Catalytic Asymmetric Crotylation of Aldehydes: Application in Total Synthesis of (-)-Elisabethadione

Article abstract of DOI:10.1002/chem.201500176

A new, highly efficient Lewis base catalyst for a practical enantio- and diastereoselective crotylation of unsaturated aldehydes with E- and Z-crotyltrichlorosilanes has been developed. The method was employed as a key step in a novel asymmetric synthesis of bioactive serrulatane diterpene (-)-elisabethadione. Other strategic reactions for setting up the stereogenic centers included anionic oxy-Cope rearrangement and cationic cyclization. The synthetic route relies on simple, high yielding reactions and avoids use of protecting groups or chiral auxiliaries.

Full text of DOI:10.1002/chem.201500176

DOI: 10.1002/chem.201500176
Communication
&
Asymmetric Catalysis
Catalytic Asymmetric Crotylation of Aldehydes:
Application in Total Synthesis of (ꢀ)-Elisabethadione
Paul S. O’Hora,[a] Celia A. Incerti-Pradillos,[a] Mikhail A. Kabeshov,[a] Sergei A. Shipilovskikh,[a, b]
Aleksandr E. Rubtsov,[b] Mark R. J. Elsegood,[a] and Andrei V. Malkov*[a]
by the low abundance and scarcity of supply of these com-
Abstract: A new, highly efficient Lewis base catalyst for
pounds from their natural sources, make them attractive syn-
a practical enantio- and diastereoselective crotylation of
thetic targets for exploring their therapeutic potential.[3–6] How-
unsaturated aldehydes with E- and Z-crotyltrichlorosilanes
ever, the lack of functional groups near the stereogenic centres
has been developed. The method was employed as a key
represents a significant challenge for stereoselective synthesis.
step in a novel asymmetric synthesis of bioactive serrula-
Our novel, general strategy for setting up the stereogenic
tane diterpene (ꢀ)-elisabethadione. Other strategic reac-
centers at C-1, C-4 and C-11 of the serrulatane skeleton relies
tions for setting up the stereogenic centers included
on enantioselective crotylation of aldehyde 8 to give syn-alco-
anionic oxy-Cope rearrangement and cationic cyclization.
hol 7 followed by stereoselective anionic oxy-Cope rearrange-
The synthetic route relies on simple, high yielding reac-
ment (AOC)[7] and ensuing cationic cyclization[8] (Scheme 1). Im-
tions and avoids use of protecting groups or chiral auxilia-
portantly, the a-methyl of the cinnamyl fragment and the syn
ries.
configuration of the homoallylic alcohol 7 play a crucial role in
assuring an efficient transfer of chirality during the AOC rear-
rangement. Of the two possible chair-like transition structures
Secondary metabolites isolated from marine soft coral Pseu-
dopterogorgia elisabethae exhibit a wide range of useful bio-
logical properties, which include antitubercular, antiinflamma-
tory, antimicrobial and cytotoxic activities,[1] while partially puri-
fied gorgonian extracts are used in commercial skin care prod-
ucts.[2] Selected representatives (1–4) of this family of marine
natural products are shown in Figure 1.
A and B, the TS B is disfavored due to the 1,3-pseudodiaxial
clash. Additionally, the TS A results in E alkene 6, which keys in
a formal 6-endo cyclization to afford the desired 1,4-trans tetra-
lin 5, as shown by Casey and co-workers.[8c]
The success of the strategy relies on the crotylation step
(8!7, Scheme 1), by which chirality is introduced into the
molecule. Herein, we present development of an efficient,
practical and scalable method for catalytic asymmetric crotyla-
tion of unsaturated aldehydes, which is then successfully ap-
plied in the enantioselective total synthesis of serrulatane di-
terpene 2 from the respective a-methyl cinnamaldehyde 8
(Scheme 1).
Potent biological activity and the relatively simple structures
of serrulatane diterpenes 1, 2 and other analogues, augmented
Despite recent advances in the development of catalytic
asymmetric allylation of carbonyl compounds with B- and Si-
based allyl reagents,[9] including contribution from our
Figure 1. Selected Pseudopterogorgia elisabethae secondary metabolites.
