Pyranyl heterocycles from inverse electron demand hetero [4+2] cycloaddition reactions of chiral allenamides as a new chiral template for constructing C-glycoside substrates

Article abstract of DOI:10.1055/s-2003-40352

A useful sequence involving stereoselective functionalization of the two olefins in pyranyl heterocycles derived from inverse electron demand hetero [4+2] cycloadditions of chiral allenamides is described here. This sequence constitutes stereo-selectively dihydroxylation or hydroboration-oxidation of the sterically accessible C5 exocyclic olefin followed by hydroboration-oxidation of the endocyclic olefin at C2/C3. The ultimate success in the removal of the C6 chiral auxiliary completes the demonstration of the concept of employing these unique hetero cycloadducts as chiral templates for constructing highly functionalized pyrans or C-glycosides.

Full text of DOI:10.1055/s-2003-40352

LETTER
1241
Pyranyl Heterocycles from Inverse Electron Demand Hetero [4+2] Cyclo-
addition Reactions of Chiral Allenamides as a New Chiral Template for
Constructing C-Glycoside Substrates
Pyranyl
H
eterocy
.
cles
f
romIn
R
verse Electron
D
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Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, U.S.A.
E-mail: hsung@chem.umn.edu
Received 7 October 2002
This paper is dedicated in memory of Professor Ray Lemieux for his life-long contributions to Organic Chemistry.
Abstract: A useful sequence involving stereoselective functional-
ization of the two olefins in pyranyl heterocycles derived from in-
verse electron demand hetero [4+2] cycloadditions of chiral
allenamides is described here. This sequence constitutes stereo-
selectively dihydroxylation or hydroboration–oxidation of the steri-
cally accessible C5 exocyclic olefin followed by hydroboration-
oxidation of the endocyclic olefin at C2/C3. The ultimate success in
the removal of the C6 chiral auxiliary completes the demonstration
of the concept of employing these unique hetero cycloadducts as
chiral templates for constructing highly functionalized pyrans or
C-glycosides.
Key words: hetero [4+2] cycloadditions, pyranyl heterocycles,
hydroboration–oxidation
We recently reported a Lewis acid mediated stereoselec-
tive removal of the chiral imidazolidinone group at the
anomeric carbon of pyranyl heterocycles2 obtained from
Scheme 1
inverse electron-demand hetero [4+2] cycloadditions of a
chiral allenamide with vinyl ketones (Scheme 1).3–7 The
ability to remove this anomeric chiral urea group in the
pyran 1 allows this imidazolidinone group to serve as a
chiral auxiliary that can be ultimately removed and re-
placed stereoselectively with allyl groups. This establish-
es one of the two concepts needed to demonstrate that the
pyran 1 could serve as a useful chiral template for synthe-
sis of highly functionalized pyranyl heterocycles C-glyco-
side related substrates8,9 such as 4.
stereoselective oxidative transformation of both olefins in
1 followed by removal of the auxiliary.
Two transformations of the C5 exocyclic olefin were car-
ried out promptly using the pyran 5 as the model substrate
obtained from inverse electron demand hetero [4+2] cy-
cloaddition of N-allenyl-N¢-methyl-4-phenyl-5-methyl-2-
imidazolidinone and 1-naphthyl vinyl ketone (Scheme 2).
Hydroboration using 9-BBN was very selective for the
exocyclic olefin in 5. After oxidation of the resulting bo-
rane using 15% aqueous NaOH and 30% aqueous H2O2,
the alcohol 610 was obtained in 73% yield as a single dias-
tereomer. Various standard protections using Ac2O, piv-
aloyl chloride [Piv-Cl], and TBSCl gave pyrans 7–9,
respectively.
In addition, we illustrated that the C2/C3 endocyclic ole-
fin in the pyran 1 could be subjected to a stereoselective
hydroboration–oxidation after mono-hydrogenation of
the C5-exocyclic olefin. This provides preliminary feasi-
bility for the second concept: Stereoselective functional-
ization of the two olefins in pyran 1. Complete realization
of this second concept would constitute development of
suitable sequences to stereoselectively functionalize both
olefins in the pyran 1: The endocyclic olefin at C2/C3 and
the sterically accessible C5 exocyclic olefin (Scheme 1).
