Efficient construction of a chiral all-carbon quaternary center by asymmetric 1,4-addition and its application to total synthesis of (+)-bakuchiol

Article abstract of DOI:10.1016/j.tetlet.2008.09.106

The conjugate addition of lithium divinylcuprate to (4S,2′E)-3-(6′-TBDPS-3′-methylhex-2′-enoyl)-4-phenyloxazolidin-2-one proceeded efficiently to create a chiral all-carbon quaternary center with a high diastereoselectivity (R:S = 95:5). The absolute configuration of the newly generated chiral center was confirmed by applying this methodology to the total synthesis of (+)-bakuchiol.

Full text of DOI:10.1016/j.tetlet.2008.09.106

Tetrahedron Letters 49 (2008) 6846–6849
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Tetrahedron Letters
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Efficient construction of a chiral all-carbon quaternary center by asymmetric
1,4-addition and its application to total synthesis of (+)-bakuchiol
*
Tomoyuki Esumi , Hiroyuki Shimizu, Akinori Kashiyama, Chizu Sasaki, Masao Toyota,
*
Yoshiyasu Fukuyama
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
a r t i c l e i n f o
a b s t r a c t
The conjugate addition of lithium divinylcuprate to (4S,20E)-3-(60-TBDPS-30-methylhex-20-enoyl)-4-phe-
nyloxazolidin-2-one proceeded efficiently to create a chiral all-carbon quaternary center with a high dia-
stereoselectivity (R:S = 95:5). The absolute configuration of the newly generated chiral center was
confirmed by applying this methodology to the total synthesis of (+)-bakuchiol.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 22 July 2008
Revised 10 September 2008
Accepted 12 September 2008
Available online 26 September 2008
Keywords:
Chiral all-carbon quaternary center
Asymmetric 1,4-addition
Asymmetric Michael addition
Vibsane-type diterpene
(+)-Bakuchiol
Total synthesis
Over the past decade, we have reported a number of unique
vibsane-type diterpenes and have studied them chemically and
biologically.1 Vibsane-type diterpenes, which are classified as 7-
membered, 11-membered, and rearranged types according to their
core ring structures, share the common C-11 chiral all-carbon qua-
ternary center in these molecules (Fig. 1). In the course of our pro-
ject aimed at asymmetric synthesis2 of vibsane-type diterpenes,
one of the most critical issue is most likely to be the development
of synthetic methods for the construction of the C-11 chiral all-car-
bon quaternary center. Efficiently generating the chiral quaternary
carbon centers3 that widely exist in the core structure of various
natural products has become a vital subject in the field of natural
products synthesis. Recently, Alexakis4 reported a versatile ap-
proach to the construction of the all-carbon quaternary stereocen-
ters by the copper-catalyzed asymmetric conjugate addition of
saturated alkyl or aryl Grignard reagents to trisubstituted cycloh-
exenones using chiral C2-symmetric imidazolidinium ligands. On
the other hand, although numerous diastereoselective 1,4-addi-
cuprate to chiral 3-(b-alkyl-b-methyl-a-enolyl)-4S-phenyloxazoli-
din-2-one, and demonstrate that this method provides a versatile
chiral quaternary carbon source for the synthesis of natural prod-
ucts by its use to the total synthesis of (+)-bakuchiol.
