Stereocontrolled synthesis of oxaspirobicycles via prins-pinacol annulation

Article abstract of DOI:10.1021/ol9014078

We have developed the stereoselective synthesis of 2-oxaspiro[m,n]alkane derivatives using the Prins-pinacol annulation of alkene diols with a wide range of aliphatic or aromatic aldehydes and ketones. This approach was further applied for the synthesis o

Full text of DOI:10.1021/ol9014078

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3834-3837
Stereocontrolled Synthesis of
Oxaspirobicycles via Prins-Pinacol
Annulation
Satish N Chavre,†,‡ Punna Reddy Ullapu,†,‡ Sun-Joon Min,*,†,‡ Jae Kyun Lee,† Ae
Nim Pae,†,‡ Youseung Kim,† and Yong Seo Cho*,†,‡
Center for Chemoinformatics Research, Life Science DiVision, Korea Institute of Science
and Technology (KIST), Seoul, 136-791, Republic of Korea, and School of Science,
UniVersity of Science and Technology (UST), Daejeon, 305-333, Republic of Korea
ys4049@kist.re.kr; sjmin@kist.re.kr
Received June 22, 2009
ABSTRACT
We have developed the stereoselective synthesis of 2-oxaspiro[m,n]alkane derivatives using the Prins-pinacol annulation of alkene diols with
a wide range of aliphatic or aromatic aldehydes and ketones. This approach was further applied for the synthesis of oxatricyclic ring system.
The 2-oxaspiro[4.5]decane/[4.4]nonane structural motif has
been featured in a number of natural products such as
bakkenolide A, wiphaphysalin F, and epansolide A (Figure
1).1 In recent years, this type of molecular structure has been
studied as an attractive synthetic target. The known
synthetic methods to construct such spiro compounds
involve Diels-Alder reactions of R-methylene lactone,2
radical cyclization of bromo alkene or alkyne,3 ring-
closing metathesis reaction of diallyl oxolane derivatives,4
lactonization of chloro sulfinyl carboxylate,5 and metal-
catalyzed insertion reaction of diazo compounds.6 How-
ever, to date, there are only a few reports of the synthesis
of substituted 2-oxaspirocyclic derivatives with quaternary
† Korea Institute of Science and Technology (KIST).
‡ University of Science and Technology (UST).
(1) (a) Massias, M.; Rebuffat, S.; Molho, L.; Chiaroni, A.; Riche, C.;
Figure 1. Natural products containing the 2-oxaspiro structure.
Bodo, B. J. Am. Chem. Soc. 1990, 112, 8112. (b) Abe, N.; Onoda, R.;
Shirahata, K.; Kato, T.; Woods, M. C.; Kitahara, Y. Tetrahedron Lett. 1968,
9, 369. (c) Misico, R. I.; Gil, R. R.; Oberti, J. C.; Veleiro, A. S.; Burton,
G J. Nat. Prod. 2000, 63, 1329.
(2) Pouwer, R. H.; Schill, H.; Williams, C. M.; Bernhardt, P. V. Eur. J.
Org. Chem. 2007, 4699.
carbon centers due to demanding control of stereoselec-
tivity. In the course of our studies toward synthesis of
(3) (a) Bertin, D.; Gigmes, D.; Marque, S. R. A.; Tordo, P. Tetrahedron
2005, 61, 8752. (b) Nagano, H.; Ohtani, Y.; Odake, E.; Nakagawa, J.; Mori,
Y.; Yajima, T. J. Chem. Res., Synop. 1999, 338.
(4) Schobert, R.; Urbina-Gonzalez, J. M. Tetrahedron Lett. 2005, 46,
3657.
(5) Satoh, T.; Sugiyama, S.; Kamide, Y.; Ota, H Tetrahedron 2003, 59,
4327.
(6) Doyle, M. P.; Dyatkin, A. B. J. Org. Chem. 1995, 60, 3035.
10.1021/ol9014078 CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

