Electrophile-induced ether transfer: Stereoselective synthesis of 2,6-disubstituted-3,4-dihydropyrans

Article abstract of DOI:10.1021/jo800704d

(Chemical Equation Presented) Stereoselective synthesis of trans-2,6-disubstituted-3,4-dihydropyrans has been achieved from a simple homoallylic alkoxyether via a three-step sequence: electrophile-induced ether transfer, cyclization, and functionalization, which is highlighted by a rare example of Ferrier rearrangement of allylic ether. This methodology was successfully implemented for the asymmetric synthesis of a C7-C17 fragment of swinholide A.

Full text of DOI:10.1021/jo800704d

SCHEME 1. Efficient Production of Sulfonyl Pyran 3
Electrophile-Induced Ether Transfer:
Stereoselective Synthesis of
2,6-Disubstituted-3,4-Dihydropyrans
Rendy Kartika, Jeffrey D. Frein, and Richard E. Taylor*
Department of Chemistry and Biochemistry and the Walther
Cancer Research Center, UniVersity of Notre Dame, 251
Nieuwland Science Hall, Notre Dame, Indiana 46556
taylor.61@nd.edu
ReceiVed April 2, 2008
methodology for the stereoselective production of polyketide
synthetic fragments,4,5 we present our approach to trans-2,6-
disubstituted-3,4-dihydropyrans highlighted by our recently
developed three-step sequence to oxygen heterocycles: elec-
trophile-induced ether transfer, cyclization, and functional-
ization.
In our recent communication, we described an efficient and
robust production of stereochemically rich 2-sulfone tetrahy-
dropyran 3 from a simple alkoxyether protected homoallylic
alcohol 1.5a Treatment of 1 with iodine monochloride followed
by trapping the corresponding chloromethyl ether intermediate4
with thiophenol and subsequent oxidation produced sulfonyl
ether 2 in high yield with excellent syn stereocontrol. Treatment
of 2 with LiHMDS led to efficient cyclization which produced
anomeric sulfonyl pyran 3 as a mixture of diastereomers,
Scheme 1.
With sulfonyl pyran 3 in hand, we envisioned a two-step
functionalization to access key oxocarbonium ion intermedi-
ate A on a path to 2,6-trans-dihyropyrans 5, Table 1. The
elimination of the anomeric sulfone using a mixture of
magnesium bromide and triethylamine assisted by ultrasound
cleanly afforded glycal 4 in 95% yield as precedented by
the previous work of Ley and co-workers.6,7 As demonstrated
by several examples in Table 1, the ionization of glycal 4
with TMSOTf in CH2Cl2 followed addition of various
nuclophiles provided the Ferrier rearrangement products 5
in excellent yield and diastereoselectivity.8 For example,
when allylic silanes were used as nucleophiles, dihydropyrans
5a and 5b were produced in excellent yields and as a single
diastereomer under both catalytic and stoichiometric amounts
of TMSOTf (entries 1-3).9 Other nucleophiles such as
organozinc, organotin (entries 4-6), and enol silanes (entries
7 and 8) also provided products 5c-5g in high yield and
diastereoselectivity. Interestingly, slight erosion in diaste-
reoselectivity was observed with a bulkier nucleophile (entry
Stereoselective synthesis of trans-2,6-disubstituted-3,4-di-
hydropyrans has been achieved from a simple homoallylic
alkoxyether via a three-step sequence: electrophile-induced
ether transfer, cyclization, and functionalization, which is
highlighted by a rare example of Ferrier rearrangement of
allylic ether. This methodology was successfully imple-
mented for the asymmetric synthesis of a C7-C17 fragment
of swinholide A.
Heterocycles are the most common ring system found in
polyketides. Their presence adds a significant degree of
conformational rigidity and are thus likely to be critical to
the pharmacophore of biologically active natural products.
2,6-Disubstituted pyrans with a variety of oxidation levels
represent a particularly common motif. A 3,4-dihydro- varient
appears in several biologically important polyketides, such
as the swinholides,1 scytophycins,2 and misakinolides.3 In
line with our recent efforts in the development of synthetic
(1) (a) Carmely, S.; Kashman, Y. Tetrahedron Lett. 1985, 26, 511. (b)
Kobayashi, M.; Tanaka, J.; Katori, T.; Matsuura, M.; Kitagawa, I. Tetrahedron
Lett. 1989, 30, 2963. (c) Kobayashi, M.; Tanaka, J.; Katori, T.; Matsuura, M.;
Yamashita, M.; Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2409. (d) Kitagawa,
I.; Kobayashi, M.; Katori, T.; Yamashita, M.; Tanaka, J.; Doi, M.; Ishida, T.
