A facile method for the synthesis of highly substituted six-membered rings: Mukaiyama-aldol-prins cascade reaction

Article abstract of DOI:10.1021/ol100937r

(Figure presented) A highly efficient cascade reaction has been developed using cheap commercially available or easily accessible starting materials. It has the ability to construct highly functionalized six-membered ring with three to four stereogenic centers in high yields.

Full text of DOI:10.1021/ol100937r

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2679-2681
A Facile Method for the Synthesis of
Highly Substituted Six-Membered Rings:
Mukaiyama-Aldol-Prins Cascade
Reaction
Hao Li and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371
teckpeng@ntu.edu.sg
Received April 23, 2010
ABSTRACT
A highly efficient cascade reaction has been developed using cheap commercially available or easily accessible starting materials. It has the
ability to construct highly functionalized six-membered ring with three to four stereogenic centers in high yields.
Cascade reactions are useful synthetic transformations as they
allow expedient and efficient construction of complex
structures.1 Among the many cascade reactions, the develop-
ment of a new cascade reaction to create highly function-
alized ring systems with the generation of multiple stereo-
genic centers in a one-pot manner is highly sought-after.2
Recently, our group has reported an efficient method for the
synthesis of highly functionalized five-membered rings in
high yields with excellent regio-, diastereo-, and enantiose-
lectivities using cascade Mukaiyama-Aldol-Prins reaction
(Scheme 1, path a).3 We envisage that by tuning the stability
of the carbocation formed via variation of the acetal olefinic
substituents, a six-membered ring (Scheme 1, path b) can
be obtained instead of the five-membered ring. Therefore, if
nonsubstituted acetal is utilized, a six-membered ring could
be formed through path b.4 Herein, we report a novel cascade
(1) For reviews of cascade reactions, see: (a) Nicolaou, K. C.; Chen,
J. S. Chem. Soc. ReV. 2009, 38, 2993. (b) Nicolaou, K. C.; Edmonds, D. J.;
Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134. (c) Tietze, L. F.;
Brasche. G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-
VCH: New York, 2006. (d) Tietze, L. F.; Beifuss, U. Angew. Chem., Int.
Ed. 1993, 32, 131. For selected examples of cascade reactions, see: (e)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem., Int.
Ed. 2003, 42, 4233. (f) Yamamoto, Y.; Momiyama, N.; Yamamoto, H.
J. Am. Chem. Soc. 2004, 126, 5962. (g) Marigo, M.; Schulte, T.; Franzen,
J.; Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 15710. (h) Casas, J.;
Engqvist, M.; Ibrahem, I. B.; Kaynak, B.; Cordova, A. Angew. Chem., Int.
Ed. 2005, 44, 1343. (i) Yang, J. W.; Hechavarria, M.; Fonseca, T.; List, B.
J. Am. Chem. Soc. 2005, 127, 15036. (j) Huang, Y. A.; Larsen, M. C. H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2005, 127, 15051. (k) Wang, Y.;
Liu, X. F.; Deng, L. J. Am. Chem. Soc. 2006, 128, 3928. (l) Brandau, S.;
Maerten, E.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 14986. (m)
Xie, H. X.; Zu, L. S.; Li, H.; Wang, J.; Wang, W. J. Am. Chem. Soc. 2007,
129, 10886. (n) Zu, L. S.; Wang, J.; Li, H.; Xie, H. X.; Wang, J.; Wang,
W. J. Am. Chem. Soc. 2007, 129, 1036. (o) Aroyan, C. E.; Miller, S. J.
J. Am. Chem. Soc. 2007, 129, 256. (p) Wu, B. F.; Wang, Y.; Liu, X.; Deng,
L. J. Am. Chem. Soc. 2007, 129, 768. (q) Vicario, J. L.; Reboredo, S.; Badia,
D.; Carrillo, L. Angew. Chem., Int. Ed. 2007, 46, 5168. (r) Wang, J.; Li,
H.; Xie, H. X.; Zu, L. S.; Shen, X.; Wang, W. Angew. Chem., Int. Ed.
2007, 46, 9050. (s) Reyes, E.; Jiang, H.; Milelli, A.; Elsner, P.; Hazell,
R. G.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 9202. (t) Cabrera,
S.; Alema, J.; Bolze, P.; Bertelsen, S.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2008, 47, 121.
(2) (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Organic Synthesis I;
Wiley-VCH: New York, 1996. (b) Nicolaou, K. C.; Snyder, S. A. Classics
in Organic Synthesis II; Wiley-VCH: New York, 2003.
(3) Li, H.; Loh, T. P. J. Am. Chem. Soc. 2008, 130, 7194.
10.1021/ol100937r  2010 American Chemical Society
Published on Web 05/20/2010

