Regioselective Prins cyclization of allenylsilanes. Stereoselective formation of multisubstituted heterocyclic compounds

Article abstract of DOI:10.1021/ol302669q

The Prins cyclization of hydroxy or amino group-containing allenylsilanes with carbonyl compounds occurred at the allenic terminus in a regio- and stereoselective manner to give the di- or trisubstituted tetrahydrofurans, tetrahydropyrans, and pyrrolidines. During the reaction, the allenic axial chirality of the starting material was efficiently transferred to the newly formed carbon chiral centers of the product.

Full text of DOI:10.1021/ol302669q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Regioselective Prins Cyclization
of Allenylsilanes. Stereoselective
Formation of Multisubstituted
Heterocyclic Compounds
Takuya Okada, Airi Shimoda, Tetsuro Shinada, Kazuhiko Sakaguchi,* and
Yasufumi Ohfune*
Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi,
Osaka 558-8585, Japan
sakaguch@sci.osaka-cu.ac.jp; ohfune@sci.osaka-cu.ac.jp
Received September 27, 2012
ABSTRACT
The Prins cyclization of hydroxy or amino group-containing allenylsilanes with carbonyl compounds occurred at the allenic terminus in a regio-
and stereoselective manner to give the di- or trisubstituted tetrahydrofurans, tetrahydropyrans, and pyrrolidines. During the reaction, the allenic
axial chirality of the starting material was efficiently transferred to the newly formed carbon chiral centers of the product.
Substituted furans, pyrans, and pyrrolidines are com-
mon structural motifs found in many natural products.
The development of efficient methods for the synthesis of
these heterocyclic compounds has received considerable
attention in organic synthesis. The Prins cyclization, which
is performed by the acidic treatment of a homoallylic
alcohol with a carbonyl compound, is one of the repre-
sentative methods for the synthesis of tetrahydropyrans,
although it often leads to a complex mixture of pro-
ducts due to the use of a strong acid or high reaction
temperature.1 On the other hand, the vinylsilane-2 and
allylsilane3-induced cyclizations (silyl-Prins reactions)
(1) (a) Snider, B. B. In Comprehensive Organic Synthesis; Trost, B. M.,
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Rychnovsky, S. D.; Marumoto, S.; Jaber, J. J. Org. Lett. 2001, 3, 3815–
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2003, 5, 2429–2432. (h) Yadav, J. S.; Reddy, B. V. S.; Reddy, M. S.;
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Commun. 2008, 3876–3878.
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3475–3476. (b) Mohr, P. Tetrahedron Lett. 1995, 36, 2453–2456. (c)
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10.1021/ol302669q
XXXX American Chemical Society

proceeded under mild conditions with complete diaster-
eocontrol due to the intermediary formation of a stabilized
β-silyl cation species to afford various heterocyclic pro-
ducts (eqs 1 and 2). During the course of our studies
regarding the Au-catalyzed reactions of R-alkynylsilanes
and allenylsilanes,4 we hypothesized that the Prins cycliza-
tion of allenylsilanes possessing an internal hydroxy or
amino group would occur at its allenic terminus to afford
heterocyclic compounds via the β-silylvinyl cation inter-
mediate (eq 3).5 The product would possess a synthetically
useful alkynyl side chain. It is of interest whether the allenic
axial chirality is transferred to the product.6 Herein, we
describe the stereoselective synthesis of substituted tetra-
hydrofurans, tetrahydropyrans, and pyrrolidines using the
Prins cyclization of allenylsilanes.
presence of TMSOTf at ꢀ78 °C in CH2Cl2 underwent
the smooth uncommon 5-endo-trig cyclization to give the
cis-2,3-disubstituted tetrahydrofuran 2a containing a sily-
lacetylene moiety as a single diastereomer (97%, dr =
>20:1, Table 1, entry 1).8,9 The quantity of TMSOTf
could be reduced to 0.1 equiv at 0 °C for 30 min to give
the tetrahydrofuran 2a in 97% yield (entry 2). A Brønsted
acid, such as p-TsOH, was also effective for this cycliza-
tion. However, the reaction required a higher temperature
and a prolonged reaction period, and the yield was mod-
erate (entry 3).