[a] Dr. P. S. O’Hora, Dr. C. A. Incerti-Pradillos, Dr. M. A. Kabeshov,
S. A. Shipilovskikh, Dr. M. R. J. Elsegood, Prof. Dr. A. V. Malkov
Department of Chemistry
Loughborough University
Loughborough, LE11 3TU (UK)
Fax: (+44)1509 22 3925
E-mail: A.Malkov@lboro.ac.uk
[b] S. A. Shipilovskikh, Dr. A. E. Rubtsov
Department of Chemistry
Perm State University
Bukireva 15, Perm, 614990 (Russia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500176.
Scheme 1. Retrosynthetic analysis of serrulatane diterpenes.
Chem. Eur. J. 2015, 21, 1 – 6
1
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
group,[10] the related crotylation methodology remains a chal-
lenging problem and is still dominated by stoichiometric chiral
B[11] and Si[12] reagents. The elegant catalytic method for croty-
lation of aldehydes or alcohols with butadiene reported by Kri-
sche[13] looks appealing but it does not match the enantio- and
distereoselectivity level shown by the Type I boron and silicon
reagents.[14] Brønsted acid catalyzed addition of commercial E-
and Z-crotylboronates to aldehydes represented a viable
option,[15] however, due to their relatively high cost and unin-
spiring preliminary attempts,[16] our focus centered on a Lewis
base catalyzed addition of easy to synthesize crotyltrichlorosi-
lanes (Z)-9a and (E)-9b to unsaturated aldehydes.[17]
It is well documented that chiral bipyridine-N,N’-dioxides are
highly efficient catalysts for asymmetric allylation of aldehydes
with allyltrichlorosilanes.[18] However, none of these catalysts
are commercially available and their syntheses either involve
lengthy sequences or give low overall yield, which makes
them unsuitable for larger scale applications. Therefore, we
now designed a new axially chiral bis-N-oxide 10 that can be
synthesized in just four easy steps from inexpensive starting
materials (Scheme 2).
turned out to be an extremely efficient catalyst producing ex-
cellent enantio- and diastereoselectivities over a whole range
of aldehydes tested. Brief screening of solvents identified di-
chloromethane as the optimal choice; propionitrile came
a close second, while THF gave only modest enantioselectivi-
ties. Catalyst 10 proved particularly efficient with unsaturated
aldehydes 16d–f (entries 7–14), though with aliphatic 16g
enantioselectivity dropped (entry 15) representing a common
trend in the catalytic allylation with allyltrichlorosilanes.[18] Dia-
stereoselectivity generally reflected the geometrical purity of
the starting crotyltrichlorosilanes (Z)-9a (Z/E 98:2) and (E)-9b
(E/Z 95:5). However, in propionitrile cinnamyl aldehydes 16d
and 16e appeared to react slightly faster with (Z)-9a giving
the syn-enriched alcohols 17d and 17e, respectively (entries 8,
11).
Therefore, the asymmetric allylation of aldehyde 16h re-
quired for the total synthesis of 2 with (Z)-9a was carried out
in propionitrile. At 0.5 mmol scale the reaction afforded syn-ho-
moallylic alcohol 17h in 85% yield and 97% ee (entry 16). Im-
portantly, applying the same reaction conditions to a larger
5 mmol scale, excellent yield and enantioselectivity retained
(yield 82%, ee 94%, entry 17) paving the way for the asymmet-
ric synthesis of 2.
Table 1. Catalytic asymmetric crotylation of aldehydes.[a]
Scheme 2. Synthesis of (ꢀ)-10 (Ar=3,5-(CF3)2-C6H3).
