An organocatalytic asymmetric allylic alkylation allows enantioselective total synthesis of hydroxymetasequirin-a and metasequirin-b tetramethyl ether diacetates

Article abstract of DOI:10.1021/ol4037055

The first highly stereoselective organocatalytic intermolecular allylic alkylation of allylic alcohols with 1,3-dicarbonyls has been developed to allow the first enantioselective total synthesis of hydroxymetasequirin-A and metasequirin-B tetramethyl ethe

Full text of DOI:10.1021/ol4037055

Letter
pubs.acs.org/OrgLett
An Organocatalytic Asymmetric Allylic Alkylation Allows
Enantioselective Total Synthesis of Hydroxymetasequirin‑A and
Metasequirin‑B Tetramethyl Ether Diacetates
Pu-Sheng Wang, Xiao-Le Zhou, and Liu-Zhu Gong*
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, 230026, China
S
* Supporting Information
ABSTRACT: The first highly stereoselective organocatalytic intermolecular allylic alkylation of allylic alcohols with 1,3-
dicarbonyls has been developed to allow the first enantioselective total synthesis of hydroxymetasequirin-A and metasequirin-B
tetramethyl ether diacetates.
ince the seminal reports by Tsuji and Trost on the
palladium-catalyzed allylic alkylation (Scheme 1a),1 this
recent decades, asymmetric organocatalysis has received
tremendous research interest and turned out to be an
indispensable alternative to access chiral substances.4 However,
organocatalytic asymmetric allylic alkylations are truly elusive
and therefore remain a formidable challenge. Herein, we
document the first highly enantioselective organocatalytic allylic
alkylation reaction of allylic alcohols with 1,3-dicarbonyls. More
importantly, this new protocol allows a concise enantioselective
total synthesis of hydroxymetasequirin-A and metasequirin-B
tetramethyl ether diacetates (Scheme 1b).
S
Scheme 1. Asymmetric Allylic Alkylation Reactions
The greatest challenge that needs to circumvent in the allylic
alkylation is undoubtedly the activation of allylic substrates by
the organocatalysts. Basically, the allylic substrates exploited in
the traditional AAA reactions are those installed with relatively
more active leaving groups, such as halides, carbonates, or
acetates (Scheme 1a).2,3 Previous explorations have indicated
that Brønsted acids or Lewis acids are able to facilitate the
conversion of allylic alcohols to π-allylic cationic species either
in combination with transition metals5 or alone6 and, therefore,
allow the reality of organocatalytic allylic alkylation reactions. In
particular, Rueping and co-workers described the first N-
triflylphosphoramide-catalyzed intramolecular enantioselective
allylic alkoxylation of phenol derivatives,7 implying that chiral
Brønsted acids might be able to activate some allylic alcohols to
accomplish more complex transformations. Thus, we envisaged
that the chiral phosphoric acids, which were capable of
catalyzing a range of interesting processes,8 might also be
able to protonate the allylic alcohol to generate a chiral ion pair
transformation has been accepted as one of the most significant
carbon−carbon or carbon−heteroatom bond forming reactions.
In particular, the asymmetric version (AAA) has been a long-
term hot project receiving worldwide attention.2 This reaction
has eventually prompted the explosive development of chiral
ligands and also led to the emergence of synthetically important
protocols, which have enabled the concise enantioselective
synthesis of structurally complicated bioactive molecules.3 In
Received: December 21, 2013
Published: January 14, 2014
© 2014 American Chemical Society
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Letter
(intermediate I),9 and then the resultant conjugate base, a
chiral phosphate, would activate 1,3-dicarbonyl compounds 2
by hydrogen bonding interaction,8b leading to an intermolec-
ular organocatalytic asymmetric allylic alkylation via inter-
mediate II (Scheme 2).
the prolonged reaction time was required to ensure a complete
conversion (entries 10−13). In particular, the reaction still
proceeded even at −35 °C and was able to give 97% ee, but
with a dramatic erosion of the yield (entry 13). In terms of the
yield and stereochemical outcome, the best results were
obtained by conducting the reaction at −20 °C (92% yield,
96% ee, entry 12).
