Novel synthetic approach to nine-membered diallylic amides: Stereochemical behavior and utility as chiral building block

Article abstract of DOI:10.1055/s-2008-1078235

An efficient approach to nine-membered diallylic cyclic amides having a variety of substituents has been developed. The synthesized amides have stable planar chirality at ambient temperature. The transformation of the enantiomerically enriched amides provides optically active compounds containing stereogenic centers in a stereospecific fashion. As a demonstration of the synthetic utility of the amides, we have synthesized (+)-γ-lycorane using such an optically active amide as a chiral building block. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078235

2518
LETTER
Novel Synthetic Approach to Nine-Membered Diallylic Amides:
Stereochemical Behavior and Utility as Chiral Building Block
Synthetic
A
pproac
a
h to Nine-M
t
e
mbe
s
red Dially
u
lic
A
mide
s
hiko Tomooka,*a,b Masaki Suzuki,b Kazuhiro Uehara,a Maki Shimada,b Toshiyuki Akiyamab
a
Institute for Materials Chemistry and Engineering, Kyushu University, Kasuga-koen 6-1, Kasuga-shi, Fukuoka 816-8580, Japan
Fax +81(92)5837810; E-mail: ktomooka@cm.kyushu-u.ac.jp
b
Department of Applied Chemistry, Tokyo Institute of Technology, Ookayama 2-12-1, Meguro-ku, Tokyo 152-8552, Japan
Received 28 May 2008
congeners with specific substituents other than a methyl
substituent at C3 and at C7.3b Here, we report a new ap-
proach to nine-membered cyclic amides with planar
chirality, having a variety of substituents at the C3 or C7
Abstract: An efficient approach to nine-membered diallylic cyclic
amides having a variety of substituents has been developed. The
synthesized amides have stable planar chirality at ambient temper-
ature. The transformation of the enantiomerically enriched amides
provides optically active compounds containing stereogenic centers position. In addition, we demonstrate the synthetic utility
in a stereospecific fashion. As a demonstration of the synthetic util-
ity of the amides, we have synthesized (+)-g-lycorane using such an
optically active amide as a chiral building block.
of the newly synthesized planar chiral cyclic amide as a
building block in the synthesis of alkaloid.
As shown in Scheme 1, our retrosynthetic analysis of the
cyclic amide 2 involves (i) an intramolecular Mitsunobu
reaction of the amide alcohol A for the construction of the
Key words: atropisomerism, amides, asymmetric synthesis, alka-
loids, planar chirality
nine-membered skeleton, (ii) a Horner–Wadsworth–Em-
mons (HWE) reaction, and (iii) a ring-closing metathesis
(RCM) for the stereoselective construction of the E- and
Z-alkene moieties. Thus, the seven-membered lactam B
would be a reasonable intermediate of this synthesis.
The planar chirality of medium-sized cycloalkenes such
as (E)-cyclooctene and (E)-cyclononene is an attractive
and potentially useful stereochemical phenomenon.1
However, the synthetic application of this class of chiral
compounds is highly limited mainly due to the lack of
O
R1
R1
HWE
reaction
Mitsunobu
reaction
functional groups other than a double bond, which would
lead to their further synthetic elaboration.2 Recently, we
have synthesized novel chiral heterocycles including
ether 1 and amide 2a with solely planar chirality
(Figure 1).3 Their chirality has been proved to be fairly
stable at ambient temperature and is readily transferred to
a variety of central chiralities in a stereospecific fashion.