This turned out to be not trivial especially during the ulti-
mate removal of the chiral imidazolidinone auxiliary at
C6. We report here a successful sequence constituting
Dihydroxylation of the C5 exocyclic olefin in 5 using sto-
ichiometric amount of OsO4 followed by hydrolysis of the
osmate ester afforded the diol 10 in 85% yield also as a
single diastereomer. When a catalytic amount of OsO4
was used, reactions were considerably slower. Pyrans 7–
10 should provide useful functional handles serving as en-
try points for further elaboration at C5 and C7 using con-
ventional methods.
Synlett 2003, No. 9, Print: 11 07 2003.
Art Id.1437-2096,E;2003,0,09,1241,1246,ftx,en;S05702ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
Having pyrans 7–10 in hand, we proceeded to functional-
ize the endocyclic olefin at C2/C3. As shown in
Scheme 3, the pyran 7 and 8, protected with an acyl and

1242
C. Rameshkumar, R. P. Hsung
LETTER
the preceding paper2 interestingly led to the bicycles 16
and 17 in excellent yields and as single diastereomers. The
stereochemistry at C6 was assigned based on the coupling
constant of C6-H being 9.0 Hz, suggesting that C6-H and
C5-H are di-axial, thereby providing a coupling constant
of 3.5 Hz for C2-H and C3-H for they are di-equatorial.
Formation of 16 and 17 is likely due to an intramolecular
trapping of the oxocarbenium ion 18 by the acyl group in
an anchimeric manner8 after the loss of the chiral imida-
zolidinone group. Based on available stereochemical as-
signment, the attack of the acyl likely proceeded in an
axial approach, and the resulting new oxocarbenium ion
19 was then by the scavenging urea nucleophile. Prelimi-
nary attempts to unravel the bicycle 16 or 17 using Lewis
acids and excess of allyltrimethylsilane were not success-
ful.
Scheme 2 a) 2.5 Equiv Ac2O, pyridine, 0 °C to r.t., 12 h. b) 2.5
Equiv Piv-Cl, pyridine, 0 °C to r.t., 16 h. c) TBSCl, imidazole, DMF,
0 °C to r.t., 4 h.
Scheme 4
While pyrans 16 and 17 are interesting structures, the py-
ran 9 in which the C5 hydroxymethyl was protected with
TBS group was useful in the final removal of the C6 urea
group (Scheme 4). Hydroboration–oxidation of 9 gave the
alcohol 20, and the subsequent allylation without protect-
ing the C3-hydroxyl group gave 21 in 70% yield as a sin-
gle diastereomer. The relative stereochemistry was
assigned using NOE experiments.11 This represents the
first completed sequence in stereoselective functionaliza-
tion of C5 exocyclic olefin and C2/C3 endocyclic olefin
followed by a stereoselective removal of the C6 imidazol-
idinone group, thereby fully demonstrating the concept of
the pyran 1 serving as a template for stereoselective con-
structions of complex pyranyl heterocycles.
Scheme 3
While the pyran 9 allows the completion of the entire se-
quence in preparation of heterocycles such as 21, to
broaden the scope, the pyran 10 could be even more ver-
satile given the two hydroxyl groups at C5 and C7
(Scheme 5). Standard conditions, using 2,2-dimethoxy
propane, led to the acetonide 22 in 50% yield (unopti-
mized), but the ensuing hydroboration using BH3⋅THF or
BH3·SMe2 failed to provide the alcohol 23. On the other
hand, hydroboration of 10 without any protection steps
using BH3·SMe2 led to the triol 24 in 55% yield after the
peroxide oxidative step. Subsequent acetonide formation,
using 2,2-dimethoxy propane, gave 23 in 42% yield.
pivaloyl group, respectively, underwent hydroboration
and oxidation smoothly using BH3⋅THF and aqueous
H2O2/NaOH to give alcohols 11 and 12 in 74% and 60%
yields, respectively, as single diastereomers. Because re-
moval of the C6 urea group in 11 using the allylation con-
ditions described in the preceding paper was not clean, the
C3 hydroxyl groups in 11 and 12 were protected using ei-
ther Ac2O or Piv-Cl to afford 14 and 15 in 86% and 75%
yields, respectively.
