Gold(I)-Catalyzed access to tetrahydropyran-4-ones from 4-(Alkoxyalkyl)oxy-1-butynes: Formal catalytic petasis-ferrier rearrangement

Article abstract of DOI:10.1002/chem.201002918

Gold cycle redesigned: By utilizing the alkynophilic effect of gold(I) complexes, a new method for the synthesis of highly substituted cis-2,6-tetrahydropyranones was developed, which represents a catalytic surrogate of the Petasis-Ferrier rearrangement (

Full text of DOI:10.1002/chem.201002918

COMMUNICATION
DOI: 10.1002/chem.201002918
Gold(I)-Catalyzed Access to Tetrahydropyran-4-ones from
4-(Alkoxyalkyl)oxy-1-butynes: Formal Catalytic Petasis–Ferrier
Rearrangement
Hyo Jin Bae, Wook Jeong, Ji Hyung Lee, and Young Ho Rhee*[a]
Tetrahydropyran-4-ones are an important structural motif
found in numerous bioactive natural products.[1] The Lewis
acid mediated rearrangement of vinyl acetal 1 (Scheme 1),
Based upon our experience in a related area,[4,5] we envi-
sioned that a gold-catalyzed cycloisomerization of 4-(alkox-
yalkyl)oxy-1-butyne 4 could offer a potential solution to this
problem (Scheme 2). In this scenario, the initial alkoxycycli-
Scheme 1. The Petasis–Ferrier rearrangement; LA=Lewis acid.
named the Petasis–Ferrier rearrangement, has recently been
developed for the synthesis of the tetrahydropyran-4-one
moiety.[2,3] In this approach, formation of the key intermedi-
ate 2 is promoted by the coordination of the Lewis acid to
the cis-vinyl acetal 1. Although this reaction provides a
unique access to cis-2,6-tetrahydropyran-4-ones 3, a stoichio-
metric amount of strong Lewis acid is usually needed. More-
over, preparation of the vinyl acetal precursor 1 requires a
multistep transformation that is generally performed under
harsh conditions. Thus, a more efficient version of this reac-
tion that overcomes the aforementioned limitations is highly
desirable.
Scheme 2. Proposed mechanism for the gold(I)-catalyzed formation of
tetrahydropyran-4-one.
zation,[4,6] followed by the scission of the C O bond gener-
À
ates an oxocarbenium ion intermediate
5 (step A,
Scheme 2), which is analogous to the intermediate 2 in the
classical Petasis–Ferrier reaction shown in Scheme 1. Se-
quential recombination of 5 via 6 provides the cycloisomeri-
zation product 7 (step B, Scheme 2). Final hydration of 7
would easily generate the tetrahydropyranone 8. Notably,
the unique catalytic activity of gold complexes allows the
use of alkynes as substrates, thereby substantially improving
the step and atom efficiency of the classical Petasis–Ferrier
reaction. Unlike the vinyl acetal 1, the acyclic precursor 4 is
most likely obtained as a mixture of diastereomers in the
proposed catalytic cycle. Moreover, little is known about the
addition of the oxocarbenium ion onto the alkoxyvinylgold
species. Thus, our main interest in designing the proposed
[a] H. J. Bae, W. Jeong, J. H. Lee, Prof. Dr. Y. H. Rhee
Department of Chemistry
POSTECH (Pohang University
of Science and Technology)
Pohang, 790-784 (Korea)
Fax : (+82)54-279-3399
E-mail: yhrhee@postech.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002918.
Chem. Eur. J. 2011, 17, 1433 – 1436
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1433

Table 1. Optimization of 11a.
catalytic cycle was to establish the diastereoselectivity of the
alkyl substituents at the 2- and 6-positions.
We began our study by using the mixed acetal 9 as a sub-
strate, which was obtained as an equimolar mixture of two
diastereomers from the homopropargylic alcohol precursor
(Scheme 3). When the electrophilic gold complex 12a[7]
Catalyst
(3 mol%)[a]
t
A
Conversion [%]
Ratio
Yield [%]
G
[min][b]
11a/11b[c]
11a[d]
1
2
3
4
5
12b
12c
12d
12e
12 f
5
100
100
77
75
100
5:1
7:1
8:1
9:1
8:1
63
69
55
46
72
15
60
60
15
[a] All the catalysts were generated in situ except for catalyst 12 f. [b] Re-
action time for the gold(I)-catalyzed cycloisomerization. [c] The ratio of
1
crude product was determined by H NMR spectroscopy with 1,3,5-trime-
thoxybenzene as an internal standard. [d] Yield of isolated product 11a.