oxacyclic ring system using Prins reaction,7 we envision
that the reaction of methylene diol 1 with aldehydes in
the presence of an appropriate Lewis acid would give rise
to an oxaspiro bicycle 4, as illustrated in Scheme 1. Thus,
the condensation of methylene diol 1 with aldehyde under
acidic conditions could generate the oxocarbenium inter-
mediate 2, which undergoes Prins cyclization followed
by prompt pinacol rearrangement to afford 3-substituted
2-oxaspiro compound.8 In this event, we imagine that
migration of the bond a, which is periplanar to the empty
p orbital, from favorable conformation 3-TS is stereo-
electronically allowed to form spiroketone 4 having a cis
relationship between the C-3 substituent and the quaternary
spirocenter.9
Scheme 2. Prins-pinacol Annulation of 8
pinacol reactions of 8 with p-nitrobenzaldehyde by screening
a broad range of Lewis acids including TMSOTf, SnCl4,
BF3·OEt2, and InCl3. Indeed, we found that the reaction of 8
with p-nitrobenzaldehyde in the presence of 3 equiv of
TMSOTf provided the corresponding oxaspirobicycle 9a in
96% yield as a single isomer, whereas the reactions promoted
by other Lewis acids gave 9a in lower yields. The relative
stereochemistry of the compound 9a was confirmed by
analysis of the X-ray single-crystal structure (Figure 2).12 It
turned out that the relative stereochemistry between the
spirocenter and the nitrophenyl group is cis.
Scheme 1. Concept of the Prins-pinacol Annulation for the
Synthesis of Oxaspirobicycles
Herein, we report an efficient, stereocontrolled synthesis
of 3-substituted 2-oxaspiro[4.5]decanes/ [4.4]nonanes using
Prins-pinacol annulation.
To verify our premise, we commenced with the preparation
of methylene diol 8 as depicted in Scheme 2. Starting from
hydroxymethyl ketone 5,10 we could synthesize dihydroxy
ketone 6 in moderate yield using Sharpless epoxidation.11
The diol 6 was protected as ketal 7, which underwent Wittig
olefination and subsequent deprotection to afford methylene
diol 8. With this substrate 8 in hand, we have tested Prins-
Figure 2. X-crystal structure of 9a with thermal ellipsoids projected
at the 50% probability level.
Encouraged by this result, we investigated the scope of
this Prins-pinacol process as shown in Table 1. Initially, the
spiroannulation of 8 with benzaldehyde and 4-chloroben-
zaldehyde under the optimized reaction condition (3.0 equiv
of TMSOTf, CH2Cl2, -78 °C, 4 h) gave the resulting
oxaspiro compounds 9 stereoselectively in excellent yields
(entries 1 and 2). In the case of the electron-rich 4-meth-
oxybenzaldehyde, however, a 1:1 mixture of two diastere-
omers was formed exceptionally (entry 3).13 The reactions
of 1 with aliphatic aldehydes such as n-hexanal and isobu-
tyraldehyde also proceeded to afford single diastereomers,
(7) (a) Cho, Y. S.; Karupaiyan, K.; Kang, H. J.; Pae, A. N.; Cha, J. H.;
Koh, H. Y.; Chang, M. H. Chem. Commun. 2003, 2346. (b) Cho, Y. S.;
Kim, H. Y.; Cha, J. H.; Pae, A. N.; Koh, H. Y.; Choi, J. H.; Chang, M. H.
Org. Lett. 2002, 4, 2025. (c) Chavre, S. N.; Choo, H.; Cha, S. N.; Pae,
A. N.; Choi, K. I.; Cho, Y. S. Org. Lett. 2006, 8, 3617. (d) Ullapu, P. R.;
Min, S.-J.; Charvre, S. N.; Choo, H.; Lee, J. K.; Pae, A. N.; Kim, Y.; Chang,
M. H.; Cho, Y. S. Angew. Chem., Int. Ed. 2009, 48, 2196.
(8) For reviews of Prins-pinacol reactions, see: (a) Overman, L. E.
Aldrichim. Acta 1995, 28, 107. (b) Overman, L. E. Acc. Chem. Res. 1992,
25, 352–359. (c) Overman, L. E.; Pennington, L. D. J. Org. Chem. 2003,
68, 7143. For other examples, see: (d) MacMillan, D. W. C.; Overman,
L. E.; Pennington, L. D. J. Am. Chem. Soc. 2001, 123, 9033. (e) Hanaki,
N.; Link, J. T.; MacMillan, D. W. C.; Overmann, L. E.; Trankle, W. G.;
Wurster, J. A. Org. Lett. 2000, 2, 223. (f) Cohen, F.; MacMillan, D. W. C.;
Overman, L. E.; Romeo, A. Org. Lett. 2001, 3, 1225. (g) Ponce, A. M.;
Overman, L. E. J. Am. Chem. Soc. 2000, 122, 8672. (h) Overman, L. E.;
Velthuisen, E. J. J. Org. Chem. 2006, 71, 1581.
(11) Paju, A.; Kanger, T.; Pehk, T.; Lopp, M. Tetrahedron 2002, 58,
7321. Unlike the orginal report, we found that the optical purity of 6 is
only 39% ee, which was determined by 1H NMR analysis of R-(-)-R-
methoxyphenyl acetate derivatives of 6. Disappointedly, our further effort
to synthesize the enantiomerically pure diol 6 has failed.
(9) Minor, K. P.; Overman, L. E. Tetrahedron 1997, 53, 8927.
(10) Taylor, R. J. K.; Wiggins, K.; Robinson, D. H. Synthesis 1990,
589.
(12) See the Supporting Information for details.
Org. Lett., Vol. 11, No. 17, 2009
3835

