Surveying approaches to the formation of carbon-carbon bonds between a pyran and an adjacent ring

Article abstract of DOI:10.1016/j.tet.2006.02.042

We have examined several methods for the stereoselective formation of carbon-carbon bonds between contiguous rings where a stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy enones, and epimerization of several α-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have proven C2-C2′ relative stereochemistry of 1-2 via a chemical correlation.

Full text of DOI:10.1016/j.tet.2006.02.042

Tetrahedron 62 (2006) 4573–4583
Surveying approaches to the formation
of carbon–carbon bonds between a pyran
and an adjacent ring
*
Jeffrey D. Frein and Tomislav Rovis
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA
Received 14 November 2005; revised 14 February 2006; accepted 15 February 2006
Available online 13 March 2006
Abstract—We have examined several methods for the stereoselective formation of carbon–carbon bonds between contiguous rings where a
stereogenic center is already present. The approaches investigated were a [1,3] oxygen to carbon rearrangement of cyclic vinyl acetals, an
intermolecular enolsilane addition into an in situ generated oxocarbenium ion, an intramolecular conjugate addition of tethered alkoxy
enones, and epimerization of several a-pyranyl cycloalkanones. These routes have been found to be complementary in several cases and have
enabled formation of both the trans:anti and cis:anti stereoisomers in good to excellent yields and varying diastereoselectivities. We have
proven C2–C20 relative stereochemistry of 1–2 via a chemical correlation.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
stereochemistry at both ends, a problem that is shared
by various other natural product targets as well.
Among the largest and most complicated non-biopolymer
molecules discovered to date are maitotoxin, prymnesin
and ciguatoxin, along with other members of the
polyether ladder toxin family.1 These molecules are
characterized by sections of fused oxacycles connected to
each other by carbon linkers. Only a handful of total
syntheses have emerged to date, including Nicolaou’s
synthesis of brevetoxin2 and Hirama’s recent synthesis of
ciguatoxin.3 No syntheses have yet appeared of the
largest members of this family, maitotoxin and prymne-
sin. At least a part of the reason for this is the
comparative complexity of subsections of maitotoxin,
compelling and challenging targets in their own right.
We became interested in the problem of how to connect
subsections of these molecules once they are assembled.
Arguably, the most obvious bond disconnections involve
the single C–C bonds that connect the fused oxacycle
subsections to each other.4 An approach to these types of
bonds must address the key issue of controlling
We chose to conduct an in-depth study of various
approaches to this type of ring juncture. Prime among
these was our intention to apply our recently developed
stereoretentive O to C rearrangement to this problem.5 In
doing so, we hoped to take advantage of the relative
facility of controlling stereochemistry in the formation of
a C–O bond and induce it to rearrange to a C–C bond,
having already paid the entropic price of bringing two
fragments together in the formation of the ‘easy’ bond.
The question that we needed to address was our ability
to control the second stereocenter in the rearrangement
(Eq. 1).6 Second, we hoped to contrast these results with
selectivities obtained in the more classical Lewis acid
induced intermolecular enolsilane addition to an in situ
generated oxocarbenium ion (Eq. 2). This method is
comparable to the rearrangement method without having
to address the issue of creating the oxocarbenium ion and
enolate via an intramolecular event, although it lacks the
possibility of providing the cis adduct via a stereo-
retentive process. Last, we wanted to exploit an
intramolecular conjugate addition of an alkoxide into
an a,b-unsaturated ketone (Eq. 3).
Keywords: Stereoretentive process; Lewis acid; Oxocarbenium ions;
[1,3]rearrangement.
*
Corresponding author. Tel.: C1 970 491 7208; fax: C1 970 491 1801;
e-mail: rovis@lamar.colostate.edu
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.042

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J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
evidence. We envisioned the chosen Lewis acid would have
the ability to control the recombination of the intermediates
and possibly form a single diastereomer in a highly selective
manner (Fig. 1).
Figure 1.
2. Results and discussion
(1)
(2)
(3)
We chose to begin our investigations with simple enolates
and oxocarbenium ions devoid of electronic or steric
features, which might dictate selectivity in the bond forming
event.8 The requisite cyclic vinyl acetals 3a–c were
prepared by ozonolysis of the corresponding cycloalkenes
4a–c using Schreiber’s conditions.9 The resulting aldehyde–
methyl esters 5a–c were treated with BF3$OEt2 and
thiophenol to yield the thioacetal–methyl esters 6a–c.
Hydrolysis of 6a–c and treatment with (COCl)2 resulted in
the acyl chloride–thioacetals 8a–c. Using conditions
reported by Ley,6d 8a–c were treated with lactol 9 and
KHMDS at K78 8C yielding the cis-tetrahydropyran esters
10a–c in high cis:trans selectivity (O95:5). 10a–c were
cyclized via Takeda’s titanocene(II)-promoted intra-
molecular carbonyl olefination of esters to yield the desired
cyclic vinyl acetals 3a–c (Scheme 1).10
Other groups have exploited various methods for the
formation of these carbon–carbon linkers.7 Suzuki and co-
workers have reported a BF3$OEt2 mediated 1,3-oxygen to
carbon rearrangement of vinyl acetals resulting in pyranyl
aldehydes in good yields (85–89%) and modest to good
C2–C20 diastereoselectivities (3:2–3:1).6i In addition, Ley
and co-workers have shown a SnCl4 mediated oxygen to
carbon rearrangement of silyl enol ethers derived from
lactols.6e,f This rearrangement affords exclusively the trans
orientation across the pyran ring with the resultant
contiguous stereocenters (C2–C20) in poor to modest
diastereoselectivities (1:1–3:1) and in good yields (79–
90%).6e,f Also, Ley and co-workers have shown the use of
the oxygen to carbon rearrangement for the formation of
various mono- and bi-cyclic ethers.6g,h
Our intitial screening of Lewis acids that would induce the
rearrangement began with BF3$OEt2 (Table 1). From our
previous work, we expected the strong Lewis acid would
allow the complexed enolate to escape from the solvent cage
prior to recombination and thus form the kinetically favored
trans-isomer.5a Under these conditions, the rearrangements
of 3a–c resulted in extremely high trans:cis selectivities
(entries 1, 5, and 9; Table 1).11 Moreover, we were pleased
that 3a and 3b (entries 1 and 5; Table 1)0also had relatively
good anti:syn selectivity for the C2–C2 bond, (79:21 and
82:18, respectively). Unfortunately, further investigations
aimed at identifying a Lewis acid capable of forming the
opposite C2–C20 stereochemistry were unsuccessful.