J. Am. Chem. Soc. 1990, 112, 3710. (e) Doi, M.; Ishida, T.; Kobayashi, M.;
Kitagawa, I. J. Org. Chem. 1991, 56, 3629. (f) Kobayashi, M.; Tanaka, J.; Katori,
T.; Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2960. (g) Tsukamoto, S.; Ishibashi,
M.; Sasaki, T.; Kobayashi, J. J. Chem. Soc., Perkin Trans. 1 1991, 3185.
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T. R.; Furusawa, E.; Furusawa, S. Pure Appl. Chem. 1986, 58, 263. (b) Ishibashi,
M.; Moore, R. E.; Patterson, G. M. L.; Xu, C. F.; Clardy, J. J. Org. Chem.
1986, 51, 5300.
(4) Liu, K.; Taylor, R. E.; Kartika, R. Org. Lett. 2006, 8, 5393.
(5) (a) Kartika, R.; Taylor, R. E. Angew. Chem., Int. Ed. 2007, 46, 6874. (b)
Kartika, R.; Taylor, R. E. Heterocycles 2007, 74, 447.
(6) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron 1989,
45, 4293.
(7) Other established strategies for the preparation of glycals: (a) Rainier,
J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380. (b) Danishefsky,
S. J.; DeNinno, S.; Lartey, P. J. Am. Chem. Soc. 1987, 109, 2082; also, see
references 12–14.
(8) Recent reviews in Ferrier Rearrangement: Ferrier, R. J. Top. Curr. Chem.
2001, 215, 153.
(3) (a) Kato, Y.; Fusetani, N.; Matsunaga, S.; Hashimoto, K.; Sakai, R.; Higa,
T.; Kashman, Y. Tetrahedron Lett. 1987, 28, 6225. (b) Tanaka, J.; Higa, T.;
Kobayashi, M.; Kitagawa, I. Chem. Pharm. Bull. 1990, 38, 2967.
(9) The 2,6-trans stereoconfiguration of dihydropyran 5a and 5h were
unambigously assigned based on ROESY experiment.
5592 J. Org. Chem. 2008, 73, 5592–5594
10.1021/jo800704d CCC: $40.75 2008 American Chemical Society
Published on Web 06/21/2008

TABLE 1. Preparation of 2,6-trans-3,4-Dihydropyran 5
this unexpected stereoselectivity is unclear to us, but it
appears the high reactivity of silyl ketene acetal clearly affects
stereoselectivity. Similar observation has been reported by
Paterson and co-workers.10 It is also important to note that
with enol silanes and ketene acetals, three equivalents of
Lewis acid were required for the reaction to achieve
completion (entries 7-10). We speculate that the stronger
Lewis basicity of the newly generated carbonyl group
compared to that of the starting ether readily competed for
the Lewis acid.
In the typical Ferrier rearrangement process, an allylic acetate
or tosylate is typically employed as the nucleofuge. In fact, to
the best of our knowledge, the use of a secondary allylic ether
for this purpose is not precedented most likely due to its poor
leaving group ability and the fact that its relatively weak Lewis
basicity may cause slow, inefficient ionization.11 However, in
our case, glycal 4 underwent rapid ionization. This reactivity is
facilitated by the pseudoaxial orientation of the methoxy group,12
a stereochemistry which is readily installed in our ether transfer
reaction, where the σ* antibonding orbital is oriented relatively
parallel to the glycal π bond. The 2,6-trans stereochemistry was
presumably assembled via subsequent axial delivery of nucleo-
philes to the newly generated oxocarbonium ion upon activa-
tion.13 Since the observed diastereoselectivity eroded with
bulkier nucleophiles, a contact-ion pair system might be involved
in our system that could potentially hinder axial delivery.
To demonstrate the applicability of our method to complex
molecule syntheses, we became interested in targeting the marine
polyketide, swinholide A, particularly the C7-C17 dihydropyran
region represented as synthetic fragment 6.14–16
Our approach to fragment 6 would begin with readily
accessible, enantiomerically pure homoallylic alcohol 7,17
Figure 1.
(11) Ley and co-workers have demonstrated similar Ferrier rearrangement
using a tertiary allylic ether for the construction of the spiroketal moiety in
okadaic acid: Ley, S. V.; Humphries, A. C.; Eick, H.; Downham, R.; Ross, A. R.;
Boyce, R. J.; Pavey, J. B. J.; Pietruszka, J. J. Chem. Soc., Perkin Trans.1 1998,
3907.