Under the optimized conditions, a variety of substrates,
including electro- and nucleophiles, were then explored (Figure
1). Significantly, this asymmetric allylic alkylation reaction was
Scheme 2. General Principle for the Chiral Brønsted Acid
Catalyzed Intermolecular Asymmetric Allylic Alkylation
Our investigation started with a benchmark allylic alkylation
reaction between (E)-1,3-bis(3,4-dimethoxyphenyl)prop-2-en-
1-ol (1a) and acetylacetone (2a) at 35 °C in the presence of
BINOL derived phosphoric acids8 (Table 1). To our delight,
Table 1. Evaluation of Brønsted Acid Catalysts and
a
Optimization of Reaction Conditions
b
c
entry B*−H
solvent
temp (°C) time (h) yield (%)
ee (%)
1
A1
A2
A3
A4
A5
A5
A5
A5
A5
A5
A5
A5
A5
toluene
toluene
toluene
toluene
toluene
THF
35
35
12
12
12
12
12
36
1
89
97
96
99
98
95
89
97
98
97
96
92
79
22
18
61
38
76
76
81
83
85
91
94
96
97
2
3
35
4
35
5
35
6
35
7
MeCN
DCM
DCE
35
8
35
1.5
1.5
12
9
35
Figure 1. Substrate scope. Unless indicated otherwise, the reaction of
1 (0.05 mmol) and 2 (0.1 mmol) was carried out at −20 °C in the
presence of A5 (10 mol %) for 36 h. Specially, the reactions of 3n and
3q were carried out at 40 °C in toluene for 24 h while the reactions of
3o and 3p were conducted at 0 °C in toluene for 24 h.
10
11
12
13
DCE
0
DCE
−10
−20
−35
24
36
72
DCE
DCE
a
Unless indicated otherwise, reactions performed with 0.05 mmol of
b
c
1a, 0.1 mmol of 2a at 0.05 M. Isolated yield. Determined by HPLC
able to tolerate a wide spectrum of 1,3-dicarbonyl compounds
bearing either a branch chain (3b−3d) or cyclic moiety (3e−
3k), giving rise to the desired product with a quaternary
stereogenic carbon in high yields (up to 97%) and with
excellent enantioselectivities (up to 98% ee) and synthetically
useful diastereoselectivities (up to >15/1). More interestingly,
the compound 3i, which was usually unable to be accessed by
virtue of the transition metal catalyzed reaction, could also be
obtained from the current organocatalytic allylic alkylation
reaction in 96% yield and with >15/1 dr and 98% ee. The
configuration of 3i was determined by X-ray crystallography
analysis of its monoketoxime derivative (see Supporting
Information). Notably, the aromatic substituent of 1,3-diaryl
allylic alcohol had an obvious impact on the reaction. For
instance, although both (E)-1,3-bis(3,4,5-trimethoxyphenyl)-
prop-2-en-1-ol (1b) and (E)-1,3-bis(4-methoxyphenyl)prop-2-
en-1-ol (1c) underwent the asymmetric allylic alkylation, the
analysis.
the reaction catalyzed by A1 proceeded cleanly to give rise to
the desired alkylation product 3a in 89% yield, albeit with a
moderate enantiomeric excess (entry 1). Various structurally
different chiral phosphoric acids (A2−A5), derived from 3,3′-
disubstituted 1,1′-bi-2-naphthols (BINOLs), were evaluated
and found that they were all able to accelerate the reaction
(entries 2−5). Among them, the phosphoric acid A5 turned out
to be the optimal catalyst, capable of offering a nearly
quantitative yield and the highest levels of enantioselectivity
(76% ee, entry 5). An examination of solvents suggested that
halogenated and ether-based solvents were beneficial to the
stereochemical control and led to a considerable improvement
in the reaction performance (entries 6−9). Basically, lowering
the temperature resulted in an enhanced enantioselectivity, but
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corresponding products 3l and 3m were generated in much
lower enantiomeric excesses in comparison with their structural
analogue (Table 1, entry 12). Simple allylic alcohols were also
able to participate in the organocatalytic allylic alkylation to
give rise to the desired products in moderate yields and
enantioselectivities (3n−3q).
