Stereoselective synthesis of bicyclic tertiary alcohols with quaternary stereocenters via intramolecular crossed benzoin reactions catalyzed by n-heterocyclic carbenes

Article abstract of DOI:10.1021/ol9019293

Bicyclic tertiary alcohols 1 bearing quaternary stereocenters at the two adjacent bridgehead positions were synthesized with high stereoselectivity via the intramolecular crossed benzoin reactions catalyzed by NHC organocatalysts.

Full text of DOI:10.1021/ol9019293

ORGANIC
LETTERS
2009
Vol. 11, No. 21
4866-4869
Stereoselective Synthesis of Bicyclic
Tertiary Alcohols with Quaternary
Stereocenters via Intramolecular
Crossed Benzoin Reactions Catalyzed
by N-Heterocyclic Carbenes
Tadashi Ema,* Yoshitaka Oue, Kumiko Akihara, Yuki Miyazaki, and
Takashi Sakai*
DiVision of Chemistry and Biochemistry, Graduate School of Natural Science and
Technology, Okayama UniVersity, Tsushima, Okayama 700-8530, Japan
ema@cc.okayama-u.ac.jp; tsakai@cc.okayama-u.ac.jp
Received August 19, 2009
ABSTRACT
Bicyclic tertiary alcohols 1 bearing quaternary stereocenters at the two adjacent bridgehead positions were synthesized with high stereoselectivity
via the intramolecular crossed benzoin reactions catalyzed by NHC organocatalysts.
Asymmetric organocatalysis is a rapidly growing area in
organic synthesis.1 Among various kinds of organocatalysts,
N-heterocyclic carbenes (NHCs), which can catalyze the
C-C bond formation via polarity inversion (Umpolung), are
one of the most powerful and useful organocatalysts.2 NHCs
are known to catalyze the benzoin reaction,3,4 the Stetter
reaction,5 the aza-Morita-Baylis-Hillman reaction,6 the
generation of homoenolate species followed by a C-C bond
formation,7 the cycloaddition of ketenes,8 the acylation of
alcohols,9 and other useful reactions.10,11
We envisioned that the NHC-catalyzed intramolecular
crossed benzoin reactions of cyclic diketones 2 would give
bicyclic compounds 1 as shown in Scheme 1. The target
compounds 1 are tertiary alcohols having quaternary stereo-
(1) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, 2005. (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005,
3, 719–724.
(4) For asymmetric NHC-catalyzed intramolecular benzoin reactions,
see: (a) Takikawa, H.; Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem.,
Int. Ed. 2006, 45, 3492–3494. (b) Enders, D.; Niemeier, O.; Balensiefer,
T. Angew. Chem., Int. Ed. 2006, 45, 1463–1467. (c) Enders, D.; Niemeier,
O.; Raabe, G. Synlett 2006, 2431–2434. (d) Li, Y.; Feng, Z.; You, S.-L.
Chem. Commun. 2008, 2263–2265.
(2) For reviews and accounts on NHC-catalyzed asymmetric synthesis,
see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res. 2004, 37, 534–541.
(b) Enders, D.; Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606–
5655. (c) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew. Chem., Int.
Ed. 2007, 46, 2988–3000. (d) Rovis, T. Chem. Lett. 2008, 37, 2–7. (e)
Enders, D.; Narine, A. A. J. Org. Chem. 2008, 73, 7857–7870.
(3) For asymmetric NHC-catalyzed intermolecular benzoin reactions,
see: (a) Knight, R. L.; Leeper, F. J. J. Chem. Soc., Perkin Trans. 1 1998,
1891–1893. (b) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41,
1743–1745. (c) Tachibana, Y.; Kihara, N.; Takata, T. J. Am. Chem. Soc.
2004, 126, 3438–3439. For the latest nonchiral version, see: (d) Enders,
(5) (a) Kerr, M. S.; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298–10299. (b) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc.
2004, 126, 8876–8877. (c) Liu, Q.; Rovis, T. J. Am. Chem. Soc. 2006, 128,
2552–2553. (d) Read de Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T. J.
Org. Chem. 2008, 73, 2033–2040. (e) Cullen, S. C.; Rovis, T. Org. Lett.
2008, 10, 3141–3144. (f) Enders, D.; Han, J.; Henseler, A. Chem. Commun.
2008, 3989–3991.
(6) (a) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466–7468.
(b) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825–2829.
D.; Henseler, A. AdV. Synth. Catal. 2009, 351, 1749–1752
.
10.1021/ol9019293 CCC: $40.75
Published on Web 10/01/2009
 2009 American Chemical Society