Ts
HO
N
HN
Ts
N
R2
R2
Ts
R2
2
A
RCM
B
Scheme 1 Retrosynthetic analysis of amide 2
For the preparation of B, the acyclic amides 4a and 4b
were initially prepared from N-allyl tosylamide and the
easily available carboxylic acids 3a or 3b, respectively
(Scheme 2). The ring-closing metathesis of the amides 4a
and 4b provided 5a and 5b (∫B) in excellent yield, respec-
tively.3 Their partial reduction using DIBAL-H provided
hemiaminals 6a and 6b,5 which serve as synthetic equiv-
alents of amide aldehydes in the subsequent Horner–
Wadsworth–Emmons reaction with 7a–c, providing the
E-esters 8b–d in good yield with high stereoselectivities
(8b: 3E/3Z = 88:12, 8c, 8d: 3E/3Z = >95:<5). The reduc-
tion of 8b–d using DIBAL-H provided 9b–d, precursors
for the final cyclization. The intramolecular Mitsunobu
reaction of 9b–d was carried out under high-dilution con-
ditions (0.01 M) with diethyl azodicarboxylate (DEAD)
or diisopropyl azodicarboxylate (DIAD) and Ph3P, pro-
viding the desired cyclic amides 2b–d in good yields (77–
90%).6,7 It should be noted that only a negligible amount
of dimerized product (<1%) was formed in these cycliza-
tion reactions. The HPLC analysis using a chiral station-
ary column shows that all the newly synthesized amides
2b–d have a fairly stable planar chirality at ambient tem-
3
N
O
7
Ts
2a
1
Figure 1
These variable stereochemical properties clearly show the
synthetic potential of planar chiral heterocycles as useful
chiral building blocks or key components of chiral re-
agents. However, the structural essence of their planar
chirality has not been elucidated fully, especially in terms
of the influence of substituents in the ring, and further
studies on the physical properties of their analogues are
necessary to address this issue. Our previous synthetic ap-
proach to 1 and 2a starts from neryl acetate; hence, the ap-
proach lacks the flexibility in the preparation of their
SYNLETT 2008, No. 16, pp 2518–2522
x
x
.x
x
.2
0
0
8
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078235; Art ID: U05608ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Approach to Nine-Membered Diallylic Amides
2519
perature.8 Furthermore, both the enantiomers of 2b–d can methyl substituent at the C3 position significantly increas-
be separated successfully by semipreparative HPLC.8–10 es the stereochemical stability of the amide, while the sub-
Time-dependent measurements of their optical purities in stituent at the C7 position has less impact on the
hexane indicate that their stereochemical stability is high- stereochemical stability. These observations may suggest
ly dependent on the substituents R1 and R2. The half-lives that the flipping of the C3–C4 olefin moiety is a rate-de-
of the optical activity for 2b, 2c, and 2d in hexane at 25 °C termining step of racemization.11 The activation parame-
are 2114, 290, and 352 hours, respectively (Equation 1).
ters for the racemization of 2b and 2d are calculated from
an Eyring plot by the analysis of the rate constants of ra-
cemization as DH = 27.0 kcal mol–1, DS = –1.68 cal mol–1
K–1 and DH = 26.3 kcal mol–1, DS = –0.36 cal mol–1 K–1,
respectively.
O
NHTs
O
Ts
DCC, DMAP
HO
N
R2
R2
CH2Cl2
0 °C → r.t.
It is noteworthy that all the cyclic amides can thus be ob-
tained easily in optically pure form by a separation of
enantiomers, and that their planar chirality can be trans-
ferred to the central chirality without the loss of stereo-
purity.12 For instance, the Pd(II)-catalyzed Cope re-
arrangement of enantioenriched (R)-2b (>98% ee) provid-
ed (3R,4S)-10 having a quaternary chiral center as a single
diastereomer in 91% yield (>98% dr, >98% ee;
Equation 2).13,14
3a: R2 = H
4a: R2 = H, 98%
4b: R2 = Me, 67%
3b: R2 = Me
O
N
OH
Grubbs I catalyst, 4a
CH2Cl2, r.t., 99%
Ts
Ts
N
DIBAL-H
or Grubbs II catalyst, 4b
CH2Cl2, r.t., 96%
CH2Cl2
–78 °C
R2
R2
5a: R2 = H
6a: R2 = H
5b: R2 = Me
6b: R2 = Me
cat. PdCl2(PhCN)2
3
N
Ts
N
Ts
CH2Cl2, r.t.
