From C-glycosides to pyranopyrans: An approach to thyrsiferol using titanium(III)-promoted redox couplings

Article abstract of DOI:10.1021/jo050465d

An approach to the pyranopyran ring system that is found in many natural products, including thyrsiferol, is described. The route entails the assembly of an α,β-unsaturated ketone (11) from geraniol and dihydropyran (23) from acetyl acetaldehyde dimethyl acetal (19) and their titanium-(III)-promoted coupling to afford a respectable 60% yield of keto alcohol 26. The σ-bond formed in this process corresponds to the pro-C₉-C₁₀ bond of thyrsiferol (4). Attempts to invert the stereochemistry at the pro-C ₁₁ center were thwarted by the congestion imparted by the presence of the vicinal TBS-ether. Consequently, cyclization of the coupling adduct under conditions developed by Olah and Prakash and co-workers led to the cis-fused pyranopyran 27. X-ray analysis of this crystalline material confirmed each of the stereochemical assignments. After much effort, it was determined that the hydroxyl group at C₁₂ could be removed by treating the derived methyl xanthate with a tri-n-butylphosphine-borane complex under radical-forming conditions. The reaction sequence worked well, despite the hindered working environment and the presence of a potentially labile C-Br bond.

Full text of DOI:10.1021/jo050465d

From C-Glycosides to Pyranopyrans: An Approach to Thyrsiferol
Using Titanium(III)-Promoted Redox Couplings
Gisele A. Nishiguchi and R. Daniel Little*
Department of Chemistry & Biochemistry, University of California, Santa Barbara, California 93106
little@chem.ucsb.edu
Received March 9, 2005
An approach to the pyranopyran ring system that is found in many natural products, including
thyrsiferol, is described. The route entails the assembly of an R,â-unsaturated ketone (11) from
geraniol and dihydropyran (23) from acetyl acetaldehyde dimethyl acetal (19) and their titanium-
(III)-promoted coupling to afford a respectable 60% yield of keto alcohol 26. The σ-bond formed in
this process corresponds to the pro-C9-C10 bond of thyrsiferol (4). Attempts to invert the
stereochemistry at the pro-C11 center were thwarted by the congestion imparted by the presence of
the vicinal TBS-ether. Consequently, cyclization of the coupling adduct under conditions developed
by Olah and Prakash and co-workers led to the cis-fused pyranopyran 27. X-ray analysis of this
crystalline material confirmed each of the stereochemical assignments. After much effort, it was
determined that the hydroxyl group at C12 could be removed by treating the derived methyl xanthate
with a tri-n-butylphosphine-borane complex under radical-forming conditions. The reaction
sequence worked well, despite the hindered working environment and the presence of a potentially
labile C-Br bond.
SCHEME 1. Formation of r-C-Glycosides via
Ti(III)-Induced Coupling
Introduction
Research into the assembly of both cis- and trans-fused
pyranopyrans continues unabated. Numerous elegant
and imaginative routes have been devised.1 Our interest
was kindled by the desire to devise and implement a
novel and straightforward means by which to convert
anhydrosugars to R-C-glycosides. Indeed, in 2002, we
published a paper detailing the manner in which we
achieved this objective.2 The approach, one example of
which is highlighted by the conversion of 1 to 3, calls for
the in situ epoxidation of a sugar glycal with freshly
prepared DMDO and the subsequent treatment of it with
titanocene dichloride/manganese, in the presence of an
electron-deficient alkene (Scheme 1). Workup reveals the
R-C-glycoside in respectable yields, with the hydroxyl
group at C3 available for additional functionalization.
We were curious to determine whether the chemistry
could be extended to more elaborate coupling partners
with an eventual goal being to apply it to the total
synthesis of natural products containing the pyranopyran
framework. Both cis- and trans-fused systems exist;
thyrsiferol (4; trans-fused),3 10-epidehydrothyrsiferol (5;
(1) For cis-fused, see: (a) Sasaki M.; Nonomura, T. M., M.; Ta-
chibana, K. Tetrahedron Lett. 1994, 35 (28), 5023-5026. (b) Groten-
breg, G. M.; Tuin, A. W.; Witte, M. D.; Leeuwenburgh, M. A.; van Boom,
J. H.; van der Marel, G. A.; Overkleeft, H. S.; Overhand, M. Synlett
2004, 5, 904-906. (c) Tan, D. S.; Schreiber, S. L. Tetrahedron Lett.
2000, 41 (49), 9509-9513. (d) Hayashi, N.; Fujiwara, K.; Murai, A.
Tetrahedron Lett. 1996, 37 (34), 6173-6176. For trans-fused, see: (e)
Kadota, I. T., H.; Sato, K.; Yamamoto, Y. J. Org. Chem. 2002, 67, 3494-
3498. (f) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001,
66, 1380-1386. For reviews, see: (g) Marmsater, F. P.; West, F. G.
Chem.-Eur. J. 2002, 8 (19) 4346-4353. (h) Evans, P. A.; Delouvrie,
B. Curr. Opin. Drug Discovery Dev. 2002, 5 (6), 986-999 and references
therein.
(2) (a) Parrish, J. D.; Little, R. D. Org. Lett. 2002, 4 (9), 1439-1442.
For a few additional references to the use of titanium(III), see: (b)
RajanBabu, T. V.; Nugent, W. A. J. Am. Chem. Soc. 1994, 116 (3),
986-97. (b) Gansauer, A.; Bluhm, H.; Rinker, B.; Narayan, S.; Schick,
M.; Lauterbach, T.; Pierobon, M. Chem.s Eur. J. 2003, 9 (2), 531-
542. (c) Gansauer, A.; Narayan, S. Adv. Synth. Catal. 2002, 344 (5),
465-475. (d) Spencer, R. P.; Schwartz, J. Tetrahedron 2000, 56 (15),
2103-2112.
(3) (a) Blunt, J. W.; Hartshorn, M. P.; McLennan, T. J.; Munro, M.
H. G.; Robinson, W. T.; Yorke, S. C. Tetrahedron Lett. 1978, 1, 69-72.
(b) Gonzalez, I. C.; Forsyth, C. J. J. Am. Chem. Soc. 2000, 122 (38),
9099-9108.
10.1021/jo050465d CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/01/2005
J. Org. Chem. 2005, 70, 5249-5256
5249

Nishiguchi and Little
FIGURE 1. Three naturally occurring pyranopyrans.
SCHEME 2. Synthesis of Enone Coupling Partner
11
SCHEME 3. Assembly of a Second Enone for
Exploratory Studies
cis-fused),4 and (+)-diplopyrone (6; cis-fused)5 are repre-
sentative examples of each variety (Figure 1). Compounds
4 and 5 are of marine origin and display antitumor
activity, while diplopyrone (6) is the main phytotoxin of
Diplodia mutila, a fungus that is believed to be one of
the principle causes in the decline of cork oak. We seek
to develop methodology that will be of sufficient general-
ity to allow the assembly of either the cis- or the trans-
fused skeleton. Herein we describe progress toward this
end.
substances were separated prior to treating 9 with
vinylmagnesium bromide and then to Swern oxidation
conditions to deliver enantiomerically pure 11 in ∼16%
yield overall.
The second coupling agent, structure 15, was synthe-
sized in six steps from racemic linalool (12) (Scheme 3).
Thus, catalyzed epoxidation using bis(acetylacetonato)-
oxovanadium(IV) and tert-butyl hydroperoxide, followed
by protection as a MOM ether, base-induced opening of
the epoxide, and periodate cleavage, afforded aldehyde
14 in a 29% yield over four steps. Once again, vinylmag-
nesium bromide and a Swern oxidation were used, this
time to generate the R,â-unsaturated ketone subunit of
15.