Scheme 1
.
Intramolecular Crossed Benzoin Reaction Catalyzed
by NHC Organocatalyst
Table 1. NHC-Catalyzed Benzoin Cyclization of 2a
temp
substrate
Et3N
product
yieldb
(%)
entry
(°C)
2
(mol %)
1
1
2
3
25
25
25
66
66
66
66
66
66
66
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
20
15
10
20
20
20
20
20
20
20
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
65
46
42
81
29
59
82
76
73
40
4
5c
6
7
8
9
10
a Conditions: 2 (0.300 mmol), NHC cat. A (0.060 mmol, 20 mol %),
Et3N (quantity indicated above), THF (1 mL), 24 h. b Isolated yield of 1.
c NHC cat. B (20 mol %) was used.
the facile stereoselective synthesis of 1 using NHC precursors
A-E (Figure 1).
We first explored the annulation of 2a, which can be
prepared most easily according to the literature,13a by using
achiral NHC precatalysts, triazolium salt A and thiazolium
salt B. The results are shown in Table 1. The reaction was
initially performed with 20 mol % of triazolium salt A and
Et3N in THF at 25 °C for 24 h to give 1a as a single
diastereomer in 65% (entry 1). The cis-configuration of 1a
was confirmed by the NOE experiment after 1a had been
converted into 3 (Scheme 2); a positive NOE was observed
for the signal of the TMS group upon irradiation of the
methyl group at the bridgehead position (Supporting Infor-
mation). The addition of 1 equiv of Et3N was necessary for
generating NHC most efficiently (entries 1-3). Increasing
the reaction temperature up to 66 °C afforded 1a in 81%
(entry 4). In contrast, the use of thiazolium salt B resulted
in a lower yield (entry 5). The substrate scope was then
investigated by using triazolium salt A. The homologues 2b,
2c, and 2e, which were prepared according to the
literature,13b-d and newly synthesized 2d and 2f were
subjected to the NHC-catalyzed reaction. In all cases, bicyclic
compounds 1b-f were obtained completely diastereoselec-
tively in moderate to high yields (entries 6-10).
Next, we examined the asymmetric desymmetrization of
2 using chiral NHCs. Chiral triazolium salt D prepared
according to the literature,14 and commercially available
chiral triazolium salts C and E were employed. NHC
precatalyst C, which has been reported by Rovis to show
high catalytic activity and enantioselectivity in the intramo-
lecular Stetter reactions,5b-e was initially used to optimize
the reaction conditions for 2a. The results are summarized
in Table S1 (Supporting Information), and the best result is
shown in Table 2 (entry 1). Despite various attempts, 38%
Figure 1. NHC organocatalysts A-E.
centers at the two adjacent bridgehead positions. Interest-
ingly, a series of homologues 1, except for racemic 1d,12
are new compounds, which may suggest that they are difficult
to prepare by other synthetic methods. Further conversions
of 1 into other new compounds can also be expected. Because
of these features, compounds 1 are the fascinating chiral
building blocks worthy of synthetic study. Here, we report
(7) (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004,
126, 14370–14371. (b) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed.
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T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098–10099. (g)
Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008,
130, 2416–2417. (h) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008,
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Catal. 2008, 350, 1885–1890. (j) Matsuoka, Y.; Ishida, Y.; Sasaki, D.; Saigo,
K. Chem.sEur. J. 2008, 14, 9215–9222.
(8) (a) Zhang, Y.-R.; He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett.
2008, 10, 277–280. (b) Zhang, Y.-R.; Lv, H.; Zhou, D.; Ye, S. Chem.sEur.
J. 2008, 14, 8473–8476. (c) He, L.; Lv, H.; Zhang, Y.-R.; Ye, S. J. Org.
Chem. 2008, 73, 8101–8103. (d) Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S.
Angew. Chem., Int. Ed. 2009, 48, 192–195.
(9) (a) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P. J. Org.
Chem. 2004, 69, 209–212. (b) Suzuki, Y.; Yamauchi, K.; Muramatsu, K.;
Sato, M. Chem. Commun. 2004, 2770–2771.
(10) (a) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006,
128, 8418–8420. (b) He, M.; Uc, G. J.; Bode, J. W. J. Am. Chem. Soc.
2006, 128, 15088–15089. (c) Chiang, P.-C.; Kaeobamrung, J.; Bode, J. W.
J. Am. Chem. Soc. 2007, 129, 3520–3521. (d) He, M.; Bode, J. W. J. Am.
Chem. Soc. 2008, 130, 418–419. (e) Struble, J. R.; Kaeobamrung, J.; Bode,
J. W. Org. Lett. 2008, 10, 957–960. (f) He, M.; Beahm, B. J.; Bode, J. W.
Org. Lett. 2008, 10, 3817–3820.
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T.; Node, M. Tetrahedron: Asymmetry 2006, 17, 1655–1662. (b) Hayashi,
Y.; Sekizawa, H.; Yamaguchi, J.; Gotoh, H. J. Org. Chem. 2007, 72, 6493–
6499. (c) Katoh, T.; Mizumoto, S.; Fudesaka, M.; Nakashima, Y.; Kajimoto,
T.; Node, M. Synlett 2006, 2176–2182. (d) Deschamp, J.; Riant, O. Org.
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Org. Lett., Vol. 11, No. 21, 2009
4867