(12) The conformation of dihydropyran 4 was deduced by 1H NMR coupling-
constant analysis.
(13) (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc. 1982, 104,
4976. (b) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25, 2383.
(14) Nicolaou’s total synthesis of swinholide A: (a) Patron, A. P.; Richter,
P. K.; Tomaszewski, M. J.; Miller, R. A.; Nicolaou, K. C. J. Chem. Soc., Chem.
Commun. 1994, 1147. (b) Richter, P. K.; Tomaszewski, M. J.; Miller, R. A.;
Patron, A. P.; Nicolaou, K. C. J. Chem. Soc., Chem. Commun. 1994, 1151. (c)
Nicolaou, K. C.; Ajito, K.; Patron, A. P.; Khatuya, H.; Richter, P. K.; Bertinato,
P. J. Am. Chem. Soc. 1996, 118, 3059. (d) Nicolaou, K. C.; Patron, A. P.; Ajito,
K.; Richter, P. K.; Khatuya, H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M. J.
Chem.-Eur. J. 1996, 2, 847.
(15) Paterson’s total synthesis of swinholide A: (a) Paterson, I.; Cumming,
J. Tetrahedron Lett. 1992, 33, 2847. (b) Paterson, I.; Smith, J. D. J. Org. Chem.
1992, 57, 3261. (c) Paterson, I.; Yeung, K. Tetrahedron Lett. 1993, 34, 5347.
(d) Paterson, I.; Smith, J. D. Tetrahedron Lett. 1993, 34, 5354. (e) Paterson, I.;
Cumming, J. G.; Smith, J. D.; Ward, R. A. Tetrahedron Lett. 1994, 35, 3405.
(f) Paterson, I.; Smith, J. D.; Ward, R. A.; Cumming, J. G. J. Am. Chem. Soc.
1994, 116, 2615. (g) Paterson, I.; Yeung, K.; Ward, R. A.; Cumming, J. G.;
Smith, J. D. J. Am. Chem. Soc. 1994, 116, 9391. (h) Paterson, I.; Cumming,
J. G.; Ward, R. A.; Lamboley, S. Tetrahedron 1995, 51, 9393. (i) Paterson, I.;
Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413. (j) Paterson, I.; Ward,
R. A.; Smith, J. D.; Cumming, J. G.; Yeung, K. Tetrahedron 1995, 51, 9437.
(k) Paterson, I.; Yeung, K.; Ward, R. A.; Smith, J. D.; Cumming, J. G.; Lamboley,
S. Tetrahedron 1995, 51, 9467.
a Yield was reported from the isolation of the major diastereomer.
b Diasteromeric ratio was determined by 1H NMR integration of the
crude reaction mixture. c Minor 2,6-cis diastereomer was isolated in
40% yield. d Reaction was carried out in toluene. e Minor 2,6-cis
diastereomer was isolated in 15% yield.
6). Furthermore, when a silyl ketene acetal was employed,
dihydropyran 5h was produced in a stereorandom fashion.
Interestingly, the diastereoelectivity could be slightly im-
proved to 3.6:1 if the activation was carried out with
BF3•OEt2 in toluene, (entries 9 and 10). The exact origin of
(16) Nakata’s synthetic approach to preswinholide A: (a) Nakata, T.;
Komatsu, T.; Nagasawa, K. Chem. ReV. Bull. 1994, 42, 2403. (b) Nakata, T.;
Komatsu, T.; Nagasawa, K.; Yamada, H.; Takahashi, T. Tetrahedron Lett. 1994,
35, 8225. (c) Nagasawa, K.; Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37,
6881. (d) Nagasawa, K.; Shimizu, I.; Nakata, T. Tetrahedron Lett. 1996, 37,
6885.
(10) (a) Paterson, I.; Smith, J. D. J. Org. Chem. 1992, 57, 3261. (b) Paterson,
I.; Smith, J. D.; Ward, R. A. Tetrahedron 1995, 51, 9413.
(17) Sabitha, G.; Sudhakar, K.; Reddy, N. M.; Rajkumar, M.; Yadav, J. S.
Tetrahedron Lett. 2005, 46, 6567.
J. Org. Chem. Vol. 73, No. 14, 2008 5593

SCHEME 2. Asymmetric Synthesis to Fragment 6
FIGURE 1. C1-C17 fragment of swinholide A.