Our previously established protocol called for the in
situ generation of an anhydrosugar from a sugar glycal
using dimethyl dioxirane (DMDO),8 followed by the
addition of the electron-deficient alkene and then by the
dropwise addition of titanocene(III) chloride.2 When
applied to tri-O-benzyl glucal (16) and the linalool-derived
agent 15, coupling was achieved in a 21% yield (two
steps) (Scheme 4). With the bromopyran coupling partner
11, the assembly was equally simple to perform, this time
proceeding in a 38% yield for the two-step sequence to
afford 18.
Having determined compound 11 to be a suitable and
effective coupling partner in glycal coupling reactions,
we turned our attention to the synthesis of the methyl-
substituted dihydropyran 23, the methyl group being
required in order to access thyrsiferol (4) or its cis-fused
analogue 5. To ensure that epoxidation would occur on
Results and Discussion
Two new coupling agents, 11 and 15, were synthesized,
and their chemistry was examined. The assembly of 11
began with geraniol (7) and was completed in six steps,
as follows (Scheme 2). Sharpless asymmetric epoxidation
proceeded in yields ranging from 77 to 95% and in 93%
ee.6 Hydrobromination of the alkene was achieved under
standard conditions using NBS in THF/water (5:1) to
afford a 64% yield of diastereomeric bromo alcohols 8.
Cyclization to the tetrahydropyran diol could be ac-
complished by treating 8 with camphorsulfonic acid in
diethyl ether in a fashion similar to that reported by
McDonald.7 Diol cleavage using sodium periodate af-
forded a mixture of aldehydes 9 and 10, the desired
â-isomer 9 in a 41% yield over two steps.3b These
(4) (a) Norte, M.; Fernandez, J. J.; Souto, M. L.; Garcia-Gravalos,
M. D. Tetrahedron Lett. 1996, 37 (15), 2671-2674. (b) Norte, M.;
Fernandez, J. J.; Souto, M. L. Tetrahedron 1997, 53 (13), 4649-4654.
(5) Evidente, A. M., L.; Spanu, E.; Franceschini, A.; Lazzaroni, S.;
Motta, A. J. Nat. Prod. 2003, 66 (2), 313-315. (b) Giorgio, E.; Maddau,
L. S., E.; Evidente, A.; Rosini, C. J. Org. Chem. 2005 70 (1), 7-13.
(6) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(7) McDonald, F. E.; Wei, X. Org. Lett. 2002, 4 (4), 593-595.
(8) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661.
5250 J. Org. Chem., Vol. 70, No. 13, 2005

From C-Glycosides to Pyranopyrans
SCHEME 4. Exploratory Coupling Reactions with Enones 11 and 15
SCHEME 5. Construction of Methyl-Substituted
Pyran Coupling Partner 23
effective and most reproducible way to obviate the
problem proved simply to ensure that the DMDO was
used immediately after drying with 4 Å molecular sieves.
Once this modification was made, the yield rose signifi-
cantly to 60%. While 1.5 equiv of 11 was used, the
unreacted material can be, and was, recycled.
With enantiomerically pure 26 in hand, we turned our
attention to the cyclization. Treatment of it with trieth-
ylsilane and trimethylsilyl triflate in methylene chloride,
under conditions developed by Olah and Prakash and
their co-workers,13 afforded a substance whose 1H NMR
spectrum indicated that the silyl group had been cleaved.
X-ray analysis of the resulting crystalline solid, 27,
confirmed that cyclization had occurred, established that
the rings were cis-fused as expected, and revealed that
the C-ring was significantly distorted from a chair
conformation (Scheme 7). Distortion allows the hydroxyl
and benzyloxymethylene units to occupy pseudoequato-
rial rather than the axial orientations that would be
required by a chair. Thus, the distortion in 27 as well as
its likely precursor, 28, is entirely reasonable. The
configuration of the newly formed stereocenter at C7 in
structure 27 is undoubtedly the consequence of a stereo-
electronically controlled addition to the cyclic oxonium
ion intermediate, 28a.
Efforts to remove the hydroxyl group from C12 of 27,
or to effect deoxygenation at earlier stages of the se-
quence, were problematic. Eventually, we discovered that
an elegant method developed by Barton and co-workers
to handle, explicitly, deoxygenation in a hindered envi-
ronment could be used.14 Of added value is the fact that
the chemistry, though reductive, does not touch the
potentially labile C-Br bond that is found in the A-ring.
Thus, when treated with borane-tri-n-butylphosphine
complex and AIBN in refluxing dioxane, the xanthate
derived from 27 succumbed; 29 was isolated in a 69%
yield, reassuring us that the oxygen can be removed
(Scheme 8).
the R-face and not afford a mixture of diastereomers, we
elected to synthesize 23 rather than 23a (see Scheme 5).
Of course this necessitates the removal of the OTBS unit
at a later stage. This decision, it turns out, led to
unforeseen difficulties (vide infra).
Pyran 23 proved accessible in sizable quantity (e.g.,
in 8 g batches) through the use of a five-step sequence
commencing with the commercially available keto acetal
19. Thus, treatment of it with 1,3-propanedithiol and
catalytic p-TsOH led smoothly to the bis-thioacetal9 (86%)
whose subsequent deprotonation (n-BuLi) and exposure
to R-benzyl glycidyl ether (20) provided a 76% yield of
the hydroxy ether 21. Treatment of 21 with mercuric
chloride in 9:1 acetonitrile/water at room temperature
exposed the carbonyl units and also initiated cyclization
leading to enantiomerically pure 22 (57%).10 Luche’s
conditions11 for reduction of 22 afforded the corresponding
allylic alcohol; protection as the TBS ether afforded 23
in 70% yield over two steps.
Our initial attempts to couple 23 with the bromopyran
11 provided disappointingly low yields of 26 (∼10-15%)
(Scheme 6). We suspected that the Ti(III)-induced ring
opening was at fault, but quickly discovered that our
difficulties could be traced to the increased lability of the
methyl-substituted epoxide 24, relative to 25.12 The most
Thus far, our efforts have led to the development of a
route to the cis-fused, but not as yet the trans-fused,
(12) (a) Hale, K. J.; Frigerion, M.; Manaviazar, S. Org. Lett. 2001,
3 (23), 3791-3794. (b) Roberts, S. W.; Rainier, J. D. Org. Lett. 2005,
ASAP. (c) Majumder, U.; Cox, J. M.; Rainier, J. D. Org. Lett. 2003, 5
(6), 913-916.
(13) (a) Sassaman, M. B.; Kotian, K. D.; Prakash, G. K. S.; Olah, G.
A. J. Org. Chem. 1987, 52, 4314-4319. (b) Nicolaou, K. C.; Hwang,
C.-K.; Nugiel, D. A. J. Am. Chem. Soc. 1989, 111, 4136-4317.
(14) Barton, D. H. R.; Jacob, M. Tetrahedron Lett. 1998, 39 (11),
1331-1334.
(9) Shapiro, R. H.; Entee, T. E., Jr.; Coffen, D. L. Tetrahedron 1968,
24, 2809-2815.
(10) Noda, Y.; Fukaya, T.; Kikuchi, M. Heterocycles 1996, 43 (2),
271-275.
(11) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
J. Org. Chem, Vol. 70, No. 13, 2005 5251

Nishiguchi and Little
SCHEME 6. Coupling the A and C Rings of the Thyrsiferol Framework
SCHEME 7. TMSOTf-Promoted Cyclization To Assemble the B-Ring of 27
SCHEME 8. Removal of the C12 Hydroxyl Group from 27 under Radical-Forming Conditions
framework. This is a clear, but presumably correctable
deficiency that can be handled simply by inverting the
stereochemistry at the hydroxy-bearing carbon, C11, of
26. Unfortunately, all attempts to do so using variations
on the Mitsunobu protocol have been unsuccessful.15 We
assume the cause of this difficulty is the highly hindered
nature of the carbon that must be attacked, and that the
presence of the adjacent OTBS group at C12 is at least
partially to blame. Several options exist and are being
explored at the present time.