Table 1. Synthesis of 2,3-Disubstituted Tetrahydrofuran
entry
acid (equiv)
temp (°C)
time (h)
yield (%)
1
2
3
TMSOTf (1.1)
ꢀ78
0
0.5
0.5
20
97
97
77
TMSOTf (0.1)
p-TsOH-H2O (1.0)
rt
Next, we investigated the substrate scope employing
various aldehydes and ketones in the presence of a catalytic
amount of TMSOTf (Figure 1). The reactions of 1 with
phenylpropionaldehyde, isobutylaldehyde, methacrolein
or m-anisaldehyde furnished the corresponding tetrahy-
drofurans 2bꢀd,f in good yields with excellent diastereos-
electivities, respectively. On the other hand, a decrease in
the drs of 2e,g was observed when the sterically bulky
pivalaldehyde or electron-donating 3,4-dimethoxybenzal-
dehyde was employed.10 This method was applicable to
ketones in the presence of TMSOTf (1 equiv) at ꢀ78 °C to
give the 2,2,3-trisubstituted tetrahydrofuran 2h,iin good yield.
To examine whether the axis chirality of the allene was
transferred to the product, the enantioenriched (aS)-1
(92% ee)7 was employed for the present cyclization
(eq 4). Treatment of (aS)-1 with TMSOTf (0.1 equiv) at
0 °C gave 2a with 78% ee.11 The ee was increased to 85%
when 1 equiv of TMSOTf was employed at ꢀ78 °C (vide
infra). The absolute configuration of 2a was assigned to
2R,3R by converting it to the MTPA ester 3.12 These
According to the report by Denmark et al.,3a TMSOTf
was proven to be an excellent Lewis acid for the Prins
cyclization of an allylsilane. Thus, our attempt toward the
Prins cyclization of an allenylsilane was investigated using
TMSOTf as the Lewis acid. To our delight, the treatment
of the β-hydroxy allenylsilane 1 containing the tert-butyl-
dimethylsilyl (TBS) group7 with benzaldehyde in the
(4) (a) Sakaguchi, K.; Okada, T.; Shinada, T.; Ohfune, Y. Tetrahe-
dron Lett. 2008, 49, 25–28. (b) Okada, T.; Oda, N.; Suzuki, H.;
Sakaguchi, K.; Ohfune, Y. Tetrahedron Lett. 2010, 51, 3765–3768. (c)
Okada, T.; Sakaguchi, K.; Shinada, T.; Ohfune, Y. Tetrahedron Lett.
2011, 52, 5740–5743. (d) Okada, T.; Sakaguchi, K.; Shinada, T.; Ohfune,
Y. Tetrahedron Lett. 2011, 52, 5744–5746.
(5) Allenylsilanes have proven to be useful carbon nucleophiles for the
intermolecular addition to carbonyl compounds in which the reaction
occurred at the allenic terminus to produce homopropargylic alcohols
and heterocyclic compounds. (a) Danheiser, R. L.; Carini, D. J. J. Org.
Chem. 1980, 45, 3927–3929. (b) Danheiser, R. L.; Carini, D. J.; Basak, A.
J. Am. Chem. Soc. 1981, 103, 1604–1606. (c) Panek, J. S. In Comprehen-
sive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press:
Oxford, 1991; Vol. 1, Chapter 2.5. (d) Jin, J.; Smith, D. T.; Weinreb, S. M.
J. Org. Chem. 1995, 60, 5366–5367. (e) Brawn, R. A.; Panek, J. S. Org.
Lett. 2009, 11, 473–476. (f) Brawn, R. A.; Panek, J. S. Org. Lett. 2009, 11,
€
4362–4365. (g) Ogasawara, M.; Okada, A.; Subbarayan, V.; Sorgel, S.;
(8) The stereochemistry of the disubstituted 2 (Table 1) and the
trisubstituted 9 (eq 7) were ascertained by the NOE experiments. The
stereochemistry of the trisubstituted compound 8 was also determined
by the NOE experiments after converting it to the corresponding
desilylated compound 10 (eq 7).
(9) The formation of the desilylated terminal alkyne product was not
observed.
(10) Even at low temperature (ꢀ78 °C), the drs of the products were
almost the same as those at 0 °C (2e: 80% yield, dr = 2:1, 2g: 78% yield,
dr = 1:1).