Entry
16
9a/9b
Solvent
Yield [%]
17/18 [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
16a
16a
16b
16b
16c
16c
16d
16d
16d
16e
16e
16e
16 f
16 f
16g
16h
16h
9a
9b
9a
9b
9a
9b
9a
9a
9b
9a
9a
9b
9a
9b
9b
9a
9a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtCN
CH2Cl2
CH2Cl2
EtCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtCN
94
91
86
81
93
89
83
83
89
92
92
88
80
82
55
85
82
98:2
4:96
98:2
4:96
95:5
5:95
98:2
99:1
5:95
98:2
99:1
3:97
98:2
4:96
4:96
99:1
99:1
92
96
92
96
85
91
95
94
98
98
97
99
98
96
50
97
94
Synthesis of 10 commenced with preparation of the
Krçhnke salt 12 by iodination of ketone 11 in pyridine (yield
73%).[10g] Krçhnke annulation of 12 with commercial (R)-myrte-
nal 13 in formamide in the presence of AcONH4 produced iso-
quinoline 14 (yield 76%), which was converted to the respec-
tive N-oxide 15 by treatment with mCPBA (yield 94%). In the
final step, an oxidative coupling[19] of 15 produced (ꢀ)-10 as
a single distereoisomer. Using 1 equiv of LDA, 10 was com-
monly isolated in 30–35% yield together with ~50% of the un-
reacted 15. Thus, based on the recovered starting material, the
yield of 10 in this protocol is 60–70%. The absolute configura-
tion of the catalyst has not been rigorously established but as-
sumed to be as shown in Scheme 2 by comparison with litera-
ture data.[18h] For the new catalyst 10, we propose the acronym
MAKDIOX (includes initials of the co-author who developed its
synthesis).
9
10
11
12
13
14
15
16
17[d]
EtCN
[a] Unless stated otherwise, the reactions were carried out on a 0.5 mmol
scale at ꢀ608C for 24 h with 2 mol% loading of (ꢀ)-10, 1.7 equiv (Z)-9a
(Z/E 98:2) or (E)-9b (E/Z 95:5) and 2.0 equiv iPr2EtN. [b] Determined by
1H NMR or GC from the crude mixture. [c] ee of the major isomer, the ab-
solute configuration is (1R,2S) for 17 and (1R,2R) for 18 (see Supporting
Information). [d] The reaction was carried out on a 5 mmol scale, for 48 h.
The efficacy of the new catalyst 10 was assessed in the
asymmetric crotylation of model aldehydes 16a–f with crotyl-
trichlorosilanes (Z)-9a and (E)-9b (Table 1). Bis-N-oxide 10
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
To progress with the total synthesis, enantiopure alcohol
(ꢀ)-17h was subjected to the AOC rearrangement using
excess KH and 1 equiv of [18]crown-6 in DME at 408C for 5 h
(Scheme 3). Stereogenic center C-4 in 20 is created during the
rearrangement, whereas C-11 is formed upon protonation of
enolate 19.[20] After a brief optimization of the quenching con-
ditions, the best results were achieved by cooling the reaction
mixture to ꢀ788C, followed by a quick addition of MeOH. In
this way, 20 was obtained with d.r. 3:1. To minimize manipula-
tion of the oxidation-prone aldehyde and to avoid epimeriza-
tion at C-11, crude 20 was subjected to Horner–Wadsworth–
Emmons alkenylation conditions[21] using phosphonate 21. The
corresponding a,b-unsaturated ester 22 was obtained in 84%
yield over 2 steps (d.r. 3:1). The diastereoisomers were not sep-
arable at this stage and the synthesis was continued with the
mixture.
Scheme 4. Completion of the total synthesis of (ꢀ)-elisabethadione 2.
demethylation of (ꢀ)-25 with BBr3 followed by aerobic oxida-
tion was examined.[8e] A clean demethylation did take place
but it was accompanied by hydrobromination of the double
bond. All attempts to eliminate HBr from this product led to
extensive decomposition.
Therefore, the synthesis continued along the route de-
scribed by Davies.[4] Partial deprotection of (ꢀ)-25 using EtSLi
yielded the corresponding bisphenol 26 in 68% yield. Impor-
tantly, in the racemic variant of the synthesis, compound 26,
obtained as a 2:1 mixture of isomers, gave crystals suitable for
X-ray crystallographic analysis,[23] which confirmed the assigned
relative configuration of the major isomer (Figure 2) and also
showed that the two isomers differ only by the configuration
at C-11.
Scheme 3. Anionic oxy-Cope rearrangement of (ꢀ)-17g.