Structure 29 is an important material for us. We intend
to convert it to structure 30, the cis-fused analogue of
thyrsiferol (4), and to compare its bioactivity with that
of the natural product.16 Efforts to do so, and to complete
the total synthesis of thyrsiferol (4), are underway.
Experimental Section
3-Bromo-5-(3-hydroxymethyl-2-methyloxiranyl)-2-meth-
yl-(2R,3R)-pentan-2-ol (8). To 100 mL of dry CH2Cl2 were
added freshly activated crushed 4 Å molecular sieves, and the
contents were cooled to 0 °C. (-)-DET (1.6 mL, 9.1 mmol) was
added, followed by Ti(O-i-Pr)4 (1.9 mL, 6.5 mmol). The reaction
was stirred at 0 °C for 10 min and cooled to - 20 °C. t-BuOOH
(42 mL of 4.7 M solution in toluene briefly dried over molecular
sieves)17 was added dropwise using an addition funnel. The
reaction was stirred at -20 °C for 30 min. Geraniol (20.0 g,
129.6 mmol) was added dropwise in 5 mL of CH2Cl2. After 1
h, the reaction was complete as judged by TLC, and the
solution was warmed to 0 °C, quenched by adding water (40
mL), and stirred for 1 h while warming to room temperature.
(15) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Martin, S. F.; Dodge,
J. A. Tetrahedron Lett. 1991, 32 (26), 3017-3020. (c) Dodge, J. A.;
Trujillo, J. I.; Presnell, M. J. Org. Chem. 1994, 59, 234-236. (d) Saiah,
M.; Bessodes, M.; Antonakis, K. Tetrahedron Lett. 1992, 33 (30), 4317-
4320.
(16) These studies will be conducted in collaboration with Dr. R. S.
Jacobs of UCSB.
(17) Hill, G. J.; Rossiter, B. E.; Sharpless, K. B. J. Org. Chem. 1983,
48, 3607-3608.
5252 J. Org. Chem., Vol. 70, No. 13, 2005

From C-Glycosides to Pyranopyrans
Twelve milliliters of a 30% aqueous solution of NaOH satu-
rated with NaCl was added, and the solution was stirred
vigorously until phase separation was observed. At this point,
the layers were separated, and the aqueous layer was ex-
tracted with CH2Cl2 (3 × 50 mL), dried with MgSO4, and
concentrated under reduced pressure. Column chromatogra-
phy using petroleum ether and diethyl ether (3:1, then 1:1)
afforded the desired epoxide as a clear liquid (17.5 g, 102.8
2H), 2.17-2.11 (m, 2H), 1.98-1.77 (m, 2H), 1.46 (s, 3H), 1.43
(s, 3H), 1.35 (s, 3H), 1.33 (s, 3H), 1.25 (s, 3H), 1.2 (s, 3H); 13C
NMR (CDCl3, 100 MHz) δ 135.5, 134.8, 118.6, 117.5, 80.8, 79.1,
76.3, 76.1, 75.7, 75.6, 57.8, 57.5, 34.0, 31.0, 30.9, 30.4, 27.8,
27.7, 23.4, 23.1, 22.7, 20.9; IR (neat) 3487, 2981, 1379, 1126,
1018, 730 cm-1
.
To 20 mL of dry CH2Cl2 was added oxalyl chloride (0.65 mL,
7.5 mmol), and the solution was cooled to -78 °C. DMSO (1.1
mL, 15 mmol) in 1 mL of CH2Cl2 was added dropwise, and
the reaction mixture was stirred for 30 min. The above allylic
alcohol mixture (1.3 g, 5.0 mmol) dissolved in 5 mL of CH2Cl2
was added, and the solution was stirred for another 30 min.
Triethylamine (3.5 mL, 25 mmol) was added dropwise at -78
°C, and the solution was stirred for 45 min and allowed to
warm to room temperature. Brine was added, and the solution
was extracted with CH2Cl2, dried with Na2SO4, and concen-
trated under reduced pressure. The crude material was
chromatographed using petroleum ether and Et2O (7:1) to
afford 1.1 g (4.2 mmol, 85%) of compound 11 as a clear oil: 1H
NMR (CDCl3, 400 MHz) δ 7.05 (dd, J ) 17.4, 10.4, 1H), 6.39
(dd, J ) 17.4, 2.0, 1H), 5.72 (dd, J ) 10.4, 2.0, 1H), 4.12-4.10
(m, 1H), 2.29-2.20 (m, 2H), 2.06-1.99 (m, 1H), 1.90-1.81 (m,
1H), 1.40 (s, 3H), 1.31 (s, 3H), 1.21 (s, 3H); 13C NMR (CDCl3,
100 MHz) δ 201.9, 131.0, 128.3, 78.3, 57.5, 33.3, 30.3, 28.8,
27.5, 20.3; IR (neat) 2979, 1698, 1610, 1398, 1080, 997, 856
cm-1; ESI+/TOF m/z 283 (M+ + Na), 261, 203, 181, 163; HRMS
(ESI) calcd for C11H17O2NaBr 283.03041, found 283.0303 [M
+ Na]+.
2-(1-Methoxymethoxy-1,5-dimethylhex-4-enyl)oxi-
rane (13). Linalool (10.0 g, 64.8 mmol) and VO(acac)2 (0.86 g,
3.2 mmol) in 250 mL of benzene were heated to reflux in a
three-neck flask equipped with a condenser and an addition
funnel. The dark green solution was refluxed for 15 min upon
which time t-BuOOH (5.5 M in decane, 17.7 mL, 97.2 mmol)
was added dropwise at 80 °C over 20 min. The solution turned
red and was refluxed for 5 h. The reaction was cooled to room
temperature, quenched with saturated Na2SO3, extracted with
Et2O (3 × 50 mL), washed with brine, dried over MgSO4, and
concentrated. The crude oil was chromatographed with EtOAc
and petroleum ether (1:6) to give the desired epoxy alcohol as
a 2:1 mixture of diastereomers (6.9 g, 40.5 mmol, 62%). The
spectral data matched the reported literature values:18 1H
NMR (CDCl3, 400 MHz) δ 5.14-5.07 (m, 1H), 2.96 (dd, J )
4.0, 2.9, 1H), 2.75 (dd, J ) 5.1, 2.8, 1H), 2.69 (dd, J ) 5.1, 4.1,
1H), 2.14-2.07 (m, 2H), 1.68 (s, 3H), 1.61 (s, 3H), 1.63-1.53
(m, 2H), 1.18 (s, 3H); ESI+/TOF m/z 193 (M+ + Na), 179, 161;
HRMS (ESI) calcd for C10H18O2Na 193.1204, found 193.1197
[M + Na]+.
To 10 mL of dry CH2Cl2 were added the above epoxy alcohol
(0.49 g, 2.9 mmol), diisopropyl ethylamine (1.5 mL, 8.8 mmol),
and a catalytic amount of DMAP (10 mg) at room temperature.
MOMCl (0.45 mL, 5.9 mmol) was added dropwise. The solution
was stirred for 20 h and the reaction quenched by adding it to
10% citric acid. The resulting solution was extracted with Et2O
(3 × 10 mL), dried over Na2SO4, and concentrated under
reduced pressure. The oil was chromatographed using petro-
leum ether and Et2O (6:1) to give the product as a mixture of
diastereomers (clear oil, 0.5 g, 2.3 mmol, 81%): 1H NMR
(CDCl3, 400 MHz) δ 5.10 (m, 1H), 4.78 (s, 3H), 3.38 (s, 3H),
3.03 (dd, J ) 4.3, 2.9, 1H), 2.67 (t, J ) 4.3, 1H), 2.53 (dd, J )
4.9, 2.9, 1H), 2.87 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.66-
1.53 (m, 2H), 1.09 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 131.7,
124.1, 124.0, 91.6, 91.5, 76.6, 75.7, 57.1, 57.0, 55.4, 43.9, 43.3,
30.2, 37.7, 25.6, 22.0, 21.7, 19.8, 18.1, 17.6; IR (neat) 2927,
1450, 1375, 1144, 1030 and 917 cm-1; ESI+/TOF m/z 237 (M+
+ Na), 183, 153, 135; HRMS (ESI) calcd for C12H22O3Na
237.1467, found 237.1467 [M + Na]+.
1
mmol, 79% yield, 93% ee determined by H NMR analysis of
the corresponding acetate and Eu(hfc)3 in C6D6):6 1H NMR
(CDCl3, 400 MHz) δ (ppm) 5.11-5.06 (m, 1H), 3.83 (dd, J )
12.0, 4.2, 1H), 3.70 (dd, J ) 12.1, 6.9, 1H), 2.98 (dd, J ) 6.8
4.1, 1H), 2.10 (m, 2H), 1.72-1.65 (m, 1H), 1.69 (s, 3H), 1.61
(s, 3H), 1.51-1.44 (m, 1H), 1.30 (s, 3H); 13C NMR (CDCl3, 100
MHz) δ 132.1, 123.3, 62.9, 61.4, 61.2, 38.5, 25.6, 23.7, 17.6,
16.7; ESI+/TOF m/z 363 (2M+ + Na), 193 (M+ + Na), 153,
135; HRMS (ESI) calcd for C10H18O2Na 193.11990, found
193.1200 [M + Na]+.
To a 5:1 mixture of THF and water (1.3 L) was added the
above epoxy alcohol (11.0 g, 64.6 mmol), and the solution was
cooled to 0 °C. NBS (11.5 g, 64.6 mmol, recrystallized from
water) was added at once, and the reaction was stirred for 2
h at 0 °C. Upon consumption of the starting material as judged
by TLC, NaCl was added, the solution was stirred, and the
layers were separated. The aqueous layer was extracted with
diethyl ether (3 × 100 mL), and the organic layer was dried
with Na2SO4. Removal of the volatiles under reduced pressure
and column chromatography using petroleum ether and di-
ethyl ether (1:9) afforded the desired product 8 as a mixture
of diastereomers (1:1) as a clear thick oil (11.0 g, 41.1 mmol,
64%): 1H NMR (CDCl3, 400 MHz) δ 4.0 (t, J ) 2, 1H), 3.97 (t,
J ) 2, 1H), 3.87-3.79 (m, 2H), 3.73 (dd, J ) 11.2, 6.6, 1H),
3.69 (dd, J ) 11.2, 6.6, 1H), 3.06 (dd, J ) 6.4, 4.6, 1H), 3.00
(dd, J ) 6.6, 4.3, 1H), 2.15-1.97 (m, 2H), 1.88-1.72 (m, 1H),
1.62-1.50 (m, 1H), 1.37 (s, 3H), 1.36 (s, 6H), 1.35 (s, 3H), 1.32
(s, 3H), 1.31 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 72.6, 70.4,
69.7, 65.8, 63.1, 62.1, 61.2, 61.1, 60.9, 60.4, 37.5, 36.7, 28.3,
29.1, 26.6, 26.4, 26.2, 26.1, 17.3, 16.6; IR (neat) 3404, 2975,
1383, 1027, 731 cm-1; ESI+/TOF m/z 289 (M+ + Na), 209;
HRMS (ESI) calcd for C10H19O3NaBr 289.04097, found 289.0420
[M + Na]+.
5-Bromo-2,6,6-trimethyl-(5R)-tetrahydropyran-2-car-
baldehyde (9, 10). To 300 mL of Et2O was added 5.6 g (21.0
mmol) of 8, followed by 1.9 g (8.2 mmol) of camphorsulfonic
acid. The reaction mixture was stirred at room temperature
for 1 h and then neutralized with triethylamine (8.2 mmol).
NaIO4 (27.3 mmol) was added, followed by 40 mL of water.
The reaction mixture was stirred at room temperature for 3
h, diluted with water, extracted with Et2O (3 × 100 mL), dried
with brine and MgSO4, and concentrated under reduced
pressure. Column chromatography using petroleum ether and
Et2O (4:1) afforded 1.0 g (4.3 mmol) of aldehyde 10 (20%) and
2.01 g (8.6 mmol) of aldehyde 9 (41%). Spectra data for
compound 9: 1H NMR (CDCl3, 400 MHz) δ 9.56 (d, J ) 1.5,
1H), 4.14-4.12 (m, 1H), 2.21-2.13 (m, 1H), 2.10-1.99 (m, 1H),
1.93-1.86 (m, 1H), 1.43 (s, 3H), 1.30 (s, 3H), 1.23 (s, 3H); 13
NMR (CDCl3, 100 MHz) δ 204.5, 78.4, 74.9, 58.3, 30.9, 26.5,
26.2, 24.4, 23.8; IR (neat) 2972, 1730, 1097, 908, 728 cm-1
C
.
1-[5-Bromo-2,6,6-trimethyl-(2S,5R)-tetrahydropyran-
2-yl]propenone (11). To 50 mL of dry THF was added
compound 9 (2.4 g, 10.2 mmol), and the solution was cooled to
0 °C. Vinylmagnesium bromide (1 M solution in THF, 15.3 mL)
was added dropwise via syringe, and the solution was stirred
for 1 h at 0 °C. The reaction mixture was quenched with
saturated NH4Cl, extracted with Et2O (3 × 30 mL), washed
with brine, dried over Na2SO4, and concentrated under reduced
pressure. The resulting crude material was chromatographed
using petroleum ether and Et2O (8:1) to afford the desired
allylic alcohol as a clear oil and as a mixture of diastereomers
(2.3 g, 8.8 mmol, 86%): 1H NMR (CDCl3, 400 MHz) δ 5.84-
5.69 (m, 2H), 5.37-5.18 (m, 4H), 3.9-3.84 (m, 2H), 3.82-3.80
(m, 1H), 3.7 (dt, J ) 6.8, 1.2, 1H), 2.61 (bs, 2H), 2.31-2.20 (m,
2-Methoxymethoxy-2,6-dimethylhept-5-enal (14). Com-
pound 13 (0.250 g, 1.2 mmol) was dissolved in 5 mL of DMSO,
(18) Bongini, A.; Cardillo, G.; Orena, M.; Porzi, G.; Sandri, S. J. Org.
Chem. 1982, 47, 4626-4633.
J. Org. Chem, Vol. 70, No. 13, 2005 5253

Nishiguchi and Little
and 2 mL of 1 N KOH was added. The resulting solution was
heated to 90 °C for 12 h. The flask was cooled to room
temperature, water and EtOAc were added, and the organic
layer was separated. The aqueous layer was extracted three
times with EtOAc, and the organic layers were combined and
washed with brine, dried using Na2SO4, and concentrated
under reduced pressure to give a light yellow oil (0.27 g, 1.2
mmol). The crude diol was used in the next step without
further purification: 1H NMR (CDCl3, 400 MHz) δ 5.08-5.03
(m, 1H), 4.71 (AB, J ) 7.7, 2H), 3.68-3.41 (m, 3H), 3.38 (s,
3H), 2.09-1.92 (m, 2H), 1.66 (s, 3H), 1.59 (s, 3H), 1.59-1.49
(m, 2H), 1.98 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 131.8,
123.9, 90.8, 80.4, 75.9, 62.7, 55.5, 36.3, 25.6, 21.8, 18.9, 17.5;
IR (neat) 3385, 2916, 1437, 1375, 1024, 951 cm-1; ESI+/TOF
m/z 255 (M+ + Na), 239, 183, 165; HRMS (ESI) calcd for
C12H24O4Na 255.1572, found 255.1568.