91%
R1
3
4
7a–c, NaH
THF, –78 °C → 0 °C
(R)-2b
(>98% ee)
(3R,4S)-10
(>98% dr, >98% ee)
DIBAL-H
EtO2C
O
7
CH2Cl2
–78 °C
HN
Ts
R2
(R3O)2P
CO2Et
Equation 2
R1
7a: R1 = Me; R3 = Et
7b: R1 = H; R3 = Et
7c: R1 = H; R3 = i-Pr
8b: R1 = Me; R2 = H, 93% (2 steps), 3E/3Z = 88:12
8c: R1 = H; R2 = Me, 87% (2 steps), 3E/3Z = >95:<5
8d: R1 = H; R2 = H, 89% (2 steps), 3E/3Z = >95:<5
Moreover, we have found that the carbanion rearrange-
ment of this class of cyclic amides proceeds in a ste-
reospecific fashion. The reaction of the enantioenriched
2a and 2b (>98% ee) with n-BuLi in THF at –78 °C af-
forded transannular aza-[2,3]-Wittig rearrangement prod-
ucts 11a and 11b (>98% dr, >98% ee), respectively, in
good yield (Equation 3). The high reactivity of the rear-
rangement would be attributable to the strain release of
the nine-membered strain as well as the fact that in the
ground state the C4 and C9 positions possibly face each
other with a short distance between them.15,16
R1
R1
DEAD or DIAD
Ph3P, THF, 0 °C
HO
R2
N
HN
Ts
R2
Ts
9b: R1 = Me; R2 = H, quant
9c: R1 = H; R2 = Me, 99%
9d: R1 = H; R2 = H, quant
2b: R1 = Me; R2 = H, 77%
2c: R1 = H; R2 = Me, 83%
2d: R1 = H; R2 = H, 90%
Scheme 2 Synthesis of amides 2b–d
R1
R1
R2
R1
3
n-BuLi
slow
at r.t.
R1
R1
N
R2
R2
THF
Ts
3
3
4
–78 °C → 0 °C
7
7
N
N
9
TsHN
R2
Ts
Ts
N
R2
7
(R)-2a: R1 = Me, R2 = Me
(R)-2b: R1 = Me, R2 = H
(R,R)-11a: R1 = Me, R2 = Me
(R,R)-11b: R1 = Me, R2 = H
Ts
70%
86%
(R)-form
(S)-form
2
t1/2 (h) of optical activity
in hexane at 25 °C
(>98% ee)
(>98% dr, >98% ee)
2a: R1 = Me, R2 = Me 4878
2b: R1 = Me, R2 = H 2114
2c: R1 = H, R2 = Me 290
Equation 3
2d: R1 = H, R2 = H
352
This transformation of planar to central chirality clearly
shows that enantioenriched cyclic amides 2 could serve as
a synthetic precursor for a variety of chiral nitrogen-con-
taining compounds with central chirality. To realize this
concept, we carried out the asymmetric synthesis of (+)-g-
lycorane (12), representative of the lycorine class of Ama-
ryllidaceae alkaloids (Scheme 3).17,18 This compound has
a cis configuration on the A ring, identical to that in the
Equation 1
A comparison of these results with the previously reported
stereochemical stability of 2a (t1/2 = 4878 h at 25 °C)3b
clearly shows that (a) the methyl substituent on the ring is
not essential for the planar chirality of amides, and (b) the
Synlett 2008, No. 16, 2518–2522 © Thieme Stuttgart · New York

2520
K. Tomooka et al.
LETTER
aza-[2,3]-Wittig rearrangement product of 2. Our synthe- reochemical behavior. The synthetic utility of the
sis started from the aza-[2,3]-Wittig rearrangement of synthesized cyclic amide has been demonstrated by the
enantiopure (R)-2d (>98% ee) under the above-mentioned asymmetric synthesis of a chiral alkaloid. Further detailed
conditions, which provided (R,R)-11d as a single stereo- mechanistic studies of the planar chirality of such hetero-
isomer in excellent yield. The group-selective hydrobora- cycles and synthetic application of this unique dynamic
tion of monosubstituted alkene of 11d using chirality are in progress.
disiamylborane, followed by an intramolecular Mitsuno-
bu reaction of the resulting amide alcohol 13 provided the
bicycloamide 14. The reductive detosylation of 14 using
Acknowledgment
This research was supported in part by a Grant-in-Aid for Scientific
Research in Priority Areas (A) ‘Creation of Biologically Functional
Molecules’ from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan, The Asahi Glass Foundation, and The
Naito Foundation.
lithium naphthalenide (LiNaph), followed by the treat-
ment with a solution of hydrochloric acid in diethyl ether
afforded the crystalline salt of 15. The benzodioxole moi-
ety (D and E rings) of lycorane was introduced by cou-
pling carboxylic acid 16 to 15. Compound 16 was
separately prepared from the commercially available pip-
eronyl alcohol in three steps.