able catalyst 12 f gave the optimal result. In this case, 8:1 se-
lectivity was assigned by NMR spectroscopic analysis of the
crude reaction mixture. After purification, the cis-tetrahy-
dropyranone 11a was isolated in 72% yield.[10]
With the optimized conditions determined, we tested an
array of substrates for the cis-2,6-tetrahydropyran-4-one syn-
thesis using the catalyst 12 f (Table 2). Introduction of a
Scheme 3. a) A preliminary study using catalyst 12a; b) structures of cat-
À
alysts 12a–f, XÀ =SbF6
.
Table 2. Examples of tetrahydropyran-4-one formation.[a]
(3 mol%) was used, the reaction was complete within 2 mi-
nutes to give two enol ether products 10a and 10b isolated
in 60 and 35% yield, respectively. The structure of the
major cis isomer 10a was confirmed by conversion to the
cis-ketone 11a in 90% yield by using a catalytic amount of
para-toluene sulfonic acid (p-TsOH, 10 mol%). Under the
same conditions, the trans-enol ether 10b was converted
into the trans-ketone 11b in 89% yield with no apparent
formation of 11a.
Substrate
Method[b] Product
Yield
[%][c,d]
1
2
3
R1 =C10H21
R1 =c-C6H11
9
13
15
A
A
A
R1 =C10H21
R1 =c-C6H11
R1 =Ph
(CH2)2
11a 72
14 70
16 73
R1 =Ph
N
ACHTUNGTRENNUNG
Even though the preliminary study confirms the viability
of the proposed reaction, the gold(I)-catalyzed cycloisomeri-
zation shows only moderate selectivity towards the cis-enol
ether 10a. In view of this result, we reasoned that the phos-
phine ligand might play a crucial role because the key event
involves an intramolecular addition of the oxocarbenium
ion onto the vinyl-gold species (step B in Scheme 2).[8] Thus,
we investigated various gold complexes for the formation of
ketone 11a by using the two-step protocol established in
Scheme 3. Interestingly, by using a less electrophilic complex
12b, the cycloisomerization step was slower than with ligand
12a, and the selectivity for the cis-tetrahydropyran-4-one
11a was improved (Table 1, entry 1).[9] Further enhancement
of the diastereoselectivity was observed when ligand 12c
was used (Table 1, entry 2). Thus, the electronic factor
seems to be crucial in optimizing the diastereoselectivity.
However, switching to bulkier (e.g., compound 12d) or
more compact trialkylphosphine ligands (e.g., compound
12e) caused a significant decrease in the conversion of the
cycloisomerization (Table 1, entries 3 and 4), even though
the selectivity was slightly higher than in the previous exam-
ples. As shown in Table 1, entry 5, the commercially avail-
4
5
6
R2 =n-C9H19
R2 =c-C6H11
R2 =(CH2)8CH=
CH2
17
19
21
A
A
A
R2 =n-C9H19
R2 =c-C6H11
R2 =(CH2)8CH=
CH2
18 68
20 78
22 71
7
8
R2 =(CH2)5CO2Et 23
A
B
R2 =(CH2)5CO2Et 24 71
25
26 51
9
27
B
28 58
10 n=1, R3 =CH3
11 n=1, R3 =CH2C- 31
(CH3)3
12 n=2, R3 =CH3
29
B
B
n=1, R3 =CH3
n=1, R3 =CH2C- 32 69
(CH3)3
n=2, R3 =CH3
34 69
30 68
N
ACHTUNGTRENNUNG
33
B
[a] Typical procedure: The substrate was treated with catalyst 12 f in
CH2Cl2 (0.05m) and p-TsOH (10 mol%) was added. [b] Method A: cata-
lyst 12 f (3 mol% loading); Method B: catalyst 12 f (5 mol% loading)
[c] Yield of isolated product [d] In all examples, 5–8% of the trans-tetra-
hydropyran-4-one isomer was obtained.
1434
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1433 – 1436

Gold(I)-Catalyzed Access to Tetrahydropyran-4-ones
COMMUNICATION
bulkier cyclohexyl group at the bis-homopropargylic posi-
tion gave a similar result to 11a (Table 2, entry 2). A phe-
nethyl group also had no negative effect (Table 2, entry 3).