(11) The product’s ee was calculated by the chiral HPLC analysis
(DAICEL, CHIRALPAK IC, 0.46 cm ꢁ 25 cm, n-Hexane/EtOH =
99:1, 0.7 mL/min, 254 nm).
(12) The MTPA ester 3 was prepared from 2a in six steps; see the
Supporting Information.
Takahashi, T. Org. Lett. 2010, 12, 5736–5739.
(6) For selected references for the transfer of the chirality of an allene
to an sp3 chirality, see: (a) Krause, N.; Hoffmann-Roeder, A. Tetra-
hedron 2004, 60, 11671–11694. (b) Ma, S. M. Pure Appl. Chem. 2006, 78,
197–208. (c) Ogasawara, M. Tetrahedron: Asymmetry 2009, 20, 259–271.
(d) Brawn, R. A.; Panek, J. S. Org. Lett. 2009, 11, 4362–4365. (e) Adams,
C. S.; Boralsky, L. A.; Guzei, I. A.; Schomaker, J. M. J. Am. Chem. Soc.
2012, 134, 10807–10810.
(7) The allenylsilane 1 was prepared by the Myers protocol; see the
Supporting Information. (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc.
1996, 118, 4492–4493. (b) Myers, A. G.; Zheng, B.; Movassaghi, M.
J. Org. Chem. 1997, 62, 7507. The allenylsilane 1 was stable for several
weeks as a solution of dichloromethane in a refrigerator (ꢀ30 °C) under
an argon atmosphere; however, the concentrated 1 decomposed under
the same conditions.
B
Org. Lett., Vol. XX, No. XX, XXXX

conversion of the optically enriched 1 (92% ee) into 2a
(85% ee at ꢀ78 °C) suggested that the reaction would involve
the sterically disfavored synclinal intermediate E,inwhichthe
oxonium ion was located on the same side of the TBS group.
Only a slight racemization of 1 occurred under the reaction
conditions. The acidic treatment of the optically active 1
[[R]28 þ113.6 (c 0.75, CHCl3)] without benzaldehyde
D
[TMSOTf (0.1 equiv), CH2Cl2, 0 °C, 0.5 h] resulted in
the complete recovery of 1 [[R]27D þ106.0 (c 0.75, CHCl3)].
According to the chiral HPLC analysis of the TMS ether 6
prepared from 1, the optical purity of 6 (95% ee) derived
from the recovered 1 was slightly lower than that of the
starting 1 (98% ee, eq 6).
Scheme 1. Proposed Mechanism
Figure 1. Synthesis of substituted tetrahydrofurans.
results indicated that the original axial chirality was effi-
ciently transferred to the products. The presence of the silyl
group would be essential for this regioselective transfor-
mation, since the tert-butyl substituted analogue 413 under
the same reaction conditions gave the 6-endo-cyclized
dihydropyran 5 (79%, dr = 7:1) via a putative allyl cation
intermediate (eq 5).14
The proposed stereochemical outcome of the present Prins
cyclization is shown in Scheme 1. The exclusive formation of
the 2,3-cis-tetrahydrofuran except for 2e,g would be derived
from the synclinal oxonium intermediate A, in which the
thermodynamically more favored E-oxonium ion than
that of Z15 was located on the opposite side of the sterically
bulky TBS group. Subsequent formation of the silyl-group-
stabilized vinyl cation B would be significantly attributed
to the silyl-group-directed regioselective 5-endo cyclization.
The reactions with sterically bulky or electron-donating
aldehydes would involve the Z-oxonium ion C and/or
antiperiplanar intermediate D due to steric and/or stereo-
electronic reasons to give a mixture of the cis- and trans-
tetrahydrofurans. The slight decrease in the ee during the
Next, we examined the Prins cyclization using the
carbobenzoxyamino (CbzNH)-substituted allenylsilane 7
(dr = >20:1), preparedby the enolateꢀClaisen rearrange-
ment of an R-acyloxy-R-alkynylsilane.4b The treatment
of 7 with PhCHO in the presence of TMSOTf (1 equiv)
at ꢀ78 °C gave a mixture of 2,3,4-trisubstituted tetrahydro-
furans 8 (47%) and 9 (15%, eq 7).8 Since both diastereo-
mers possessed the same 2,3-cis relationships, they would be
produced via the synclinal conformation A (Scheme 1).