References and Notes
(1) For reviews, see: (a) Marshall, J. A. Acc. Chem. Res. 1980,
13, 213. (b) Nakazaki, M.; Yamamoto, K.; Naemura, K.
Top. Curr. Chem. 1984, 125, 1. (c) Schlögl, K. Top. Curr.
Chem. 1984, 125, 27. (d) Eliel, E. L.; Wilen, S. H.; Mander,
L. N. Stereochemistry of Organic Compounds; Wiley: New
York, 1994, 1172–1175.
(Sia)2BH then
H2O2, NaOH
n-BuLi
N
Ts
THF
–78 °C → 0 °C
94%
THF, 0 °C
98%
TsHN
(R)-2d
(>98% ee)
(R,R)-11d
(>98% dr, >98% ee)
(2) For recent studies on planar chiral medium-sized rings, see:
(a) Sudau, A.; Münch, W.; Nubbemeyer, U. J. Org. Chem.
2000, 65, 1710. (b) Nubbemeyer, U. Eur. J. Org. Chem.
2001, 1801; and references cited therein. (c) Deiters, A.;
Mück-Lichtenfeld, C.; Fröhlich, R.; Hoppe, D. Chem. Eur. J.
2002, 8, 1833. (d) Gauvreau, D.; Barriault, L. J. Org. Chem.
2005, 70, 1382. (e) Larionov, O. V.; Corey, E. J. J. Am.
Chem. Soc. 2008, 130, 2954.
DEAD
Ph3P
1) LiNaph
THF
HO
2) 1 N HCl
N
THF, 0 °C
96%
N
TsHN
Et2O, 84%
H2
Ts
Cl–
(2 steps)
13
14
15
(3) (a) Tomooka, K.; Komine, N.; Fujiki, D.; Nakai, T.;
Yanagitsuru, S. J. Am. Chem. Soc. 2005, 127, 12182.
(b) Tomooka, K.; Suzuki, M.; Shimada, M.; Yanagitsuru, S.;
Uehara, K. Org. Lett. 2006, 8, 963.
Br
O
O
CO2H
EDC⋅HCl
Et3N, DMAP
16
H
Pd(PPh3)4
DIPEA
(4) For ring-closing-metathesis-based seven-membered lactam
synthesis, see: (a) Fu, G. C.; Nguyen, S. T.; Grubbs, R. H.
J. Am. Chem. Soc. 1993, 115, 9856. (b) Vo-Thanh, G.;
Boucard, V.; Sauriat-Dorizon, H.; Guibé, F. Synlett 2001,
37.
Br
H
O
N
DMF, 110 °C
84%
CH2Cl2, r.t.
96%
O
O
17
(5) The 1H NMR analysis of 6a and 6b revealed a trace amount
of the aldehyde tautomer was contained (<5%).
(6) General Procedure of the Synthesis of Amide 2 from 9
To a solution of Ph3P (96.2 mg, 0.368 mmol) in anhydrous
THF (10 mL) at 0 °C was added DEAD (0.166 mL of 40
wt% in toluene, 0.366 mmol) and 9b (42.4 mg, 0.137 mmol)
dissolved in anhydrous THF (4 mL). The resulting mixture
was stirred at that temperature for 4 h, concentrated in vacuo,
and the residue was purified by silica gel chromatography
(hexane–EtOAc, 10:1 to 5:1) to afford 30.7 mg (77%) of 2b
as a white solid and a trace amount of dimerized product
(<1%, analyzed by 1H NMR).
1) H2, Pd/C
MeOH, r.t.
99%
A
H
H
N
H
H
H
N
H
O
O
O
E
D
C
B
2) LAH
THF, 70 °C
82%
O
O
(+)-12
18
Scheme 3 Asymmetric synthesis of (+)-g-lycorane (12)
The C ring was constructed by an intramolecular Mizoro-
ki–Heck reaction of 17 using Pd(PPh3)4 and Hünig’s
base.19 Finally, the asymmetric synthesis of (+)-12 was
accomplished by the reduction of the remaining alkene in
the A ring and of the carbonyl moiety in the C ring by H2/
Pd on carbon and LiAlH4, respectively. Thus, the asym-
metric synthesis of (+)-lycorane was achieved from planar
chiral amide (R)-2d in eight steps, with an overall yield of
49%. (–)-Lycorane can be synthesized from (S)-2d using
the same strategy.
