Construction of all-carbon quaternary stereocenters by zinc-mediated barbier-type allylation in aqueous media

Article abstract of DOI:10.3987/COM-12-S(N)31

Stereoselective construction of an all-carbon quaternary stereocenter by Barbier-type allylation in aqueous media is described. Sugar-derived aldehydes, 2,3-O-isopropylidene-D-glyceraldehyde and 2,4-O-benzylidene-D-threose, were reacted with geranyl chlor

Full text of DOI:10.3987/COM-12-S(N)31

HETEROCYCLES, Vol. 86, No. 1, 2012
147
HETEROCYCLES, Vol. 86, No. 1, 2012, pp. 147 - 153. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 11th June, 2012, Accepted, 10th July, 2012, Published online, 13th July, 2012
DOI: 10.3987/COM-12-S(N)31
CONSTRUCTION
STEREOCENTERS
OF
BY
ALL-CARBON
QUATERNARY
BARBIER-TYPE
ZINC-MEDIATED
ALLYLATION IN AQUEOUS MEDIA
Ken-ichi Takao,* Tomo Miyashita, Nozomi Akiyama, Takuya Kurisu, Kohei
Tsunoda, and Kin-ichi Tadano*
Department of Applied Chemistry, Keio University, Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
takao@applc.keio.ac.jp; tadano@applc.keio.ac.jp
Abstract – Stereoselective construction of an all-carbon quaternary stereocenter
by Barbier-type allylation in aqueous media is described. Sugar-derived aldehydes,
2,3-O-isopropylidene-D-glyceraldehyde and 2,4-O-benzylidene-D-threose, were
reacted with geranyl chloride in the presence of zinc powder to provide !-adducts
bearing quaternary stereocenters with good stereoselectivity.
Quaternary stereocenters are found in a wide range of complex natural products and pharmaceuticals. For
example, (+)-hyperforin (1),1 (+)-perforatumone (2),2 and (+)-vibsanin A (3)3 share a structural motif with
a common all-carbon quaternary stereogenic center (Figure 1). In developing a method for the synthesis
of these natural products, we were faced with the challenge of developing a practical method to
synthesize the quaternary stereocenter. The construction of quaternary stereocenters remains a difficult
problem in organic synthesis.4 One approach to this challenge is the use of 3,3’-disubstituted allymetal
reagents. Although extensive research has been carried out developing stereoselective carbonyl allylation
reactions,5 the synthesis of organic compounds containing quaternary stereocenters through the addition
of allylmetals to aldehydes is still a challenge.6 The majority of nucleophilic addition reactions using
organometallic reagents involve lithium and magnesium. These reactions require the strict exclusion of
moisture. Some classes of the Barbier-type allylation, however, do not require rigorously anhydrous
reaction conditions and can be performed effectively in aqueous media.7 Zinc is the most popular metal
for this type of reaction because it is easy to handle and stable in air. Herein, we describe the construction
of an all-carbon quaternary stereocenter using a diastereoselective zinc-mediated Barbier-type allylation
of chiral aldehydes in aqueous media.
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
This paper is dedicated to Professor Dr. Ei-ichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 1, 2012
O
O
O
OH
O
O
OH
O
O
O
O
O
O
(+)-vibsanin A (3)
(+)-hyperforin (1)
(+)-perforatumone (2)
Figure 1. Structures of (+)-hyperforin, (+)-perforatumone, and (+)-vibsanin A
To achieve the desired Barbier-type allylation, the reaction was investigated using easily available sugar
derivatives as chiral aldehydes.8 We observed that 2,3-O-isopropylidene-D-glyceraldehyde (4)9
stereoselectively reacted with geranyl chloride (5)10 in the presence of zinc powder in a mixture of
aqueous NH4Cl–THF11 at –5 °C (Table 1). The reaction produced !-adducts with complete
regioselectivity which were separated into 3R-isomers 7-A/7-B (4R/4S = 1:4) and 3S-isomers 7-C/7-D
(4R/4S = 5:1) by column chromatography in yields of 6% and 77%, respectively (entry 1).12 When using 5,
(3S,4R)-isomer 7-C was the major product. By using neryl chloride (6)13 in place of 5 as the allyl halide,
(3S,4S)-isomer 7-D with the opposite configuration of the quaternary stereocenter (4-position) was
preferentially obtained, but a decrease in stereoselectivity was observed (entry 2).
Table 1. Barbier-type allylation of aldehyde 4
OH
OH
O
O
2
3
4
O
O
Cl
Cl
Zn powder
O
7-A (3R,4R)
7-B (3R,4S)
CHO
or
+
O
aq. NH4Cl/THF
(2 : 1)
–5 °C
OH
OH
O
O
4
O
O
5
6
7-C (3S,4R)
7-D (3S,4S)
A + B
Yield A/Ba
C + D
Yield C/Da
Entry Allyl Halide
1
2
6%
4%
1:4
2:1
77%
68%
5:1
1:2
5
6
a Ratio was determined by 1H NMR analysis.

HETEROCYCLES, Vol. 86, No. 1, 2012
149
The stereochemistry of the newly formed contiguous stereocenters in adducts 7 was determined by
chemical transformation as shown in Scheme 1. The major isomers 7-C/7-D (dr = 5:1) were hydrolyzed
to triols, which were subjected to oxidative cleavage followed by reduction of the resultant aldehyde to
afford the enantioenriched alcohol (+)-8. By comparing the optical rotation of (+)-8 with that of the
23
known (–)-8,14 whose absolute stereochemistry had been determined {["]D +13.2 (c 1.04, CHCl3) for
synthetic (+)-8; lit.14 ["]D –16.9 (c 1.23, CHCl3) for authentic (–)-8}, the configuration of the quaternary
stereocenter in 7-C was assigned as (R). The oxidation of 7-C/7-D provided ketone 9 as a (4R):(4S) = 5:1
mixture, while 7-A/7-B (dr = 1:4) provided a (4R):(4S) = 1:4 mixture of 9. Therefore, all the
configurations at the 4-position in adducts 7A-D were unambiguously assigned. To determine the
configurations at the 3-position, 7-A/7-B and 7-C/7-D were treated with acid. The migration of the
isopropylidene group occurred in only 7-A/7-B, affording trans-dioxolane 10-A/10-B. These results
indicate that 7-A/7-B are 2,3-syn isomers and 7-C/7-D are 2,3-anti isomers.15
O
7-C + 7-D
(dr = 5:1)
O
Dess–Martin
oxidation
HO
1) aq. AcOH
4
O
or
7-C + 7-D
(dr = 5:1)
2) NaIO4
3) NaBH4
For 7-C/7-D,
99% (4R:4S = 5:1)
For 7-A/7-B,
7-A + 7-B
(dr = 1:4)
75%
100% (4R:4S = 1:4)
(+)-8
9
O
O
p-TsOH
p-TsOH
7-A + 7-B
(dr = 1:4)
no reaction
7-C + 7-D
(dr = 5:1)
HO
acetone
95%
acetone
10-A + 10-B
(dr = 1:4)
Scheme 1. Determination of the stereochemistry at C3 and C4 in 7
To expand the scope of this reaction, we explored the use of other sugar-derived aldehydes. The use of
2,4-O-benzylidene-D-threose (11), prepared from D-galactose in a two-step reaction,16 was found to be
effective in generating the quaternary stereocenter with (S)-configuration (Table 2).17 Although the
reaction temperature was increased from –5 °C to room temperature in order to complete the reaction, the
Barbier reaction of 11 with 5 resulted in good stereoselectivity, similar to that observed in the reaction of
4. (4R,5S)-Isomer 12-B was preferentially obtained along with (4R,5R)-isomer 12-A (12-A/12-B = 1:5) in
68% yield (entry 1).18 When the reaction was conducted using 6, (4R,5R)-isomer 12-A was obtained as
the major isomer in slightly lower yield and stereoselectivity (entry 2).

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HETEROCYCLES, Vol. 86, No. 1, 2012
Table 2. Barbier-type allylation of aldehyde 11
OH
OH
OH
OH
O
O
4
5
O
O
Ph
Ph
OH
Zn powder
12-A (4R,5R)
12-B (4R,5S)
O
+ 5 or 6
OH
OH
OH
OH
aq. NH4Cl/THF
Ph
O
CHO
(2 : 1)
r.t.
11
O
O
O
O
Ph
Ph
12-C (4S,5R)
12-D (4S,5S)
A + B
C + D
Yield A/Ba
Yield C/Da
Entry Allyl Halide
1
2
5
6
68%
51%
1:5
4:1
4%
4%
5:1
2:1
a Ratio was determined by 1H NMR analysis.
Repeating a similar transformation to that of Scheme 1, the stereochemistry of the quaternary
stereocenters in adducts 12 was assigned (Scheme 2). The hydrolyzed products, 13-A/13-B, prepared
from 12-A/12-B (dr = 1:5) were recrystallized to provide the almost diastereomerically pure form of 13-B,
which was then converted into highly enantioenriched (–)-8.19 The stereochemistry of the 4-position in 12
was determined by NOE experiments of the isopropylidene derivatives 14-A/14-B and 14-C/14-D.
OH
OH
HO
HO
1) NaIO4
aq. AcOH
HO
13-B
12-A + 12-B
(dr = 1:5)
80 °C
77%
2) NaBH4
78%
(–)-8
13-A + 13-B
(dr = 1:5)
O
O
O
p-TsOH
Me2C(OMe)2
p-TsOH
Me2C(OMe)2
O
O
O
12-A + 12-B
(dr = 1:5)
12-C + 12-D
(dr = 5:1)
O
O
DMF
63%
DMF
69%
Ph
Ph
14-A + 14-B
(dr = 1:5)
14-C + 14-D
(dr = 5:1)
Scheme 2. Determination of the stereochemistry at C4 and C5 in 12

HETEROCYCLES, Vol. 86, No. 1, 2012
151
The stereochemical outcomes obtained in the reaction of 4 or 11 can be explained using the transition
states depicted in Scheme 3. Through a combined experimental and theoretical mechanistic investigation,
the zinc-mediated Barbier-type allylations in aqueous media were estimated to proceed through a
six-membered chair-like transition state.20 In addition, organozinc reagents have a tendency to form a
chelate complex involving the carbonyl and the #-alkoxy group.21 Therefore, the reaction of 4 or 11 with
5 preferentially produces 7-C or 12-B in accordance with the #-chelation/six-membered model. The lower
stereoselectivity observed in the case of 6 may be caused by the steric repulsion of the homoprenyl group
adopting an axial position in the six-membered transition state.
R
O
O
Cl
H
Zn
O
Zn
Zn
12-B
11 + 5
7-C
HO
4 + 5
Zn
H
Cl
O
O
R
O
R = prenyl
Ph
Scheme 3. Plausible transition states for the Barbier reactions of 4 and 11
In conclusion, we have developed a stereoselective construction of an all-carbon quaternary stereocenter
through a zinc-mediated Barbier-type allylation of sugar-derived aldehydes in aqueous media. This
reaction can be performed without the need of rigorously anhydrous conditions, providing a practical and
operationally simple method for the construction of quaternary stereocenters. Further studies and
applications of this work to natural product synthesis are in progress and will be reported in due course.
ACKNOWLEDGEMENTS
This work was supported in part by the MEXT-Supported Program for the Strategic Research Foundation
at Private Universities, 2012-2016.
REFERENCES AND NOTES
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HETEROCYCLES, Vol. 86, No. 1, 2012
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12. Barbier-type allylation of aldehyde 4 with 5: To a stirred solution of 4 (10.1 g, 77.7 mmol) in THF
(60 mL) and 20wt% aqueous NH4Cl (160 mL) was added zinc powder (24.0 g, 312 mmol). The
mixture was cooled to –5 °C and a solution of 5 (8.99 g, 51.9 mmol) in THF (20 mL) was added
dropwise over 1.5 h. After being stirred at –5 °C for 14 h, the mixture was filtered through a pad of
Celite and washed with EtOAc (100 mL). The combined filtrate and washings were washed with
saturated brine (100 mL), dried and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (EtOAc/hexane, 1:70) to provide 0.83 g (6%) of 7-A/7-B
(dr = 1:4) and 10.6 g (77%) of 7-C/7-D (dr = 5:1). Compound 7-C/7-D (dr = 5:1) was obtained as a
colorless oil: TLC Rf 0.61 (EtOAc/hexane, 1:3); IR 3490, 2985, 2915 cm–1; 1H NMR (300 MHz) for
7-C $ 0.99 (s, 3H), 1.34 (s, 3H), 1.41 (s, 3H), 1.42-1.52 (m, 2H), 1.59 (s, 3H), 1.68 (s, 3H), 1.85-1.97
(m, 2H), 2.02 (br d, 1H, J = 3.2 Hz, OH), 3.75 (br dd, 1H, J = 3.2, 2.8 Hz), 3.85-3.95 (m, 2H), 4.16
(dt, 1H, J = 2.8, 7.1 Hz), 5.03 (dd, 1H, J = 17.5, 1.3 Hz), 5.03-5.15 (m, 1H), 5.14 (dd, 1H, J = 10.9,
1.3 Hz), 5.78 (dd, 1H, J = 17.5, 10.9 Hz); 13C NMR (75 MHz) for 7-C $ 17.7, 18.1, 22.5, 25.3, 25.6,
26.4, 37.9, 42.9, 64.3, 76.4, 76.7, 107.4, 114.2, 124.6, 131.3, 143.0; HRMS calcd for C16H28O3 (M+)

HETEROCYCLES, Vol. 86, No. 1, 2012
153
m/z 268.2038, found 268.2027.
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stereoselectivity.
18. Barbier-type allylation of aldehyde 11 with 5: To a stirred solution of 11 (263 mg, 1.38 mmol) in
20wt% aqueous NH4Cl (6 mL) was added zinc powder (604 mg, 9.23 mmol). The mixture was
cooled to 0 °C and a solution of 5 (159 mg, 0.920 mmol) in THF (3 mL) was added dropwise. After
being stirred at room temperature for 72 h, the mixture was filtered through a pad of Celite and
washed with CH2Cl2. The combined filtrate and washings were diluted with H2O (40 mL) and
saturated brine (10 mL) and extracted with CH2Cl2 (20 mL ! 4). The combined extracts were dried
and concentrated under reduced pressure. The residue was purified by column chromatography on
silica gel (EtOAc/hexane, 1:10) to provide 216 mg (68%) of 12-A/12-B (dr = 1:5) and 12.1 mg (4%)
of 12-C/12-D (dr = 5:1). Compound 12-A/12-B (dr = 1:5) was obtained as a colorless oil: TLC Rf
1
0.47 (EtOAc/hexane, 1:2); IR 3443, 2969, 2920 cm–1; H NMR (500 MHz) for 12-B $ 1.12 (s, 3H),
1.46-1.62 (m, 2H), 1.56 (s, 3H), 1.66 (s, 3H), 1.90-1.95 (m, 2H), 2.81 (br, 1H, OH), 3.14 (br, 1H,
OH), 3.69 (d, 1H, J = 6.5 Hz), 3.82 (m, 1H), 3.92 (dd, 1H, J = 6.5, 1.2 Hz), 4.07 (dd, 1H, J = 12.1,
1.5 Hz), 4.24 (dd, 1H, J = 12.1, 1.8 Hz), 5.07 (m, 1H), 5.07 (dd, 1H, J = 17.5, 1.5 Hz), 5.15 (dd, 1H,
J = 10.9, 1.5 Hz), 5.53 (s, 1H), 5.92 (dd, 1H, J = 17.5, 10.9 Hz), 7.33-7.39 (m, 3H), 7.47-7.49 (m,
2H); 13C NMR (125 MHz) for 12-B $ 17.6, 18.2, 22.5, 25.6, 37.4, 43.9, 64.8, 72.4, 76.4, 79.4, 100.6,
113.6, 124.8, 125.8 (2C), 128.1 (2C), 128.8, 131.2, 137.7, 143.4; HRMS calcd for C21H30O4 (M+) m/z
346.2144, found 346.2139.
19. By the similar transformation, the configuration of the quaternary stereocenter in 12-C was assigned
as (R).
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Stivanello, and G. Tagliavini, J. Org. Chem., 1996, 61, 2731.
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