(Table 2).14 Similarly, the reaction of 10 with various
aromatic and aliphatic aldehydes proceeded to generate the
corresponding oxaspirobicycles exclusively although the
yields of the reactions slightly decreased in comparison of
the previous results. The structure of the compound 11a was
elucidated by analysis of the X-ray single crystal.12 Ketones
also worked well under our Prins-pinacol process in most
cases. In the case of acetophenone, however, we could isolate
only the consequent ketal derivative in 60% yield, which is
presumably formed due to high stability of ketone as well
as more kinetically favorable ketalization.
Table 1. Scope of the Prins-pinacol Annulation of 8 with
Various Aldehydes and Ketones
entry
R1
R2
product
yielda (%)
1
2
3
4
5
6
7
8
9
Ph
H
H
H
H
H
9b
9c
9d
9e
9f
9g
9h
9i
93
95
98b
98
96
92
90
92c
85
4-Cl-Ph
4-MeO-Ph
n-Pent
i-Pr
Table 3. Scope of the Prins-pinacol Annulation of 15 with
Various Aldehydes
-(CH2)5-
-(CH2)4-
entry
R
product
yielda (%)
1
2
3
4
5
6
Ph
4-F-Ph
3-MeO-Ph
4-Me-Ph
CH3
17a
17b
17c
17d
17e
17f
73
78
75
65
81
70
n-Bu
Ph
Me
Me
9j
a Isolated yield. b Ratio ) 1:1 (see ref 13). c Ratio ) 2:1.
CH3(CH2)4
respectively (entries 4 and 5). When ketones were used as
substrates, despite their low reactivities, we could effectively
obtain 3,3-disubstituted 2-oxaspirobicycles in high yields
(entries 6-9). While the spiroannulation of 8 with 2-hex-
anone gave a 2:1 mixture of two diastereomers (entry 8),
the reaction of acetopheone proved to be diastereoselective,
leading to only the cis isomer (entry 9). The structure of 9j
was determined by observing NOE enhancement between
C3 methyl hydrogens and C9 methylene hydrogens (see the
Supporting Information).
a Isolated yield.
Finally, to demonstrate the utility of our process further,
we attempted the formation of the oxatricyclic ring system
using diol 15 as a substrate (Table 3). Following the literature
procedure,15 we easily prepared hydrindenone 13 in two steps
starting from cyclohexenone 12 (Scheme 3). Exomethylena-
tion of 13 followed by dihydroxylation afforded the desired
diol 15 in 30% yield along with a comparable amount of
regioisomer 16. The assignment of the stereochemistry of
Table 2. Scope of the Prins-pinacol Annulation of 10 with
Various Aldehydes and Ketones
Scheme 3. Formation of Oxatricyclic Ring System
entry
R1
R2
product
yielda (%)
1
2
3
4
5
6
7
8
9
4-NO2-Ph-
Ph
4-Cl-Ph
4-MeO-Ph
n-Pent
i-Pr
H
H
H
H
H
H
11a
11b
11c
11d
11e
11f
11g
11h
11i
88
80
83
85b
82
85
62
70
65c
d
15 resulted from the assumption that the addition of OsO4
to exomethylene moiety in 14 occurred in the opposite side
-(CH2)5-
-(CH2)4-
n-Bu
Ph
Me
Me
(13) We have realized that a 1:1 mixture of 9d and 9d′ (diastereomer)
was produced in Table 1, whereas we obtained 11d as a single isomer in
Table 2. Although we cannot clarify the discrepancy between two reactions,
we assume that epimerization at the C3 position took place because the
carbocation intermediate generated by acid-catalyzed ring opening is
significantly stabilized by the 4-methoxyphenyl group.
10
11j
a Isolated yield. b See ref 13. c Ratio ) 2:1. d The corresponding ketal
was formed in 60% yield.
(14) The diol 10 was prepared following the same reaction sequences
as used in Scheme 2 starting from R-hydroxymethyl cyclohexanone.
(15) (a) Bal, S. A.; Marfat, A.; Helquist, P. J. Org. Chem. 1982, 47,
5045. (b) Tsantali, G. G.; Takakis, I. M. J. Org. Chem. 2003, 68, 6455.
Next, we extended our protocol to synthesize 2-oxaspiro-
[4,5]decane derivatives using methylene diol 10 as a substrate
3836
Org. Lett., Vol. 11, No. 17, 2009