First, (4S,20E)-3-(60-TBDPS-30-methylhex-20-enoyl)-4-phenylox-
azolidin-2-one (3), a chiral acceptor suitable for asymmetric 1,4-
addition, was prepared from 4-pentyn-1-ol (1) in 3 steps as shown
in scheme 1. Specifically, 1 was converted to the corresponding
iodoalkene by employing the Negishi protocol,7 and then a hydro-
xy group was protected as a TBDPS ether to give the 5-iodo-4-
methylpentenol derivative 2 in 98% yield over 2 steps. The reaction
of 2 with N-lithiated chiral oxazolidinone reagent, which was gen-
erated in situ by the treatment of (S)-(+)-4-phenyl-2-oxazolidinone
with n-butyllithium, was performed in the presence of 10 mol %
Pd(PPh3)4 under CO atmosphere (0.4 MPa) in THF at room temper-
ature giving rise to 3 in 78% yield.8
With the chiral Michael acceptor
3 in hand, our efforts
focused on diastereoselective additions to 3 to create the quater-
nary carbon center by examining several vinylcopper(I) reagents,
because an introduced vinyl group is convenient for subsequent
transformations to appropriate functional groups. First
(vinyl)2CuMgBr species generated from vinylmagnesium bromide
(10 equiv) and CuI (1 equiv) were investigated. The reaction of 3
with (vinyl)2CuMgBr in THF at ꢀ78 °C gave the desired 1,4-
adduct 4 in moderate yield (Table 1, entry 1). In this case, no
formation of the other diastereoisomer 5 was observed in the
1H NMR spectrum of the crude mixture, but an unexpected vinyl
tions of a,b-unsaturated carboxylic acid derivatives bearing chiral
auxiliary5,6 have been reported, this kind of approach has remained
unexplored for creating chiral quaternary stereocenters. Herein,
we report efficient construction of the chiral all-carbon quaternary
center with a vinyl moiety that would permit post-functional
group manipulation by the conjugate addition of lithium divinyl-
* Corresponding authors. Tel.: +81 88 602 8435 (Y.F.); fax: +81 88 655 3051.
E-mail address: fukuyama@ph.bunri-u.ac.jp (Y. Fukuyama).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.106

T. Esumi et al. / Tetrahedron Letters 49 (2008) 6846–6849
6847
O
H
O
O
O
7
OH
O
Y
7
4
4
O
7
O
OH
8
OH
X
4
O
8
O
8
11
11
11
O
O
1
1
1
neovibsanin A: X=OCH3, Y =CH3
neovibsanin B: X=CH3, Y =OCH3
(rearranged type)
vibsanin C
(7-membered type)
vibsanin B
(11-membered type)
OH
(+)-bakuchiol
Figure 1. Structures of vibsane-type diterpenes and (+)-bakuchiol.
O
O
I
O
N
c
a, b
Ph
78%
98% (2 steps)
OH
OTBDPS
2
1
OTBDPS
3
Scheme 1. Preparation of 3. Reagents and conditions: (a) Me3Al, Cp2ZrCl2, 1,2-dichloroethane, then I2, THF; (b) TBDPSCl, Et3N, DMAP, CH2Cl2; (c) (S)-(+)-4-phenyl-2-
oxazolidinone, n-BuLi, THF, then 2, 10 mol % Pd(PPh3)4, CO (0.4 MPa).
Table 1
Asymmetric 1,4-addition of the trisubstituted
a
,b-unsaturated carboxylic acid derivative 3
O
O
O
O
N
O
O
H
N
O
N
O
O
reagent, add.
3
S
Ph
solv., temp., time
R
Ph
Ph
OTBDPS
OTBDPS
OTBDPS
5
4
6
Entry
Reagent (equiv)
Add. (equiv)
Solv.
Temp. (°C)
Time (h)
Yield of 4 (%)
(3:4:5:6)a
1
2
3
4
5
H2C@C(H)MgBr (10)
H2C@C(H)MgBr (5)
H2C@C(H)MgBr (2.5)
n-BuLi (3.9)/(vinyl)4Sn (0.9)
PhLi (6.7)/(vinyl)4Sn (1.9)
CuI (1)
CuI (1)
CuI (1)
CuCN (2)
CuCN (4)
THF
THF
THF
THF
Et2O
ꢀ78
12
12
12
14
19
47
26
(0:43:0:57)
(65:26:0:9)
(73:18:0:8)
(76:24:0:0)
(0:95:5:0)
ꢀ78
b
ꢀ78
—
—
b
ꢀ78
ꢀ78 to ꢀ50
79
a
The ratio was determined by 1H NMR (400 MHz) of the crude mixture.