Allylations of 14 and 15 using 1.5 equivalents of SnBr4
and 4.0 equivalents of allyltrimethylsilane as described in
Synlett 2003, No. 9, 1241–1246 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Pyranyl Heterocycles from Inverse Electron Demand Hetero [4+2] Cycloaddition Reactions
1243
as shown in Scheme 7. Successful per-methylation of the
triol 24 using NaH and MeI led to the trimethoxy deriva-
tive 32 in 90% yield. After screening a variety of other
Lewis acids, it was found that 1.5 equivalents of SnCl4
worked effectively as the Lewis acid, and in the presence
of allyltrimethylsilane, the desired allylation product 33
was isolated in 62% yield with 12-15:1 diastereomeric ra-
tios.
Equipped with the finding that a stronger Lewis acid
would now be more feasible in the removal of the imida-
zolidinone at C6 without destroying the pyranyl ring, the
triol 24 was subjected to periodate cleavage using NaIO4
in the presence of HOAc to give the ketone 34 in 82%
yield. The ketone 34 represents a very important interme-
diate because it can be transformed into various pyranyl
heterocycles that do not bear the methylene unit at C5 as
those described above. In addition, the ketone 34 will al-
low functionalization at the C4 position.
Scheme 5
However, attempts on allylation to remove the imidazoli-
dinone group in 23 or 24 led to mostly fragmentation of
the pyranyl ring or deacetonization even when the C3-OH
was protected with a TBS or Ac group.
The diol 10 was then protected using various silyl group
combinations to give 25 and 26 as shown in Scheme 6.
While hydroboration of 25 or 26 was successful, the ensu-
ing allylation and removal of the chiral imidazolidinone
group at C6 was not successful using 27 and 28, or using
29 and 30 (Note: Both are derived from 28) in which the
C3 secondary hydroxyl group was also silylated. Desilyl-
ation and/or decomposition of the pyranyl ring again oc-
curred.
To finally achieve successful removal of the chiral imida-
zolidinone group at C6 position of these highly function-
alized pyranyl heterocycles, two sequences were pursued
Scheme 7
Reduction of the ketone 34 using NaBH4 led to a 1:1 mix-
ture of the corresponding diol. On the other hand, a direct-
ed reduction using NMe4B[OAc]3H gave exclusively the
3,5-anti-diol [90% yield], and methylation using the same
condition above gave 35 in 73% overall yield. Allylation
of 35 using SnCl4 provided the desired pyranyl heterocy-
cle 36 in 65% yield but with a dr of 2:1. These two se-
quences truly complete the demonstration that pyrans
derived from hetero [4+2] cycloadditions of chiral allena-
mides can be employed as a chiral template for synthesis
of highly functionalized oxygen heterocycles.
Although the isomeric ratio is low for 36, mechanistically,
it fits quite reasonably as shown in Scheme 8. When the
oxocarbenium intermediate 38a is derived from 37
Scheme 6
Synlett 2003, No. 9, 1241–1246 ISSN 1234-567-89 © Thieme Stuttgart · New York

1244
C. Rameshkumar, R. P. Hsung
LETTER
(X = H and Y = Me), the C5-Me group would assume a
pseudo-axial position, thereby blocking the approaching
of allyltrimethylsilane equatorially from bottom face.
While this could further enhance the anomerically favored
axial addition and lead to a diastereomeric ratio of 6-9:1,2
the pseudo-axial C5-OMe group in the oxocarbenium in-
termediate 38b derived from 35 (X = H and Y = OMe)
could be less effective for it could rotate away from the
bottom face.
References
(1) A recipient of 2001 Camille Dreyfus Teacher-Scholar
Award and McKnight Faculty Award.
(2) Berry, C. R.; Rameshkumar, C.; Tracey, M. R.; Wei, L.-L.;
Hsung, R. P. Synlett 2003, 791.
(3) For reviews on allenes see: (a) Saalfrank, R. W.; Lurz, C. J.
In Methoden der organischen Chemie (Houben–Weyl);
Kropf, H.; Schaumann, E., Eds.; Georg Thieme Verlag:
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Allenes in Organic Synthesis; John Wiley and Sons: New
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Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499.