In the endgame, bisphenol 26 was first oxidized to the re-
spective ortho-quinone by CAN, followed by treatment with
TsOH in benzene to afford (ꢀ)-elisabethadione 2 (d.r. 20:1,
20% yield from alcohol (ꢀ)-24), the enantiomer of the natural
product. The synthesized compound exhibited [a]D =ꢀ267
(c = 0.16, CHCl3), opposite in sign but closely matching the ab-
solute value reported by Davies: [a]D = +278 (c = 0.58,
The final stereogenic center C-1 was installed through the
cationic cyclization of 22 upon treatment with MeSO3H to
afford the tetralin derivative 23 (Scheme 4). Importantly, the re-
action proceeded with high stereoselectivity giving only the
1
trans isomer (d.r. >25:1) in 84% yield, as evidenced by H NMR
spectroscopy.
Next, hydrogenation of the double bond in 23
using H-Cube (10% Pd/C) followed by reduction of
the ester with DIBAL-H afforded primary alcohol 24
as a 3:1 mixture of C-11 isomers in 84% overall yield.
At this point, the isomers showed slightly different Rf
values on TLC but gave a clear baseline separation
on an analytical HPLC column. Therefore, separation
of 500 mg of the mixture was successfully accom-
plished by preparative HPLC to furnish pure (ꢀ)-24
(d.r. 20:1). Since this intermediate was employed by
Davies and co-workers[4,5g] in their synthesis of com-
pounds 2-4, it marks the formal total syntheses of all
these secondary metabolites.[22]
To complete the synthesis of (ꢀ)-2, alcohol (ꢀ)-24
was oxidized to the respective aldehyde using Dess–
Martin periodinane (DMP) followed by Wittig alkeny-
Figure 2. Crystal structure of 26 (left) and epi-26 (right) highlighting relative stereochem-
istry. The isomers differ only by the position of C(18) and H(11) on C(11), manifested by
lation to afford (ꢀ)-25. Next, as a possible shortcut to
(ꢀ)-elisabethadione 2, a one-pot sequence involving disorder at C(11).
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
3
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
CHCl3).[4] Other spectral data were also identical to those re-
ported in the literature.[4]
2485–2490. For the formal total synthesis of 3 and 4, see: h) J. Preindl,
C. Leitner, S. Baldauf, J. Mulzer, Org. Lett. 2014, 16, 4276–4279.
[6] For selected examples of total syntheses of other serrulatane diter-
penes, see a) A. Majdalani, H.-G. Schmalz, Synlett 1997, 1303–1305; b) T.
Geller, H.-G. Schmalz, J. W. Bats, Tetrahedron Lett. 1998, 39, 1537–1540;
c) F. Dehmel, J. Lex, H.-G. Schmalz, Org. Lett. 2002, 4, 3915–3918;
d) J. M. H. Lu, M. V. Perkins, H. J. Greisser, Tetrahedron 2013, 69, 6468–
6473.
[7] For the most relevant examples of the AOC rearrangement, see a) L. A.
Paquette, C. A. Teleha, R. T. Taylor, G. D. Maynard, R. D. Rogers, J. C. Gal-
lucci, J. P. Springer, J. Am. Chem. Soc. 1990, 112, 265–277; b) L. A. Pa-
quette, R. E. Maleczka Jr, J. Org. Chem. 1991, 56, 912–913; c) E. Lee, I.-J.
Shin, T.-S. Kim, J. Am. Chem. Soc. 1990, 112, 260–264; d) L. A. Paquette,
G. D. Maynard, Angew. Chem. Int. Ed. Engl. 1991, 30, 1368–1370; Angew.
Chem. 1991, 103, 1392–1394; e) L. A. Paquette, G. D. Maynard, J. Am.
Chem. Soc. 1992, 114, 5018–5027; f) K. Tomooka, S.-Y. Wie, T. Nakai,
Chem. Lett. 1991, 43–46.
[8] For the most relevant examples of cationic cyclizations, see a) E. J.
Corey, S. E. Lazerwith, J. Am. Chem. Soc. 1998, 120, 12777–12782;
b) J. P. Davidson, E. J. Corey, J. Am. Chem. Soc. 2003, 125, 13486–13489;
c) R. Appelbe, M. Casey, A. Dunne, E. Pascarella, Tetrahedron Lett. 2003,
44, 7641–7644; d) K. Surendra, G. Rajendar, E. J. Corey, J. Am. Chem.