Scheme 4. Total Synthesis of Hydroxymetasequirin-A and
Metasequirin-B Tetramethyl Ether Diacetates
The current enantioselective allylic alkylation holds great
synthetic importance and could be applicable to the synthesis of
natural products, for example, hydroxymetasequirin-A and
metasequirin-B (Scheme 3). These two compounds were
Scheme 3. Retrosynthetic analysis of Hydroxymetasequirin-
A and Metasequirin-B Tetramethyl Ether Diacetates
isolated from the heartwood of M. glyptostroboides by A. Enoki
and co-workers in 1977.10 Due to the high polarity, the two
natural products were identified after their phenol and hydroxyl
groups were entirely methylated and acetylated, respectively.
The metasequirin-B, presumably formed from hydroxymetase-
quirin-A, represents a structurally unique norlignan bearing a
dibenzocycloheptene skeleton fused with a tetrahydrofuran
(THF) system. Over the past several decades, a number of
endeavors have been directed toward the synthesis of
metasequirin-B.11 However, the total synthesis of metasequr-
in-B has not been accomplished, yet.
Retrosynthetic analysis of metasequirin-B tetramethyl ether
diacetate (5) indicated that the dibenzocycloheptene skeleton
could be disconnected at the aryl−aryl bond, which would be
assembled by an intramolecular aryl−aryl coupling reaction.
The tetrahydrofuran moiety is principally able to be prepared
by a ring-closing ether formation protocol from 1,2,4-triol 6,
which could be accessed from a sequential procedure consisting
of an α-hydroxylation of γ-lactone 7 and reduction. The key
intermediate 7 was proposed to be synthesized by cascade
Sharpless asymmetric dihydroxylation12 and lactonization of
chiral building block 8, which could be obtained from the
current organocatalytic asymmetric allylic allylation reaction.
The synthetic route to approach metasequirin-B is shown in
Scheme 4. Under the optimized conditions, the asymmetric
allylic alkylation between (E)-1,3-bis(3,4-dimethoxyphenyl)-
prop-2-en-1-ol (1a) and methyl acetoacetate gave rise to the
desired product as a 1:1 mixture of two isomers. The exposure
of the diastereomeric mixture to benzene-1,2-diamine and p-
toluenesulfonic acid (p-TsOH) led to the deacetylation reaction
and furnished 8 in an overall 90% yield in two steps and with
86% ee. The intermediate 8 was directly transformed into 9 in a
65% yield and with 99% ee by a sequential Sharpless
asymmetric dihydroxylation and lactonization. The protection
of the hydroxyl group of 9 with tert-butyldimethylsilyl chloride
led to the formation of compound 7 in a 92% yield. An
oxidative hydroxylation of the lactone 7 with LiHMDS/
MoOPH13 completely generated 10 with >15:1 dr. At this
stage, a direct reduction of the crude α-hydroxy lactone 10 with
NaBH4 furnished the triol 6 in an overall 88% yield in two steps
from 7. The treatment of the triol 6 with TsCl/DMAP at 0 °C
gave rise to the tetrahydrofuran-type intermediate 11, followed
by a deprotection of the TBS group and an acetylation of both
hydroxyl groups to provide hydroxymetasequirin-A tetramethyl
ether diacetate 4 in a 79% yield from the triol 6. Then, we
screened a variety of reaction conditions to directly convert 4 to
metasequirin-B tetramethyl ether diacetate (5),14 but failed.