The reaction mixture was not purified.
b
adduct 6 was obtained in 57% yield. While we suspected that the
generation of 6 might arise from the excess vinylmagnesium
bromide, we decreased the amount of vinylmagnesium bromide
to 2.5 or 5 equiv (entries 2 and 3). However, these reaction con-
ditions could not suppress the formation of 6, but considerably
decreased the reaction rate.9 Subsequently, we examined the
1,4-addition of 3 by using (vinyl)2CuCNLi2 that was generated
from tetravinyltin with n-BuLi and CuCN, resulting in the sole
formation of the desired 1,4-adduct with a high diastereoselec-
tivity in spite of poor conversion rate (entry 4). We suspected
that the low reactivity of the (vinyl)2CuCNLi2 was due to coexis-
ting tetrabutyltin. Thus tetraalkyltin free vinyllithium that was
prepared from tetravinyltin with PhLi was treated with CuCN
to yield the (vinyl)2CuCNLi2, which was subjected to the 1,4-
addition reaction with 3. The reaction proceeded smoothly and
furnished a diastereomeric mixture of the vinyl adducts 4 and
5 (95:5) in 79% yield.10 The absolute configuration of the newly
created all-carbon quaternary center for 4 and 5 was tentatively

6848
T. Esumi et al. / Tetrahedron Letters 49 (2008) 6846–6849
M
M
R'
R'
R
S
CH3
CH3
X
R'
X
R'
H3C
O
O
M
O
O
H3C
M
O
O
O
O
>>
N
O
N
O
X
N
O
5
X
N
Ph
Ph
O
R
Ph
7
8
4
Scheme 2. Proposed mechanism for the facial selectivity of asymmetric 1,4-addition.
OMe
OH
d—f
a—c
4
77% (3 steps)
71% (3 steps)
OTBDPS
OTBDPS
9
10
OMe
j
g—i
s
(+)-bakuchiol
89%
50% (3 steps)
11
Scheme 3. Total synthesis of (+)-bakuchiol. Reagents and conditions: (a) LiOH, 30% H2O2, THF–H2O, 0 °C to rt; (b) EtOH, EDCꢁHCl, 4-DMAP, CH2Cl2; (c) LiAlH4, THF, 0 °C; (d)
Dess–Martin periodinate, CH2Cl2; (e) p-methoxyphenylmagnesium bromide, THF, 0 °C; (f) MsCl, 4-DMAP, CH2Cl2; (g) HF/pyr/MeCN (1:3:5); (h) Dess–Martin periodinate,
CH2Cl2; (i) Me2CHP+Ph3ꢁBrꢀ, n-BuLi, THF, 0 °C; (j) MeMgI, 175 °C.
assigned as (R) and (S), respectively, based on the following
O
O
O
mechanistic considerations: The substrate 3 is most likely to pre-
fer the s-cis conformer 7 over the s-trans one 8 due to the steric
interaction between a b-methyl group and an oxazolidinone
moiety as depicted in scheme 2. The divinylcopper(I) reagent fa-
vors an approach from si-face of 7, which avoids a bulky phenyl
group.
Confirmation of the absolute configuration for the quaternary
stereogenic center that was tentatively assigned was unambigu-
ously made by converting 4 with a (R) chirality to a chirality-
defined natural product, (+)-bakuchiol,11 which was isolated from
seeds of Psoralea corylifolia L.
O
O
N
O
N
H2C=C(H)MgBr, CuI
Ph
Ph
THF, -78 ºC, 18 hr
88%
OTBDPS
OTBDPS
13
12
Scheme 4. Asymmetric 1,4-addition of the disubstituted
derivative 12.