In comparison with both cases, the oxocarbenium inter-
mediate 38c derived from 32 (X = OMe and
Y = CH2OMe) would provide the steric shielding of the
bottom face. Additional steric interactions between the X
group and Y group could also drive the CH2OMe group
further back toward the bottom face. This enhanced
shielding would provide the best diastereoselectivity in
the ensuing addition of allyltrimethylsilane in the case of
32.
(c) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869.
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H. E.; Hiemstra, H.; Rutjes, F. P. T. Org. Lett. 2001, 3,
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Simons, C.; Megati, S.; Nishimura, H.; Maeda, Y.; Mitsuya,
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2413. (x) For an account on living polymerization of
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Scheme 8
We have described here a complete sequence suitable for
stereoselective functionalization of the two olefins in pyr-
anyl heterocycles derived from inverse electron demand
hetero [4+2] cycloadditions of chiral allenamides. This
sequence constitutes stereoselective dihydroxylation or
hydroboration of the sterically accessible C5 exocyclic
olefin followed by hydroboration–oxidation at the en-
docyclic olefin at C2/C3. The ultimate success in the re-
moval of the chiral auxiliary at C6 demonstrates the
concept of using these hetero cycloadducts as chiral
templates for constructing highly functionalized pyrans or
C-glycoside related substrates.
Macromolecules 1998, 31, 6741.
(5) For highly stereoselective [4+2] cycloaddition reactions of
chiral allenamides, see: (a) Wei, L.-L.; Hsung, R. P.; Xiong,
H.; Mulder, J. A.; Nkansah, N. T. Org. Lett. 1999, 1, 2145.
(b) Wei, L.-L.; Xiong, H.; Douglas, C. J.; Hsung, R. P.
Tetrahedron Lett. 1999, 40, 6903.
Acknowledgment
Support from NSF [CHE-0094005] and J&J PRI are greatly appre-
ciated.
Synlett 2003, No. 9, 1241–1246 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Pyranyl Heterocycles from Inverse Electron Demand Hetero [4+2] Cycloaddition Reactions
1245
(6) For our other studies using chiral allenamides, see:
(a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.;
Mulder, J. A.; G rebe, T. P. Org. Lett. 2002, 4, 2417.
(b) Rameshkumar, C.; Xiong, H.; Tracey, M. R.; Berry, C.
R.; Yao, L. J.; Hsung, R. P. J. Org. Chem. 2002, 67, 1339.
(c) Xiong, H.; Hsung, R. P.; Berry, C. R.; Rameshkumar, C.
J. Am. Chem. Soc. 2001, 123, 7174. (d) Xiong, H.; Hsung,
R. P.; Wei, L.-L.; Berry, C. R.; Mulder, J. A.; Stockwell, B.
Org. Lett. 2000, 2, 2869.
(7) For our synthesis of allenamides, see: (a) Wei, L.-L.;
Mulder, J. A.; Xiong, H.; Zificsak, C. A.; Douglas, C. J.;
Hsung, R. P. Tetrahedron 2001, 57, 459. (b) Xiong, H.;
Tracey, M. R.; Grebe, T. P.; Mulder, J. A.; Hsung, R. P. Org.
Synth., 2003, accepted.
12.5 Hz, 1 H), 4.77 (d, J = 9.0 Hz, 1 H), 4.83 (dd, J = 2.5,
5.5 Hz, 1 H), 4.91 (dd, J = 3.5, 10.5 Hz, 1 H), 5.72 (s, 1 H),
7.20–8.4 (m, 12 H). 13C NMR (75 MHz, CDCl3): d = 163.4,
150.1, 137.5, 134.0, 133.7, 131.3, 129.1, 128.9, 128.5,
128.4, 128.1, 127.4, 126.5, 126.2, 126.0, 125.8, 124.9, 99.2,
85.0, 70.0, 66.1, 59.4, 57.9, 28.4, 14.8. IR (thin film): 3377
(s), 3053 (w), 2925 (s), 2854 (m), 1677 (s), 1440 (m) cm–1.