Soc. 2014, 136, 642–645; e) J. Deng, R. Li, Y. Luo, J. Li, S. Zhou, Y. Li, J.
Hu, A. Li, Org. Lett. 2013, 15, 2022–2025.
[9] For recent overviews, see a) S. E. Denmark, J. Fu, Chem. Rev. 2003, 103,
2763–2794; b) J. W. J. Kennedy, D. G. Hall, Angew. Chem. Int. Ed. 2003,
42, 4732–4739; Angew. Chem. 2003, 115, 4880–4887; c) M. Yus, J. C.
Gonzꢃlez-Gꢄmez, F. Foubelo, Chem. Rev. 2011, 111, 7774–7854.
In conclusion, we developed a new bis-N-oxide catalyst for
a scalable, highly enantioselective crotylation of unsaturated
aldehydes with E- and Z-crotyltrichlorosilanes. Salient features
of the new catalyst are: i) the synthesis involves four easy steps
from inexpensive, commercially available starting materials and
is amendable to scale up; ii) the new protocol is highly stereo-
selective and does not require chiral resolution or separation
of diastereoisomers. The enantioselective crotylation method
plays a pivotal role in a novel strategy for assembling the
structural core of serrulatane diterpenes, which was illustrated
by the asymmetric total synthesis of ent-elisabethadione 2,
a member of the Pseudopterogorgia elisabethae family of bioac-
tive marine natural products. Other key steps to install the
challenging stereogenic centers include anionic oxy-Cope rear-
rangement and cationic cyclization. The synthetic route relies
on simple, high yielding reactions and avoids use of protecting
groups or chiral auxiliaries. A more detailed investigation into
the scope of the catalytic asymmetric crotylation and develop-
ment of new synthetic applications are currently underway.
ˇ
´
[10] a) A. V. Malkov, L. Dufkovꢃ, L. Farrugia, P. Kocovsky, Angew. Chem. Int. Ed.
2003, 42, 3674–3677; Angew. Chem. 2003, 115, 3802–3805; b) A. V.
Acknowledgements
ˇ
´
Malkov, M. Bell, F. Castelluzzo, P. Kocovsky, Org. Lett. 2005, 7, 3219–
ˇ
3222; c) A. V. Malkov, P. Ramꢁrez-Lꢄpez, L. Biedermannovꢃ, L. Rulꢁsek, L.
We thank the Leverhulme Trust for the Research grant F00
261AD and LU for studentships to P.O.H. and C.A.I.P.
ˇ
´
Dufkovꢃ, M. Kotora, F. Zhu, P. Kocovsky, J. Am. Chem. Soc. 2008, 130,
ˇ
´
5341–5348; d) A. V. Malkov, M. A. Kabeshov, M. Barłꢄg, P. Kocovsky,
Chem. Eur. J. 2009, 15, 1570–1573; e) A. V. Malkov, M. Barłꢄg, Y. Jewkes,
ˇ
ˇ
´
J. Mikusek, P. Kocovsky, J. Org. Chem. 2011, 76, 4800–4804; f) A. V.
Keywords: allylation · asymmetric catalysis · rearrangement ·
stereoselectivity · total synthesis
ˇ
ˇ
´
Malkov, O. Kysilka, M. Edgar, A. Kadlcꢁkovꢃ, M. Kotora, P. Kocovsky,
Chem. Eur. J. 2011, 17, 7162–7166; g) A. V. Malkov, S. Stoncius, M. Bell,
ˇ
ˇ
F. Castelluzzo, P. Ramꢁrez-Lꢄpez, L. Biedermannovꢃ, V. Langer, L. Rulꢁsek,
ˇ
´
P. Kocovsky, Chem. Eur. J. 2013, 19, 9167–9185.
[11] a) H. C. Brown, P. K. Jadhav, J. Am. Chem. Soc. 1983, 105, 2092–2093;
b) H. C. Brown, K. S. Bhat, J. Am. Chem. Soc. 1986, 108, 293–294; c) J.
Garcia, B. Kim, S. Masamune, J. Org. Chem. 1987, 52, 4831–4832; d) R. P.