(7) All new compounds were fully characterized by 1H NMR,
13C NMR, and IR spectroscopy.
Data for Selected Compounds
Compound 2b: 1H NMR (300 MHz, CDCl3): d = 7.67 (d,
J = 8.4 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 5.47 (ddd,
J = 11.4, 10.8, 4.2 Hz, 1 H), 5.43–5.34 (m, 1 H), 5.24 (dd,
J = 11.4, 4.5 Hz, 1 H), 4.26 (d, J = 9.9 Hz, 1 H), 3.89 (dd,
J = 14.1, 4.2 Hz, 1 H), 3.05 (dd, J = 14.1, 10.8 Hz, 1 H), 3.00
(d, J = 9.9 Hz, 1 H), 2.44 (s, 3 H), 2.22–2.06 (m, 2 H), 1.99–
1.70 (m, 2 H), 1.55 (s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 143.0, 136.3, 134.2 (2 C), 132.2, 131.1, 129.7, 127.1,
59.0, 44.3, 27.0, 26.5, 21.7, 17.3. IR (reflection): 2934, 1597,
1452, 1324, 1158, 1095, 1023, 960, 869, 821, 767, 714, 658,
596 cm–1. Mp 123 °C. For R-isomer (>98% ee): [a]D27 –65.3
In summary, we have described an efficient synthetic ap-
proach to planar chiral cyclic amides and their ste-
Synlett 2008, No. 16, 2518–2522 © Thieme Stuttgart · New York

LETTER
(c 0.80, CHCl3); for S-isomer (>98% ee): [a]D27 +67.7 (c
Synthetic Approach to Nine-Membered Diallylic Amides
2521
CDCl3): d = 143.1, 134.8, 129.5, 128.2, 127.5, 127.3, 57.5,
0.88, CHCl3). Anal. Calcd for C16H21NO2S: C, 65.95; H,
7.26; N, 4.81; S, 11.00. Found: C, 65.55; H, 7.24; N, 4.70; S,
11.52.
47.3, 36.5, 27.8, 22.9, 21.6, 20.9. IR (neat): 2924, 1598,
1450, 1343, 1161, 1092, 848, 817, 659, 593 cm–1. [a]D
25
–98.6 (c 1.31, CHCl3).