(13) Carreira, E. M.; Hastings, C. A.; Shepard, M. S.; Yerkey, L. A.;
Millward, D. B. J. Am. Chem. Soc. 1994, 116, 6622–6630.
(14) The relative configuration of the product was not determined.
(15) (a) Cremer, D.; Gauss, J.; Childs, R. F.; Blackburn, C. J. Am.
Chem. Soc. 1985, 107, 2435–2441. (b) MacMillan, D. W. C.; Overman,
L. E. J. Am. Chem. Soc. 1995, 117, 10391–10392.
Org. Lett., Vol. XX, No. XX, XXXX
C

The treatment of the homologous analogue 11 with
PhCHO in the presence of TMSOTf (0.1 equiv) at 0 °C
facilitated the 6-endo tetrahydropyran formation to give 12
as a mixture of the diastereomers (cis/trans = 3.5:1) in
quantitative yield (eq 8).16,17 The dr of 12 was improved to
6:1 when treated at ꢀ78 °C. An excellent diastereoselec-
tivity (20:1) was observed when the reaction was per-
formed using CH3CN as the solvent.
Scheme 2. Synthesis of Pyrrolidine Derivatives
possessed the 1,2-trans-substituents, presumably because
the reaction proceeded through the iminium ion inter-
mediate F in which the substituent R was located trans to
the Cbz group to avoid the severe steric repulsion. The
fused bicyclic pyrrolidine 1720 was also synthesized from
the succinimide-containing allenylsilane 1622 in a similar
manner.
In summary, The Prins cyclization of the hydroxy or
amino group-containing allenylsilanes with aldehydes
gave various 2,3-disubstituted tetrahydrofurans, tetrahy-
dropyrans, and pyrrolidines having an alkynyl substituent.
The formation of a stable β-silylvinyl cation intermedi-
ate would play an essential role in promoting this
reaction. The axial chirality of the allenylsilane was
efficiently transferred to the newly formed two contig-
uous carbon stereocenters of the product. Application
of this silylalleneꢀPrins cyclization for the synthesis of
biologically important compounds is in progress in our
laboratories.
Finally, we examined the synthesis of nitrogen-contain-
ing heterocyclic compounds using the allenylsilanes 13 and
16 (Scheme 2).18 Although TMSOTf was not effective for
the reaction of 13 with paraformaldehyde,19 the use of
TFA (4 equiv)3c underwent a smooth 5-endo cyclization to
give the pyrrolidine 14 (83%). The reaction with acetalde-
hyde furnished the 2,3-disubstituted pyrrolidine 1520 as a
single diastereomer (93%).21 Contrary to the 1,2-cis-tetra-
hydrofuran formation from the alcohol 1, the product 15
(16) The relative configuration of 12 was assigned by the J values
between the methine protons (major isomer: 2.4 Hz, minor isomer:
9.9 Hz).
(17) The trial for the formation of the four-membered heterocyclic
compounds using 4-(tert-butyldimethylsilyl)buta-2,3-dien-1-ol (18) and
benzyl 4-(tert-butyldimethylsilyl)buta-2,3-dienylcarbamate (19) was un-
successful; see the Supporting Information.
(18) The allenylsilanes 13 and 16 were prepared from 1; see the
Supporting Information.
Acknowledgment. This study was financially supported
by a Grant-in-Aid (16201045 and 19201045) for Scientific
Research from the Japan Society of the Promotion of
Science (JSPS). We thank the Daicel Corporation for the
chiral HPLC analysis of the allenyl compound 6.
(19) The reaction using TMSOTf as the Lewis acid afforded 14 in low
yield (32%).
(20) The relative configurations of 15 and 17 were determined by the
NOE experiments; see the Supporting Information.
(21) The reaction of 13 with PhCHO resulted in the almost complete
recovery of 13 with a trace amount of the isomerized alkyne 20 (eq 9).
Supporting Information Available. Full experimental
details and characterization data of all the synthetic
products are available. This material is available free of
charge via the Internet at http://pubs.acs.org.
ꢁ
(22) Judd, W. R.; Ban, S.; Aube, J. J. Am. Chem. Soc. 2006, 128,
13736–13741.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX