Stereoelectronic versus steric tuning in the prins cyclization reaction: Synthesis of 2fi-trans pyranyl motifs

Article abstract of DOI:10.1021/ol900196w

The use of carboalkoxyl allenic alcohol for the efficient synthesis of pyranyl motifs via Prlns cycllzatlon Is described. This method provides easy access to 2,6-trans dlhydropyrans In good yield and high dlastereoselectlvlty.

Full text of DOI:10.1021/ol900196w

ORGANIC
LETTERS
2009
Vol. 11, No. 8
1741-1743
Stereoelectronic versus Steric Tuning in
the Prins Cyclization Reaction:
Synthesis of 2,6-trans Pyranyl Motifs
Xu-Hong Hu, Feng Liu, and Teck-Peng Loh*
DiVision of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological UniVersity, Singapore 637371, Singapore
teckpeng@ntu.edu.sg
Received January 30, 2009
ABSTRACT
The use of carboalkoxyl allenic alcohol for the efficient synthesis of pyranyl motifs via Prins cyclization is described. This method provides
easy access to 2,6-trans dihydropyrans in good yield and high diastereoselectivity.
Functionalized pyran rings have featured prominently in a
wide variety of natural products1 and therefore have been a
popular target for organic chemists.2 Among the many
popular methods available,3 the Prins cyclization reaction
involving a homoallylic alcohol and an aldehyde is one of
the most efficient methods.4 Many groups, including ours,
have contributed to this approach, which allows easy and
practical access to 2,6-cis tetrahydropyrans.5 Despite sig-
nificant advancement in this area, Prins cyclization leading
to the highly selective 2,6-trans pyranyl motifs is still not
available.6 Recently, we demonstrated that R-alkoxy tethered
homoallylic alcohol can undergo Prins cyclization with
various aldehydes to afford the 2,6-trans tetrahydropyrans,
albeit with low selectivity (cis/trans ) 50/50).7 We believe
that the carbonyl group stabilizes the δ+ of the oxo-
carbenium,8 therefore forcing the carbonyl group to adopt
the axial orientation. As a consequence, it leads to the
formation of the 2,6-trans tetrahydropyran selectively. The
low selectivity observed in those reactions is probably due
to the competing 1,3-diaxial interaction versus the lone pair
(1) (a) Nicolaou, K. C.; Synder, S. A. Classics in Total Synthesis: Wiley-
VCH: Weinhein, 2003. (b) Smith, A. B., III; Fox, R. J.; Razler, T. M. Acc.
Chem. Res. 2008, 41, 675–687. (c) Faulkner, D. J. Nat. Prod. Rep. 2000,
17, 7–55.
(2) (a) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 10772–
10773. (b) Posp´ısˇil, J.; Marko´, I. E. J. Am. Chem. Soc. 2007, 129, 3516–
3517. (c) Ichige, T.; Okano, Y.; Kanoh, N.; Nakata, M. J. Am. Chem. Soc.
2007, 129, 9862–9863. (d) Su, Q.; Panek, J. S. J. Am. Chem. Soc. 2004,
126, 2425–2430.
(5) For examples, see: (a) Jaber, J. J.; Mitsui, K.; Rychnovsky, S. D. J.
Org. Chem. 2001, 66, 4679–4686. (b) Jasti, R.; Vitale, J.; Rychnovsky,
S. D. J. Am. Chem. Soc. 2004, 126, 9904–9905. (c) Tadpetch, K.;
Rychnovsky, S. D. Org. Lett. 2008, 10, 4839–4842. (d) Evans, P. A.; Cui,
J.; Gharpure, S. J. Org. Lett. 2003, 5, 3883–3885. (e) Yang, X. F.; Mague,
J. T.; Li, C. J. J. Org. Chem. 2001, 66, 739–747. (f) Yadav, V. K.; Kumar,
N. V. J. Am. Chem. Soc. 2004, 126, 8652–8653. (g) Huang, H.; Panek,
J. S. Org. Lett. 2001, 3, 1693–1696. (h) Chan, K. P.; Loh, T. P. Org. Lett.
2005, 7, 4491–4494.