Compound 2c: 1H NMR (300 MHz, CDCl3): d = 7.66 (d,
J = 8.1 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H), 5.47–5.24 (m, 3
H), 4.40 (dd, J = 10.2, 3.9 Hz, 1 H), 3.82 (dd, J = 14.2, 4.2
Hz, 1 H), 3.00 (dd, J = 10.2, 9.9 Hz, 1 H), 2.80 (dd, J = 14.2,
11.9 Hz, 1 H), 2.43 (s, 3 H), 2.33–2.28 (m, 1 H), 2.03–1.96
(m, 1 H), 1.91–1.83 (m, 1 H), 1.69 (s, 3 H), 1.67–1.52 (m, 1
H). 13C NMR (75 MHz, CDCl3): d = 143.0, 138.1, 135.9,
132.8, 129.6, 128.4, 127.1, 126.1, 53.2, 45.0, 32.1, 29.4,
25.3, 21.6. IR (neat): 2934, 1319, 1149, 983, 893, 815, 734,
655, 597, 547 cm–1. For R-isomer (>98% ee): [a]D28 –88.8 (c
1.23, CHCl3); for S-isomer (>98% ee): [a]D29 +88.5 (c 1.60,
CHCl3). Anal. Calcd for C16H21NO2S: C, 65.95; H, 7.26; N,
4.81. Found: C, 65.92; H, 7.26; N, 4.68.
Compound 17; 60:40 rotamer ratio (# denotes major,
* denotes minor rotamer signals): 1H NMR (300 MHz,
CDCl3): d = 6.96* (s, 1 H), 6.95# (s, 1 H), 6.76* (s, 1 H),
6.71# (s, 1 H), 6.04# (d, J = 10.2 Hz, 1 H), 5.99–5.96* (m, 1
H), 5.96 (s, 2 H), 5.80–5.73# (m, 1 H), 5.68–5.63* (m, 1 H),
5.23* (d, J = 9.9 Hz, 1 H), 4.62# (dd, J = 4.8, 2.1 Hz, 1 H),
4.04–3.98* (m, 1 H), 3.64# (dd, J = 9.0, 6.0 Hz, 1 H), 3.32–
3.13 (m, 1 H), 2.54–2.37 (m, 1 H), 2.14–1.58 (m, 6 H). 13
C
NMR (75 MHz, CDCl3): d = 167.1*, 167.0#, 148.6*, 148.5#,
147.4#, 147.3*, 132.6#, 132.4*, 129.0, 128.0, 125.8*, 125.0#,
112.7#, 109.8*, 108.0*, 107.3#, 102.1*, 102.0#, 57.0*, 55.3#,
47.0#, 44.8*, 36.6*, 35.6#, 27.6#, 25.3*, 22.7#, 22.1*, 21.0#,
20.2*. IR (neat): 2922, 1631, 1482, 1440, 1374, 1239, 1109,
1035, 932, 863, 732, 617 cm–1. [a]D25 –146.4 (c 0.86,
CHCl3).
Compound 2d: 1H NMR (300 MHz, CDCl3): d = 7.67 (d,
J = 8.1 Hz, 2 H), 7.31 (d, J = 8.1 Hz, 2 H), 5.63 (dddd,
J = 11.4, 11.1, 4.8, 1.2 Hz, 1 H), 5.40–5.24 (m, 3 H), 4.41
(dd, J = 9.9, 3.3 Hz, 1 H), 3.83 (dd, J = 14.1, 4.2 Hz, 1 H),
3.00 (dd, J = 9.9, 9.9 Hz, 1 H), 2.84 (dd, J = 14.1, 11.7 Hz, 1
H), 2.43 (s, 3 H), 2.37–2.30 (m, 1 H), 2.26–2.17 (m, 1 H),
1.77–1.65 (m, 1 H), 1.58–1.45 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 143.1, 136.9, 135.8, 131.7, 129.7, 128.8, 127.1,
126.1, 53.4, 44.0, 30.2, 26.6, 21.7. IR (reflection): 3016,
2934, 2869, 1920, 1806, 1661, 1596, 1459, 1347, 988 cm–1.
For R-isomer (>98% ee): [a]D25 –114.2 (c 1.21, CHCl3); for
S-isomer (>98% ee): [a]D26 +118.9 (c 1.97, CHCl3). Anal.
Calcd for C15H19NO2S: C, 64.95; H, 6.90; N, 5.05; S, 11.56.
Found: C, 65.22; H, 7.07; N, 4.92; S, 11.25.
Compound 18: 1H NMR (300 MHz, CDCl3): d = 7.52 (s, 1
H), 6.69 (s, 1 H), 5.99 (d, J = 1.2 Hz, 1 H), 5.98 (d, J = 1.2
Hz, 1 H), 5.70–5.63 (m, 1 H), 5.36 (dd, J = 9.9, 2.4 Hz, 1 H),
4.02 (dd, J = 5.7, 4.8 Hz, 1 H), 3.69 (d, J = 9.6 Hz, 1 H), 3.67
(d, J = 9.6 Hz, 1 H), 3.62–3.56 (m, 1 H), 2.53–2.44 (m, 1 H),
2.29–2.18 (m, 1 H), 2.07–1.70 (m, 3 H). 13C NMR (75 MHz,
CDCl3): d = 161.8, 150.5, 146.9, 135.6, 125.9, 125.3, 123.0,
107.6, 107.4, 101.6, 56.6, 42.4, 37.1, 34.2, 30.0, 25.2. IR
(neat): 2885, 1645, 1609, 1465, 1387, 1349, 1269, 1244,
1036, 933, 770, 703 cm–1. [a]D24 –111.4 (c 0.38, CHCl3).
Compound 12: 1H NMR (300 MHz, CDCl3): d = 6.61 (s, 1
H), 6.49 (s, 1 H), 5.89 (d, J = 1.2 Hz, 1 H), 5.88 (d, J = 1.2
Hz, 1 H), 4.02 (d, J = 14.1 Hz, 1 H), 3.37 (ddd, J = 9.3, 9.0,
3.6 Hz, 1 H), 3.22 (d, J = 14.1 Hz, 1 H), 2.75 (ddd, J = 11.7,
4.5, 4.5 Hz, 1 H), 2.39 (dd, J = 4.8, 4.5 Hz, 1 H), 2.25–2.11
(m, 2 H), 2.08–1.97 (m, 1 H), 1.80–1.60 (m, 3 H), 1.55–1.30
(m, 4 H). 13C NMR (75 MHz, CDCl3): d = 146.0, 145.6,
133.1, 127.3, 108.4, 106.3, 100.7, 63.0, 57.2, 53.9, 39.6,
37.5, 31.9, 30.6, 29.5, 25.4. IR (neat): 2925, 1505, 1483,
1376, 1318, 1230, 1138, 1040, 938, 867 cm–1. [a]D25 +15.0
(c 0.44, EtOH) {lit.17 [a]D20 +17.1 (c 0.25, EtOH)}. MS
(ESI+): m/z = 258 [M + H]+.