MS (EI): m/z (% relative intensity) = 445.2(90) [M+],
118.9(100); m/z calcd for C27H29N2O4: 445.21273. Found:
445.21270.
A General Procedure for BH3 Hydroboration Using 9. To
a solution of 12.0 mg of the TBS ether 9 (0.022mmol) in
anhyd THF (1 mL) at r.t. was added BH3⋅THF (0.44 mL)
complex (2.0 equiv, 1 M solution in THF, 0.044 mmol). The
reaction mixture was stirred for 2 h at r.t., and was quenched
carefully with drop wise addition of excess of 30% aq H2O2
and 15% aq NaOH. The mixture was then stirred vigorously
for 30 min at r.t. The resultant mixture was extracted with
Et2O [2 × 5 mL] and EtOAc [5 mL], and the combined
extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. Silica gel flash chromatography
(40% EtOAc in hexanes) of the crude provided alcohol 20
(7.40 mg, 60% yield) as a colorless oil.
(8) (a) Postema, M. H. D. Tetrahedron 1992, 48, 8545.
(b) Postema, M. H. D. C-Glycoside Synthesis; CRC Press:
Ann Arbor, 1995. (c) Levy, D. E.; Tang, C. The Chemistry
of C-Glycosides, 1st ed., Vol. 13; Pergamon Press: Oxford,
1995.
(9) Parker, K. A. Pure Appl. Chem. 1994, 66, 2135.
(10) For selected experimental procedures and characterizations:
9BBN Hydroboration-Oxidation of 5. To a solution of
29.0 mg of pyran 5 (0.071 mmol) in 3 mL of anhyd THF at
r.t. was added 0.48 mL of 9BBN (2.5 equiv, 0.5 M solution
in THF, 0.18 mmol). The resulting mixture was stirred at r.t.
for 1 h, and was quenched with excess of 30% aq H2O2 and
15% aq NaOH via drop wise addition. After which, the
reaction mixture was refluxed for 3 h. The solution was then
cooled to r.t. and extracted with Et2O (2 × 10 mL) and
EtOAc (10 mL). The combined extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Silica gel flash chromatography (60% EtOAc in hexanes) of
the crude led to the desired alcohol 6 (22.2 mg, 73% yield).
6: Rf = 0.33 (60% EtOAc in hexanes); [a]D20 = –95.5 (c 0.58,
CHCl3). 1H NMR (500 MHz, CDCl3): d = 0.58 (ddd, J = 2.0,
12.0, 17.0 Hz, 1 H), 0.75 (d, J = 7.0 Hz, 3 H), 1.65 (ddd,
J = 5.0, 9.0, 11.0 Hz, 1 H), 2.48 (m, 1 H), 2.72 (s, 3 H), 3.65
(m, 2 H), 3.89 (dq, J = 3.5, 9.0 Hz, 1 H), 4.64 (dd, J = 3.5,
11.0 Hz, 1 H), 4.73 (d, J = 9.0 Hz, 1 H), 4.90 (dd, J = 2.0,
6.0, Hz, 1 H), 6.31 (dd, J = 2.0, 4.0 Hz, 1 H), 7.10–8.30 (m,
12 H). 13C NMR (75 MHz, CDCl3): d = 163.9, 150.6, 138.0,
134.1, 133.8, 130.8, 129.1, 128.3, 128.0, 127.8, 126.3,
126.0, 125.8, 125.1, 101.8, 81.9, 62.9, 58.8, 58.2, 38.8, 28.5,
19.4, 15.0. IR (thin film): 3400 (m), 3058 (w), 2925 (s), 2890
(m), 1681 (s), 1640 (w), 1434 (m)cm–1. MS (EI): m/z (%
relative intensity) = 429.2(40) [M+], 411.1(100); m/z calcd
for C27H29N2O3: 429.21782, found 429.21780.
20: Rf = 0.20 (40% EtOAc in hexanes). 1H NMR (500 MHz,
toluene-d8): d = –0.01 (s, 3 H), 0.04 (s, 3 H), 0.34 (d, J = 6.5
Hz, 3 H), 1.00 (s, 9 H), 1.76 (ddd, J = 4.0, 11.5, 20.5 Hz, 1
H), 2.51 (s, 3 H), 2.62 (m, 1 H), 2.81 (dt, J = 4.0, 9.5 Hz, 1
H), 3.11 (dd, J = 6.0, 14.5 Hz, 1 H), 3.70 (dd, J = 5.5, 10.0
Hz, 1 H), 3.88 (t, J = 10.0 Hz, 1 H), 4.10 (m, 1 H), 4.46 (d,
J = 8.5 Hz, 1 H), 5.05 (d, J = 9.0 Hz, 1 H), 5.87 (brs, 1 H),
7.01–8.45 (m, 12 H). 13C NMR (75 MHz, toluene-d8): d =
162.5, 139.5, 135.7, 134.1, 132.4, 127.9, 127.6, 127.3,
127.4, 125.7, 125.3, 125.2, 125.0, 86.4, 82.9, 66.4, 60.2,
58.7, 57.2, 41.2, 33.2, 28.5, 25.8, 14.8, –5.5, –5.7 (missing 4
peaks due to overlap, and missing 1 additional peak). IR
(thin film): 3377 (w), 3013 (w), 2954 (s), 2919 (s), 2848 (m),
1707 (m), 1507 (m), 1460 (s) cm–1. MS (LCMS): m/z (%
relative intensity) = 561.2 (10) [M+], 191 (100).
A General Procedure for Lewis Acid Mediated
Allylation Using 20.
To a solution of 5.0 mg of alcohol 20 (8.9 mmol) in 0.5 mL
of anhyd CH2Cl2 at –78 °C were added 5.8 mg of SnBr4 (1.5
equiv, 17.8 mmol) and 5.6 mL of allyltrimethylsilane (4
equiv, 35.6 mmol). The resultant mixture was warmed to r.t.
and stirred for 12 h before it was quenched with sat. aq
NH4Cl (0.5 mL). The crude mixture was extracted with
CH2Cl2 (3 × 5 mL) and the combined extracts were dried
over Na2SO4, filtered, and concentrated under reduced
pressure. Silica gel flash chromatography (10% EtOAc in
hexanes) of the crude furnished the desired pyran 21 (2.56
mg, 70% yield).
OsO4 Dihydroxylation of 5. To a solution of 80.0 mg of
pyran 5 (0.20 mmol) in 10 mL of anhyd CH2Cl2 at –78 °C
were added 4.0 mL of TMEDA (0.27 mmol) and drop wise
via a syringe a solution of 66.7 mg of OsO4 [0.27 mmol] in
2 mL of CH2Cl2. After the solution was stirred for 30 min at
–78 °C, it was carefully concentrated under reduced
pressure. The resulting residue was dissolved in THF (10
mL) and H2O (1 mL). After adding 2 g of NaHSO3 to the
crude mixture, the reaction mixture was refluxed at 75 °C for
12 h. The solution was then cooled to r.t., and extracted with
EtOAc (3 × 15 mL). The combined extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Silica gel flash column chromatography (80% EtOAc in
hexanes) of the crude furnished the desired diol 10 (70.3 mg,
85% yield) as a thick colorless oil.
21: Rf = 0.35 (10% EtOAc in hexanes). [a]D20 = +35.0 (c
0.20, CH2Cl3). 1H NMR (500 MHz, toluene-d8): d = –0.02 (s,
3 H), –0.01 (s, 3 H), 0.34 (s, 9 H), 1.02 (ddd, J = 5.5, 8.5,
14.5 Hz, 1 H), 1.78 (m, 2 H), 2.24 (ddd, J = 6.5, 7.5, 13.5 Hz,
1 H), 2.33 (ddd, J = 6.0, 8.5, 12.5 Hz, 1 H), 2.39 (d, J = 2.0
Hz, 1 H), 3.34 (dd, J = 6.0, 9.5 Hz, 1 H), 3.39 (dd, J = 4.5,
9.5 Hz, 1 H), 3.91 (m, 1 H), 4.33 (ddd, J = 3.0, 6.0, 15.0 Hz,
1 H), 5.05 (dd, J = 10.0, 20.5 Hz, 1 H), 5.66 (brs, 1 H), 5.96
(m, 1 H), 6.82–8.01 (m, 7 H). 13C NMR (75 MHz, toluene-
d8): d = 145.2, 141.8, 139.8, 131.0, 129.1, 127.8, 127.5,
127.4, 125.7, 125.4, 123.3, 82.5, 80.7, 79.6, 69.8, 64.5, 46.5,
40.2, 27.9, 25.7, –5.5, –5.7 (missing 1 signal). IR (thin film):
3430 (m), 3013 (w), 2941 (m), 2873 (m), 1640 (s), 1413 (m),
1149 (s) cm–1. MS (EI): m/z (% relative intensity) = 413.1
(10) [M+ + H], 141.4 (45), 79.8 (100); m/z calcd for
C25H36N3O3SiNa: 435.2331 [M+ + Na]. Found: 435.2344.
