Highly enantio- and diastereoselective vinylogous aldol reaction by LiCl-assisted BINOL-titanium species

Article abstract of DOI:10.1021/ol300946j

The first highly enantio- and diastereoselective vinylogous aldol reaction between propionyl acetate-derived Brassard's diene and aldehydes was accomplished by titanium-lithium combined Lewis acid, affording δ-hydroxy-γ-methyl-β-methoxy acrylates. This methodology was utilized in convenient and concise construction of the polypropionate moiety in cystothiazole A and melithiazole C.

Full text of DOI:10.1021/ol300946j

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2734–2737
Highly Enantio- and Diastereoselective
Vinylogous Aldol Reaction by
LiCl-Assisted BINOLÀTitanium Species
Guowei Wang, Baomin Wang, Shuai Qi, Jinfeng Zhao, Yuhan Zhou, and Jingping Qu*
State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and
Technology, Faculty of Chemical, Environmental and Biological Science and
Technology, Dalian University of Technology, Dalian 116023, P. R. China
qujp@dlut.edu.cn
Received April 12, 2012
ABSTRACT
The first highly enantio- and diastereoselective vinylogous aldol reaction between propionyl acetate-derived Brassard’s diene and aldehydes was
accomplished by titaniumÀlithium combined Lewis acid, affording δ-hydroxy-γ-methyl-β-methoxy acrylates. This methodology was utilized in
convenient and concise construction of the polypropionate moiety in cystothiazole A and melithiazole C.
The asymmetric vinylogous Mukaiyama aldol (AVMA)
reaction has emerged as one of the most applied CÀC bond-
forming transformations in the total synthesis of complex
structures.1 Among all the O-silyl dienolates that have been
developed, the synthetic equivalents of acetoacetate represent
a group of promising reagents as their addition to aldehydes
provides easy access to optically pure δ-hydroxy-β-ketoesters,
versatile key intermediates in the synthesis of biologically
active natural products and commercial drugs.2,3 Meanwhile,
scarce attention has been devoted to the homologous propio-
nyl acetate derived dienolate,4 and no effective catalytic
methodology has been exploited for the AVMA reaction with
propionyl acetate derivatives in terms of both high enantio-
and diastereoselectivity. The vinylogous aldol addition of
propionyl acetate dienolate to aldehyde would deliver
δ-hydroxyl carbonyl compounds with vicinal hydroxymethyl
stereogenic centers which occur frequently in natural products
and pose a great challenge to the organic chemists.
(3) For selected examples of acetoacetate derived dienes, see: (a) Sato,
M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm. Bull. 1994, 42,
839. (b) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117,
12360. (c) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles
1995, 41, 1435. (d) Rosa, M. D.; Soriente, A.; Scettri, A. Tetrahedron:
Asymmetry 2000, 11, 3187. (e) Soriente, A.; Rosa, M. D.; Stanzione, M.;
Villano, R.; Scettri, A. Tetrahedron: Asymmetry 2001, 12, 959. (f) Evans,
D. A.; Murry, J. A.; Kozlowski, M. C. J. Am. Chem. Soc. 1996, 118,
5814. (g) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem. Soc. 1999,
€
121, 669. (h) Kruger, J.; Carreira, E. M. J. Am. Chem. Soc. 1998, 120,
€
837. (i) Pagenkopf, B. L.; Kruger, J.; Stojanovic, A.; Carreira, E. M.
Angew. Chem., Int. Ed. 1998, 37, 3124. (j) Shimada, Y.; Matsuoka, Y.; Irie,
R.; Katsuki, T. Synlett 2004, 57. (k) Le, J. C.; Pagenkofp, B. L. Org. Lett.
2004, 6, 4097. (l) Denmark, S. E.; Beutner, G. L. J. Am. Chem. Soc. 2003,
125, 7800. (m) Denmark, S. E.; Beutner, G. L.; Wynn, T.; Eastgate, M. D. J.
Am. Chem. Soc. 2005, 127, 3774. (n) Denmark, S. E.; Heemstra, J. R., Jr. J.