Short, S. Masamune, J. Am. Chem. Soc. 1989, 111, 1892–1894; e) E. J.
Corey, C. Yu, S. S. Kim, J. Am. Chem. Soc. 1989, 111, 5495–5496; f) W. R.
Roush, A. E. Walts, L. K. Hoong, J. Am. Chem. Soc. 1985, 107, 8186–
8190; g) W. R. Roush, A. D. Palkowitz, K. Ando, J. Am. Chem. Soc. 1990,
112, 6348–6359; h) W. R. Roush, K. Ando, D. B. Powers, A. D. Palkowitz,
R. L. Halterman, J. Am. Chem. Soc. 1990, 112, 6339–6348; i) E. Canales,
K. G. Prasad, J. A. Soderquist, J. Am. Chem. Soc. 2005, 127, 11572–11573.
[12] a) H. Kim, S. Ho, J. L. Leighton, J. Am. Chem. Soc. 2011, 133, 6517–6520;
b) L. M. Suen, M. L. Steigerwald, J. L. Leighton, Chem. Sci. 2013, 4, 2413–
2417.
[1] a) S. A. Look, W. Fenical, G. K. Matsumoto, J. Clardy, J. Org. Chem. 1986,
51, 5140–5145; b) A. D. Rodrꢁguez, C. Ramꢁrez, Org. Lett. 2000, 2, 507–
510; c) A. D. Rodrꢁguez, C. Ramirez, J. Nat. Prod. 2001, 64, 100–102;
d) A. Ata, R. G. Kerr, C. E. Moya, R. S. Jacobs, Tetrahedron 2003, 59,
4215–4222; e) T. J. Heckrodt, J. Mulzer, Top. Curr. Chem. 2005, 244, 1–
41; f) X. Dai, Z. Wan, R. G. Kerr, H. M. L. Davies, J. Org. Chem. 2007, 72,
1895–1900; g) F. Berrue, R. G. Kerr, Nat. Prod. Rep. 2009, 26, 681–710.
[2] A. Kijjoa, P. Sawanwong, Mar. Drugs 2004, 2, 73–82.
[3] For the total syntheses of 1, see: a) R. R. Cesati, III, J. De Armas, A. H.
Hoveyda, J. Am. Chem. Soc. 2004, 126, 96–101; b) H. M. L. Davies, A. M.
Walji, Angew. Chem. Int. Ed. 2005, 44, 1733–1735; Angew. Chem. 2005,
117, 1761–1763; c) J. S. Yadav, A. K. Basak, P. Srihari, Tetrahedron Lett.
2007, 48, 2841–2843; d) T. G. Elford, S. Nave, R. P. Sonawane, V. K. Ag-
garwal, J. Am. Chem. Soc. 2011, 133, 16798–16801; e) J. S. Yadav, B.
Thirupathaiah, A. Al Khazim Al Ghamdi, Eur. J. Org. Chem. 2012, 2072–
2076. For the formal total synthesis of 1, see: f) M. Harmata, X. Hong,
Tetrahedron Lett. 2005, 46, 3847–3849.
[13] a) J. R. Zbieg, E. Yamaguchi, E. L. McInturff, M. J. Krische, Science 2012,
336, 324–327; b) E. L. McInturff, E. Yamaguchi, M. J. Krische, J. Am.
Chem. Soc. 2012, 134, 20628–20631.
[14] S. E. Denmark, E. J. Weber, Helv. Chim. Acta 1983, 66, 1655–1660.
[15] a) S. Lou, P. N. Moquist, S. E. Schaus, J. Am. Chem. Soc. 2006, 128,
12660–12661; b) V. Rauniyar, D. G. Hall, Angew. Chem. Int. Ed. 2006, 45,
2426–2428; Angew. Chem. 2006, 118, 2486–2488; c) V. Rauniyar, H.
Zhai, D. G. Hall, J. Am. Chem. Soc. 2008, 130, 8481–8490; d) P. Jain, J. C.
Antilla, J. Am. Chem. Soc. 2010, 132, 11884–11886; e) C. A Incerti-Pradil-
los, M. A. Kabeshov, A. V. Malkov, Angew. Chem. Int. Ed. 2013, 52, 5338–
5341; Angew. Chem. 2013, 125, 5446–5449; f) T. Miura, Y. Nishida, M.
Morimoto, M. Murakami, J. Am. Chem. Soc. 2013, 135, 11497–11500;
g) P. Motloch, I. Valterovꢃ, M. Kotora, Adv. Synth. Catal. 2014, 356, 199–
[4] For the total syntheses of 2, see: H. M. L. Davies, X. Dai, Tetrahedron
2006, 62, 10477–10484 and ref. [1e].
[5] For the total syntheses of 3 and 4, see: a) K. C. Nicolaou, G. Vassiliko-
giannakis, W. Mꢂgerlein, R. Kranich, Angew. Chem. Int. Ed. 2001, 40,
2482–2486; Angew. Chem. 2001, 113, 2543–2547; b) K. C. Nicolaou, G.
Vassilikogiannakis, W. Mꢂgerlein, R. Kranich, Chem. Eur. J. 2001, 7, 5359–
5371; c) A. I. Kim, S. D. Rychnovsky, Angew. Chem. Int. Ed. 2003, 42,
1267–1270; Angew. Chem. 2003, 115, 1305–1308; d) N. Waizumi, A. R.
Stankovic, V. H. Rawal, J. Am. Chem. Soc. 2003, 125, 13022–13023;
e) D. C. Harrowven, D. D. Pascoe, D. Demurtas, H. O. Bourne, Angew.
Chem. Int. Ed. 2005, 44, 1221–1222; Angew. Chem. 2005, 117, 1247–
1248; f) A. A. Boezio, E. R. Jarvo, B. M. Lawrence, E. N. Jacobsen, Angew.
Chem. Int. Ed. 2005, 44, 6046–6050; Angew. Chem. 2005, 117, 6200–
6204; g) H. M. L. Davies, X. Dai, M. S. Long, J. Am. Chem. Soc. 2006, 128,
ˇ
ˇ
204; h) F. Hessler, A. Korotvicka, D. Necas, I. Valterovꢃ, M. Kotora, Eur. J.
Org. Chem. 2014, 2543–2548.
[16] At 0.5 mmol scale, crotylation of 16g with Z-crotylboronic acid pinacol
ester using chiral phosphoric acid (R)-TRIP (10 mol%), refs. [14d,e], pro-
duced alcohol 17g in 78% yield and 90% ee. However, at a larger
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
4
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Communication
5 mmol scale, under the same conditions, the reaction turned sluggish
and was accompanied by a substantial drop in enantioselectivity (40%
ee).
pova, M. V. Varaksin, E. V. Tretyakov, G. V. Romanenko, D. V. Stass, V. I.
Ovcharenko, J. Org. Chem. 2009, 74, 2870–2872; e) I. S. Kovalev, V. L. Ru-
sinov, O. N. Chupakhin, Chem. Heterocycl. Compd. 2009, 45, 176–181.
[20] In model studies using homoallylic alcohol derived from simple a-
methyl cinnamaldehyde, variation of quenching conditions resulted in
diastereomeric ratios between 3:1 and 1:2.
[17] Isomerically enriched 9a and 9b are routinely synthesized in our labo-
ratory on a 10 g scale by adapting the following protocols: a) J. Tsuji, M.
Hara, K. Ohno, Tetrahedron 1974, 30, 2143–2146; b) M. Kira, T. Hino, H.
Sakurai, Tetrahedron Lett. 1989, 30, 1099–1102; c) K. Iseki, Y. Kuroki, M.
Takahashi, S. Kishimoto, Y. Kobayashi, Tetrahedron 1997, 53, 3513–3526.
For details, see Supporting Information.
[18] a) M. Nakajima, M. Saito, M. Shiro, S. Hashimoto, J. Am. Chem. Soc.
1998, 120, 6419–6420; b) T. Shimada, A. Kina, S. Ikeda, T. Hayashi, Org.
Lett. 2002, 4, 2799–2801; c) T. Shimada, A. Kina, T. Hayashi, J. Org.
[21] M. A. Blanchette, W. Choy, J. T. Davis, A. P. Essenfeld, S. Masamune, W. R.
Roush, T. Sakai, Tetrahedron Lett. 1984, 25, 2183–2186.
[22] Overall, alcohol (ꢀ)-24 was synthesized in 10 steps from 1,3,4-trime-
thoxybenzene. Davies and co-workers (refs. [4,5g]) obtained (+)-24
from the same starting material in the same number of steps but
through a different set of reactions.
Chem. 2003, 68, 6329–6337; d) R. Hrdina, I. Valterovꢃ, J. Hodacovꢃ, I.
[23] Crystal Data for 26: C21H32O3, Mr =332.46, 0.86ꢅ0.60ꢅ0.04 mm3, mono-
clinic, P21/c, a=18.179(3), b=7.3992(10), c=14.334(2) ꢆ, b=99.856(2)8,
ˇ
ˇ
Cꢁsarovꢃ, M. Kotora, Adv. Synth. Catal. 2007, 349, 822–826; e) A. V.
Malkov, M.-M. Westwater, A. Gutnov, P. Ramꢁrez-Lꢄpez, F. Friscourt, A.
V=1899.6(5) ꢆ3, Z=4, 1calcd =1.162Mgmꢀ3 m(MoKa)=0.08 mmꢀ1
, , l=
ˇ
ˇ
ˇ
´
´
Kadlcꢁkovꢃ, J. Hodacovꢃ, Z. Rankovic, M. Kotora, P. Kocovsky, Tetrahe-
0.71073 ꢆ, T=150 K, 2qmax =61.28, 21151 data measured, 5734 inde-
pendent reflections, Rint =0.035, R [F2 >2s(F2), 4047 data]=0.049, wR
[F2, all data]=0.143, residual electron density within ꢁ0.52 eꢆꢀ3. For
details, see Supporting Information. CCDC-999272 (26) contains the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
ˇ
dron 2008, 64, 11335–11348; f) R. Hrdina, M. Dracꢁnsky, I. Valterovꢃ, J.
Hodacovꢃ, I. Cꢁsarovꢃ, M. Kotora, Adv. Synth. Catal. 2008, 350, 1449–
1456; g) A. Kadlcꢁkovꢃ, R. Hrdina, I. Valterovꢃ, M. Kotora, Adv. Synth.
Catal. 2009, 351, 1279–1283; h) A. Kadlcꢁkovꢃ, I. Valterovꢃ, L. Duchꢃ-
ckovꢃ, J. Roithovꢃ, M. Kotora, Chem. Eur. J. 2010, 16, 9442–9445; i) B.
Bai, L. Shen, J. Ren, H.-J. Zhu, Adv. Synth. Catal. 2012, 354, 354–358; j) B.
Bai, H.-J. Zhu, W. Pan, Tetrahedron 2012, 68, 6829–6836.
ˇ
ˇ
ˇ
ˇ
ˇ
[19] a) R. A. Abramovitch, J. Campbell, E. E. Knaus, A. Silhankova, J. Hetero-
cycl. Chem. 1972, 9, 1367–1371; b) Y. Tagawa, K. Hama, Y. Goto, M.
Hamana, Heterocycles 1992, 34, 2243–2246; c) S. E. Denmark, Y. Fan, Tet-
rahedron: Asymmetry 2006, 17, 687–707; d) O. N. Chupakhin, I. A. Ute-
Received: January 15, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Asymmetric Catalysis
P. S. O’Hora, C. A. Incerti-Pradillos,
M. A. Kabeshov, S. A. Shipilovskikh,
A. E. Rubtsov, M. R. J. Elsegood,
A. V. Malkov*
&& – &&
Si-mple! A new catalyst for a practical
and scalable enantio- and diastereose-
lective crotylation of unsaturated alde-
hydes has been developed. The method
was employed as a key step in a novel
asymmetric route to bioactive serrula-
tane diterpene (ꢀ)-elisabethadione (see
scheme). Other strategic reactions for
setting up the stereogenic centers in-
cluded anionic oxy-Cope rearrangement
and cationic cyclization.
Catalytic Asymmetric Crotylation of
Aldehydes: Application in Total
Synthesis of (ꢀ)-Elisabethadione
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!