10: Rf = 0.32 (80% EtOAc in hexanes). [a]D20 = –33.0 (c
0.60, CHCl3). 1H NMR (500 MHz, CDCl3): d = 0.76 (d,
J = 6.5 Hz, 1 H), 1.05 (d, J = 17.5 Hz, 1 H), 1.80 (dd, J = 3.5,
17.5 Hz, 1 H), 2.72 (s, 3 H), 3.33 (t, J = 11.0 Hz, 1 H), 3.42
(brs, 1 H), 3.90 (dq, J = 7.0, 13.0 Hz, 1 H), 3.96 (dd, J = 3.5,
Synlett 2003, No. 9, 1241–1246 ISSN 1234-567-89 © Thieme Stuttgart · New York

1246
C. Rameshkumar, R. P. Hsung
LETTER
Periodic Cleavage of 24. To a solution of 30.0 mg of the
triol 24 (0.064 mmol) in of MeOH/H2O (5 mL, 5:1) at r.t.
was added 69.0 mg of NaIO4 (5 equiv, 0.32 mmol) and a
drop of HOAc. The reaction mixture was stirred for 3 h at r.t.
before it was concentrated and dissolved in EtOAc. The
crude organic solution was washed with sat. aq Na2S2O3 (3
mL) and H2O. The aqueous layer was extracted with EtOAc
(3 × 5 mL), and the combined extracts were dried over
Na2SO4, filtered, and concentrated under reduced pressure.
Silica gel flash chromatography (80% EtOAc in hexanes) of
the crude furnished the desired ketone 34 in 84% yield (23.0
mg).
H), 3.33 (dd, J = 3.6, 16.2 Hz, 1 H), 3.92 (dq, J = 6.6, 8.7 Hz,
1 H), 4.48 (ddd, J = 4.2, 6.6, 10.2 Hz, 1 H), 4.90 (br s, 1 H),
5.14 (d, J = 9.0 Hz, 1 H), 5.34 (d, J = 4.5 Hz, 1 H), 7.20–8.25
(m, 12 H). 13C NMR (75 MHz, CDCl3): d = 193.8, 161.0,
137.1, 135.2, 128.7, 128.6, 128.4, 128.3, 128.2, 126.3,
125.8, 125.6, 124.2, 123.2, 84.0, 79.0, 71.0, 56.5, 44.5, 29.7,
14.2 (missing 4 peaks due to overlap, and missing 1
additional peak). IR (thin film): 3414 (m), 3047 (w), 2977
(s), 2875 (s), 1716 (s), 1681 (s) cm–1. MS (LCMS): m/z (%
relative intensity) = 431.1 (10) [M+], 413.1 (100).
(11) When substituents at C5 and C6 are trans in these pyranyl
heterocycles such as 21, we observed strong NOE between
protons at C2 and C3 presumably because these two protons
are not necessarily locked in di-axial relationship unlike
those in pyrans where C5 and C6 substituents are cis.
34: Rf = 0.30 (80% EtOAc in hexanes). [a]D20 = –61.0 (c
0.25, CHCl3). 1H NMR (300 MHz, CDCl3): d = 0.76 (d,
J = 6.6 Hz, 3 H), 2.57 (dd, J = 6.3, 16.2 Hz, 1 H), 2.83 (s, 3
Synlett 2003, No. 9, 1241–1246 ISSN 1234-567-89 © Thieme Stuttgart · New York