IR (neat) 2929, 1699, 1610, 1451, 1400, 1143, 1025 cm-1. ESI+/
TOF m/z 249 (M+ + Na), 147, 135, 107; HRMS (ESI) calcd for
C13H22O3Na 249.1467, found 249.1466.
Preparation of DMDO. Dimethyldioxirane was prepared
following the literature procedure.19 Upon collection of the
DMDO in acetone, the solution was cooled to 0 °C and diluted
with the same volume of water and 10 mL of CH2Cl2. The
organic layer was extracted and washed 6 times with a 0.05
M pH 7.0 buffer solution. This solution was stored at -20 °C
until ready for use. Just prior to the epoxidation reaction, the
DMDO solution was predried with freshly activated, crushed
4 Å molecular sieves.
1-(4,5-Bis-benzyloxy-6-benzyloxymethyl-3-hydroxytet-
rahydropyran-2-yl)-4-methoxymethoxy-4,8-dimethylnon-
7-en-3-one (17). Tri-O-benzylglycal (0.10 g, 0.24 mmol) was
dissolved in 5 mL of CH2Cl2 and cooled to 0 °C. DMDO (0.1 M
in CH2Cl2/acetone, 5 mL) was added to the reaction and the
mixture stirred until the reaction was determined to be
complete by TLC (30 min). The solvents were removed under
reduced pressure, and the crude material was dried under
vacuo. The crude epoxide was dissolved in 3 mL of anhydrous,
deaerated THF. To this solution was added 15 (0.1 g, 0.46
mmol). A green solution of Cp2TiCl [prepared by mixing Cp2-
TiCl2 (0.18 g, 0.7 mmol) and manganese powder (38 mg, 0.7
mmol) in 3 mL of THF for 45 min] was added to the epoxide
via cannula. The reaction immediately turned yellow, then red.
Stirred was continued at room temperature for 1 h. The
reaction was worked up by adding 0.1 M HCl and extracting
with Et2O (3 × 20 mL). The organic layer was washed with
satd NaHCO3, dried with brine and MgSO4, and concentrated
to give a thick orange syrup. The crude material was chro-
matographed using petroleum ether and EtOAc (3:1, then 1:1)
to give the desired product 17 (33 mg, 0.05 mmol, 21% for two
steps) as mixture of diastereomers in the form of a clear oil:
1H NMR (CDCl3, 400 MHz) δ 7.37-7.25 (m, 5H), 5.03 (m, 1H),
4.71-4.47 (m, 9H), 3.95-3.88 (m, 2H), 3.76-3.59 (m, 5H), 3.39
(s, 3H), 2.77-2.71 (m, 2H), 1.97-1.76 (m, 5H), 1.65 (s, 3H),
In 10 mL of Et2O and 5 mL of water was dissolved the above
diol (0.3 g, 1.3 mmol); NaIO4 (0.41 g, 1.9 mmol) was added all
at once. The reaction was stirred at room temperature for 1
h, and the water layer was removed and extracted with Et2O.
The combined organic extracts were washed with brine, dried
with Na2SO4, and concentrated under reduced pressure. The
crude aldehyde (0.156 g, 0.78 mmol, 60%) was used in the next
step without further purification: 1H NMR (CDCl3, 400 MHz)
δ 9.53 (s, 1H), 5.06 (m, 1H), 4.73 (AB, J ) 7.2, 2H), 3.42 (s,
3H), 2.06-2.00 (m, 2H), 1.77-1.58 (m, 2H), 1.68 (s, 3H), 1.60
(s, 3H), 1.30 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 203.5, 132.4,
123.4, 91.9, 82.2, 55.8, 35.6, 25.6, 21.5, 17.7, 17.6; IR (neat)
2929, 1732, 1452, 1377, 1142, 1029, 917 cm-1
.
4-Methoxymethoxy-4,8-dimethylnona-1,7-dien-3-one
(15). To 2 mL of THF was added vinylmagnesium bromide (1
M in THF, 1.1 mL), and the flask was cooled to 0 °C.
Compound 14 (0.15 g, 0.75 mmol) in 0.5 mL of THF was then
added dropwise, and the resulting solution was stirred for 30
min at 0 °C prior to quenching with satd NH4Cl. The organic
layer was separated, washed with brine, dried with Na2SO4,
and concentrated under reduced pressure. Column chroma-
tography using petroleum ether and Et2O (5:1) afforded the
product as a clear oil (0.123 g, 0.54 mmol, 72%). The reaction
was repeated starting with 12 mmol of compound 14 and a
similar yield (70%) was obtained: 1H NMR (CDCl3, 400 MHz)
δ 5.93-5.77 (m, 2H), 5.33-5.27 (m, 2H), 5.19 (m, 1H), 5.17
(m, 1H), 5.05 (m, 2H), 4.75-4.66 (m, 4H), 3.99 (m, 1H), 3.93
(m, 1H), 3.46 (d, J ) 4.1, 1H), 3.42 (d, J ) 5.4, 1H), 3.39 (s,
3H), 3.39 (s, 3H), 2.05-1.96 (m, 4H), 1.74-1.66 (m, 1H), 1.64
(s, 6H), 1.57 (s, 6H), 1.53-1.49 (m, 2H), 1.40-1.30 (m, 1H),
1.20 (s, 3H), 1.13 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 136.4,
136.1, 131.5, 124.3, 124.1, 117.3, 116.8, 91.9, 90.9, 81.3, 80.9,
77.8, 77.3, 55.6, 36.2, 34.9, 25.6, 21.7, 21.6, 19.8, 18.1, 17.5;
IR (neat) 3442, 2925, 1452, 1376, 1139, 1027, 919 cm-1; ESI+/
TOF m/z 251 (M+ + Na), 179, 161, 121; HRMS (ESI) calcd for
C13H24O3Na 251.1623 found 251.1621
To 20 mL of CH2Cl2 was added oxalyl chloride (0.54 mL,
6.2 mmol), and the resulting solution was cooled to -78 °C.
DMSO (0.88 mL, 12.3 mmol) in 5 mL of CH2Cl2 was added
dropwise, and the solution was stirred for 30 min. The above
allylic alcohol (0.94 g, 4.1 mmol) dissolved in 5 mL of CH2Cl2
was added dropwise at -78 °C, and the solution was stirred
for another 30 min. Triethylamine (2.9 mL, 20.5 mmol) was
added, and the solution was allowed to warm to 0 °C over 1 h.