Next, we explored the effect of the alkyl group at the acetal
position.[11] Introduction of a longer alkyl group (Table 2,
entry 4) provided the ketone 18 in 68% yield, whereas in-
troduction of a cyclohexyl group increased the yield of
ketone 20 to 78% (Table 2, entry 5). Significant chemoselec-
tivity was noted. Thus, substrates that had a terminal olefin
(Table 2, entry 6) or an ester group (entry 7) also showed
good reactivity with no significant loss in yield. Next, we ex-
plored the structural effect of the homopropargylic position.
Acyclic substrates with an alkyl substituent at the propargyl-
ic position (Table 2, entries 8 and 9) required a higher cata-
lyst loading (5 mol%) for complete conversion into the cor-
responding tetrahydropyranones and were isolated in lower
yields than in previous examples. However, cyclic substrates
were converted into the corresponding cis-tetrahydropyra-
nones in good yields (Table 2, entries 10–12).[12]
rious racemization during the cycloisomerization (by isomer-
isation of intermediates E and F) and should be more pro-
nounced when the cyclization of the oxocarbenium ion is
slow.[15] Because of this concern, our next task was to inves-
tigate the enantioenriched substrate 35 for the tetrahydro-
pyranone formation.[16] By using the optimized conditions,
this compound was converted into the corresponding ketone
36 in good yield (Scheme 5).
Although the origin of the diastereoselectivity awaits fur-
ther studies, there seems to be a direct correlation between
the electronic effect of the phosphine ligands and the diaste-
reoselectivity. As depicted in Scheme 4, the initial hetero-
Scheme 5. Preparation of enantioenriched 37.
The complete conversion of enantiomeric excess (ee) in
this step was confirmed by the stereoselective reduction
(over 10:1 diastereosomeric ratio (d.r.)) of 36 with LiAlH4,
which generated cis-2,6-dialkyl-4-hydroxytetrahydropyran 37
in 87% yield. Although the possibility of the oxonia-Cope
pathway could not be verified by experiments at this stage,
the result shown in Scheme 5 firmly establishes the viability
of the current method in tetrahydropyran synthesis.
Finally, it should be noted that the scope of the products
accessed by the gold(I)-catalyzed cycloisomerization can be
easily expanded to more densely functionalized tetrahydro-
pyranones because cyclic enol ethers are involved as an in-
termediate. For example, catalytic dihydroxylation of the cy-
cloisomerized intermediate 10a gave 3-hydroxytetrahydro-
pyran-4-one 38 in 88% yield as a single diastereomer
(Scheme 6).[17] This highlights a unique additional advantage
of the proposed catalytic cycloisomerization reaction.
Scheme 4. Mechanistic proposal for the stereoselectivity of the reaction.
cyclization–fragmentation of mixed acetal diastereomers C
and D should generate two isomeric oxocarbenium ions C’
and D’. The inherent preference of the cycloisomerization
step towards the cis-enol ether strongly suggests that the ox-
ocarbenium ion C’ is the less stable, and easily isomerizes to
the more stable ion D’.[13] Under these conditions, the cycli-
zation of C’ should be slower to increase the selectivity for
the formation of the cis-enol ether. This analysis is in good
agreement with the experimental data on the rate of the cy-
cloisomerization, as shown in Table 1.
Scheme 6. Catalytic dihydroxylation of 10a to give substituted tetrahy-
dropyranone 38; NMO=N-methylmorpholine-N-oxide.
In summary, we have developed a new method to access
highly substituted tetrahydropyran-4-ones, using a gold(I)-
catalyzed cycloisomerization of the 4-(alkoxyalkyl)oxy-1-
ynes as the key transformation. Of particular note is the
unique effect of the phosphine ligand on the stereoselectiv-
ity of the tetrahydropyranone formation. Detailed mechanis-
tic studies, as well as their application in the total synthesis
The mechanistic aspect of the proposed reaction could be
further complicated by a competing oxonia-Cope pathway
(Scheme 4).[14] This undesirable pathway may lead to delete-
Chem. Eur. J. 2011, 17, 1433 – 1436
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1435

Y. H. Rhee et al.
Angew. Chem. Int. Ed. 2008, 47, 2263–2266; b) C. Kim, H. J. Bae,
J. H. Lee, W. Jeong, H. Kim, V. Sampath, Y. H. Rhee, J. Am. Chem.
Soc. 2009, 131, 14660–14661; c) C. Kim, W. Lim, Y. H. Rhee, Bull.