(3) (a) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K.
J. Am. Chem. Soc. 1989, 111, 5330–5334. (b) Burke, S. D.; Ng, R. A.;
Morrison, J. A.; Alberti, M. J. J. Org. Chem. 1998, 63, 3160–3161. (c)
Sherry, B. D.; Maus, L.; Laforteza, B. N.; Toste, F. D. J. Am. Chem. Soc.
2006, 128, 8132–8133. (d) Trost, B. M.; Yang, H.; Wuitschik, G. Org.
Lett. 2005, 7, 4761–4764. (e) Clarke, P. A.; Martin, W. H. C.; Hargreaves,
J. M.; Wilson, C.; Blake, A. J. Chem. Commun. 2005, 1061–1063.
(4) (a) Crosby, S. R.; Harding, J. R.; King, C. D.; Parker, G. D.; Willis,
C. L. Org. Lett. 2002, 4, 577–580. (b) Kataoka, K.; Ode, Y.; Matsumoto,
M.; Nokami, J. Tetrahedron 2006, 62, 2471–2483. (c) Zhang, W. C.;
Viswanathan, G. S.; Li, C. J. Chem. Commun. 1999, 291–292. (d) Chan,
K. P.; Loh, T. P. Tetrahedron Lett. 2004, 45, 8387–8390.
(6) [4 + 2] Annulation of chiral crotylsilanes: (a) Huang, H.; Panek,
J. S. J. Am. Chem. Soc. 2000, 122, 9836–9837. (b) Lowe, J. T.; Panek,
J. S. Org. Lett. 2005, 7, 3231–3234. Vinylsilane-terminated cyclizations:
(c) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J. Org.
Chem. 1997, 62, 3426–3427.
(7) Chan, K. P.; Seow, A. H.; Loh, T. P. Tetrahedron Lett. 2007, 48,
37–41.
10.1021/ol900196w CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society

stabilization of the oxo-carbenium by the alkoxy group
(Scheme 1). We envisage that removal of the 1,3-diaxial
and TMSBr (1.2 equiv) in CH2Cl2 (0.1 M) at 0 °C.10 The
results are summarized in Table 1. In all cases, the expected
Table 1. Cyclization of R-Methyl Allenic Alcohol 1 with
Scheme 1
.
Interplay between 1,3-Diaxial Interaction and
Stereoelectronic Effect
Aldehydesa
entry
R
time (h) products (yield, %)c dr (trans: cis)
1
2
3
4
5
6
c-C6H11
(CH3CH2)2CH
(CH3)3C
(CH3)2CHCH2
PhCH2CH2
Ph
2
2a (84), 2a′ (12)
2b (75), 2b′ (6)
2c/c′ (84)
2d (73), 2d′ (8)
2e (70), 2e′ (13)
2f f (75), 2f′ (8)
87:13d
2
93:7d
1.5
1.5
2
92:8e
90:10d
84:16d
89:11d
3
a Reactions were performed with 1 (0.3 mmol, dissolved in 1 mL of
CH2Cl2, syringe pump addition), aldehyde (0.36 mmol), TMSBr (0.36
mmol), and In(OTf)3 (0.03 mmol) in CH2Cl2 (2 mL) at 0 °C. b Stereochemistry
assigned by NOESY experiments. c Isolated yield based on allenic alcohol.
d Determined by isolated yields of respective isomers. e Determined by 1H
NMR. f X-ray crystal structure of 2f is shown in Figure 1.
interaction by using allenic alcohols instead of the homoal-
lylic alcohols may lead to higher 2,6-trans selectivity
(Scheme 2). In this Letter, we describe a highly efficient
2,6-trans dihydropyrans products were obtained in good
yields and good selectivities (Table 1, entries 1-6). The
findings also showed that the use of aliphatic or aromatic
aldehydes had no apparent effect on the diastereoselectivity.
Scheme 2. Proposed Cyclization Pathway Using Allenic
Alcohol through a Distorted Chair Transition State
Figure 1. Single crystal X-ray structure of 2f.