As stated above, recently we have developed a Lewis acid-
mediated highly stereoretentive [1,3] rearrangement of
vinyl acetals, wherein the selectivity is controlled by tight
ion pairing of the resulting oxocarbenium ion and Lewis
acid coordinated enolate intermediate.5 Should the gener-
ated ions escape the solvent cage prior to recombination, the
trans product would predominate. However, if recombi-
nation occurs faster, the cis product would result. In many
cases, either isomer may be prepared by simple choice
of Lewis acid system—BF3$OEt2 proved to be trans
selective while Me3Al/BF3$OEt2 afforded products of
stereoretention, with a crossover study providing conclusive
From our previous findings, we knew that the use of Me3Al–
BF3$OEt2 (4/1) results in a highly stereoretentive rearran-
gement.5a These conditions proved unsuccessful with the
trisubstituted alkenes in this study (entries 3, 6, and 10;
Table 1) which we interpret as due to the increased steric
requirement of the trisubstituted alkene. However, adjust-
ment of the acidity of the Lewis acid to Et2AlCl provided a
partial solution, potentially due to a slightly more reactive

J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
4575
Scheme 1.
Table 1.
Entry
n
Lewis acid
cis:transa
cis (anti:syn)a
trans (anti:syn)a
Yield (%)b
1
2
3
4
0
0
0
0
BF3$OEt2
FeCl3
Me3Al/BF3$OEt2
Et2AlCl
!1:O99
16:84
40:60
NA
79:21
81:19
71:29
78:22
90
87
75
86
74:26
62:38
69:31
c
c
70:30
5
6
7
8
1
1
1
1
BF3$OEt2
4:96
O99:!1
72:28
63:37
82:18
58:42
86:14
75:25
88
81
84
75
Me3Al/BF3$OEt2
Et2AlCl
Me2AlCl
55:45
92:8
78:22
79:21
9
2
2
2
2
BF3$OEt2
Me3Al/BF3$OEt2
Et2AlCl
2:98
52:48
69:31
58:42
55:45
52:48
52:48
57:43
52:48
92
68
90
88
c
10
11
12
38:62
72:28
89:11
d
Et2AlCl/PPh3
a Ratios were determined by GC analysis.
b Isolated yield.
c Reaction conducted using 4 equiv Me3Al and 1 equiv BF3$OEt2.
d Reaction conducted using 1.5 equiv Et2AlCl and 1.65 equiv PPh3.
enolate intermediate. The Et2AlCl mediated rearrangement
presumably proceeds via tight ion-pairing and results in
modest to good cis:trans selectivities for entries 4, 7, and 11
in Table 1 (70:30, 92:8, and 72:28, respectively).
The results of this substitution study, shown in Table 3, are
comparable to the results from the [1,3] O to C rearrangement
and the epimerization studies (Tables 1 and 2, respectively).
Compound 1a illustrates a higher selectivity for the cis isomer
than in the two previous methods (entry 2; Table 3). While the
C2–C20 selectivities for the cis isomer of 1b and 1c (entries 4
and 6, respectively) were disappointing, the room temperature
enolsilane addition afforded the a-pyranyl cyclopentanone
(1a) with good stereoselectivity for the formation of the
cis:anti diastereomer (entry 2). The enolsilane addition to
the oxocarbenium ion derived from 11 at K78 8C yielded the
a-pyranyl cycloalkanones (2a–c) in high trans:cis diastereos-
electivities with modest C2–C20 diastereoselectivities (entries
1, 3, and 5; Table 3).
Previous work had established that the cis-isomer is
thermodynamically preferred, relative to the trans-isomer,
due to reduced diaxial interactions and Ley has exploited
this aspect to access the cis-isomer by epimerizing the trans-
isomer with TMSOTf at 23 8C.6c,d,12 As a result, our
attention was focused on the ability to epimerize the
stereocenter at the anomeric carbon (C2) in the reaction
products. Treatment of the trans-ketone 2a–c (products of
entries 1, 3, and 5, respectively, in Table 3) with BF3$OEt2
at room temperature resulted in a highly efficient method for
the epimerization to the cis-ketones 1a–c (Table 2). All
entries showed high cis:trans selectivity and 1a exhibited
good C2–C20 diastereoselectivity (entry 1).
Finally, our attention shifted to forming these bonds via an
intramolecular conjugate addition. These types of reactions
have been employed previously in the synthesis of
substituted pyran compounds using a variety of bases
including catalytic amounts of KOt-Bu.13 Under these
conditions (Table 4), the selectivities observed were
comparable to the selectivities obtained in the previously
Our attention nextfocused onforming products1a–c and 2a–c
via a Lewis acid mediated intermolecular substitution reaction
of an anomeric acetate (11) and enolsilanes (12a–c).

4576
J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
Table 2.
Entry
n
cis:transa
cis (anti:syn)a
trans (anti:syn)a
Yield (%)b
1
2
3
0
1
2
93:7
97:3
99:1
80:20
50:50
50:50
92:8
79:21
50:50
98
96
97
a Ratios were determined by GC analysis.
b Isolated yield.
Table 3.
Entry
n
Temperature
(8C)
Time (h)
cis:transa
cis (anti:syn)a
trans (anti:syn)a
Yield (%)b
1
2
0
0
K78
23
1
12
4:96
98:2
64:36
76:24
64:36
64:36
90
86
3
4
1
1
K78
23
1
12
3:97
98:2
70:30
52:48
77:23
66:34
94
87
5
6
2
2
K78
23
1
12
!1:O99
99:1
37:63
52:48
57:43
66:34
92
92
a Ratios were determined by GC analysis.
b Isolated yield.
Table 4.
Entrya
n
Temperature
(8C)
Time (min)
cis:transb
cis (anti:syn)b
trans (anti:syn)b
Yield (%)c
1
2
0
0
K78
0
30
10
16:84
96:4
74:26
77:23
81:19
94:6
83
88
3
4
1
1
K78
0
30
10
18:82
98:2
60:40
55:45
74:26
60:40
84
86
5
6
2
2
K78
0
30
10
48:52
89:11
55:45
52:48
62:38
55:45
85
90
a Starting materials used as O95:5 isomerically enriched favoring the defined olefin isomer.
b Ratios of C2/C20 isomers, determined by GC analysis.
c Isolated yield.
listed methods (Tables 1–3). Stereoselectivities in the
synthesis of the cis isomer were good to excellent in all
the systems that were explored (entries 2, 4, and 6; Table 4).
In addition, the C2–C20 selectivities were poor to modest for
systems 1a–c (entries 2, 4, and 6, respectively). The
selectivity towards the trans isomers (2a–c) were modest
at best for all three substrates and the C2–C20 selectivities
were poor to good (entries 1, 3, and 5; Table 4). In all
entries, the yields of the conjugate addition products were
good (84–90%).

J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
4577
Scheme 2.
a comparison of spectroscopic data, it was established that the
major isomer was that shown as 18a, corresponding to the
rearrangement product anti 2a. This route was also performed
on substrates 1a and 2b. The assignment of stereochemistry in
1b–c and 2c was based on analogies derived from predictable
GC retention times of the product diastereomers. Thus, all
reactions resulted in the anti isomer (C2–C20) as the major
product. We propose that the C2–C20 anti selectivity is a result
of the recombination of the oxocarbenium ion and Lewis acid
complexed enolate in the lowest energy staggered confor-
mation when the two hydrogen atoms are anti-periplanar
(Fig. 3). cis:trans Selectivity in the rearrangement is a result of
the recombination from either a contact (cis) or solvent
separated (trans) ion pair. The cis:trans selectivity in the
intermolecular oxocarbenium/enolsilane addition mirror this
model (Fig. 3). The epimerization studies reflect thermodyn-
amic (cis) stability.