Org. Chem. 2007, 72, 5668. (o) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org.
Lett. 2005, 7, 5657. (p) Wang, G.; Zhao, J.; Zhou, Y.; Wang, B.; Qu, J. J.
Org. Chem. 2010, 75, 5326. (q) Yoshinari, T.; Ohmori, K.; Suzuki, K. Chem.
Lett. 2010, 39, 1042. (r) Xu, Q.; Yu, J.; Han, F.; Hu, J.; Chen, W.; Yang, L.
Tetrahedron: Asymmetry 2010, 21, 156. (s) Ratjen, L.; Garcia, P. G.; Lay,
F.; Beck, M. E.; List, B. Angew. Chem., Int. Ed. 2011, 50, 754.
(1) For reviews of catalytic AVMA reactions, see: (a) Casiraghi, G.;
Zanardi, F.; Appendino, G.; Rassu, G. Chem. Rev. 2000, 100, 1929. (b)
Soriente, A.; Rosa, M. D.; Villano, R.; Scettri, A. Curr. Org. Chem. 2004,
8, 993. (c) Denmark, S. E.; Heemstra, J. R., Jr.; Beutner, G. L. Angew.
Chem., Int. Ed. 2005, 44, 4682. (d) Casiraghi, G.; Battistini, L.; Curti, C.;
Rassu, G.; Zanardi, F. Chem. Rev. 2011, 111, 3076. (e) Pansare, S. V.;
Paul, E. K. Chem.;Eur. J. 2011, 17, 8770.
(2) For selected examples in total synthesis, see: (a) Kim, Y.; Singer,
R. A.; Carreira, E. M. Angew. Chem., Int. Ed. 1998, 37, 1261. (b)
Paterson, I.; Davis, R. D. M.; Heimann, A. C.; Marquez, R.; Meyer,
A. Org. Lett. 2003, 5, 4477. (c) Aubele, D. L.; Wan, S.; Floreancig, P. E.
Angew. Chem., Int. Ed. 2005, 44, 3485. (d) Custar, D. W.; Zabawa, T. P.;
Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 804. (e) Tenenbaum, J. M.;
Morris, W. J.; Custar, D. W.; Scheidt, K. A. Angew. Chem., Int. Ed.
2011, 50, 5892. (f) Wang, J.; Crane, E. A.; Scheidt, K. A. Org. Lett. 2011,
13, 3086.
(4) Rosa, M. D.; Acocella, M. R.; Rega, M. F.; Scettri, A. Tetra-
hedron: Asymmetry 2004, 15, 3029.
(5) (a) Gerth, K.; Irschik, H.; Reichenbach, H.; Trowitzsch, W.
J. Antibiot. 1980, 33, 1474. (b) Trowitzsch, W.; Reifenstahl, G.; Wray,
V.; Gerth, K. J. Antibiot. 1980, 33, 1480. (c) Ojika, M.; Suzuki, Y.;
Tsukamoto, A.; Sakagami, Y.; Fudou, R.; Yoshimura, T.; Yamanaka,
S. J. Antibiot. 1998, 51, 275. (d) Suzuki, Y.; Ojika, M.; Sakagami, Y.;
€
Fudou, R.; Yamanka, S. Tetrahedron 1998, 54, 11399. (e) Bohlendorf,
B.; Herrmann, M.; Hecht, H. J.; Sasse, F.; Forche, E.; Kunze, B.;
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r
10.1021/ol300946j
Published on Web 05/23/2012
2012 American Chemical Society

Cystothiazole A and melithiazole C represent a group of
fungicidal β-methoxy acrylate antibiotics which have been
isolated from different strains of myxobacteria.5 As shown
in Scheme 1, they share a common pharmacophoric poly-
propionate moiety linked to a bisthiazole, a thiazoleÀ
thiazoline, or a single thiazole ring system via a double
bond. Several total synthesis attempts have been accom-
plished toward compounds of this group, and the syn-
methylmethoxy(hydroxy) vicinal stereogenic centers could
be concisely constructed by asymmetric Evans aldol reac-
tion (catalytic or chiral auxiliary assisted), ring-opening of
methyl oxirane, or crotylation of dimethyl acetal.6 How-
ever, in all of these reports, additional multisteps were
needed to extend the carbon chain for construction of the
β-methoxy acrylate moiety. Consequently, with the goal of
a more convenient and faster synthetic strategy, we con-
sidered the AVMA reaction between aldehyde and the
propionyl acetate derived Brassard’s diene 17 as a poten-
tially powerful tool for simultaneous formation of the
vicinal stereogenic centers and the β-methoxy acrylate
moiety. Based on the two points mentioned above, we
started our research to investigate the AVMA reaction
between aldehydes and Brassard-type diene 1, and in this
paper we describe our efforts toward this goal.
