 35.8, 67.8, 74.9, 177.9;
Anal. Calcd for C17H34O4: C, 67.51; H, 11.33. Found: C,
67.34; H, 11.10.
to afford diol ester 8 (0.270 g, 97%) as a pale yellow oil.
24
½aꢁD ¼ ꢀ1:1 ðc 1:0; CHCl3Þ; IR (neat): c 3369 (OH), 2924,
1
2853, 1741 (CO), 1465, 1438, 1171, 1051 cmꢀ1; H NMR

C. Zhang et al. / Tetrahedron: Asymmetry 18 (2007) 2185–2189
2189
4.7. (+)-Tanikolide 1
solution of (R)-4-hydroxy-4-hydroxymethylhexa-
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A
decanoic acid 7 (151.6 mg, 0.5 mmol) and triethylamine
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25
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þ2:9 ðc 0:65; CHCl3Þ); IR (KBr): c 3360 (OH), 2953,
2921, 2850, 1731(CO), 1469, 1270, 1082 cmꢀ1; H NMR
1
(400 MHz, CDCl3): d 0.88 (t, J = 6.8 Hz, 3H), 1.18–1.39
(m, 18H), 1.56–2.00 (m, 6H), 2.40–2.55 (m, 2H), 2.64 (br
s, 1H), 3.55 (dd, J = 12.0, 6.0 Hz, 1H), 3.67 (dd, J = 12.0,
6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): 14.2, 16.7,
22.7, 23.5, 26.6, 29.3, 29.5, 29.6 (·3), 29.8, 30.0, 31.9,
36.7, 67.4, 86.6, 171.8; Anal. Calcd for C17H32O3: C,
71.79; H, 11.34. Found: C, 71.90; H, 11.33.
13. (a) Mukaiyama, T.; Sakito, Y.; Asami, M. Chem. Lett. 1978,
1253–1256; (b) Mukaiyama, T.; Sakito, Y.; Asami, M. Chem.
Lett. 1979, 705–708.
14. Ishida, A.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1978, 51,
2077–2081.
15. Racemic 10 was obtained from racemic tanikolide: Chen, Q.;
Deng, H.; Zhao, J.; Lu, Y.; He, M.; Zhai, H. Tetrahedron
2005, 61, 8390–8393.
Acknowledgement
We are grateful to Mr. Shinji Ishihara (Intrumental Anal-
ysis Center of Yokohama National University) for his tech-
nical assistance in the Elemental analyses.
16. (S)-9 was obtained in a similar manner to (R)-9 starting from
(R)-2-(anilinomethyl)prrolidine.