(4)
With these results in hand, we wanted to apply this
technique to a system containing a heteroatom in both
ring segments. Therefore, enolsilane 14 was prepared
according to methods reported by Gallagher and co-
workers.14b When acetal 11 and enolsilane 14 were treated
with BF3$OEt2 at K78 8C, the trans-isomers 15 (Eq. 4) were
the only observed diastereomers.15 A control experiment
was performed in order to determine whether the more
bulky silyl group (TBS / TMS) caused a significant change
in the diastereoselectivity observed for the all carbon system
(1b and 2b); no significant change in diastereoselectivity
was observed at either K78 or 23 8C.16
Determination of C2–C20 stereochemistry was not trivial
due to our inability to separate the C2–C20 diastereomers
formed from the reaction products. As a result, we resorted
toachemicalcorrelationtoprove stereochemistry(Scheme 2).
First, a Baeyer–Villiger oxidation of ketone 2a affords the
lactone 17. The reduction of 17 with LAH yielded the two
diastereomeric diols 18a and 18b (3:1), separable by column
chromatography on silica gel. The major isomer 18a was then
mono-protected with TBDMSCl and oxidized with Dess–
Martin periodinane yielding the ketone 20. Chelate controlled
reduction of 20 with Zn(BH4)2 resulted in a single
diastereomer, 21.17 Zn(BH4)2 delivers the hydride in
a manner, which leaves a syn relationship between C2 and
C20 (Fig. 2). Following the deprotection of 21 with TBAF and
Figure 3.
3. Conclusions
In summary, we have investigated the formation of carbon–
carbon bonds between adjacent rings via a stereoretentive
rearrangement of cyclic vinyl acetals, an intermolecular
addition of an enolsilane into an oxocarbenium ion, and an
intramolecular conjugate addition of an u-hydroxy-a,b-
unsaturated ketones. Furthermore, we have shown that the
product ratios obtained from the epimerization studies
(Table 2) are indeed at their equilibrium positions, as
justified by the similar results shown in Tables 3 and 4. The
[1,3] oxygen to carbon rearrangement proved the best route
for synthesizing the trans:anti diastereomer for substrates 2a
Figure 2.

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J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
Figure 4.
and 2b in 70% yield for each of the desired diastereomers
(Fig. 4). The enolsilane addition into an in situ generated
oxocarbenium ion afforded the cis:anti diastereomer in 65%
yield for substrate 1a (Fig. 4). The synthesis of substrates 1b,
1c, and 2c proceeded in a non-selective manner and
unfortunately, the synthesis of the C2–C20 syn diastereomers
inall cases provedto bestereoselectively inaccessible bythese
approaches. The most promising result that we have identified
is the selective assembly of bis-pyrans such as 16, of particular
relevance to key subsections of the polyether ladder toxins.
Efforts at elaborating these substrates to probe the behavior of
fully functionalized substrates are ongoing.
MgSO4, filtered, and concentrated to provide 9.85 g (89%)
of aldehyde–methyl ester 5a as colorless oil.
A 250 mL round bottomed flask was charged with 1.68 g
(12.9 mmol) of 5a and 40 mL of CH2Cl2 then cooled to
K50 8C. Next, 2.91 g (26.45 mmol) of PhSH and 4.58 g
(32.25 mmol) of BF3$OEt2 were added successively. The
mixture was stirred at K50 8C for 30 min, then poured into
a little ice-water and extracted with CH2Cl2. The organic
layer was washed successively with 30 mL portions of 7%
aq KOH, H2O, and brine. The organic layer was dried over
MgSO4, filtered and concentrated to yield 4.22 g (98%) of
thioacetal–methyl ester 6a as a yellow oil.
A 50 mL round bottomed flask was charged with thioacetal–
methyl ester 6a (4.22 g, 12.69 mmol), 3.56 g (63.46 mmol)
of KOH, and 40 mL of acetone. The mixture was stirred
overnight and then acidified with concd HCl to pH 4. The
reaction mixture was extracted with EtOAc (3!50 mL) and
washed with 100 mL H2O. The combined organic layers
were dried over MgSO4, filtered and concentrated to yield a
black oil. The crude product was purified by standard acid/
base workup to yield 3.6 g (89%) of thioacetal-acid 7a.
4. Experimental
4.1. General
4.1.1. General procedure for the synthesis of cyclic vinyl
acetals. A 500 mL, three necked, round bottomed flask with
a glass tube to admit ozone, a calcium chloride drying tube,
and a glass stopper is charged with 5.109 g (75.0 mmol) of
cyclopentene 4a, 250 mL of CH2Cl2, 50 mL of MeOH, and
2.0 g of anhydrous NaHCO3. After the apparatus is cooled
to ca. K78 8C, ozone is bubbled through the solution as it is
stirred (flow rate Z4.0 lpm; 50 V). Ozone addition is
stopped when the solution turns blue. Argon is passed
through until the blue color is discharged and then the cold
bath is removed. The solution is filtered into a 1-L, round-
bottomed flask and 80 mL of benzene is added. The volume
is reduced to approximately 50 mL by rotary evaporation.
After dilution with 225 mL of CH2Cl2 the flask is cooled to
0 8C and 16 mL (113 mmol) of TEA and 21.24 mL
(225 mmol) of Ac2O are added via syringe, and the solution
is stirred under an argon atmosphere at 0 8C for 15 min. The
ice bath is removed and stirring is continued for 4 h. The
solution is washed with 150 mL portions of aq 0.1 N HCl,
10% aq NaOH, and H2O. The organic layer is dried over
A 25 mL round bottomed flask was charged with 1.0 g
(3.14 mmol) of thioacetal-acid 7a, five drops of dry DMF,
and 10.0 mL of benzene, then cooled to 0 8C and 1.24 g
(9.73 mmol) of (COCl)2 was added dropwise. After
addition, the reaction mixture was allowed to warm to
room temperature and stirred for 2 h. Excess reagents and
solvent were removed by rotary evaporation and the residue
was twice treated with 10 mL of benzene and concentrated
by rotary evaporation. Reaction yielded 1.04 g (98%) of
thioacetal–acyl chloride 8a as a yellow oil.
To a stirred solution of lactol 9 (0.547 g, 2.94 mmol) in
10 mL THF at K78 8C was added a solution of KHMDS in
toluene (0.5 M, 5.94 mL, 2.97 mmol) dropwise, and the
reaction mixture was warmed to 0 8C over 5 min before

J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
4579
cooling to K78 8C. A solution of thioacetal–acyl chloride
8a (1.04 g, 3.09 mmol) in 5 mL THF was added dropwise,
and the reaction mixture was stirred for 2 h at K78 8C
before quenching with satd aq NH4Cl (20 mL). Next,
distilled water (20 mL) was added and the aqueous layer
was extracted with Et2O (3!25 mL). The combined
organic extracts were dried over MgSO4, filtered, and
concentrated to yield a yellow oil. Purification by flash
column chromatography, eluting with 15% EtOAc in
hexanes with 1% TEA, provided 1.10 g (76%) of ester
10a as a yellow oil in O95:5 cis:trans diastereoselectivity.
25.5 mg (0.15 mmol) of silyl enol ether 12b, and 1.0 mL of
CH2Cl2. The reaction was then cooled to K78 8C and 19 mL
(0.15 mmol) of BF3$OEt2 was added dropwise. After 1 h at
K78 8C, the reaction was quenched by the addition of
1.0 mL satd aq Na2CO3 and extracted with Et2O (3!
10 mL). The organics were combined and washed with
H2O, then satd aq NaHCO3. The organic layer was then
dried over MgSO4, filtered, and concentrated to yield 21.2 mg
(94%) of 3:97 (cis:trans) mixture of ketones 1b and 2b.
4.1.5. General procedure for the conjugate addition. To a
flame dried 5 mL round bottomed flask was added 10.0 mg
(0.036 mmol) of hydroxy-ketone 13a and 0.5 mL of THF.
The reaction was cooled to 0 8C and 1.0 mg (0.0072 mmol)
of KOtBu was added. After 10 min, the reaction was
quenched with 0.5 mL of satd aq NH4Cl and extracted with
Et2O (3!10 mL). The organic layers were combined and
washed with brine, dried over MgSO4, filtered and
concentrated to afford 8.8 mg (88%) of 96:4 (cis:trans)
mixture of ketones 1a and 2b.
˚
Finely powdered 4 A MS (400 mg), Mg turnings (120 mg,
4.94 mmol), and Cp2TiCl2 (1.03 g, 4.12 mmol) were placed
in a flask and dried by heating with a heat gun under reduced
pressure (2–3 mmHg). During this procedure care was taken
not to sublime Cp2TiCl2. After cooling, THF (5 mL) and
P(OEt)3 (1.37 g, 8.24 mmol) were added successively with
stirring at room temperature under argon. Within 15 min,
the reaction mixture turned dark green and then dark brown
with slight evolution of heat. After 3 h, the ester 10a (0.5 g,
1.03 mmol) in 10 mL THF was added to the reaction
mixture dropwise over 20 min. After stirring for 3 h, the
reaction was quenched by addition of aq 1 M NaOH
(20 mL) and then the insoluble materials were filtered off
through Celite and washed with Et2O. The layers were
separated, and the aqueous layer was extracted with Et2O
(3!30 mL). The combined organic extracts were washed
with aq 1 M NaOH, stirred with deactivated charcoal, and
dried over MgSO4. The slurry was then filtered and
concentrated. The residue was purified by flash column
chromatography, eluting with 25% EtOAc in hexanes
containing 1% TEA, to afford 138 mg (32%) of cyclic
vinyl acetal 3a as a colorless oil.
4.1.6. Determination of C2–C20 stereochemistry. A
25 mL round bottomed flask was charged with 370 mg
(1.63 mmol) of ketone 2a, 3.3 mL of aq 0.5 M NaHCO3
(1.63 mmol), and 6.0 mL of CH2Cl2. m-CPBA (564 mg,
3.27 mmol, purity 77% max) was added portionwise at
room temperature and the reaction was allowed to stir
overnight. The reaction was quenched by addition of 15%
aq Na2SO3 (5 mL) and stirred at room temperature for 1 h.
The layers were separated and the organic layer was washed
with 5 mL portions of H2O, 5% aq NaHCO3, H2O, and
brine. The organic layer was dried over MgSO4, filtered, and
concentrated to yield 255 mg (55%) of lactone 17.
To a 125 mL round bottomed flask charged with 255 mg
(0.908 mmol) of lactone 17 and 30.0 mL of Et2O was
added portionwise 111 mg (2.937 mmol) of LAH. The
reaction was stirred for 12 h, then cooled to 0 8C and
added to the reaction flask 0.111 mL of H2O, 0.111 mL
of 15% aq NaOH, and 0.333 mL of H2O (Fieser
workup).18 The reaction was allowed to stir until the
gray solution turned clear. The precipitate was filtered off
and the filtered solution was then concentrated to afford a
crude oil. The crude oil was purified by flash column
chromatography using 90% EtOAc in hexanes as eluant
to yield 146 mg (56%) of diol 18a and 50.6 mg (19%) of
diol 18b.
4.1.2. General procedure for rearrangement of cyclic
vinyl ethers. To a flame dried 5 mL round bottomed flask
was added 5.0 mg (0.019 mmol) of cyclic vinyl ether 3b and
1.0 mL of toluene. The reaction mixture was cooled to
K78 8C and BF3$OEt2 (2.7 mL, 0.021 mmol) was added
dropwise. The reaction was allowed to stir until 3b was
completely consumed as seen by TLC, then quenched with
2 mL of satd aq Na2CO3 and separated layers. The aqueous
layer was extracted with EtOAc (3!3 mL). The combined
organic layers were dried over MgSO4, filtered, and
concentrated to afford 4.4 mg (88%) of a 2:98 (cis:trans)
mixture of ketones 1b and 2b.
4.1.3. General procedure for the epimerization of trans-
ketone (2) to cis-ketone (1). To a flame dried 5 mL round
bottomed flask containing 100 mg (0.438 mmol) of ketone
2b and 5.0 mL of CH2Cl2 was added dropwise at room
temperature 124 mg (0.876 mmol) of BF3$OEt2. The
mixture was stirred for 12 h and quenched with 7.0 mL of
satd aq Na2CO3. The layers were separated and the aqueous
layer was extracted with EtOAc (3!10 mL). The combined
organic layers were dried over MgSO4, filtered, and
concentrated to yield 96 mg (96%) of a 98:2 (cis:trans)
mixture of ketones 1b and 2b.
A 25 mL round bottomed flask was charged with 40 mg
(0.140 mmol) of diol 18a and 2.0 mL of dry DMF. The
reaction was cooled to 0 8C and then successively added
11.4 mg (0.168 mmol) of imidazole and 21.9 mg
(0.145 mmol) of TBDMSCl. After 15 min, the reaction
was diluted with 5.0 mL of Et2O and 5.0 mL of H2O. The
layers were separated and the aqueous layer was extracted
with Et2O (3!10 mL). The combined organic layers were
dried over MgSO4, filtered, and concentrated to afford
50 mg (89%) of alcohol 19.
A 5 mL round bottomed flask was charged with 50 mg
(0.125 mmol) of alcohol 19, trace amount of NaHCO3,
84.4 mg (0.200 mmol) of Dess–Martin periodinane, and
1.0 mL of DCM and stirred for 12 h at room temperature.
4.1.4. General procedure for the intermolecular enolsi-
lane addition reaction. To a flame dried 5 mL round
bottomed flask was added 22.8 mg (0.10 mmol) of lactol 11,

4580
J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
The reaction mixture was diluted with 2.0 mL satd aq
NaHCO3 and 2.0 mL of satd aq Na2S2O3, then extracted
with Et2O (3!5 mL). The combined organics were washed
with 5 mL portions of H2O and brine. The organic layer was
dried over MgSO4, filtered, and concentrated to afford
48 mg (96%) of ketone 20.
IR (NaCl, neat) 2931, 2858, 1711 cmK1; HRMS (FABC)
calcd for C17H31O2, 267.2324. Found 267.2331.
4.2.1.4. (20R*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cyclohexanone (2b). Following the general procedure
afforded 2b, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.341 (15% EtOAc/hex); 1H NMR
(300 MHz, CDCl3) d 4.11 (1H, ddd, JZ10.6, 8.1, 3.3 Hz),
3.92 (1H, ddd, JZ9.9, 5.9, 4.0 Hz), 3.69 (1H, m), 3.51 (1H,
m), 2.53–2.66 (2H, m), 2.37–2.49 (1H, m), 2.20–2.32 (4H, m),
2.07–2.20 (1H, m), 1.45–2.00 (20H, m), 1.13–1.40 (22H, m),
0.77–0.88 (6H, m); 13C NMR (75 MHz, CDCl3) d 212.6,
212.1, 72.4, 71.8, 69.1, 69.0, 54.2, 53.0, 42.9, 41.5, 33.8, 32.8,
30.4, 30.2, 29.8, 29.7, 29.7, 29.4, 28.9, 27.3, 26.1, 24.4,
23.3, 23.0, 19.0, 18.8, 14.4; IR (NaCl, neat) 2931, 2858,
1710 cmK1; HRMS (FABC) calcd for C17H31O2, 267.2324.
Found 267.2331.
To a stirred solution of 20.0 mg (0.0502 mmol) of ketone 20
in ether (1.0 mL) was added dropwise a 0.14 M solution of
Zn(BH4)219 in ether at K10 8C, and the mixture was stirred
at the same temperature for 0.5 h. After quenching with satd
aq NH4Cl (2.0 mL), the resulting mixture was dried over
MgSO4, filtered through a pad of Celite, and concentrated to
yield 19 mg (94%) of alcohol 21.
A 5 mL round bottomed flask was charged with 20 mg
(0.050 mmol) of alcohol 21, a solution of TBAF in THF
(1.0 M, 0.10 mmol, 0.1 mL), and 0.5 mL of THF. The
reaction was allowed to stir at room temperature for 12 h,
then quenched with 1.0 mL satd aq NaHCO3. The aqueous
layer was extracted with EtOAc (3!5 mL) and the
combined organic layers were washed with 10.0 mL brine,
and dried over MgSO4. The slurry was filtered and
concentrated to afford 14.0 mg (97%) of diol 18a.
4.2.1.5. (20S*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cycloheptanone (1c). Following the general procedure
afforded 1c, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.455 (15% EtOAc/hex); 1H NMR
(400 MHz, CDCl3) d 3.51 (1H, ddd, JZ12.7, 6.1, 1.6 Hz),
3.18 (1H, m), 2.30–2.62 (3H, m), 2.16–2.19 (1H, m),
1.00–1.98 (23H, m), 0.85 (3H, t, JZ7.0 Hz); 13C NMR
(100 MHz, CDCl3) d 216.8, 215.4, 79.3, 79.0, 78.3, 58.5, 58.4,
44.4, 44.4, 36.7, 36.5, 32.1, 31.9, 31.7, 30.0, 29.7, 29.6, 29.5,
28.8, 28.5, 28.1, 27.4, 26.2, 25.7, 25.6, 25.4, 24.9, 23.9, 22.8,
14.3; IR (NaCl, neat) 2930, 2856, 1702 cmK1; HRMS
(FABC) calcd for C18H33O2, 281.2481. Found 281.2486.
4.2. Compound characterization
4.2.1. a-Pyranyl-cycloalkonones (1a–c, 2a–c).
4.2.1.1. (20S*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cyclopentanone (1a). Following the general procedure
afforded 1a, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.429 (15% EtOAc/hex); 1H NMR
(400 MHz, CDCl3) d 3.65 (2H, d, JZ11.3 Hz), 3.56 (1H,
ddd, JZ10.9, 3.4, 1.9 Hz), 3.19 (2H, m), 0.95–2.33 (46H, m),
0.84 (3H, t, JZ7.0 Hz), 0.84 (3H, t, JZ9.6 Hz); 13C NMR
(100 MHz, CDCl3) d 220.0, 219.9, 78.5, 78.2, 77.9, 76.8, 53.8,
53.3, 39.6, 39.5, 36.6, 32.0, 31.6, 31.5, 29.9, 29.5, 29.4, 27.7,
26.4, 25.6, 25.5, 24.4, 23.8, 22.8, 21.3, 21.2, 14.3; IR (NaCl,
neat) 2931, 2857, 1738 cmK1; HRMS (FABC) calcd for
C16H29O2, 253.2168. Found 253.2177.
4.2.1.6. (20R*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cycloheptanone (2c). Following the general procedure
afforded 2c, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.417 (15% EtOAc/hex); 1H NMR
(400 MHz, CDCl3) d 3.87 (2H, ddd, JZ15.0, 6.7, 2.6 Hz),
3.72(1H, m), 3.61(1H, m), 2.68–2.81 (2H, m), 2.20–2.65 (7H,
m), 2.06–2.18 (1H, m), 1.12–1.98 (44H, m), 0.80–0.92 (6H,
m); 13C NMR (100 MHz, CDCl3) d 215.8, 214.5, 72.4, 72.2,
72.0, 71.4, 56.5, 55.5, 44.1, 42.2, 33.1, 32.9, 32.2, 32.2, 30.3,
30.1, 29.9, 29.7, 29.6, 28.8, 27.7, 27.6, 26.9, 26.0, 25.0,
24.7, 23.0, 19.1, 18.8, 14.5; IR (NaCl, neat) 2930, 2856,
1702 cmK1; HRMS (FABC) calcd for C18H33O2, 281.2481.
Found 281.2486.
4.2.1.2. (20R*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cyclopentanone (2a). Following the general procedure
afforded 2a, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.365 (15% EtOAc/hex); 1H NMR
(300 MHz, CDCl3) d 3.78–3.94 (2H, m), 3.56–3.67 (1H, m),
1.10–2.38 (47H, m), 0.82–0.94 (6H, m); 13C NMR (75 MHz,
CDCl3) d 220.1, 219.4, 73.3, 72.4, 69.9, 69.6, 52.8, 51.9, 39.5,
32.7, 32.2, 31.1, 29.7, 29.0, 28.9, 27.7, 26.4, 26.3, 26.0, 25.3,
23.0, 21.2, 21.0, 19.0, 14.5; IR (NaCl, neat) 2931, 2857,
1738 cmK1; HRMS (FABC) calcd for C16H29O2, 253.2168.
Found 253.2177.
4.2.2. Cyclic vinyl acetals (3a–c).
4.2.2.1. (2R*,6S*)-2-(Cyclopent-1-enyloxy)-6-hexyl-
tetrahydro-pyran (3a). Following the general procedure
afforded 3a as a yellow oil: RfZ0.309 (25% EtOAc/hex
with 1% TEA); 1H NMR (400 MHz, CDCl3) d 4.66 (1H, d,
JZ9.4 Hz), 3.89 (1H, m), 3.37 (1H, m), 1.06–1.88 (22H,
m), 0.84 (3H, t, JZ6.2 Hz); 13C NMR (100 MHz, CDCl3) d
96.4, 92.1, 69.0, 36.4, 36.2, 33.1, 32.0, 31.3, 30.6, 30.0,
29.6, 25.6, 22.8, 22.3, 17.7, 14.3; IR (NaCl, neat) 2932,
2858 cmK1; HRMS (FABC) calcd for C16H29O2,
253.2168. Found 253.2176.
4.2.1.3. (20S*,60S*)-2-(6-Hexyl-tetrahydro-pyran-2-yl)-
cyclohexanone (1b). Following the general procedure
afforded 1b, a yellow oil, as a mixture of C2–C20
diastereomers: RfZ0.429 (15% EtOAc/hex); 1H NMR
(400 MHz, CDCl3) d 3.71 (1H, ddd, JZ11.2, 6.2, 1.5 Hz);
3.51 (1H, ddd, JZ10.2, 9.0, 1.3 Hz), 3.22 (2H, m), 2.20–2.49
(6H, m), 0.95–2.40 (44H, m), 0.80–0.90 (6H, m); 13C NMR
(100 MHz, CDCl3) d 212.7, 212.1, 78.5, 78.3, 76.5, 76.0, 56.7,
56.1, 42.9, 42.0, 36.8, 36.6, 32.1, 31.7, 30.5, 30.0, 29.5, 29.4,
29.2, 28.5, 28.2, 28.0, 25.8, 25.6, 24.4, 24.0, 23.8, 22.8, 14.3;
4.2.2.2. (2R*,6S*)-2-(Cyclohex-1-enyloxy)-6-hexyl-
tetrahydro-pyran (3b). Following the general procedure
afforded 3b as a yellow oil: RfZ0.283 (25% EtOAc/hex
with 1% TEA); 1H NMR (400 MHz, CDCl3) d 4.65 (1H, d,
JZ9.2 Hz), 3.89 (1H, m), 3.37 (1H, m), 1.05–1.89 (24H,
m), 0.84 (3H, t, JZ6.2 Hz); 13C NMR (100 MHz, CDCl3) d

J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
4581
96.7, 92.1, 69.0, 36.4, 36.2, 33.1, 32.0, 31.3, 30.6, 30.0,
29.5, 25.7, 25.6, 22.8, 22.3, 17.7, 14.3; IR (NaCl, neat)
2932, 2858 cmK1; HRMS (FABC) calcd for C17H31O2,
267.2324. Found 267.2329.
5.5 Hz, major), 4.09 (1H, m, minor), 4.01 (1H, m, major),
3.91 (d, 1H, JZ3.6 Hz, minor), 3.78–3.85 (2H, m), 3.70
(1H, d, JZ3.2 Hz, major), 3.62 (1H, ddd, JZ11.6, 8.1,
5.1 Hz, major), 2.50–2.64 (1H, m), 2.35–2.46 (1H, m),
2.02–2.27 (1H, m), 1.86–2.00 (1H, m), 1.52–1.80 (7H, m),
1.38–1.50 (1H, m), 1.06–1.38 (13H, m), 0.84 (3H, t, JZ
6.6 Hz); 13C NMR (100 MHz, CDCl3) d 210.3, 208.1, 85.1,
85.0, 73.3, 73.1, 69.6, 69.1, 64.4, 64.8, 37.9, 37.2, 31.8,
30.9, 30.4, 29.2, 29.1, 28.2, 28.4, 26.9, 25.9, 25.6, 25.5,
25.2, 23.8, 22.6, 18.6, 18.2, 14.1; IR (NaCl, neat) 2930,
2857, 1723 cmK1; HRMS (FABC) calcd for C16H29O3,
269.2117. Found 269.2113.
4.2.2.3. (2R*,6S*)-2-(Cyclohept-1-enyloxy)-6-hexyl-
tetrahydro-pyran (3c). Following the general procedure
afforded 3c as a yellow oil: RfZ0.278 (25% EtOAc/hex
with 1% TEA); 1H NMR (400 MHz, CDCl3) d 4.66 (1H, m),
3.88 (1H, m), 3.37 (1H, m), 1.05–1.89 (26H, m), 0.84 (3H, t,
JZ6.2 Hz); 13C NMR (100 MHz, CDCl3) d 96.4, 92.1, 69.0,
36.4, 36.2, 33.1, 32.0, 31.4, 30.6, 30.0, 29.6, 29.5, 25.7,
25.6, 22.8, 22.3, 17.7, 14.3; IR (NaCl, neat) 2931,
2858 cmK1; HRMS (FABC) calcd for C18H33O2,
281.2481. Found 281.2489.
4.2.5. Determination of C2–C20 stereochemistry (17–21).
4.2.5.1. (20R*,60S*)-60-Hexyl-octahydro-[2,20]-bipyra-
nyl-6-one (17). Following the general procedure 17 was
isolated as a yellow oil: RfZ0.179 (25% EtOAc/hex) major
isomer, RfZ0.120 (25% EtOAc/hex) minor isomer; 1H
NMR (400 MHz, CDCl3) d 4.30 (1.5H, ddd, JZ3.5, 8.0,
11.11 Hz), 4.19–4.25 (1.25H, m), 3.87 (1H, m), 3.55–3.67
(4H, m), 2.50–2.61 (2.75H, m), 2.36–2.48 (2.75H, m), 1.18–
2.11 (60H, m), 0.85 (3H, t, JZ7.0 Hz); 13C NMR
(100 MHz, CDCl3) d 171.8, 171.6, 82.8, 80.6, 73.2, 72.8,
72.4, 70.7, 32.9, 32.0, 31.0, 30.0, 29.9, 29.7, 29.5, 28.7,
26.4, 26.1, 26.0, 24.6, 23.8, 22.8, 18.7, 18.6, 18.4, 14.3; IR
(NaCl, neat) 2931, 2857, 1736, 1241, 1049 cmK1; HRMS
(FABC) calcd for C16H29O3, 269.2117. Found 269.2113.
4.2.3. Hydroxy ketones (13a–c).
4.2.3.1. 2-(5-Hydroxy-undecylidene)-cyclopentanone
(13a). Compound 13a was prepared from the Horner–
Wadsworth–Emmons reaction of undecanoic d-lactol and
diethyl 2-oxocyclohexylphosphonate and was isolated as
the Z isomer as a yellow oil: RfZ0.138 (25% EtOAc/hex);
1H NMR (400 MHz, CDCl3) d 6.5 (1H, dddd, JZ2.8, 2.8,
7.5, 10.2 Hz), 3.55 (1H, m), 2.54 (2H, t, JZ7.0 Hz), 2.29
(2H, t, JZ7.7 Hz), 2.13 (2H, q, JZ7.0 Hz), 1.90 (2H, quint.,
JZ7.7 Hz), 1.19–1.67 (15H, m), 0.84 (3H, t, JZ6.4 Hz);
13C NMR (100 MHz, CDCl3) d 207.5, 137.7, 136.1, 71.9,
38.8, 37.8, 37.2, 32.0, 29.8, 29.5, 26.9, 25.8, 24.7, 22.8,
20.0, 14.3; IR (NaCl, neat) 3430, 2929, 2857, 1718,
1647 cmK1; HRMS (EIC) Calcd for C16H28O2, 252.2089.
Found 252.2084.
4.2.5.2. 1-(S*)-(6-(S*)-Hexyl-tetrahydro-pyran-2-
(R*)-yl)-pentane-1,5-diol (18a). Following the general
procedure 18a was isolated as a clear oil: RfZ0.242 (90%
1
EtOAc/hex); H NMR (400 MHz, CDCl3) d 3.77 (1H, m),
4.2.3.2. 2-(5-Hydroxy-undecylidene)-cyclohexanone
(13b). Compound 13b was prepared via the ring opening
of 1b with Me2BBr and Et3N and was isolated as the E
3.55–3.64 (3H, m), 3.42 (1H, dddd, JZ4.1, 4.1, 8.8,
13.3 Hz), 2.25 (1H, s), 1.82 (1H, s), 1.18–1.79 (22H, m),
0.85 (3H, t, JZ6.4 Hz); 13C NMR (100 MHz, CDCl3) d
73.1, 73.0, 72.4, 62.9, 32.8, 32.0, 31.9, 31.2, 29.5, 29.1,
26.2, 24.9, 22.8, 22.3, 18.3, 14.3; IR (NaCl, neat) 3344,
2930, 2858, 1077, 1037 cmK1; HRMS (FABC) calcd for
C16H33O3, 273.2430. Found 273.2427.
1
isomer as a yellow oil:20 RfZ0.142; H NMR (400 MHz,
CDCl3) d 6.68 (1H, t, JZ4.3 Hz), 3.55 (1H, m), 2.39 (2H,
m), 2.32 (2H, m), 2.15 (2H, m), 1.94 (2H, m), 1.25–1.65
(15H, m), 0.86 (3H, t, JZ5.5 Hz); 13C NMR (100 MHz,
CDCl3) d 199.9, 145.3, 140.0, 72.1, 38.8, 37.7, 37.4, 32.0,
29.7, 29.6, 28.9, 26.2, 25.8, 25.6, 23.4, 22.8, 14.3; IR (NaCl,
neat) 3431, 2928, 2856, 1666 cmK1; HRMS (EIC) calcd
for C17H30O2, 266.2246. Found 266.2248.
4.2.5.3. 1-(R*)-(6-(S*)-Hexyl-tetrahydro-pyran-2-
(R*)-yl)-pentane-1,5-diol (18b). Following the general
procedure 18b was isolated as a clear oil: RfZ0.328 (90%
EtOAc/hex); 1H NMR (400 MHz, CDCl3) d 3.74 (1H, ddd,
JZ4.3, 4.3, 8.8 Hz), 3.61 (2H, t, JZ6.0 Hz), 3.54 (1H, ddd,
JZ2.5, 8.4, 10.3 Hz), 3.34 (1H, ddd, JZ2.7, 7.8, 10.7 Hz),
2.77 (1H, s), 1.83 (1H, s), 1.18–1.75 (22H, m), 0.84 (3H, t,
JZ6.4 Hz); 13C NMR (100 MHz, CDCl3) d 73.7, 72.4, 72.0,
62.9, 32.9, 32.6, 32.4, 32.0, 29.5, 29.4, 26.7, 26.0, 22.8,
21.9, 18.6, 14.3; IR (NaCl, neat) 3402, 2932, 2858,
1040 cmK1; HRMS (FABC) calcd for C16H33O3,
273.2430. Found 273.2441.
4.2.3.3. 2-(5-Hydroxy-undecylidene)-cycloheptanone
(13c). Compound 13c was prepared from the Horner–
Wadsworth–Emmons reaction of undecanoic d-lactol and
diethyl 2-oxocycloheptylphosphonate and was isolated as
the Z isomer as a yellow oil: RfZ0.150 (25% EtOAc/hex);
1H NMR (400 MHz, CDCl3) d 6.54 (1H, t, JZ7.46 Hz),
3.55 (1H, m), 2.56 (2H, m), 2.39 (2H, m), 2.13 (2H, m),
1.20–1.76 (21H, m), 0.85 (3H, t, JZ6.4 Hz); 13C NMR
(100 MHz, CDCl3) d 206.0, 140.9, 139.0, 71.9, 43.5, 37.7,
37.3, 32.0, 31.6, 30.0, 29.5, 28.1, 27.3, 25.8, 25.4, 25.1,
22.8, 14.3; IR (NaCl, neat) 3433, 2927, 2855, 1686,
1616 cmK1; HRMS (FABC) calcd for C18H33O2,
281.2481. Found 281.2482.
4.2.5.4. 5-(t-Butyl-dimethyl-silanyloxy)-1-(S*)-(6-
(S*)-hexyl-tetrahydro-pyran-2-(R*)-yl)-pentan-1-ol
(19). Following the general procedure 19 was isolated as a
clear oil: RfZ0.424 (25% EtOAc/hex); 1H NMR (400 MHz,
CDCl3) d 3.77 (1H, m), 3.54–3.62 (3H, m), 3.42 (1H, ddd,
JZ4.3, 4.3, 8.8 Hz), 2.01 (1H, d, JZ3.9 Hz), 1.18–1.79
(22H, m), 0.86 (9H, s), 0.85 (3H, t, JZ7.2 Hz), 0.01 (6H, s);
13C NMR (100 MHz, CDCl3) d 73.1, 72.4, 63.4, 33.0, 32.2,
32.0, 31.3, 29.5, 29.1, 26.2, 24.8, 22.8, 22.4, 18.4, 18.3,
14.3, K5.1; IR (NaCl, Neat) 3434, 2930, 2857, 1100,
4.2.4. Bipyranyl ketone (16).
4.2.4.1. (20R*,60S*)-60-Hexylhexahydro-2H, 20H-2,20-
bipyran-3(4H)-one (16). Following the general procedure
afforded 16 as a yellow oil: RfZ0.175 (15% EtOAc/hex);
1H NMR (400 MHz, CDCl3) d 4.17 (1H, ddd, JZ11.7, 5.5,

4582
J. D. Frein, T. Rovis / Tetrahedron 62 (2006) 4573–4583
1040 cmK1; HRMS (FABC) calcd for C22H47O3Si,
387.3294. Found 387.3296.
4. For examples of total synthesis or synthetic studies for natural
products, see: (a) Sakamoto, Y.; Matsuo, G.; Matsukura, H.;
Nakata, T. Org. Lett. 2001, 3, 2749–2752. (b) Nicolaou, K. C.;
Postema, M. H. D.; Yue, E. W.; Nadin, A. J. Am. Chem. Soc.
1996, 118, 10335–10336. (c) Trost, B. M.; Rhee, Y.-H. Org.
Lett. 2004, 6, 4311–4313. (d) Sasaki, M.; Shida, T.;
Tachibana, K. Tetrahedron Lett. 2001, 42, 5725–5728. (e)
Fujiwara, K.; Kobayashi, M.; Yamamoto, F.; Aki, Y.;
Kawamura, M.; Awakura, D.; Amano, S.; Okano, A.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46,
5067–5069. (f) Halim, R.; Brimble, M. A.; Merten, J. Org.
Lett. 2005, 7, 2659–2662. (g) Bondar, D.; Liu, J.; Mu¨ller, T.;
Paquette, L. A. Org. Lett. 2005, 7, 1813–1816. (h) Peng, X.;
Bondar, D.; Paquette, L. A. Tetrahedron 2004, 60, 9589–9598.
(i) Evans, D. A.; Rajapakse, H. A.; Hemaka, A.; Stenkamp, D.
Angew. Chem., Int. Ed. 2002, 41, 4569–4573. (j) Paquette,
L. A.; Peng, X.; Bondar, D. Org. Lett. 2002, 4, 937–940. (k)
Micalizio, G. C.; Roush, W. R. Org. Lett. 2001, 3, 1949–1952.
(l) Awakura, D.; Fujiwara, K.; Murai, A. Synlett 2000,
1733–1736. (m) Amano, S.; Fujiwara, K.; Murai, A. Synlett
1997, 1300–1302.
4.2.5.5. 5-(t-Butyl-dimethyl-silanyloxy)-1-(6-(S*)-
hexyl-tetrahydro-pyran-2-(R*)-yl)-pentan-1-one (20).
Following the general procedure 20 was isolated as a clear
oil: RfZ0.282 (10% EtOAc/hex); 1H NMR (400 MHz,
CDCl3) d 4.12 (1H, dd, JZ4.3, 4.3 Hz), 3.58 (2H, t, JZ
6.4 Hz), 3.42 (1H, m), 2.59 (1H, ddd, JZ1.8, 1.8, 6.2 Hz),
2.53 (1H, ddd, JZ1.8, 1.8, 6.2 Hz), 1.92 (1H, m), 1.20–1.67
(19H, m), 0.86 (9H, s), 0.85 (3H, t, JZ6.0 Hz), 0.01 (6H, s);
13C NMR (100 MHz, CDCl3) d 212.8, 78.5, 74.4, 63.1, 38.4,
35.3, 32.6, 32.0, 30.7, 29.6, 26.2, 25.8, 25.2, 22.8, 20.2,
19.7, 18.5, 14.3, K5.1; IR (NaCl, neat) 2930, 2857, 1717,
1101 cmK1; HRMS (FABC) calcd for C22H45O3Si,
385.3138. Found 385.3128.
4.2.5.6. 5-(t-Butyl-dimethyl-silanyloxy)-1-(S*)-(6-(S*)-
hexyl-tetrahydro-pyran-2-(R*)-yl)-pentan-1-ol (21).
Following the general procedure 19 was isolated as a clear
oil: RfZ0.424 (25% EtOAc/hex); 1H NMR (400 MHz,
CDCl3) d 3.77 (1H, m), 3.54–3.62 (3H, m), 3.42 (1H, ddd,
JZ4.3, 4.3, 8.8 Hz), 2.01 (1H, d, JZ3.9 Hz), 1.18–1.79
(22H, m), 0.86 (9H, s), 0.85 (3H, t, JZ7.2 Hz), 0.01 (6H, s);
13C NMR (100 MHz, CDCl3) d 73.1, 72.4, 63.4, 33.0, 32.2,
32.0, 31.3, 29.5, 29.1, 26.2, 24.8, 22.8, 22.4, 18.4, 18.3, 14.3,
5. (a) Zhang, Y.; Reynolds, N. T.; Manju, K.; Rovis, T. J. Am.
Chem. Soc. 2002, 124, 9720–9721. (b) Zhang, Y.; Rovis, T.
Tetrahedron 2003, 59, 8979–8987.
6. (a) For other examples of O–C rearrangements see: (a) Ferrier,
R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455–1458. (b)
Ferrier, R. J.; Middleton, S. Chem. Rev. 1993, 93, 2779–2831.
(c) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin
Trans. 1 1999, 2665–2667. (d) Dixon, D. J.; Ley, S. V.; Tate,
E. W. J. Chem. Soc., Perkin Trans.1 2000, 2385–2394. (e)
Dixon, D. J.; Ley, S. V.; Tate, E. W. Synlett 1998, 1093–1095.
(f) Dixon, D. J.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin
Trans. 1 1998, 3125–3126. (g) Buffet, M. F.; Dixon, D. J.;
Edwards, G. L.; Ley, S. V.; Tate, E. W. J. Chem. Soc., Perkin
Trans. 1 2000, 1815–1827. (h) Dixon, D. J.; Ley, S. V.; Tate,
E. W. J. Chem. Soc., Perkin Trans. 1 2000, 1829–1836. (i)
Takahashi, M.; Suzuki, H.; Moro-Oka, Y.; Ikawa, T.
Tetrahedron Lett. 1982, 23, 4031–4034.
K5.1; IR (NaCl, Neat) 3434, 2930, 2857, 1100, 1040 cmK1
;
HRMS (FABC) calcd for C22H47O3Si, 387.3294. Found
387.3296.
Acknowledgements
Financial support has been provided by the National
Institute of General Medical Sciences (GM65407). We
thank Merck Research Laboratories, GlaxoSmithKline,
Amgen, Boehringer Ingelheim, and Eli Lilly for unrestricted
support. T.R. is a fellow the Alfred P. Sloan Foundation.
T.R. thanks the Monfort Family Foundation for a Monfort
Professorship.
7. For examples of reductive coupling using SmI2 see: (a) Hung,
S.-C.; Wong, C.-H. Angew. Chem., Int. Ed. 1996, 35,
2671–2674. (b) Vlahov, I. R.; Vlahova, P. I.; Linhardt, R. J.
J. Am. Chem. Soc. 1997, 119, 1480–1481. (c) Miquel, N.;
Doisneau, G.; Beau, J.-M. Angew. Chem., Int. Ed. 2000, 39,
4111–4114. (d) Chiara, J. L.; Sesmilo, E. Angew. Chem., Int.
Ed. 2002, 41, 3242–3246. (e) Aurrecoechea, J. M.; Gil, J. H.;
Lopez, B. Tetrahedron 2003, 59, 7111–7121. For an example
of insertion into B–C bonds using glycosylidene carbenes see:
(f) Wenger, W.; Vasella, A. Helv. Chim. Acta 2000, 83,
1542–1560. For examples of nucleophilic addition into
oxocarbenium ions see: (g) Hoffman, M. G.; Schmidt, R. R.
Liebigs Ann. Chem. 1985, 2403–2419. (h) Kunz, H.; Mu¨ller, B.;
Weissmu¨ller, J. Carbohydr. Res. 1987, 171, 25–34. (i) Palmacci,
E. R.; Seeberger, P. H. Org. Lett. 2001, 3, 1547–1550.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2006.02.
042
8. (a) Shenoy, S. R.; Woerpel, K. A. Org. Lett. 2005, 7,
1157–1160. (b) Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2000, 122, 168–169. (c) Ayala, L.;
Lucero, C. G.; Romero, J. A. C.; Tabacco, S. A.; Woerpel,
K. A. J. Am. Chem. Soc. 2003, 125, 15521–15528.
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