Korean Chem. Soc. 2010, 31, 1465–1466.
of bioactive natural products are currently ongoing in our
laboratory and will be reported in due course.
[5] For recent reviews of gold-catalyzed reactions, see: a) A. S. K.
Hashmi, Chem. Rev. 2007, 107, 3180–3211; b) Z. Li, C. Brouwer, C.
He, Chem. Rev. 2008, 108, 3239–3265; c) D. J. Gorin, B. D. Sherry,
F. D. Toste, Chem. Rev. 2008, 108, 3351–3378; d) A. Fꢁrstner, P. W.
Davies, Angew. Chem. 2007, 119, 3478–3519; Angew. Chem. Int. Ed.
2007, 46, 3410–3449; e) D. J. Gorin, F. D. Toste, Nature 2007, 446,
395–403; f) P. Belmont, E. Parker, Eur. J. Org. Chem. 2009, 6075–
6089; g) A. Fꢁrstner, Chem. Soc. Rev. 2009, 38, 3208–3221.
[6] For selected examples of the tandem gold(I)-catalyzed reaction by
using a cyclization–fragmentation strategy, see: a) P. Dubꢂ, F. D.
Toste, J. Am. Chem. Soc. 2006, 128, 12062–12063; b) L. Zhang, J.
Am. Chem. Soc. 2005, 127, 16804–16805; c) S. E. An, J. Jeong, B.
Baskar, J. Lee, J. Seo, Y. H. Rhee, Chem. Eur. J. 2009, 15, 11837–
11841; d) H.-S. Yeom, Y. Lee, J. Jeong, E. So, S. Hwang, J.-E. Lee,
S. S. Lee, S. Shin, Angew. Chem. 2010, 122, 1655–1658; Angew.
Chem. Int. Ed. 2010, 49, 1611–1614.
Experimental Section
Preparation of 11a: A solution of 9 (80 mg, 0.28 mmol) in CH2Cl2
(5.6 mL, 0.05m) was added to the catalyst 12 f (6.6 mg, 0.0085 mmol) in a
flask equipped with a septum. The resulting solution was stirred at room
temperature for 15 min. When the reaction was complete (monitored by
TLC), triethylamine (0.1 mL) was added and the solution was stirred for
10 min. The reaction mixture was passed through a pad of celite and con-
centrated under reduced pressure. The residual oil was diluted with THF
(5.6 mL) followed by para-toluene sulfonic acid monohydrate (p-
TsOH·H2O, 5.4 mg, 0.028 mmol) and the resulting solution was stirred at
room temperature for 1 h. Triethylamine (0.2 mL) was then added and
the solution was stirred for 10 min. The resulting reaction mixture was fil-
tered through a pad of silica gel and concentrated under reduced pres-
sure. The residual oil was purified by flash chromatography on silica gel
(hexane/ether 90:10) to give 11a as a yellow oil (52 mg, 0.20 mmol, 72%
yield). Rf =0.21 (hexane/ether 90:10); 1H NMR (300 MHz, CDCl3): d=
0.87 (t, J=6.7 Hz, 3H), 1.17–1.55 (m, 20H), 1.56–1.74 (m, 1H), 2.13–2.27
(m, 2H), 2.29–2.41 (m, 2H), 3.48–3.62 (m, 1H), 3.70 ppm (ddq, J=11.3,
6.1, 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.3, 22.3, 22.9, 25.5,
29.5, 29.7, 29.7, 29.8, 32.1, 36.7, 47.8, 49.7, 73.4, 77.3, 208.0 ppm; IR: n˜ =
2925, 2852, 1666, 1155 cmÀ1; HRMS: m/z: calcd for C16H30O2: 254.2246
found; 254.2249.
[7] For synthesis of the gold complex 12a, see: S. Shin, Bull. Korean
Chem. Soc. 2005, 26, 1925–1926.
[8] For selected examples that address the ligand effect on divergent
pathways in gold-catalyzed reactions, see: a) M. Alcarazo, T. Stork,
A. Anoop, W. Thiel, A. Fꢁrstner, Angew. Chem. 2010, 122, 2596–
2600; Angew. Chem. Int. Ed. 2010, 49, 2542–2546; b) A. Z. Gon-
zꢃlez, F. D. Toste, Org. Lett. 2010, 12, 200–203; c) B. Baskar, H. J.
Bae, S. E. An, J. Y. Cheong, Y. H. Rhee, A. Duschek, S. F. Kirsch,
Org. Lett. 2008, 10, 2605–2607.