for 30 min, 2a was added. Surprisingly, the enantiomeric
purity, but not the yield, increased up to 78% ee (entry 6).
To improve both yield and enantioselectivity, the reaction
temperature (entries 7-9), base (entries 7, 10-12), and
solvent (entries 12-15) were surveyed. The highest enan-
tiomeric purity of 1a was achieved at 23 °C, although the
yield needed to be improved (entry 7). Curiously, neither
substrate 2a nor distinct byproduct could be isolated through-
out this survey even when 1a was obtained in a low yield.
The use of Cs2CO3 as a base gave the highest yield (entry
12). When the reaction was performed in the presence of
Cs2CO3 in CH2Cl2 at 23 °C, (+)-1a was obtained in 50%
yield with 78% ee (entry 15).
Scheme 2
.
Derivatization of 1a To Determine Relative
Configuration
Table 2. NHC-Catalyzed Asymmetric Benzoin Cyclization of
2aa
temp
NHC
base
(mol %)
yieldb eec
Scheme 3. Determination of Absolute Configuration of (+)-1a
entry (°C) (mol %)
solvent
(%)
(%)
1
2
3
4
rt
rt
rt
rt
rt
rt
23
30
60
23
23
23
23
23
23
C(20)
D(20)
E(20)
E(20)
E(20)
E(20)
E(30)
E(30)
E(30)
E(30)
E(30)
E(30)
E(30)
E(30)
E(30)
Et3N (20)
Et3N (20)
Et3N (20)
DBU (20)
DBU (20)
DBU (20)
DBU (30)
DBU (30)
DBU (30)
THF
THF
toluene trace
toluene
toluene
toluene
toluene
toluene
toluene
61
12
-38
30
d
69
58
78
75
65
25
d
15
19
12
25
41
64
5a
6a
7
8
9
10
11
12
13
14
15
i-Pr2NEt (30) toluene trace
K2CO3 (30)
Cs2CO3 (30)
Cs2CO3 (30)
Cs2CO3 (30)
Cs2CO3 (30)
toluene
toluene
THF
MeCN
CH2Cl2
29
48
42
e
76
70
71
d
50
78
a Conditions: 2a (0.300 mmol), NHC cat. (quantity indicated above),
base (quantity indicated above), solvent (1 mL for entries 1-4, 6 mL for
entries 5-15), 24 h. NHC was generated after 2a had been added (entries
1-5), or 2a was added after NHC had been generated (entries 6-15).
b Isolated yield of 1a. c Determined by chiral GC (CP-cyclodextrin-ꢀ-2,3,6-
M-19 column). The sign of the enantiomeric purity is that of the specific
rotation. d Not determined. e Complex mixture.
The absolute configuration of (+)-1a was determined by
chemical correlation as shown in Scheme 3. The chiral
intermediate (+)-4, whose relative and absolute configura-
tions had been established, was prepared from 2-methyl-1,3-
cyclohexanedione in four steps according to the literature.13a
Ozonolysis of (+)-4 gave aldehyde (+)-5, which was
converted into bicyclic compound (+)-6 by using triazolium
salt A in Figure 1. Deprotection of the MOM group in (+)-6
followed by the Dess-Martin oxidation of the hydroxy group
in (+)-7 resulted in (+)-1a with >99% ee.
To examine the substrate scope, the reaction conditions
optimized for 2a (conditions I) were applied to 2b-f. The
results are summarized in Table 3. To our delight, 1b, 1d,
and 1f were obtained in 97, 98, and 81% ee, respectively
(entries 1, 5, and 9), which indicates that the reaction
conditions optimized for 2a are suitable for the enantiose-
lective formation of the six-membered ring. When we
increased the reaction temperature to improve the yield
(conditions II), we found that the enantiomeric purities of
1b and 1f increased (entries 2 and 10) although that of 1d
decreased slightly (entry 6). In particular, it should be noted
that 1b was obtained completely stereoselectively (>99% ee,
>99% de) in a higher yield at a higher temperature. On the
other hand, 1c and 1e were obtained in much lower
enantiomeric purities under conditions I (entries 3 and 7),
which indicates that in the case of the five-membered ring
formation, enantioselectivity is sensitive to the size of the
ee was the highest value, which forced us to change the NHC
catalyst. The use of triazolium salt D also resulted in a low
enantioselectivity (entry 2), although Suzuki and Takikawa
have reported that triazolium salt D functions as an excellent
catalyst for an asymmetric benzoin cyclization.14 NHC
precatalyst E, developed by Bode and co-workers,10a was
then examined. When Et3N was used as a base, almost no
reaction proceeded (entry 3). The acidity of triazolium salt
E with the N-substituted mesityl group is considered to be
much lower than that of C and D. When DBU was used as
a base, the reaction proceeded to give 1a in 69% ee (entry
4).
Encouraged by this result, we decided to optimize the
reaction conditions. To suppress side reactions such as the
intermolecular benzoin reaction, the substrate concentration
was changed from 0.3 to 0.05 M, with the result that the
isolated yield was improved slightly (entry 5). Another side
reaction that we supposed was the base-catalyzed aldol
reaction of 2a. To minimize this possibility, NHC was
allowed to generate before the addition of 2a; after a solution
of triazolium salt E and DBU in toluene had been stirred
4868
Org. Lett., Vol. 11, No. 21, 2009