catalytic conditions.7 Previously, our group reported a
novel combined Lewis acid8 catalyst BINOLÀTiÀ
H2OÀLiCl (BTHL) that was generated in situ by equal
molar combination of hydrolyzed BINOLÀTi species and
weak Lewis acid LiCl (Figure 1) to effectively promote the
AVMA reaction between aldehydes and acetoacetate-
derived Brassard’s diene.3p We reasoned that the terminal
methyl substituent at C4 position of the diene 1 may
facilitate its facial discrimination toward the attacked
aldehyde in aldol reaction compared with its acetoacetate
analogue.
Figure 1. Proposed structure for (R)-BTHL: weak Lewis acid
(LiCl) assisted BINOLÀTi species.
We initiated our research employing 5 mol % of the
catalytic (R)-BTHL in the addition of Brassard’s diene 1 to
benzaldehyde at 25 °C in THF. To our delight, this
reaction delivered the linear aldol product 3a in 80% yield
with perfect enantio- and diasteroselectivity (99.4% ee and
dr = 98:2), while only 19% of cycloadduct 4a was yielded
(Table 1, entry 1). The configuration of the double bond in
3a was identified as Z via the NOE difference spectroscopy
by measurement of the alkene hydrogen and the γ-methyl
hydrogen. To the best of our knowledge, this is the first
example of highly both enantio- and diastereoselective
AVMA reaction of propionyl acetate derived Brassard’s
diene with aldehydes.
Scheme 1. Examples of Antibiotics Isolated from Myxobacteria
and Our Retrosynthetic Analaysis
Table 1. Various (R)-BINOL-Ti Species Catalyzed AVMA
Reaction of Brassard’s Diene 1 with Benzaldehyde 2aa
For the AVMA reaction of Brassard’s diene 1 with
aldehyde, the challenge would mainly lie in the triple
selectivities: not only the inherent enantio- and diastereos-
electivity but also the chemoselectivity that a competitive
hetero-DielsÀAlder reaction could also happen under the
entry BINOL/Ti(O-i-Pr)4/H2O/LiCl 3ab (%) drc eec (%) 4ab (%)
(6) For selected examples of total synthesis, see: (a) Williams, D. R.;
Patnaik, S.; Clark, M. P. J. Org. Chem. 2001, 66, 8463. (b) Bach, T.;
Heuser, S. Angew. Chem., Int. Ed. 2001, 40, 3184. (c) Bach, T.; Heuser, S.
Chem.;Eur. J. 2002, 8, 5585. (d) Kato, K.; Nishimura, A.; Yamamoto,
Y.; Akita, H. Tetradron Lett. 2002, 43, 643. (e) Deroy, P. L.; Charette,
A. B. Org. Lett. 2003, 5, 4163. (f) Shao, J.; Panek, J. S. Org. Lett. 2004, 6,
3083. (g) Clough, J. M.; Dube, H.; Martin, B. J.; Pattenden, G.; Reddy,
K. S.; Waldron, I. R. Org. Biomol. Chem. 2006, 4, 2906. (h) Takayama,
H.; Kato, K.; Kimura, M.; Akita, H. Heterocycles 2007, 71, 75. (i)
Gebauer, J.; Arseniyadis, S.; Cossy, J. Org. Lett. 2007, 9, 3425. (j)
Gebauer, J.; Arseniyadis, S.; Cossy, J. Eur. J. Org. Chem. 2008, 2701.