[9] By using 1H NMR spectroscopy, it was confirmed that the ratio of
10a to 10b (after the cycloisomerization step) was comparable to
the ratio of 11a to 11b.
Acknowledgements
[10] When 9 was treated with strong oxophilic Lewis acids, such as
BF3OEt2, neither 10 nor 11 was obtained in any significant amount.
[11] All the mixed acetal substrates were prepared by the coupling of
the homopropargylic alcohol with the enol ether precursor in good
yields. For a detailed procedure of the coupling reaction, see the
Supporting Information.
This work was supported by the National Research Foundation of Korea,
which is funded by the Korean Government (nos.: 2010–0009458 and
2008–0061957 from the NRF). The authors also thank the BK21 program
for the graduate fellowship.
[12] Unlike the terminal alkynes, internal alkynes (both methyl- and
phenyl-substituted) were unreactive under the reaction conditions.
[13] For a discussion on the configurational stability of oxocarbenium
ions, see: a) D. Cremer, J. Gauss, R. F. Childs, C. Blackburn, J. Am.
Chem. Soc. 1985, 107, 2435–2441; b) L. Liu, P. E. Floreancig,
Angew. Chem. 2010, 122, 6030–6033; Angew. Chem. Int. Ed. 2010,
49, 5894–5897.
[14] For studies on the competition between the Prins pathway and the
oxonia-Cope pathway in the tetrahydropyran synthesis, see: a) R.
Jasti, C. D. Anderson, S. D. Rychnovsky, J. Am. Chem. Soc. 2005,
127, 9939–9945; b) L. D. M. Lolkema, C. Semeyn, L. Ashek, H.
Hiemstra, W. N. Speckamp, Tetrahedron 1994, 50, 7129–7140;
c) W. R. Roush, G. J. Dilley, Synlett 2001, 0955–0959.
[15] a) For an in-depth discussion of racemization in the related Prins re-
action in tetrahydropyran synthesis, see: R. Jasti, S. D. Rychnovsky,
J. Am. Chem. Soc. 2006, 128, 13640–13648; b) for a recent review
on the Prins cyclization in tetrahydropyran synthesis, see: C. Olier,
M. Kaafarani, S. Gastaldi, M. P. Bertrand, Tetrahedron 2010, 66,
413–445.
Keywords: diastereoselectivity
Petasis–Ferrier reaction · tetrahydropyranones
· gold · isomerization ·
[1] a) V. Baliah, R. Jeyaraman, L. Chandrasekaran, Chem. Rev. 1983,
83, 379–423; b) M. J. Cloninger, L. E. Overman, J. Am. Chem. Soc.
1999, 121, 1092–1093; c) K. N. Cossey, R. L. Funk, J. Am. Chem.
Soc. 2004, 126, 12216–12217; d) S. Das, L.-S. Li, S. C. Sinha, Org.
Lett. 2004, 6, 123–126; e) W. Tu, L. Liu, P. E. Floreancig, Angew.
Chem. 2008, 120, 4252–4255; Angew. Chem. Int. Ed. 2008, 47, 4184–
4187; f) W. J. Morris, D. W. Custar, K. A. Scheidt, Org. Lett. 2005, 7,
1113–1116.
[2] a) N. A. Petasis, S.-P. Lu, Tetrahedron Lett. 1996, 37, 141–144;
b) A. B. Smith III, R. J. Fox, T. M. Razler, Acc. Chem. Res. 2008, 41,
675–687.
[3] For selected applications of the Petasis–Ferrier rearrangement in
the total synthesis of natural products, see: a) A. B. Smith III, T. Bo-
sanac, K. Basu, J. Am. Chem. Soc. 2009, 131, 2348–2358; b) A. B.
Smith III, V. Simov, Org. Lett. 2006, 8, 3315–3318; c) A. B. Smith
III, E. F. Mesaros, E. A. Meyer, J. Am. Chem. Soc. 2006, 128, 5292–
5299.
[16] A detailed synthetic procedure of 35 can be found in the Supporting
Information.
[17] The structure of compound 38 was determined by using 1H NMR
spectroscopy.
[4] a) H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong, D. T. Thangadurai, I.-
C. Hwang, Y. H. Rhee, Angew. Chem. 2008, 120, 2295–2298;
Received: October 10, 2010
Published online: January 12, 2011
1436
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 1433 – 1436