Table 3. Substrate Scope of the NHC-Catalyzed Asymmetric
Benzoin Cyclization of 2a
Figure 2. Wieland-Miescher ketone.
enantiomeric purity of 1e showed an improvement (entry
8), whereas that of 1c did not (entry 4).
Although the aldehyde-ketone crossed benzoin reactions
are unfavorable as compared with conventional aldehyde-
aldehyde benzoin reactions, a quaternary stereocenter can
be installed in the former case.2b-e,3d,4,14,15 Here we have
synthesized bicyclic tertiary alcohols 1 with two consecutive
quaternary stereocenters via the NHC-catalyzed intramo-
lecular crossed benzoin reactions. We expect the utility of
the products 1 as chiral synthons; for example, 1b is
reminiscent of an important compound, Wieland-Miescher
ketone (Figure 2), which has been used in the total synthesis
of more than 50 natural products including taxol.16 The
exploitation of the synthetic utility of 1 is currently in
progress.
Acknowledgment. This work was supported by the
Okayama Foundation for Science and Technology. We thank
Dr. T. Katagiri (Okayama University) for the use of an
ozonizer. We are grateful to the SC-NMR Laboratory of
Okayama University for the measurement of NMR spectra.
Supporting Information Available: Synthetic procedures,
optimization of the reaction conditions for asymmetric
cyclization of 2a using NHC cat. C, determination of relative
and absolute configurations of (+)-1a, and copies of NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
a Conditions I: 2 (0.300 mmol), NHC cat. E (30 mol %), Cs2CO3 (30
mol %), CH2Cl2 (6 mL), 23 °C, 24 h. Conditions II: the same as conditions
I except that the reaction was done under reflux. Conditions III: condition
in entry 1 of Table 2 (23 °C). b The major enantiomer of 1 obtained under
conditions I is shown, in which absolute configuration is tentatively assigned
by the analogy of that of (+)-1a. c Isolated yield of 1. d Determined by
chiral GC (CP-cyclodextrin-ꢀ-2,3,6-M-19 column). The major enantiomer
eluted second in all cases.
OL9019293
(15) (a) Quaternary Stereocenters; Christoffers, J., Baro, A., Eds.; Wiley-
VCH: Weinheim, 2005. (b) Bella, M.; Gasperi, T. Synthesis 2009, 1583–
1614
.
(16) (a) Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem., Int. Ed. 1971,
10, 496–497. (b) Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–
1621. (c) Bui, T.; Barbas, C. F., III Tetrahedron Lett. 2000, 41, 6951–
6954.
adjacent ring. In view of this trend, we employed catalyst C
under the reaction conditions optimized for 2a, which is
shown in entry 1 of Table 2 (conditions III). As a result, the
Org. Lett., Vol. 11, No. 21, 2009
4869