Prins cyclization method for synthesizing 2,6-trans dihy-
dropyrans using allenic alcohols and aldehydes promoted by
an indium salt catalyst.
It is worth noting that the major isomers of tetra-substituted
dihydropyrans were found to have the 2,6-trans relative
stereochemistries as assigned by NOESY experiments. The
relative stereochemistry of one of the cyclization products
(2f) was further confirmed by a single crystal X-ray structure
as depicted in Figure 1.
Initial efforts were focused on the reactions of R-methyl
allenic alcohol bearing an n-butyl ester group9 with a wide
range of aldehydes in the presence of In(OTf)3 (0.1 equiv)
With these intriguing results, we further explored the
reactions using a bulky silicon-substituted allenic alcohol
(Table 2, substrate 3) under the same conditions as stated
above. To our delight, the Prins cyclization proceeded
smoothly to afford the desired products with excellent
diastereoselectivities (up to >99:1). In addition, both aliphatic
(8) For applications of the lone pair of an ester group in the stabilization
of oxo-carbenium in asymmetric synthesis, see: (a) Gung, B. W.; Xue, X.;
Roush, W. R. J. Am. Chem. Soc. 2002, 124, 10692–10697, and references
therein. (b) Loh, T. P.; Wang, R. B.; Sim, K. Y. Tetrahedron Lett. 1996,
37, 2989–2992. For a detailed study on the electrostatic attraction and
anomeric effect on the stabilization of oxo-carbenium, please refer to: (c)
Chamberland, S.; Ziller, J. W.; Woerpel, K. A. J. Am. Chem. Soc. 2005,
127, 5322–5323. (d) Ayala, L.; Lucero, C. G.; Romero, J. A. C.; Tabacco,
S. A.; Woerpel, K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528, and
references therein. (e) Mulzer, J.; Meyer, F.; Buschmann, J.; Luger, P.
Tetrahedron Lett. 1995, 36, 3503–3506.
(10) Allenic alcohols and aldehydes could generate aldol-type adducts
through 1,3-transposition of oxygen, and thus the reactions were performed
at lower temperature with dropwise addition of a decreased concentration
of allenic alcohols using syringe pump over a period of 1 h. For reactions
of allenic alcohols and aldehydes promoted by Lewis acid, see: (a) Trost,
B. M.; Jonasson, C.; Wuchrer, M. J. Am. Chem. Soc. 2001, 123, 12736–
12737. (b) Yu, C. M.; Kim, Y. M.; Kim, J. M. Synlett 2003, 1518–1520.
(9) Preparation of allenic alcohols: (a) Lin, M. J.; Loh, T. P. J. Am.
Chem. Soc. 2003, 125, 13042–13043. (b) Xia, G.; Yamamoto, H. J. Am.
Chem. Soc. 2007, 129, 496–497. (c) Yi, X. H.; Meng, Y.; Hua, X. G.; Li,
C. J. J. Org. Chem. 1998, 63, 7472–7480. (d) Nakagawa, T.; Kasatkin, A.;
Sato, F. Tetrahedron Lett. 1995, 36, 3207–3210.
1742
Org. Lett., Vol. 11, No. 8, 2009

result we observed previously.12 Subsequently, Prins-type
cyclization of homopropargylic alcohol III with another
equivalent of cyclohexanecarboxaldehyde13 took place, lead-
ing to unexpected product 6. However, the ester-substituted
allenic alcohols (substrates 1 and 3) underwent Prins cy-
clization without any detection of the homopropargylic
transfer product.
