Construction of two vicinal quaternary carbons by asymmetric allylic alkylation: Total synthesis of hyperolactone C and (-)-biyouyanagin A

Article abstract of DOI:10.1002/anie.200902908

Call on triple A: Palladium-catalyzed asymmetric allylic alkylation (Pd-AAA; see scheme) has enabled a concise and efficient synthesis of hyperolacto ne C and (-)-biyouyanagin A in only six (20% Overall yield) and seven (8% overall yield) steps, respectively. The enantiomers of these natural products were also prepared by exploiting the same methodology.

Full text of DOI:10.1002/anie.200902908

Angewandte
Chemie
DOI: 10.1002/anie.200902908
Natural Products
Construction of Two Vicinal Quaternary Carbons by Asymmetric
Allylic Alkylation: Total Synthesis of Hyperolactone C and
(ꢀ)-Biyouyanagin A**
Chao Du, Liqi Li, Ying Li, and Zhixiang Xie*
Dedicated to Professor Zhen Yang on the occasion of his 50th birthday
The motif of two vicinal quaternary carbon centers is found in
a wide range of bioactive natural products such as hyper-
olactones A–C[1] and (ꢀ)-biyouyanagin A[2] (Scheme 1). The
interesting biological activities and unique structures of these
compounds have stimulated many total syntheses.[3] In gen-
application of Pd-AAA reactions in the construction of single
quaternary carbon centers.[6] However, to the best of our
knowledge, there is no precedent for using Pd-AAA reactions
to install two vicinal quaternary carbon centers. In our
synthetic studies toward hyperolactone C (3) and (ꢀ)-
biyouyanagin A (4), we have devised a novel synthetic
strategy which features the use of Pd-AAA to construct the
key vicinal quaternary carbon stereocenters. As shown in
Scheme 2, we envisioned that if nucleophilic b-ketoester 5
and electrophilic allylic donor isoprene monoepoxide 6 could
Scheme 1. Natural products with two vicinal quaternary carbon
centers.
eral, the stereoselective construction of two vicinal quater-
nary carbon centers relys on substrate control. Only a few
ꢀ
catalytic asymmetric C C bond-forming reactions have been
useful for constructing all-carbon quaternary stereocenters.[4]
The catalytic asymmetric synthesis of two vicinal quaternary
carbon centers with high diastereoselectivity and enantiose-
lectivity remains a formidable challenge.
Scheme 2. Proposed construction of two vicinal quaternary carbon
centers and the synthetic plan for hyperolactone C and (ꢀ)-biyouyana-
gin A.
Palladium-catalyzed asymmetric allylic alkylation (Pd-
AAA) reactions, which were pioneered by Trost et al., have
proven to be a powerful method for the preparation of a wide
variety of chiral building blocks with high diatereo- and
enantioselectivity.[5] Trost et al. have also demonstrated the
be coupled by a Pd-AAA reaction, then a short and efficient
synthesis of hyperolactone C (3) could be realized after
lactonization of the Pd-AAA product 7. Subsequently, a
photoinduced [2+2] cycloaddition reaction between hyper-
olactone C (3) and 8 would give (ꢀ)-biyouyanagin A (4). This
strategy would not only provide a powerful method to
construct two vicinal quaternary carbon centers in a highly
stereoselective manner, but would also help gain entry to a
range of hyperolactone C and biyouyanagin A analogues
through diverted total synthesis.[7] Herein, we report our
successful construction of two vicinal quaternary carbon
centers by a Pd-AAA reaction. By using this strategy, concise
and efficient total syntheses of hyperolactone C (3) and (ꢀ)-
biyouyanagin A (4) have been achieved. The unnatural
enantiomer, ent-hyperolactone C and (+)-biyouyanagin A,
have also been prepared simply by switching the chiral ligand
[*] C. Du, L. Li, Y. Li, Dr. Z. X. Xie
State Key Laboratory of Applied Organic Chemistry
College of Chemistry and Chemical Engineering
Lanzhou University, Lanzhou, 730000 (China)
E-mail: xiezx@lzu.edu.cn
[**] We are grateful for the financial support provided by the Basic
Research Program (973 Program) of China (grant no.
2010CB833203) and the National Natural Science Foundation of
China (grant nos. 20621091 and 20772050). We thank Mingji Dai
(Columbia University) for helpful discussions.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902908.