a,b-carboxylic acid
nally, demethylation of 11 with MeMgI11b accomplished the total
synthesis of (+)-bakuchiol.13
Scheme 3 shows our synthetic route to (+)-bakuchiol. The
oxazolidinone moiety of the 1,4-adduct 4 was hydrolized by
LiOH–H2O2, and the resultant carboxylic acid was again con-
verted to an ethyl ester with ethanol and EDCꢁHCl, and then re-
duced with LiAlH4 to furnish alcohol 9 in good yield. Dess–
Martin oxidation of 9 gave an aldehyde which was reacted with
p-methoxyphenylmagnesiumbromide followed by mesylation
and elimination of the generated hydroxy group, producing only
the desired (E)-methoxyphenyl derivative 10 in 77% yield over
two steps. Deprotection of TBDPS group by treatment of 10 with
HF–pyridine genarated a primary hydroxy group, which was oxi-
dized with Dess–Martin reagent to an aldehyde, which in turn
was subjected to Wittig olefination, giving rise to methylbakuch-
iol 11 in moderate yield. The spectroscopic data12 of 11 were
identical with methylbakuchiol11e derived from natural (+)-bak-
uchiol. The optical rotation of synthetic methylbakuchiol (11)
In conclusion, we have developed an efficient and facile meth-
odology for constructing chiral all-carbon quaternary center via
asymmetric 1,4-addition of (vinyl)2CuCNLi2 to (4S,20E)-3-(60-
TBDPS-30-methylhex-20-enoyl)-4-phenyloxazolidin-2-one (3). To
the best of our knowledge, this is the first example of the construc-
tion of a chiral all-carbon quaternary center by asymmetric 1,4-
addition of a vinyl nucleophile to a tri-substituted alkene including
a chiral auxiliary (see Scheme 4). Additionally, we have achieved
the total synthesis of (+)-bakuchiol from the 1,4-adduct 4 in 20%
overall yield over 10 steps. As part of further application of this
methodology, synthetic studies of some vibsane-type diterpenes
are now in progress.
Acknowledgments
with an (S)-configuration {½a D18
ꢂ
+28.4 (c 1.07, CHCl3)} was consis-
tent with that of natural methylbakuchiol {½a D29
ꢂ
+31.18 (c 1.45,
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan (Priority Area, 18032085) and the Open
CHCl3)}.11e Thus, the absolute configuration of the quaternary
carbon center of 4 could be unambiguously established as (R). Fi-

T. Esumi et al. / Tetrahedron Letters 49 (2008) 6846–6849
6849
room temperature and the mixture was stirred for 30 min. The reaction
mixture was diluted with ether (10 mL) and the formed white precipitate was
removed by filtration through the glass filter (3 G) under argon atmosphere,
the residue was washed with ether (5 mL). The dark red filtrate was added to
the suspension of CuCN (1.36 g, 15.1 mmol) in ether (8 mL) via cannula at
ꢀ78ꢀC, and then the reaction mixture was allowed to warm to 0ꢀC and stirred
until the solution turned to dark green suspension (ca. 2 min). The supernatant
was added to the solution of 3 (2.02 g, 3.80 mmol) in ether (8 mL) via cannula
at ꢀ78 °C, and then the reaction mixture was stirred for 16 h at ꢀ50 °C. The
reaction mixture was diluted with 10% NH4OH (80 mL) and stirred for 30 min,
and then filtered through the Celite, extracted with ether (3 ꢃ 80 mL). The
combined ether layers were dried with MgSO4, filtered, and concentrated to
give the residue, which was purified by column chromatography (SiO2,
Research Center Fund from the Promotion and Mutual Aid Corpo-
ration from Private Schools of Japan.
References and notes
1. Fukuyama, Y.; Esumi, T. J. Synth. Org. Chem. Jpn. 2007, 65, 585–597 and
references cited therein.
2. Yuasa, H.; Makado, G.; Fukuyama, Y. Tetrahedron Lett. 2003, 44, 6235–6239.
3. (a) Fuji, K. Chem. Rev. 1993, 93, 2037–2066; (b) Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Christffers, J., Baro, A., Eds.;
Wiley-VCH: Germany, 2005; (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369–396;
(d) Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou, Q.-L. J. Am. Chem.
Soc. 2006, 128, 2780–2781; (e) Hashimoto, T.; Naganawa, Y.; Maruoka, K. J. Am.