Compound (3S,4R)-10: 1H NMR (300 MHz, CDCl3): d =
7.72 (d, J = 8.1 Hz, 2 H), 7.32 (d, J = 8.1 Hz, 2 H), 5.53 (dd,
J = 17.4, 10.8 Hz, 1 H), 5.43 (ddd, J = 17.1, 10.5, 8.4 Hz, 1
H), 5.04 (dd, J = 10.5, 1.5 Hz, 1 H), 4.98 (dd, J = 17.1, 1.5
Hz, 1 H), 4.98 (d, J = 10.8 Hz, 1 H), 4.88 (d, J = 17.4 Hz, 1
H), 3.50 (dd, J = 9.9, 7.5 Hz, 1 H), 3.44 (d, J = 9.6 Hz, 1 H),
3.16 (dd, J = 9.9, 9.9 Hz, 1 H), 3.01 (d, J = 9.6 Hz, 1 H), 2.44
(s, 3 H), 2.33–2.24 (m, 1 H), 1.02 (s, 3 H). 13C NMR (75
MHz, CDCl3): d = 143.3, 139.1, 134.1, 133.8, 129.6, 127.3,
118.2, 114.2, 58.2, 53.3, 51.0, 47.0, 21.8, 21.7. IR (neat):
2965, 1346, 1155, 1094, 1052, 922, 813, 711, 663, 587 cm–1.
[a]D19 –6.5 (c 1.03, CHCl3).
(8) Analytical and semipreparative-scale HPLC were carried
out with a chiral stationary column [CHIRALCEL OD-H
(4.6 × 250 mm or 20 × 250 mm)] equipped with a UV
detector and a CD spectropolarimeter.
(9) The absolute configurations of 2b and 2c were speculated on
the basis of the similarity of the CD spectra of 2a and 2d.
(10) Enantioenriched 2 can be prepared via the fractional
crystallization of its ammonium salt with chiral carboxylic
acid, see ref. 3b.
(11) The detailed transition-state analysis of racemization by ab
initio calculation is in progress.
(12) The enantiopurity of 2a–d remains unchanged in the solid
state(crystal) at –30 °C for at least one year.
(13) Pd(II)-catalyzed Cope rearrangement, see: Overman, L. E.;
Jacobsen, E. J. J. Am. Chem. Soc. 1982, 104, 7225.
(14) The absolute stereochemistry of 10 was deduced from the
configuration of 2b and the steric course of the reactions.
(15) In general, the aza-Wittig rearrangement is considerably
slower than the corresponding oxa-Wittig rearrangement. To
enhance the reactivity of the aza-Wittig rearrangement,
several contrivances have been developed. For reviews, see:
(a) Vogel, C. Synthesis 1997, 497. (b) Tomooka, K. In The
Chemistry of Organolithium Compounds, Vol. 2;
Compound (R,R)-11d: 1H NMR (300 MHz, CDCl3): d = 7.75
(d, J = 8.1 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 2 H), 5.83–5.69 (m,
2 H), 5.36–5.32 (m, 1 H), 5.07 (dd, J = 9.0, 0.9 Hz, 1 H), 5.00
(dd, J = 17.1, 0.6 Hz, 1 H), 4.54 (d, J = 9.6 Hz, 1 H), 3.92–
3.84 (m, 1 H), 2.42 (s, 3 H), 2.37–2.29 (m, 1 H), 2.12–1.88
(m, 2 H), 1.77–1.67 (m, 1 H), 1.58–1.47 (m, 1 H). 13C NMR
(75 MHz, CDCl3): d = 143.3, 138.4, 137.2, 130.2, 129.7,
127.3, 127.2, 117.6, 51.5, 41.8, 24.8, 22.8, 21.6. IR (neat):
3278, 2925, 1433, 1331, 1160, 1084, 915, 814, 709, 660
cm–1. [a]D25 –86.1 (c 1.27, CHCl3).