of ring juncture hydrogen. With this substrate 15 in hand,
the reaction of 15 with aromatic and aliphatic aldehydes
under the previously optimized conditions gave oxatricycle
compounds in high yields. Again, only the single isomers
were obtained in all cases. We clearly confirmed the structure
of 17 by various NMR techniques including NOE experiment
(see the Supporting Information). In fact, the NOE correlation
of H5a-H1, H1′-H3, and Me(C3)-H3a in 17e indicated that
the stereochemical relationship of hydrogen(C5a)-ketone(C9)
hydrogen(C3a)-methyl(C3) is cis-trans-cis. Accordingly,
these results showed that the stereoselectivity in our Prins-
pinacol process toward oxatricyclic system is well pre-
served. Unfortunately, attempts to carry out the reactions
of 15 with ketones failed to give the desired 3,3-
disubstituted products.
are tolerated under the reaction condition. The excellent
efficiency and stereoselectivity observed in this process
represent an advance in the construction of molecular
architectures containing substituted 2-oxaspirobicycle deriva-
tives. In this regard, we have successfully applied this
protocol to build a novel oxatricyclic ring structure. The
further studies of this methodology for the total synthesis of
structurally related natural products are currently in progress
and will be reported in due course.
Acknowledgment. We are grateful to the Korea Institute
of Science and Technology (KIST) for financial support of
this research (2E21010, 2K01640).
Supporting Information Available: General experimental
procedure, characterization data for all new compounds, and
data for X-ray crystal structure analysis of 9a and 11a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, we have developed an efficient and stereo-
controlled method for the synthesis of 2-oxaspiro[4,5]decanes/
[4,4]nonanes using Prins-pinacol annulation of methylene
diol promoted by Lewis acid. In this event, we have shown
that a wide range of aromatic/aliphatic aldehydes and ketones
OL9014078
Org. Lett., Vol. 11, No. 17, 2009
3837