Chem. Soc. 2008, 130, 2434–2435.
hexane–EtOAc = 10:1) to give
4 (1.69 g, 3.00 mmol, 79%, dr = 95: 5) as a
slightly yellow oil. Data for 4: ½a D18
ꢂ
ꢀ180.7 (c 0.26, CHCl3); IR 1710, 1780 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d 7.64 (d, J = 7.6 Hz, 4H), 7.26–7.44 (m, 11H), 5.82
(dd, J = 10.4, 17.6 Hz, 1H), 5.39 (dd, J = 4.0, 8.8 Hz, 1H), 4.94 (dd, J = 1.2, 10.4 Hz,
1H), 4.82 (dd, J = 1.2, 17.6 Hz, 1H), 4.61 (t, J = 8.8 Hz, 2H), 4.23 (dd, J = 3.6,
8.8 Hz, 1H), 3.57 (m, 2H), 3.17 (d, J = 14.8 Hz, 1H), 2.87 (d, J = 14.4 Hz, 1H), 1.44
(m, 2H), 1.03 (s, 12H); 13C NMR (100 MHz, CDCl3) d 153.8, 145.2, 139.2, 135.6,
134.1, 129,6, 129.1, 128.7, 127.7, 126.2, 112.5, 69.6, 64.4, 57.8, 44.1, 39.8, 36.8,
27.4, 26.9, 22.8, 19.3; HRMS m/z (EI) [MꢀH]+ calcd for C34H40NO4Si, 554.2727;
found, 554.2696.
4. Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am.
Chem. Soc. 2006, 128, 8416–8417.
5. For reviews on diastereoselective 1,4-aditions of
a,b-unsaturated carboxylic
acid derivatives, see: (a) Yamamoto, Y. Angew. Chem., Int. Ed. Engl. 1986, 25,
947–1038; (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171–196; (c)
Alexakis, A.; Benhaim, C. Eur. J. Org. Chem. 2002, 3221–3236.
6. (a) Oppolzer, W.; Loher, H. J. Helv. Chim. Acta 1981, 64, 2808–2907; (b)
Oppolzer, W.; Moretti, R.; Godel, T.; Meunier, A.; Loher, H. Tetrahedron Lett.
1983, 24, 4971–4974; (c) Tomioka, K.; Suenaga, T.; Koga, K. Tetrahedron Lett.
1986, 27, 369–372; (d) Melnyk, O.; Stephan, E.; Pourcelot, G.; Cresson, P.
Tetrahedron 1992, 48, 841–850; (e) Li, G.; Russell, K. C.; Jarosinski, M. A.; Hruby,
V. J. Tetrahedron Lett. 1993, 34, 2565–2568; (f) Williams, D. R.; Li, J. Tetrahedron
Lett. 1994, 35, 5113–5116; (g) Qian, X.; Russell, K. C.; Boteju, L. W.; Hruby, V. J.
Tetrahedron 1995, 51, 1033–1054; (h) van Heerden, P. S.; Benzuidenhoudt, B. C.
B.; Ferreira, D. Tetrahedron Lett. 1997, 38, 1821–1824; (i) Williams, D. R.; Kissel,
W. S.; Li, J. J. Tetrahedron Lett. 1998, 8593–8596; (j) Soloshonok, V. A.; Cai, C.;
Hruby, V. J. Tetrahedron Lett. 2000, 41, 9645–9649; (k) Dambacher, J.; Bergdahl,
M. Org. Lett. 2003, 5, 3539–3541; (l) Pérez, L.; Bernes, S.; Quintero, L.; Parrodi, C.
A. Tetrahedron Lett. 2005, 46, 8649–8652.
11. For isolation and structure determination, see: (a) Mehta, G.; Nayak, U. R.;
Dev, S. Tetrahedron Lett. 1966, 4561–4567; (b) Crabduff, J.; Miller, J. A. J.
Chem. Soc. (C) 1968, 2671–2673; (c) Vig, O. P.; Vig, A. K.; Chugh, O. P.;
Gupta, K. C. J. Indian Chem. Soc. 1976, 53, 366–370; (d) Wu, C.-Z.; Cai, X. F.;
Dat, N. T.; Hong, S. S.; Han, A.-R.; Seo, E.-K.; Hwang, B. Y.; Nan, J.-X.; Lee, D.;
Lee, J. J. Tetrahedron Lett. 2007, 48, 8861–8864; For enantioselective total
synthesis, see: (e) Takano, S.; Shimazaki, Y.; Ogasawara, K. Tetrahedron Lett.
1990, 31, 3325–3326.
12. Data for methylbakuchiol (11): ½a D18
ꢂ
+28.4 (c 1.07, CHCl3); 1H NMR (CDCl3,
400 MHz) d 7.27 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 6.26 (d, J = 16.4 Hz,
1H), 6.06 (d, J = 16.4 Hz, 1H), 5.88 (dd, J = 10.8, 17.6 Hz, 1H), 5.11 (quint. t,
J = 1.6, 7.2 Hz, 1H), 5.03 (dd, J = 1.2, 10.8 Hz, 1H), 5.01 (dd, J = 1.2, 17.6 Hz), 3.80
(s, 3H), 1.95 (dt, J = 4.0, 7.6 Hz, 2H), 1.67 (d, J = 0.8 Hz, 3H), 1.58 (d, J = 0.8 Hz,
3H), 1,49 (m, 2H), 1.20 (s, 3H); 13C NMR (CDCl3, 100 MHz) d 158.8, 146.1, 135.9,
131.4, 130.8, 127.2, 126.6, 124.9, 114.0, 111.9, 55.4, 42.6, 41.4, 25.8, 23.5, 23.3,
17.7; HRMS m/z (EI) [M]+ calcd for C19H26O, 270.1984; found, 270.1969.
7. Horn, D. E. V.; Negishi, E. J. Am. Chem. Soc. 1978, 100, 2252–2254.
8. Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; Vol. 2, pp 2399–2423.
9. When the same conditions as entry 2 in table was applied to the Michael
addition
of
(4S,20E)-3-(60-TBDPS-30-methylhex-20-enoyl)-4-phenyloxazo-
13. Data for synthetic (+)-bakuchiol: ½a D18
ꢂ
+26.0 (c 0.45, CHCl3); 1H NMR (CDCl3,
lidin-2-one (12) that lacked the methyl group in 3, the reaction proceeded
smoothly to furnish a sole stereoisomer 13 in 88% yield (Scheme 4). This result
is consistent with the Williums’s result.6f In the case of 3, the presence of the b-
methyl group presumably interfered with the conjugated attack of
vinylcuprate, favoring the 1,2-addition of excess vinyl Grignard reagents to
the oxazolidione auxiliary.
300 MHz) d 7.24 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 8.4 Hz, 2H), 6.25 (d, J = 16.2 Hz,
1H), 6.05 (d, J = 16.2 Hz, 1H), 5.87 (dd, J = 10.8, 17.4 Hz, 1H), 5.10 (quint. t,
J = 1.5, 6.9 Hz, 1H), 5.03 (dd, J = 1.2, 10.8 Hz, 1H), 5.00 (dd, J = 1.2, 17.4 Hz, 1H),
1.95 (dt, J = 7.5, 9.0 Hz, 2H), 1.67 (d, J = 0.9 Hz, 3H), 1.59 (s, 3H), 1.48 (m, 2H),
1.19 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 154.7, 146.0, 135.9, 131.4, 130.9,
127.4, 126.5, 124.9, 115.4, 112.0, 42.6, 41.4, 25.8, 23.4, 23.3, 17.7; HRMS m/z
(EI) [M]+ calcd for C18H24O, 256.1821; found, 256.1827.
10. Typical procedure for asymmetric 1,4-addition: PhLi (ca. 1.9 mol/L in n-butyl
ether, 13.4 mL, 25.5 mmol) was added to tetravinyltin (1.38 mL, 7.60 mmol) at