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in the Pd-AAA reaction and changing the coupling partner in
ing the reaction after 30 minutes at room temperature, none
the photoinduced [2+2] cycloaddition reaction.
of the desired product 7 was isolated. After careful analysis of
1
As shown in Scheme 3, the synthesis of the Pd-AAA
precursor b-ketoester 5 commenced with benzaldehyde and
methyl acetoacetate, which were converted into d-hydroxy-b-
oxo-pentanoate 10 by using the dianion method developed by
Huchin and Weiler.[8] After treatment of 10 with TsN3 in
the H and 13C NMR spectra of all the compounds that were
isolated, we found that the major product was 13 (61.3%
yield) as well as 14 (30.6% yield) and 15 (2.1% yield). The
formation of 13 suggested that the expected Pd-AAA
reaction for the construction of the two vicinal quaternary
carbon centers did take place, but that the branched product 7
underwent further intramolecular carbonate migration (see
7!13) via a five-membered-ring intermediate to form 13 as a
result of the prolonged reaction time.
The above hypothesis turned out to be correct: when the
reaction was quenched within ten minutes, the desired
branched product 7 and its linear isomer 14 were obtained
in 66% and 31% yield, respectively (Scheme 5). Product 7
was unstable at room temperature and it slowly underwent
Scheme 3. Synthesis of b-ketoester 5. Reagents and conditions:
a) NaH, THF, 08C, 0.5 h; then nBuLi, THF, 0.5 h; benzaldehyde, THF,
2 h, 92%; b) TsN3, Et3N, MeCN, 2 h, 88%; c) DMP, CH2Cl2, 2 h, RT,
91%; d) [Rh2(OAc)4], CH2Cl2, RT, 54%. DMP=Dess–Martin period-
inane, THF=tetrahydrofuran, Ts=p-toluenesulfonyl.
CH3CN, the corresponding a-diazo-b-ketoester 11 was
obtained in 88% yield.[9] Exposure of 11 to Dess–Martin
periodinane in CH2Cl2 at room temperature led to the
formation of the corresponding a-diazo-b-ketoesters 12.[10]
Then 12 was smoothly transformed into b-ketoester 5 in the
presence of a catalytic amount of [Rh2(OAc)4] in CH2Cl2
through a hydrogen migration process.[11]
With 5 in hand, the key Pd-AAA reaction was inves-
tigated. As shown in Scheme 4, b-ketoester 5 was treated with
ligand (R,R)-L1 (3 mol%) and [Pd2(dba)3]·CHCl3 (1 mol%)
in the presence of isoprene monoepoxide 6.[12] Upon quench-
Scheme 5. Construction of two vicinal quaternary carbon centers by
Pd-AAA. Reagents and conditions: a) (R,R)-L1 or (R,R)-L2 (3 mol%),
[Pd2(dba)3]·CHCl3 (1 mol%), CH2Cl2, RT, 10 min; b) TBSCl, imid, DMF,
RT, 75%. DMF=N,N-dimethylformamide, imid=imidazole,
TBS=tert-butyldimethylsilyl.
lactonization to form hyperolactone C (3). After separation
of the isomers, the primary alcohol of 7 was protected as its
TBS ether 16. It was found that the Pd-AAA reaction took
place with high diastereoselectivity (8.7:1) and excellent
enantioselectivity (95% ee), even though a low branched to
linear regioisomeric ratio was obtained (7/14 = 2.1:1). To
improve the selectivity of the reaction, ligand (R,R)-L2 was
used. This time the desired product 7 was obtained with
higher diastereoselectivity (26:1) and better enantioselectiv-
ity (99% ee), but in slightly lower yields for both 7 (59%) and
14 (26%). When ligand (R,R)-L2 was switched to (S,S)-L2,
ent-7 could be synthesized (Table 1, entry 2).
Scheme 4. Attempted Pd-AAA of ketone 5. Reagents and conditions:
a) (R,R)-L1 (3 mol%; see Scheme 5 for structure), [Pd2(dba)3]·CHCl3
(1 mol%), CH2Cl2, RT, 30 min. dba=trans,trans-dibenzylideneacetone.
With these optimized reaction conditions, we sought to
probe the scope of the Pd-AAA reaction with respect to the
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nature of the b-ketoester component. Therefore, b-ketoesters
5a–5d were prepared by a similar protocol to that described
in Scheme 3. As summarized in Table 1, 5a–5d reacted
smoothly with isoprene monoepoxide 6 under the reaction
condition developed with (R,R)-L2 as the chiral ligand.
Substrates with various substitution patterns gave the
expected products in moderate yield, with high diastereose-
lectivity, and excellent enantioselectivity (99% ee). Both
electron-rich (entry 3) and electron-poor (entry 4) function-
Scheme 6. Synthesis of hyperolactone C. Reagents and conditions:
a) PTSA (20 mol%), CH2Cl2, RT, 1 h, 85%. PTSA=toluene-p-sulfonic
acid.
Table 1: Palladium-catalyzed asymmetric allylic alkylation of ketone 7 with catalyst (R,R)-L2.
To synthesize (ꢀ)-biyouyana-
gin A (4), ent-zingiberene (ent-8)[13]
was prepared according to the pro-
cedure reported by Nicolaou
et al.[3f,g] The preparation of 4 was
achieved by employing the reported
biomimetic photoinduced [2+2] cy-
cloaddition (Scheme 7).[3f,g,14] All
the spectroscopic data of synthetic
1H,
Entry
Substrate
d.r. (7/14)[a]
Product[b]
Yield [%][c]
ee [%][a]
(ꢀ)-biyouyanagin A
(4;
13C NMR, IR, and HRMS) are
consistent with those of the natural
1
5 (R1 =Ph, R2 =Me)
5
26:1 (2.1:1)
23:1
16
ent-16
59
54
99
99
2[d]
product.[2]
(+)-Biyouyanagin A,
(ent-7/14=2.3:1)
32:1 (1.8:1)
53:1 (1.6:1)
8.3:1 (2.8:1)
56:1 (2.2:1)
5a (R1 =p-OMeC6H4, R2 =Et)
5b (R1 =p-ClC6H4, R2 =Et)
5c (R1 =isopropyl, R2 =Me)
5d (R1 =(CH2)2OBn, R2 =Me
16a
16b
16c
16d
57
68
55
48
99
99
99
99
which is the unnatural enantiomer
of (ꢀ)-biyouyanagin A (4), could
also been synthesized through the
[2+2] cycloaddition of ent-hypero-
lactone C (ent-3) and zingiberene
(8; Scheme 7). Compound 8 was
isolated from the powder Zingiber
officinale Roscoe.[15] Notably, irra-
diation of a mixture of zingiberene
(8) and hyperolactone C (3) under
3
4
5
6
[a] 7/14=regioisomeric ratio of branched to linear compounds. [b] Determined from analysis of the TBS
ether 16 by HPLC on a chiral stationary phase. [c] Yield of isolated product 7 after column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate 2:1). [d] (S,S)-L2 was used. Bn=
benzyl.
alities on the aromatic ring could be accommodated. Isopro-
pyl and benzyloxyethyl substitutents (entries 5 and 6) also
gave similar results.
the same reaction condition led to a complex mixture.
In summary, we have developed a successful strategy for
the construction of two vicinal quaternary carbon centers with
Having developed an efficient Pd-AAA protocol to
construct the two vicinal quaternary carbon centers in
hyperolactone C (3) and (-)-biyouyanagin A (4), we then
proceeded to finish the total synthesis of hyperolactone C. As
we mentioned before, intermediate 7 slowly underwent
lactonization to generate hyperolactone C (3). This process
was significantly accelerated by treatment with a catalytic
amount of PTSA in CH2Cl2 at room temperature, and
hyperolactone C (3) was generated with d.r. 26:1 in 85%
yield after 1 hour (Scheme 6). Kraus and Wei[3d] reported that
the diastereomer of 7, which was isolated as the by-product in
their elegant synthesis of racemic hyperolactone C, could not
be converted into a lactone using heat, acid (PTSA), or base
(tBuOK, NaH, or KH) catalysis. After careful analysis and
comparison of the NMR data for both the by-product
reported by Kraus and Wei and 13 obtained by us, we
discovered that the so-called diastereomer of 7 was actually
13 (see the Supporting Information). The spectroscopic data
Scheme 7. Total synthesis of natural (ꢀ)-biyouyanagin A (4) and its
enantiomer (+)-biyouyanagin A. Reagents and conditions: a) hn, 3,
(1.0 equiv), ent-8 (4.0 equiv), 2’-acetonaphthone (1.0 equiv), CH2Cl2,
58C, 8 h, 39%, b) hn, ent-3, (1.0 equiv), ent-8 (6.0 equiv), 2’-acetonaph-
thone (1.0 equiv), CH2Cl2, 58C, 8 h, 43%.
1
of our synthetic hyperolactone C (3; H, 13C NMR, IR, and
HRMS) are consistent with those of the natural product.[1]
Ent-hyperolactone C was also prepared by us using the same
method.
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high diatereoselectivity (up to 56:1) and excellent enantiose-
lectivity (99% ee) by using a palladium-catalyzed asymmetric
allylic alkylation reaction. This strategy has enabled the
concise and efficient total syntheses of natural hyperolacto-
ne C and (ꢀ)-biyouyanagin A from benzaldehyde in only six
and seven steps, respectively. The corresponding overall
yields were 20% and 8%. The unnatural enantiomer ent-
hyperolactone C and (+)-biyouyanagin A were also prepared
by simply switching the chiral ligand in the Pd-AAA reaction
and by changing the coupling partner in the final photo-
induced [2+2] cycloaddition reaction.
Received: May 30, 2009
Revised: July 28, 2009
Published online: September 11, 2009
Keywords: asymmetric allylic alkylation · natural products ·
.
palladium · quaternary carbon centers
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[15] See the Supporting Information.
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