(7) For HDA reaction of Brassard’s diene with aldehydes, see: (a)
Togni, A. Organometallics 1990, 9, 3106. (b) Fan, Q.; Lin, L.; Liu, J.;
Huang, Y.; Feng, X.; Zhang, G. Org. Lett. 2004, 6, 2185. (c) Fan, Q.; Lin,
L.; Liu, J.; Huang, Y.; Feng, X. Eur. J. Org. Chem. 2005, 3542. (d) Du,
H.; Zhao, D.; Ding, K. Chem.;Eur. J. 2004, 10, 5964. (e) Lin, L.; Fan,
Q.; Qin, B.; Feng, X. J. Org. Chem. 2006, 71, 4141. (f) Lin, L.; Chen, Z.;
Yang, X.; Liu, X.; Feng, X. Org. Lett. 2008, 10, 1311. (g) Lin, L.; Kuang,
Y.; Liu, X.; Feng, X. Org. Lett. 2011, 13, 3868.
1d
2
1:1:1:1
1:1:1:1
1:1:0:0
1:1:1:0
1:1:0:1
80
94
55
96
58
98:2
99:1
99.4
99.6
19
6
3
64:36 79.4
52:48 29.6
44
4
4
5
92:8
92.7
41
a Unless specially noted, all reactions were performed with 0.5 mmol of
benzaldehyde and 1 mmol of Brassard’s diene 1 in 2 mL of THF at 25 °C
over 16 h. b Isolated yield. c Determined by HPLC analysis using chiral OJ-
H column. d The catalyst loading is 5 mol % and reaction time is 40 h.
An increase of the (R)-BTHL loading to 10 mol %
greatly depressed the HDA pathway and afforded the
aldol product 3a almost exclusively (yield 94%, dr = 99:1,
Org. Lett., Vol. 14, No. 11, 2012
2735

ee = 99.6%, entry 2). Some comparison experiments
were then carried out to highlight the indispensability of
both H2O and LiCl in the high performance of BTHL
(entries 3À5, Table 1). At first, the simple equal molar
combination of (R)-BINOL and Ti(O-i-Pr)4 was tested
under identical conditions, and the desired aldol product
3a was obtained in only 55% yield with disappointing
selectivities (dr = 64:36, 79% ee, entry 3), while 44%
yield of the HDA product 4a was produced. When the
(R)-BINOLÀTi complex was hydrolyzed with 1 equiv of
water and used as catalyst,9 the aldol product 3a was
dominantly obtained with only a trace of 4a, whereas the
enantio- and diastereoselectivity dropped dramatically
(dr = 52:48, 29.6% ee, entry 4). When LiCl was added to
the (R)-BINOLÀTi complex in the absence of H2O, both
the enantio- and diastereoselectivity were increased signif-
icantly (dr = 92:8, 93% ee, entry 5), while the poor
selectivity of aldol/HDA product sustained compared with
entry 2. All these experiments demonstrated that the
presence of both LiCl and H2O was essential for the high
performance of BHTL.
The substrate generality of this methodology was then
investigated utilizing 10 mol % of (R)-BTHL, and the
results are summarized in Table 2. Various substituted
benzaldehydes 2aÀk, bearing an electron-donating and -
withdrawing group on the benzene ring, smoothly pro-
ceeded through the aldol reaction with Brassard’s diene 1
to afford the target compounds with excellent yields and
enantio- and diastereoselectivities (82À94% yields, dr =
98:2À99:1, 98À99% ee, entries 1À11, Table 2). The fur-
aldehyde and cinnamaldehyde were also tolerated with
excellent results (entries 12 and 13). Moreover, aliphatic
aldehydes were also suitable substrates, although an ex-
tended time to 40 h was needed for acceptable yields.
Linear aliphatic aldehyde 2nÀp underwent the aldol reac-
tion smoothly in good yields with excellent stereoselectiv-
ities (yield 67À75%, dr = 99:1, 99% ee, entries 14À16).