Table 2. Prins Cyclization of Allenic Alcohol with Aldehydesa
The carboalkoxyl group adjacent to the allenic alcohol
moiety performed two functions: (1) stereoelectronic induc-
tion to form the desired intermediate I (Scheme 2) with 2,6-
trans configuration through stabilization of the δ+ oxo-
carbenium and (2) efficient suppression of the unwanted
oxonia-Cope rearrangement due to the electron-withdrawing
property of the ester functional group, as suggested by
Roush.14 As a consequence, the reactive intermediate I
favored the direct Prins cyclization prior to oxonia-Cope
rearrangement.
entry product
R
time (h) yield (%)c dr trans/cisd
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
o-C6H11
(CH3CH2)2CH
(CH3)3C
1
90
84
86
82
80
83
68
64
96:1
96:4
1.5
1
1.5
1.5
2
94:6
CH3(CH2)6CH2
(CH3)2CHCH2
PhCH2CH2
Ph
>99:1
>99:1
93:7
4g
4h
2.5
3
>99:1
>99:1
m-NO2-C6H4
a For the conditions, see Table 1, footnote a. b Stereochemistry assigned
by NOESY experiments. c Isolated yield based on allenic alcohol. d trans/cis
1
ratios were determined by H NMR.
In conclusion, we have developed a general method that
allows easy access to 2,6-trans pyranyl motifs. Prins cy-
clization using carboalkoxyl allenic alcohols is the key to
the success of this method. The ester group provides an
anomeric effect8c-e as well as lone pair stabilization of the
δ+ of the oxo-carbenium intermediate. It also suppresses the
propargyl transfer process. The use of the allenic alcohols
instead of the homoallylic alcohols removes the 1,3-steric
repulsion of the ester group with hydrogen through a distorted
six-membered ring transition state, thus promoting the ester
group to adopt the axial orientation preferentially. We believe
that this method of tuning the stereoelectronic versus steric
effect to direct the reaction pathway will become a prevailing
strategy in organic synthesis. The ester functional group in
the product has the advantage of being convertible to other
functional groups such as alcohols, alkenes, etc. Application
of this Prins cyclization method toward the synthesis of
natural products is now in progress.
and aromatic aldehydes gave the desired dihydropyrans in
good yields (Table 2, entries 1-7).
Of mechanistic interest, we carried out the reaction of
alkyl-substituted allenic alcohol 5 with cyclohexanecarbox-
aldehyde (Scheme 3). In this case, 2,6-cis-dicyclohexyl
Scheme 3
dihydropyran 6 was obtained.11 No crossover product 7 was
detected. A plausible mechanism was proposed to account
for this phenomenon (as shown in Scheme 4). During this
Acknowledgment. We thank Dr. Yong-Xin Li (Nanyang
Technological University) for X-ray analyses. We gratefully
acknowledge the Nanyang Technological University and the
Singapore Ministry of Education Academic Research Fund
Tier 2 (No. T206B1221; T207B1220RS) for financial support
of this research.
Scheme 4. Proposed Mechanism of Cyclization of
Alkyl-Substituted Allenic Alcohol with Aldehyde
Supporting Information Available: Additional experi-
mental procedures and characterization data for the reactions
products including one CIF file. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL900196W
(12) The allenic alcohol can undergo propargylic transfer in the presence
of aldehyde and Lewis acid via oxo-carbenium[3,3]-sigmatropic rearrange-
ment. Lee, K. C.; Lin, M. J.; Loh, T. P. Chem. Commun. 2004, 2456–
2457.
(13) For Prins cyclization of homopropargylic alcohols with aldehydes,
see: (a) Miranda, P. O.; Ram´ırez, M. A.; Mart´ın, V. S.; Padro´n, J. I. Org.
Lett. 2006, 8, 1633–1636. (b) Miranda, P. O.; D´ıaz, D. D.; Padro´n, J. I.;
Bermejo, J.; Mart´ın, V. S. Org. Lett. 2003, 5, 1979–1982. (c) Chavre, S. N.;
Choo, H.; Cha, J. H.; Pae, A. N.; Choi, K. I.; Cho, Y. S. Org. Lett. 2006,
8, 3617–3619.
process, homopropargylic transfer reaction occurred before
the Prins cyclization reaction. This is consistent with the
(11) Stereochemistry of 6 was determined by NOESY.
(14) Roush, W. R.; Dilley, G. T. Synlett 2001, 955–959.
Org. Lett., Vol. 11, No. 8, 2009
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