The reaction was quenched with brine, the layers were
separated, the aqueous layer was extracted three times with
CH2Cl2, and the organic layers were dried with Na2SO4 and
concentrated under reduced pressure. Column chromatogra-
phy using petroleum ether and Et2O (4:1) afforded 0.9 g (4.0
mmol) of the product 15 as a light yellow oil (97%): 1H NMR
(CDCl3, 400 MHz) δ 6.97 (dd, J ) 17.2, 10.4, 1H), 6.36 (dd, J
) 17.2, 2.0, 1H), 5.69 (dd, J ) 10.4, 2.0, 1H), 5.06-5.01 (m,
1H), 4.65 (AB, J ) 7.1, 2H), 3.38 (s, 3H), 1.94 (q, J ) 7.7, 2H),
1.80-1.73 (m, 1H), 1.68-1.59 (m, 1H), 1.64 (s, 3H), 1.56 (s,
3H), 1.38 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 201.4, 132.2,
130.7, 128.8, 123.5, 92.4, 83.7, 56.1, 37.6, 25.6, 22.0, 19.9, 17.6;
1.63-1.59 (m, 1H), 1.65 (s, 3H), 1.56 (s, 3H), 1.32 (s, 3H); 13
C
NMR (CDCl3, 100 MHz) δ 213.5, 138.0, 132.0, 128.5, 128.4,
128.3, 127.9, 127.7, 127.6, 123.6, 91.9, 84.7, 78.6, 75.5, 75.4,
73.6, 73.3, 73.1, 73.0, 72.8, 71.5, 70.0, 68.3, 55.7, 37.6, 33.3,
25.6, 22.2, 21.2, 17.6; IR (neat) 3450, 2925, 1713, 1454, 1076,
1027, 734 cm-1; ESI+/TOF m/z 1343 (2M+ + Na), 683 (M+
+
Na), 581, 289; HRMS (ESI) calcd for C40H52O8Na 683.3560,
found 683.3575 [M + Na]+.
3-(4,5-Bis-benzyloxy-6-benzyloxymethyl-3-hydroxytet-
rahydropyran-2-yl)-1-(5-bromo-2,6,6-trimethyltetrahy-
dropyran-2-yl)propan-1-one (19). Tri-O-benzylglycal (0.30
g, 0.7 mmol) was dissolved in 5 mL of CH2Cl2, and the solution
was cooled to 0 °C. DMDO (0.1 M in CH2Cl2/acetone, 10 mL)
was added and the solution stirred until completion as
determined by TLC (30 min). The solvents were removed under
reduced pressure, and the material was dried under vacuo.
The crude epoxide was dissolved in 15 mL of anhydrous,
deaerated THF. To this solution was added 11 (0.280 g, 1.1
mmol). A green solution of Cp2TiCl [prepared by mixing Cp2-
TiCl2 (0.30 g, 1.2 mmol) and manganese powder (0.10 g, 1.8
mmol) in 10 mL of THF for 45 min] was added to the epoxide
via cannula. The reaction mixture immediately turned yellow,
then red. The solution was stirred at room temperature for 1
h, prior to addition of 0.1 M HCl and extraction with Et2O (3
× 25 mL). The organic layer was washed with satd NaHCO3,
dried with brine and MgSO4, and concentrated to give a thick
orange syrup that was chromatographed using petroleum
ether and Et2O (2:1, then 1:1) to give the desired product 18
as a clear oil (0.19 g, 0.27 mmol, 38% for two steps): 1H NMR
(CDCl3, 400 MHz) δ 7.37-7.22 (m, 15H), 4.73-4.95 (m, 6H),
3.98-3.89 (m, 2H), 3.79-3.60 (m, 5H), 2.89-2.68 (m, 2H),
(19) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem Ber. 1991,
124, 2377. (b) Gilbert, M.; Ferrer, M.; Sanchez-Baeza, F.; Messeguer,
A. Tetrahedron 1997, 53 (25), 8643-8650.
5254 J. Org. Chem., Vol. 70, No. 13, 2005

From C-Glycosides to Pyranopyrans
2.18-2.08 (m, 2H), 2.04-1.88 (m, 2H), 1.83-1.69 (m, 2H), 1.42
(s, 3H), 1.34 (s, 3H), 1.28 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 214.3, 138.0, 137.5, 128.6, 128.5, 128.4, 127.9, 127.8, 127.7,
127.6, 79.5, 78.5, 75.5, 75.4, 73.7, 73.3, 73.2, 72.9, 71.6, 69.9,
68.3, 31.7, 29.8, 28.2, 27.4, 27.2, 25.4, 22.1; IR (neat) 3450,
2926, 1709, 1454, 1074, 907, 728 cm-1; ESI+/TOF m/z 717/
719 (M+ + Na), 473, 457, 337, 310, 303, 282, 219, 173; HRMS
(ESI) calcd for C38H47O7NaBr 717.2403, found 717.2376 [M +
Na]+.
22 (0.66 g, 2.8 mmol) was dissolved in ethanol, and CeCl3‚
7H2O (1.4 g, 3.7 mmol) was added. The reaction mixture was
sonicated for 5 min or until all of the solids dissolved. The flask
was cooled to -78 °C, and NaBH4 (0.16 g, 4.3 mmol) in EtOH
was added. The reaction was stirred for 1 h at -78 °C, diluted
with ethyl acetate, and allowed to warm to room temperature.
Saturated NaHCO3 was added, and the reaction was extracted
with EtOAc (3 × 50 mL). The organic phase was dried using
Na2SO4 and concentrated under reduced pressure to afford a
clear thick oil. The unstable allylic alcohol was dissolved in
20 mL of dry CH2Cl2, and imidazole (0.35 g, 5.1 mmol) was
added, followed by TBSCl (0.64 g, 4.2 mmol) and a catalytic
amount of DMAP (10 mg). The reaction mixture was stirred
for 24 h at room temperature. Water was added to quench the
reaction and the solution extracted with CH2Cl2 three times
(20 mL). The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The resulting crude
material was chromatographed using petroleum ether and
Et2O (5:0.5) to give the desired product as a clear oil (23, 0.68
g, 1.96 mmol, 70% for two steps): 1H NMR (CDCl3, 400 MHz)
δ 7.29-7.40 (m, 5H), 4.61 (AB, J ) 12.1, 2H), 4.50 (m, 1H),
4.42 (m, 1H), 4.17 (m, 1H), 3.68 (dd, J ) 10.3, 6.5, 1H), 3.52
(dd, J ) 10.3, 4.1, 1H), 2.00 (m, 1H), 1.77 (dd, J ) 1.4, 0.9,
1H), 1.67 (ddd, J ) 18.7, 10.4, 8.1, 1H), 0.90 (s, 3H), 0.085 (s,
3H), 0.075 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 151.7, 138.1,
128.4, 127.8, 127.6, 101.4, 73.9, 73.3, 72.1, 63.6, 34.3, 25.9, 19.9,
18.2, -4.7; IR (neat) 2953, 1674, 1252, 1070, 836; IR (neat)
2927, 2856, 1673, 1384, 1251, 1064, 834 cm-1; LREI-MS m/z
291 (M+ - t-Bu), 199, 183, 157, 143, 117; HRMS (EI) calcd for
C16H23O3Si [M - t-Bu]+ 291.141648, found 291.142537 [M -
t-Bu]+.
3-[6-Benzyloxymethyl-4-(tert-butyldimethylsilanyloxy)-
3-hydroxy-2-methyl-(2S,3S,4R,6R)-tetrahydropyran-2-
yl]-1-(5-bromo-2,6,6-trimethyl-(2S,5R)-tetrahydropyran-
2-yl)propan-1-one (26). Adduct 23 (0.50 g, 1.43 mmol) was
dissolved in anhydrous CH2Cl2, and 0.50 g of 4 Å crushed
molecular sieves was added. The flask was cooled to -78 °C
and a dry solution of DMDO was added via cannula. The
reaction mixture was stirred until completion (about 10 min)
as judged by TLC, and concentrated under reduced pressure.
Due to the instability of the epoxide, it was used immediately
for the next reaction without further purification: 1H NMR
(CDCl3, 400 MHz) δ 7.39-7.27 (m, 5H), 4.58 (s, 2H), 4.13 (dd,
J ) 9.8, 6.9, 1H), 3.86-3.81 (m, 1H), 3.52 (m, 2H), 2.85 (s,
1H), 1.86 (ddd, J ) 13.1, 6.9, 1.2, 1H), 1.32 (ddd, J ) 13.2,
11.5, 9.9, 1H), 0.91 (s, 9H), 0.12 (s, 3H), 0.10 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 138.1, 128.4, 127.7, 127.7, 83.4, 73.3, 72.2,
67.4, 65.8, 60.8, 32.8, 30.9, 25.7, 20.9, 18.1, -4.76, -4.91.