The crotonaldehyde 2q and phenylpropanal 2r were also
well tolerated (entries 17 and 18).
Table 2. (R)-BTHL-Catalyzed AVMA Reaction of Brassard’s
Diene 1 with Various Aldehydesa
entry
R
yieldb (%) syn/antic
eec (%)
99
1
C6H5 (2a)
94
92
92
88
93
90
94
91
93
93
82
95
96
75
71
67
48
86
99:1
99:1
99:1
99:1
99:1
99:1
98:2
99:1
99:1
99:1
98:2
99:1
99:1
99:1
99:1
99:1
99:1
99:1
2
p-CH3C6H4 (2b)
o-CH3OC6H4 (2c)
p-CH3OC6H4 (2d)
3,4,5-(CH3O)3C6H2 (2e)
o-ClC6H4 (2f)
99
3
99
4
99
5
99
6
99
7
p-ClC6H4 (2g)
98
8
p-BrC6H4 (2h)
o-FC6H4 (2i)
99 (R, R)e
99
9
10
11
12
13
p-FC6H4 (2j)
99
p-NO2C6H4 (2k)
2-furyl (2l)
98
99
C6H5CHdCH (2m)
99
14d n-C3H7 (3n)
15d n-C4H9 (2o)
16d n-C5H11 (2p)
17d CH3CHdCH (2q)
99
99
99
99
18
C6H5CH2CH2 (2r)
99
a Unless specially noted, all reactions were performed with 0.5 mmol
of aldehyde 2aÀr and 1 mmol of Brassard’s diene 1 in 2 mL of THF at
25 °C over 16 h. b Isolated yield. c Determined by HPLC analysis using
indicated chiral columns. d Over 40 h. e The absolute configuration was
determined unambigously by X-ray crystal analysis; see below.
NaOH in methanol to afford the cycloproduct 4h in 25%
yield for two steps with maintained stereoselectivity (dr =
98:2, 98% ee). Solvent screening revealedthatinCHCl3 the
quick isomerization was accomplished in 30 min, and
followed by annulation, 60% yield of the lactone 4h was
obtained albeit with epimerization (dr = 89:11, 92% ee).
The lactone 4h shares the same subunit with many biolo-
gically active natural products, such as prelactones, leio-
dermatolide, and disdodermatolide,10 which greatly
expands the scope of this methodology. The absolute
configuration of 4h was unambiguously determined to be
(5R,6R) by X-ray crystal analysis,11 and the aldol product
3h was assigned to be (4R,5R) accordingly.12 The absolute
configuration of the hydroxyl carbon center parallels that
which we observed in the previous report.3p
We have previously revealed that the Brassard-type
diene derived Z aldol product would transform to a
thermodynamically more stable E isomer under acidic
conditions.3p However, when the aldol product 3h was
treated with TFA in THF at 0 °C, the isomerization was
rather slow (Scheme 2). We reasoned that the γ-methyl
group posed a steric hindrance which decreased the energy
difference of the E/Z isomers. After being stirred over 24 h,
without purification, the residue was treated with 1 M
(10) For recent examples of total synthesis, see: (a) Yamashita, Y.;
Saito, S.; Ishitani, H.; Kobayashi, S. Org. Lett. 2002, 4, 1221. (b) Yadav,
J. S.; Reddy, M. S.; Prasad, A. R. Tetrahedron Lett. 2005, 46, 2133. (c)
(8) For review of combined acid in asymmetric catalyst design, see:
(a) Yamamoto, H.; Futatsugi, K. Angew. Chem., Int. Ed. 2005, 44, 1924.
For selected examples, see: (b) Kitamura, M.; Suga, S.; Kawai, K.;
Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071. (c) Oishi, M.; Aratake, S.;
Yamamoto, H. J. Am. Chem. Soc. 1998, 120, 8271. (d) Ishihara, K.;
Kobayashi, J.; Inanaga, K.; Yamamoto, H. Synlett 2001, 393. (e)
Ishitani, H.; Komiyama, S.; Kobayashi, S. Angew. Chem., Int. Ed.