Ultimately, a two-step reaction sequence, including mono-
bromination of one of two aryl substituents and a palladium
catalyzed intramolecular C−H/C−X biaryl coupling,15 was able
to furnish metasequirin-B tetramethyl ether diacetate (5) in an
overall 26% yield in two steps without observation of the other
atropisomer, but regioisomer 13 was isolated in 36% yield. All
of the spectroscopic data of the synthetic hydroxymetasequirin-
A tetramethyl ether diacetate and metasequirin-B tetramethyl
ether diacetate are in agreement with those reported
previously.16
In conclusion, we have developed the first highly
enantioselective organocatalytic intermolecular allylic alkylation
of allylic alcohols with 1,3-dicarbonyls. More importantly, this
reaction allowed the first enantioselective total synthesis of
hydroxymetasequirin-A tetramethyl ether diacetate (9 steps,
37% overall yield) and metasequirin-B tetramethyl ether
diacetate (11 steps, 10% overall yield). Moreover, the finding
that chiral Brønsted acids were able to efficiently control the
stereoselection of the allylic alkylation involving 1,3-dicarbonyls
actually points out that the related organocatalytic alkylation
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Letter
Petruzziello, D.; De Vincentiis, F.; Cozzi, P. G. Eur. J. Org. Chem. 2011,
647.
(7) Rueping, M.; Uria, U.; Lin, M.-Y.; Atodiresei, I. J. Am. Chem. Soc.
reactions of other soft nucleophiles would be accessed by virtue
of such a strategy.
2011, 133, 3732.
ASSOCIATED CONTENT
■
(8) For pioneering work in the field of chiral BINOL-phosphoric
acids, see: (a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew.
Chem., Int. Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. Reviews on BINOL-phosphoric acids:
(c) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348, 999.
(d) Terada, M. Chem. Commun. 2008, 4097. (e) Adair, G.; Mukherjee,
S.; List, B. Aldrichimica Acta 2008, 41, 31. (f) Terada, M. Synthesis
2010, 1929. (g) Terada, M. Bull. Chem. Soc. Jpn. 2010, 101. (h) Yu, J.;
Shi, F.; Gong, L. Z. Acc. Chem. Res. 2011, 44, 1156.
S
* Supporting Information
Complete experimental procedures and characterization data
for the prepared compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
(9) For recent reciews about asymmetric ion-pairing catalysis, see:
*E-mail: gonglz@ustc.edu.cn.
Notes
(a) Avila, E. P.; Amarante, G. W. ChemCatChem 2012, 4, 1713.
(b) Briere, J. F.; Oudeyer, S.; Dallab, V.; Levacher, V. Chem. Soc. Rev.
̀
2012, 41, 1696. (c) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. Nat.
Chem. 2012, 4, 603. (d) Brak, K.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2013, 52, 534. (e) Mahlau, M.; List, B. Angew. Chem., Int. Ed. 2013,
52, 518.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(10) Enoki, A.; Takahama, S.; Kitao, K. Mokuzai Gakkaishi 1977, 23,
587.
We are grateful for financial support from the NSFC
(21232007), NSFC (21302177), and MOST (973 Project
2010CB833300).
(11) (a) Sancea
3363. (b) Kramer, B.; Waldvogel, S. R. Angew. Chem., Int. Ed. 2004, 43,
2446. (c) Hackeloer, K.; Schnakenburg, G.; Waldvogel, S. R. Eur. J.
́
u, J. Y.; Dhal, R.; Brown, E. Tetrahedron 1994, 50,
̈
Org. Chem. 2011, 6314. (d) Hackeloer, K.; Schnakenburg, G.;
̈
REFERENCES
■
Waldvogel, S. R. Org. Lett. 2011, 13, 916. (e) Hackeloer, K.;
Waldvogel, S. R. Tetrahedron Lett. 2012, 53, 1579.
̈
(1) For the first allylic alkylation, see: (a) Tsuji, J.; Takahashi, H.;
Morikawa, M. Tetrahedron Lett. 1965, 6, 4387. For the first
asymmetric allylic alkylation, see: (b) Trost, B. M.; Fullerton, T. J. J.
Am. Chem. Soc. 1973, 95, 292.
(12) (a) Jacobsen, E. N.; Marko, I.; Mungall, W. S.; Schroeder, G.;
Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 1968. (b) Kolb, H. C.;
Van Nieuwenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994, 94, 2483−
2547.