ence of TiBr4.6 Unfortunately, only the Mukaiyama-Aldol
product was obtained (Table 1, entry 1). Replacing the
trimethylsilyl (TMS) group with the more robust triisopro-
pylsilyl (TIPS) group gave the desired product, albeit in low
yield (Table 1, entry 2). Fortunately, the yield of the product
could be increased dramatically when ꢀ-disubstituted silyl
enol ethers were used (Table 1, entries 3-8). The desired
product was obtained as a single isomer at C3-5 but with
moderate diastereoselectivity at C1 (ca. 2:1 diastereomeric
mixture). These results suggested that the substituent at the
ꢀ position of the silyl enol ether plays an important role in
the cascade process. Especially noteworthy is that ꢀ-substi-
tuted brominated silyl enol ether reacts with acetal l to afford
the desired product in good yield (Table 1, entry 8). This
reaction further expanded the scope of this method. Since
the bromine can easily be removed or functionalized, other
cyclohexane building blocks could potentially be obtained.
Next, we investigated the asymmetric version of this
reaction using optically pure cyclic acetal 5.7 The results
are summarized in Table 2. In all cases, the desired products
were obtained in good yields. Similar to the nonasymmetric
version, the two diastereomers were obtained and easily
separated by column chromatography. It is important to note
Scheme 1. Our Proposed Hypothesis
reaction involving the Mukaiyama-Aldol-Prins (MAP)
cascade reaction to create highly functionalized six-
membered ring systems with the generation of up to four
new stereogenic centers in a one-pot manner. This method
provides a fast access to a wide variety of cyclohexane
skeletons which are important building blocks in the synthesis
of complex molecules.
Initially, cyclohexenyloxytrimethylsilane reacted with the
commercially available 4,4-diethoxybut-1-ene5 in the pres-
Table 2. MAP Cascade Reactions Using Chiral Acetala
Table 1. Mukaiyama-Aldol-Prins Reaction To Form
Six-Membered Ringa, b
a Mukaiyama-Aldol-Prins reactions were run with 2 equiv of TiBr4,
1 equiv of acetal, and 1.2 equiv of silyl enol ether under N2 atmosphere.
b Nonsubstituted acetal was purchased from Sigma-Aldrich. c Isolated yield.
a Mukaiyama-Aldol-Prins reactions were run with 2 equiv of TiBr4,
1 equiv of acetal, and 1.2 equiv of silyl enol ether under N2 atmosphere.
b Isolated yield. c Diastereomeric ratios were determined by 1H and 13C NMR
analyses. d Four isomers, but isolated yield is based on the major set of
two isomers.
d
Diastereomeric ratios were based on H and 13C NMR analyses. e Only
1
Mukaiyama-Aldol reaction product was obtained in 70% yield. f Four
isomers, but isolated yield is determined by the major set of two isomers.
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Org. Lett., Vol. 12, No. 12, 2010

that both of the diastereomers were obtained as a single
isomer (>99:1) as determined by H and 13C NMR. The
relative and absolute stereochemistry of the major product
of one of the compounds was confirmed by the X-ray
crystallography (Figure 1, refer to the Supporting Informa-
1
Scheme 2. Confirmation of the Relative and Absolute
Stereochemistry of the Minor Product in Table 1, Entry 5, and
Table 2, Entry 3
a single isomer after removal of the bromine. We are in
the process of applying this strategy to the synthesis of
natural products.
Acknowledgment. We gratefully acknowledge the Nan-
yang Technological University and Singapore Ministry of
Education Research Fund Tier 2 (No. T206B1221) for the
financial support of this research and Dr. Y.-X. Li (Nanyang
Technological University) for X-ray support.
Figure 1. X-ray crystal structure of the major isomer of product in
Supporting Information Available: Additional experi-
mental procedures, chromatograms, cif file of crystal-
lographic data and spectral data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Table 2, entry 5.
tion). Removal of the bromine atom in both diastereomers
led to identical diastereomers (Scheme 2).
OL100937R
In summary, we have developed a highly efficient
cascade reaction using cheap commercially or easily
accessible starting materials to construct a highly func-
tionalized six-membered ring with three to four stereogenic
centers in high yields. When chiral acetal 5 was employed,
the desired cyclohexane derivatives could be obtained as
(4) (a) Chan, K. P.; Loh, T. P. Org. Lett. 2005, 7, 4491. (b) Liu, F.;
Loh, T. P. Org. Lett. 2007, 9, 2063. (c) Hu, X. H.; Liu, F.; Loh, T. P. Org.
Lett. 2009, 11, 1741.
(5) Sigma-Aldrich product no. 307246.
(6) Balme, G.; Gore, J. J. Org. Chem. 1983, 48, 3336.
(7) Zhao, Y. J.; Chng, S. S.; Loh, T. P. J. Am. Chem. Soc. 2007, 129,
492.
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