1-Benzyloxy-3-[2-(2-methyl[1,3]dithian-2-ylmethyl)[1,3]-
dithian-2-yl]-(2R)-propan-2-ol (21). Acetyl acetaldehyde
dimethyl acetal (5 mL, 38 mmol) was dissolved in benzene (190
mL, 0.5 M) and added to a round-bottomed flask equipped with
stir bar, condenser, and Dean-Stark trap. 1,3-Propanedithiol
(7.6 mL, 75 mmol) was added, followed by p-toluenesulfonic
acid (38 mg, 1 mg/mmol). The reaction mixture was refluxed
for 48 h, cooled to room temperature, washed with saturated
NaHCO3, dried with brine and Na2SO4, and concentrated to
give a yellow solid. The solid was recrystallized from 50%
dichloromethane and hexanes to give the bis-dithiane as a
white crystalline solid in 86% yield (8.7 g, 33 mmol). The
spectra data matched the reported literature values:10 mp )
1
74-75 °C (lit.10 mp ) 76-77 °C); H NMR (CDCl3, 400 MHz)
δ 4.20 (t, J ) 4.8, 1H), 2.90-3.01 (m, 4H), 2.67-2.83 (m, 4H),
2.29 (d, J ) 4.9, 1H), 2.00-2.12 (m, 2H), 1.77-1.90 (m, 2H),
1.61 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 48.5, 46.7, 43.2,
31.1, 28.4, 26.8, 25.1, 24.7.
The above solid (3.0 g, 11 mmol) was dissolved in 100 mL
of anhydrous THF and was added to a round-bottomed flask.
The solution was cooled to 0 °C, and n-BuLi (1.6 M in THF,
8.4 mL, 14 mmol) was added dropwise via an addition funnel.
The solution turned yellow and was stirred at 0 °C for 1 h.
Benzyl-(R)-glycidyl ether (20, 2.2 g, 14 mmol) dissolved in 10
mL of THF was added at 0 °C, and the reaction mixture was
allowed to warm to room temperature and stirred for 12 h.
The reaction was quenched with saturated NH4Cl, extracted
with diethyl ether (3 × 50 mL), washed with brine, and dried
using MgSO4. The solvent was removed under reduced pres-
sure. Upon silica gel chromatography using ethyl acetate and
hexanes (1:3), 3.6 g (8.4 mmol) of a thick yellow gum (21) was
obtained in 76% yield: 1H NMR (CDCl3, 400 MHz) δ 7.27-
7.36 (m, 5H), 4.60 (s, 2H), 4.30 (m, 1H), 3.43-3.52 (m, 2H),
3.17 (d, J ) 3.0, 1H), 2.72-3.02 (m, 11H), 2.34-2.47 (m, 2H),
2.04 (s, 3H), 1.92-2.00 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ
137.9, 128.3, 127.6, 127.5, 74.2, 73.1, 68.1, 52.5, 50.1, 49.1, 42.8,
28.5, 27.2, 27.1, 27.0, 26.8, 24.8, 24.4; IR (neat) 3450, 2902,
1420, 1273, 1094, 735 cm-1; LREI-MS m/z 430, 323, 133;
HRMS (EI) calcd for C20H30O2S4 430.112868 [M + H], found
430.112569.
A solution of Cp2TiCl was prepared by stirring Cp2TiCl2
(0.89 g, 3.6 mmol) and manganese (0.32 g, 5.7 mmol) in
anhydrous, deaerated THF (15 mL) for 1 h (or until the
solution turned lime green). This solution was added rapidly
via syringe to a flask containing the above epoxide (0.52 g,
1.43 mmol) and 11 (0.56 g, 2.2 mmol), in THF (20 mL) at room
temperature. The reaction immediately turned yellow, then
red-brown, and was stirred for 45 min. The reaction was
quenched with 0.1 M HCl, extracted with diethyl ether,
washed with saturated NaHCO3, and dried with brine and
MgSO4 to afford the crude material as an orange syrup.
Chromatography using petroleum ether and diethyl ether (6:
1) afforded the desired product 26 as a clear oil (0.54 g, 0.86
mmol, 60%). Unreacted compound 11 was recovered and
recycled (0.17 g, 0.65 mmol). 1H NMR (CDCl3, 400 MHz) δ
7.36-7.27 (m, 5H), 4.55 (AB, J ) 12.3, 2H), 3.94 (dd, J ) 7.5,
4.6, 1H), 3.85 (ddd, J ) 11.2, 9.1, 5.2, 1H), 3.47 (dd, J ) 10.0.
6.4, 1H), 3.37 (dd, J ) 10.0, 4.2, 1H), 3.24 (dd, J ) 9.1, 2.2,
1H), 2.82-2.63 (m, 2H), 2.27 (d, J ) 2.2, 1H), 2.15-2.08 (m,
2H), 2.03-1.92 (m, 2H), 1.83 (ddd, J ) 12.6, 5.1, 2.2, 1H),
1.78-1.69 (m, 2H), 1.40 (m, 1H), 1.40 (s, 3H), 1.35 (s, 3H), 1.29
2-Benzyloxymethyl-6-methyl-(2R)-2,3-dihydropyran-4-
one (22). Compound 21 (130 mg, 0.3 mmol) was dissolved in
a mixture of acetonitrile and water (3 mL, 9:1) at room
temperature. HgCl2 (270 mg, 1 mmol) was added in one
portion, and the reaction mixture turned cloudy yellow, then
pink. The solution was stirred at room temperature for 4 h,
filtered through a pad of Celite, and washed with ether three
times. The filtrate was washed with water and brine, dried
over MgSO4, and concentrated under reduced pressure to give
the crude material that was chromatographed using ethyl
acetate and hexanes (2:3) to afford 41 mg (0.18 mmol) of the
product as a clear oil (57%). The reaction was repeated starting
with 3.0 mmols of compound 21, and similar yields (55%) were
obtained: 1H NMR (CDCl3, 400 MHz) δ 7.39 (m, 5H), 5.32 (bs,
1H), 4.63-4.56 (AB, J ) 12.3, 2H), 4.50-4.56 (m, H), 3.64-
3.72 (m, 2H), 2.62 (dd, J ) 16.7, 14, 1H), 2.30 (ddd, J ) 17,
3.7, 1, 1H), 2.02 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 192.3,
137.4, 128.4, 127.6, 127.6, 104.9, 78.0, 73.4, 70.6, 37.3, 21.0;
IR (neat) 2864, 1661, 1606, 1396, 1334, 1088, 737 cm-1. LREI-
MS m/z 233 (M+ + H), 147, 133, 111; HRMS (EI) calcd for
C14H17O3 233.117770 [M + H]+, found 233.117282.
(s, 3H), 1.24 (s, 3H), 0.89 (s, 9H), 0.10 (s, 3H), 0.09 (s, 3H); 13
C
[2-Benzyloxymethyl-6-methyl-(2R,4R)-3,4-dihydro-2H-
pyran-4-yloxy]-tert-butyldimethylsilane (23). Compound
NMR (CDCl3, 100 MHz) δ 215.2, 138.2, 128.3, 127.6, 80.5, 79.7,
76.4, 75.4, 73.2, 73.2, 70.4, 68.1, 58.2, 37.1, 29.7, 28.9, 28.1,
J. Org. Chem, Vol. 70, No. 13, 2005 5255

Nishiguchi and Little
27.4, 27.2, 25.7, 25.3, 25.2, 23.8, 17.9, -4.1, -4.7; IR (neat)
3575, 2929, 2856, 1709, 1454, 1254, 1079, 836, 776 cm-1; ESI+/
TOF m/z 649/651 (M+ + Na), 627/629 (M+ + H), 609/611, 477/
479; HRMS (ESI) calcd for C31H52O6BrSi 627.27110 [M + H]+,
found 627.2731.