(13) (a) Vedejs, E. J. Am. Chem. Soc. 1974, 96, 5944. (b) Taschner,
M. J.; Aminbhavi, A. S. Tetrahedron Lett. 1989, 30, 1029.
(14) The classical oxidants for direct Aryl−Aryl coupling including
FeCl3/SiO2, PhI(OTFA)2/BF3·OEt2, and DDQ/MsOH failed to be
applicable for the coupling reaction of 4.
(2) For general reviews of asymmetric allylic alkylation, see:
(a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395.
(b) Trost, B. M. Chem. Pharm. Bull. 2002, 50, 1. (c) Trost, B. M. J.
Org. Chem. 2004, 69, 5813. (d) Falciola, C. A.; Alexakis, A. Eur. J. Org.
Chem. 2008, 3765. (e) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47,
258. (f) Trost, B. M. Org. Process Res. Dev. 2012, 16, 185.
(3) For general reviews of development of chiral ligands for AAA and
its application, see: (a) Trost, B. M. Acc. Chem. Res. 1996, 29, 355.
(b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921.
(c) Trost, B. M.; Fandrick, D. R. Aldrichimica Acta 2007, 40, 59.
(d) Rios, I. G.; Rosas-Hernandez, A.; Martin, E. Molecules 2011, 16,
970. (e) Hong, A. Y.; Stoltz, B. M. Eur. J. Org. Chem. 2013, 2745.
(4) For general reviews of organocatalysis, see: (a) Dalko, P. I.;
Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (b) Seayad, J.; List,
B. Org. Biomol. Chem. 2005, 3, 719. (c) Lelais, G.; MacMillan, D. W. C.
Aldrichimica Acta 2006, 39, 79. (d) Pellissier, H. Tetrahedron 2007, 63,
9267. (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (f) Barbas, C. F., III. Angew. Chem., Int. Ed. 2008, 47,
42. (g) MacMillan, D. W. C. Nature 2008, 455, 304. (h) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(15) (a) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581. (b) Bringmann, G.; Gulder, T.; Gulder, T.
A. M.; Breuning, M. Chem. Rev. 2011, 111, 563. (c) Yamaguchi, J.;
Yamaguchi, A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960.
(d) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 7865.
(16) See the Suporting Information.
(5) For selected examples of transition metal-catalyzed asymmetric
allylic alkylations with allyl alcohols, see: (a) Stary, I.; Stara,
́
G.;
Kocovsky, P. Tetrahedron Lett. 1993, 34, 179. (b) Ozawa, F.;
̂
Okamoto, H.; Kawagishi, S.; Yamamoto, S.; Minami, T.; Yoshifuji,
M. J. Am. Chem. Soc. 2002, 124, 10968. (c) García-Yebra, C.; Janssen,
J. P.; Rominger, F.; Helmchen, G. Organometallics 2004, 23, 5459.
(d) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am. Chem. Soc.
2005, 127, 4592. (e) Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006,
128, 6314. (f) Yamashita, Y.; Gopalarathnam, A.; Hartwig, J. F. J. Am.
Chem. Soc. 2007, 129, 7508. (g) Usui, I.; Schmidt, S.; Breit, B. Org.
Lett. 2009, 11, 1453. (h) Jiang, G. X.; List, B. Angew. Chem., Int. Ed.
2011, 50, 9471. (i) Yasuda, S.; Kumagai, N.; Shibasaki, M. Heterocycles
2012, 86, 745. (j) Krautwald, S.; Sarlah, D.; Schafroth, M. A.; Carreira,
E. M. Science 2013, 340, 1065. (k) Hamilton, J. Y.; Sarlah, D.; Carreira,
E. M. J. Am. Chem. Soc. 2013, 135, 994. (l) Tao, Z. L.; Zhang, W. Q.;
Chen, D. F.; Adele, A.; Gong, L. Z. J. Am. Chem. Soc. 2013, 135, 9255.
(6) For reviews of direct nucleophilic SN1-type allylic alkylations with
allyl alcohols, see: (a) Rueping, M.; Nachtsheim, B. J. Beilstein J. Org.
Chem. 2010, 6, 1. (b) Emer, E.; Sinisi, R.; Capdevila, M. G.;
979
dx.doi.org/10.1021/ol4037055 | Org. Lett. 2014, 16, 976−979