1998, 37, 3186. (f) Hanawa, H.; Hashimoto, T.; Maruoka, K. J. Am.
Chem. Soc. 2003, 125, 1708. (g) Li, P.; Yamamoto, H. J. Am. Chem. Soc.
2009, 131, 16628. (h) Cheon, C. H.; Kanno, O.; Toste, F. D. J. Am.
Chem. Soc. 2011, 133, 13248.
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Paterson, I.; Dalby, S. M.; Roberts, J. C.; Naylor, G. J.; Guzman, E. A.;
Isbrucker, R.; Pitts, T. P.; Linley, P.; Divlianska, D.; Reed, J. K.; Wright,
A. E. Angew. Chem., Int. Ed. 2011, 50, 3219. (d) Smith, A. B., III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto,
H.; Jones, D. R.; Kobayashi, J. J. Am. Chem. Soc. 2000, 122, 8654. (e)
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Lemos, E. D.; Poree, F. H.; Commerc-on, A.; Betzer, J. F.; Pancrazi, A.;
Ardisson, J. Angew. Chem., Int. Ed. 2007, 46, 1917.
(11) CCDC 867439 (4h) is available free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(12) For the assumed transition state for the syn-diastereoselectivity,
see the Supproting Information.
(9) (a) Kitamoto, D.; Imma, H.; Nakai, T. Tetrahedron Lett. 1995, 36,
1861. (b) Takizawa, S.; Somei, H.; Jayaprakash, D.; Sasai, H. Angew.
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2736
Org. Lett., Vol. 14, No. 11, 2012

easily synthesized from compound 7 according to the
reported procedure via olefin cross-metathesis (Scheme 3).
We believe that this methodology provides a common
strategy for convenient and concise construction of the
polypropionate moiety in all the related antibiotics.
Scheme 2. Lactonization of 3h and the Structure of 4h Deter-
mined by X-ray Crystal Analysisa
Scheme 3. Formal Synthesis of Melithiazole C and Cystothia-
zole A
a Ellipsoids set at 30% probability.
With elucidation ofthe syn stereochemistry ofthe vicinal
stereogenic centers which is consistent with the above-
mentioned β-methoxy acrylate fungicides, we set out to
examine the versatility of this methodology in the synthesis
ofthesestructures. Wechosethe tributylstannylacrolein2s
as the starting aldehyde because we reasoned that the
tributylstannyl group was a good synthetic handle for
further Stille coupling. Using (R)-BTHL as catalyst, the
aldehyde 2s reacted smoothly with Brassard’s diene 1 to
afford the desired compound 5 in perfect yield up to 94%.
The aldol product 5 was then treated with TFA in CHCl3
to undergo the Z/E isomerization. However, the tributyl-
stannyl group was detached unexpectedly, and product 6
was obtained in 63% yield with simultaneously thorough
Z/E isomerization of the double bond in the acrylate
moiety, and the epimerization could be avoided with
well-controlled reaction time and conditions (syn/anti =
98:2, ee = 98%). The hydroxyl group of compound 6 was
then methylated using TMSCHN2 in the presence of
In conclusion, we have described the first highly enantio-
and diastereoselective AVMA reaction of propionyl acet-
ate derived Brassard’s diene with aldehydes catalyzed by
LiCl assisted BINOLÀTi species. The methodology fea-
tures high stereoselectivity and a wide aldehydes tolerance
under mild conditions. In addition, the utility of this
protocol was demonstrated in the convenient and formal
synthesis of cystothiazole A and melithiazole C.
Acknowledgment. We acknowledge financial support
from the National Natural Science Foundation of China
(Nos. 20972022, 21076035) and the “111” project of
Ministry of Education of China.
Supporting Information Available. Experimental pro-
cedures, spectral and analytical data, and crystallo-
graphic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
BF3 OEt2 affording the known building block 7 in 33%
yield. Both cystothiazole A6i and melithiazole C6j could be
3
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
2737