(s, 3H), 2.42 (ddd, J ) 11.8, 9.4, 2.2, 1H), 2.31-2.21 (m, 1H),
2.15-2.09 (m, 1H), 1.92 (dt, J ) 13.7, 3.0, 1H), 1.87-1.78 (m,
2H), 1.75-1.64 (m, 1H), 1.56-1.47 (m, 2H), 1.47-1.40 (m, 1H),
1.44 (s, 3H), 1.34 (s, 3H), 1.29 (s, 3H), 1.25 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 214.3, 138.4, 128.3, 127.6, 84.0, 79.5, 78.9,
75.1, 74.6, 73.5, 73.2, 70.0, 67.9, 58.7, 37.5, 31.3, 30.8, 29.7,
27.9, 27.5, 24.2, 23.5, 19.6, 19.1; IR (neat) 2932, 1454, 1371,
1206, 1052, 907, 728 cm-1; ESI+/TOF m/z 611/609 (M+ + Na),
521/519/ 413; HRMS (ESI) calcd for C27H39O5NaS2Br 609.13145
[M + Na]+, found 609.1303 [M + Na]+
The above xanthate (60 mg, 0.1 mmol) was dissolved in 25
mL of dioxane. n-Bu3P‚BH3 (44 mg, 0.2 mmol) was added, and
the solution was degassed by bubbling argon through it for
30 min. The solution was heated to reflux, and AIBN (5 mg,
0.03 mmol) was added in portions 1 mg every 30 min. The
reaction was heated for 4 h, upon which time it was judged to
be complete by TLC. The solution was cooled to room temper-
ature, the solvent was removed under reduced pressure, and
the crude material was chromatographed using petroleum
ether and Et2O (10%) to give 33 mg (0.07 mmol) of the desired
product 29 (69%): 1H NMR (CDCl3, 400 MHz) δ 7.35-7.27
(m, 5H), 4.57 (AB, J ) 12.1, 2H), 4.31-4.25 (m, 1H), 3.88 (dd,
J ) 12.4, 4.1, 1H), 3.49 (dd, J ) 9.7, 5.4, 1H), 3.38 (dd, J )
9.8, 5.8, 1H), 3.45 (dd, J ) 4.5, 1.8, 1H), 3.04 (dd, J ) 11.1,
2.3, 1H), 2.25 (qd, J ) 13.2, 3.8, 1H), 2.12 (dq, J ) 13.4, 4.1,
1H), 1.99-1.92 (m, 1H), 1.90-1.82 (m, 2H), 1.81-1.65 (m, 4H),
1.55-1.48 (m, 3H), 1.45 (s, 3H), 1.33 (s, 3H), 1.30 (s, 3H), 1.11
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.6, 128.3, 127.6,
127.4, 83.6, 75.0, 75.0, 74.1, 73.1, 69.8, 69.5, 58.9, 37.4, 31.4,
30.9, 28.0, 27.3, 24.1, 23.6, 22.5, 21.5, 20.2; IR (neat) 2933,
1455, 1371, 1097, 1017, 732 cm-1; ESI+/TOF m/z 503/505 (M+
+ Na), 423, 401, 311; HRMS (ESI) calcd for C25H37O4NaBr
503.17674 [M + Na]+, found 503.1773 [M + Na]+.
2-Benzyloxymethyl-6-[5-bromo-2,6,6-trimethyl-(2S,5R)-
tetrahydropyran-2-yl]-8a-methyl-(2R,4R,4aS,6S,8aS)-oc-
tahydropyrano[3,2-b]pyran-4-ol (27). Compound 26 (0.20
g, 0.32 mmol) was dissolved in anhydrous CH2Cl2 (5 mL) and
cooled to 0 °C. Et3SiH (0.15 mL, 0.96 mmol) was added,
followed by the dropwise addition of TMSOTf (0.16 mL, 0.64
mmol). The reaction mixture was stirred at 0 °C for 15 min,
quenched with saturated NaHCO3, extracted with CH2Cl2,
dried with MgSO4, and concentrated under reduced pressure.
The crude material was chromatographed using petroleum
ether and diethyl ether to afford the product 27 as a white
solid (80.6 mg, 0.16 mmol, 51%): mp ) 147-149 °C; 1H NMR
(CDCl3, 400 MHz) δ 7.37-7.28 (m, 5H), 4.58 (AB, J ) 12.1,
2H), 4.08 (m, 1H), 3.97 (td, J ) 7.9, 2.2, 1H), 3.86 (dd, J )
12.5, 4.1, 1H), 3.48 (dd, J ) 10.0, 4.9, 1H), 3.43 (dd, J ) 10.0,
5.1, 1H), 3.26 (d, J ) 2.2, 1H), 3.08 (dd, J ) 10.9, 3.1, 1H),
2.31-2.09 (m, 4H), 1.93-1.75 (m, 2H), 1.75-1.59 (m, 4H),
1.54-1.48 (m, 1H), 1.45-1.34 (m, 6H), 1.30 (s, 3H), 1.30 (s,
3H), 1.29 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 138.3, 128.3,
127.6, 127.6, 82.7, 81.9, 75.1, 74.9, 73.8, 73.2, 70.7, 69.5, 68.1,
58.7, 35.6, 32.4, 31.5, 30.9, 29.7, 28.0, 27.9, 23.9, 23.5, 19.8;
IR (neat) 3412.4, 2924, 1454, 1370, 1095, 909, 729 cm-1; ESI+/
TOF m/z 519/521 (M+ + Na), 497/499 (M+ + H), 479/477, 426,
381, 327; HRMS (ESI) calcd for C25H38O5Br 497.18971[M +
H]+ C25H38O5NaBr 519.17165 [M + Na]+, found 497.1887 [M
+ H]+, 519.1700 [M + Na]+
6-Benzyloxymethyl-2-(5-bromo-2,6,6-trimethyl-(2R,5R)-
tetrahydropyran-2-yl)-4a-methyl-(2S,4aS,6R,8aS)-octahy-
dropyrano[3,2-b]pyran (29). To 15 mL of dry THF was
added 27 (70 mg, 0.14 mmol) followed by NaH (7 mg, 0.17
mmol). The solution was stirred for 30 min, and CS2 (42 µl,
0.7 mmol) was added via syringe. The reaction mixture was
stirred at room temperature for another 30 min, and MeI (42
µl, 0.67 mmol) was added. Upon stirring for 2 h, the reaction
mixture was quenched with water, extracted with Et2O (3 ×
10 mL), dried with Na2SO4, and concentrated. Column chro-
matography using petroleum ether and 1% Et2O afforded the
desired xanthate (80 mg, 0.136 mmol) in 97% yield: 1H NMR
(CDCl3, 400 MHz) δ 7.37-7.27 (m, 5H), 5.65 (t, J ) 8.6, 1H),
4.57 (AB, J ) 12.2, 2H), 4.22-4.17 (m, 1H), 3.87 (dd, J ) 12.4,
3.99, 1H), 3.53-3.41 (m, 3H), 3.05 (dd, J ) 11.2, 2.2, 1H), 2.56
Acknowledgment. We thank the University of
California Cancer Research Coordinating Committee
(CRCC) for their support of this research. G.N. ex-
presses her gratitude to the Tokuyama family for a
Tokuyama Fellowship during a portion of the time in
which this research was conducted.
Supporting Information Available: 1H and 13C NMR
spectra as well as X-ray data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO050465D
5256 J. Org. Chem., Vol. 70, No. 13, 2005