Compound 13: 1H NMR (300 MHz, CDCl3): d = 7.76 (d,
J = 8.1 Hz, 2 H), 7.29 (d, J = 8.1 Hz, 2 H), 5.65 (ddd, J = 9.6,
3.6, 3.3 Hz, 1 H), 5.12 (ddd, J = 9.6, 4.5, 2.1 Hz, 1 H), 4.95–
4.85 (m, 1 H), 3.79–3.62 (m, 3 H), 2.42 (s, 3 H), 2.04–1.75
(m, 5 H), 1.63–1.42 (m, 2 H), 1.36–1.23 (m, 1 H). 13C NMR
(75 MHz, CDCl3): d = 143.2, 138.3, 130.9, 129.6, 126.9,
126.4, 60.9, 51.1, 34.9, 34.2, 24.8, 24.2, 21.6. IR (neat):
3274, 2928, 1598, 1432, 1327, 1159, 1094, 1021, 915, 815,
663 cm–1. [a]D26 –153.5 (c 1.10, CHCl3).
Compound 14: 1H NMR (300 MHz, CDCl3): d = 7.69 (d,
J = 8.1 Hz, 2 H), 7.28 (d, J = 8.1 Hz, 2 H), 5.83–5.70 (m, 2
H), 3.96 (d, J = 6.9 Hz, 1 H), 3.45 (ddd, J = 14.1, 7.5, 4.5 Hz,
1 H), 3.17 (ddd, J = 9.9, 8.4, 7.5 Hz, 1 H), 2.40 (s, 3 H),
2.03–1.89 (m, 3 H), 1.80–1.49 (m, 4 H). 13C NMR (75 MHz,
Rappoport, Z.; Marek, I., Eds.; John Wiley and Sons:
Chichester, 2004, 749–828.
Synlett 2008, No. 16, 2518–2522 © Thieme Stuttgart · New York

2522
K. Tomooka et al.
LETTER
(16) The X-ray crystal structure analysis shows that the distance
between C4 and C9 of 2a is 3.8 Å (Figure 2). The present
rearrangement should proceed via a deprotonation of the C9
equatorial proton and an inversion of the configuration at the
carbanion chiral center. It has been reported that [2,3]-Wittig
rearrangement proceeds with inversion of configuration at
the migrating terminus, see: (a) Verner, E. J.; Cohen, T.
J. Am. Chem. Soc. 1992, 114, 375. (b) Tomooka, K.;
Igarashi, T.; Watanabe, M.; Nakai, T. Tetrahedron Lett.
1992, 33, 5795.
(17) (+)-g-Lycorane was obtained by Kotera in his degradation
studies of lycorine, see: Kotera, K. Tetrahedron 1961, 12,
248.
(18) Six different asymmetric syntheses of g-lycorane(12) have
been reported thus far, see: (a) Yoshizaki, H.; Satoh, H.;
Sato, Y.; Nukui, S.; Shibasaki, M.; Mori, M. J. Org. Chem.
1995, 60, 2016. (b) Ikeda, M.; Ohtani, S.; Sato, T.; Ishibashi,
H. Synthesis 1998, 1803. (c) Banwell, M. G.; Harvey, J. E.;
Hockless, D. C. R. J. Org. Chem. 2000, 65, 4241. (d)Dong,
L.; Xu, Y.-J.; Cun, L.-F.; Cui, X.; Mi, A.-Q.; Jiang, Y.-Z.;
Gong, L.-Z. Org. Lett. 2005, 7, 4285. (e) Fujioka, H.;
Murai, K.; Ohba, Y.; Hirose, H.; Kita, Y. Chem. Commun.
2006, 832. (f) Chapsal, B. D.; Ojima, I. Org. Lett. 2006, 8,
1395.
N
Ts
4
B: Heq
9
(19) Mori and co-workers constructed the C ring of g-lycorane by
Hax
3.8 Å
a Pd-catalyzed Mizoroki–Heck reaction, see ref. 18a.
Figure 2
Synlett 2008, No. 16, 2518–2522 © Thieme Stuttgart · New York