After protecting alcohol 7 as a MOM ether, the ether-transfer
reaction with thiophenol-triethylamine workup, and subse-
quent oxidation afforded sulfonylether 8 in good yield with
high stereocontrol. LiHMDS mediated cyclization followed
by elimination of the anomeric sulfone under MgBr2 and TEA
afforded 2,3-dihydropyran 9 in 74% yield over two steps.
Exposure of 9 to the Ferrier reaction conditions with
allyltrimethylsilane and very low catalyst loading of TMSOTf
produced 3,4-dihydropyran 10 in nearly quantitative yield
and as a single diastereomer. Removal of the BPS ether with
TBAF unmasked the primary alcohol which was then
oxidized with Dess-Martin periodinane18 to aldehyde 11. Both
steps proceeded in high yields. Aldehyde 11 was then
subjected to a syn-aldol reaction with oxazolidinone 12 under
Evans’ protocol19 to afford aldol adduct 13 in 82% yield.
Subsequent O-methylation20 followed by reductive removal
of the auxiliary completed our synthetic route to dihydropyran
6. The spectroscopic analyses of fragment 6 were in a
complete agreement to those reported by Nicolaou and co-
workers.14d
In contrast to traditional methods, our ether transfer
chemistry provides direct access to orthogonally protected
syn-1,3-diol structural units. The method has now been
applied to both acyclic as well as pyran fragments common
to polyketides. The current strategy is highlighted by
electrophile-induced ether transfer reaction which subse-
quently installs the functionality with the requisite stereo-
chemistry for the rare examples of allylic ether Ferrier
rearrangement to provide 2,6-disubstituted-3,4-dihydropyrans.
The broad scope of the method and scalability is demonstrated
by its successful application to the construction of C7-C17
fragment of swinholide A. Further applications and extensions
of the methodology are currently ongoing in our laboratory
and will be reported in due course.
Experimental Section
Representative Procedures for the Ferrier Rearrangement
of Glycal 4 with Allyltrimethylsilane. Dihydropyran 4 (100 mg,
0.489 mmol) was dissolved in CH2Cl2 (10 mL), and the solution
was cooled to -78 °C. After addition of allyltrimethylsilane (0.23
mL, 1.47 mmol), a freshly prepared 1 M solution of TMSOTf
buffered with oven-dried solid NaHCO3 (0.98 mL, 0.98 mmol) was
then added dropwise. The reaction mixture was stirred for 5 min
and then quenched with phosphate buffer (pH 7.00, 20 mL). After
separation of layers, the aqueous layer was extracted with CH2Cl2
(2 × 20 mL). The organic layers were then combined, dried over
1
MgSO4, and concentrated under vacuum. H NMR of the crude
reaction mixture indicated >20:1 diastereomeric ratio. The crude
material was purified with silica gel column using 95:5 hexanes:
EtOAc solvent system to give the Ferrier rearrangement product
5a as clear oil in 91% yield (95.0 mg, 0.443 mmol). 1H NMR (500
MHz, CDCl3): δ (ppm) ) 7.31 - 7.28 (2H, m), 7.25 - 7.20 (3H,
m), 5.82 (1H, m), 5.78 - 5.70 (2H, m), 5.01 (1H, m), 4.98 (1H,
m), 4.25 (1H, m), 3.95 (1H, dddd, J ) 6.5, 6.5, 6.0, 6.0 Hz), 2.92
(1H, dd, J ) 13.5, 7.0 Hz), 2.75 (1H, dd, J ) 13.5, 6.0 Hz), 2.36
(1H, m), 2.23 (1H, m), 2.02 - 1.98 (2H, m). 13C NMR (125 MHz,
CDCl3): δ (ppm) ) 138.7, 134.8, 129.3, 129.2, 128.2, 126.1, 124.1,
116.7, 72.5, 69.1, 41.8, 38.8, 30.0. IR (cm-1): f ) 3064, 3030, 2924,
1496, 1455, 1075, 914, 700. HRMS-FAB (M - H)+ ) 213.1279
calculated for C15H17O, experimental ) 213.1279.
Acknowledgment. R.K. thanks the University of Notre Dame
for the financial support through the Reilly Fellowship award.
J.D.F. is a Walther Cancer Research Center postdoctoral fellow.
Supporting Information Available: Full experimental and
characterization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(19) Gage, J. R.; Evans, D. A. Org. Syn. 1990, 68, 83.
(20) Mitchell, I. S.; Pattenden, G.; Stonehouse, J. Org. Biomol. Chem. 2005,
3, 4412.
JO800704D
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