Connective synthesis of polysubstituted tetrahydropyrans by a novel and stereocontrolled metallo-ene/Intramolecular Sakurai Cyclization sequence

Article abstract of DOI:10.1021/jo025899c

A novel methodology based upon the allylmetalation step followed by an Intramolecular Sakurai Cyclization (IMSC) provides an efficient access to a variety of tetrahydropyran derivatives. This new strategy nicely complements our initial protocol that embodied a tandem ene reaction/IMSC sequence. Both mono- and dihydroxy-tetrahydropyrans could be easily assembled with complete stereocontrol at the various chiral centers.

Full text of DOI:10.1021/jo025899c

Con n ective Syn th esis of P olysu bstitu ted Tetr a h yd r op yr a n s by a
Novel a n d Ster eocon tr olled Meta llo-en e/In tr a m olecu la r Sa k u r a i
Cycliza tion Sequ en ce
Bernard Leroy and Istva´n E. Marko´*
De´partement de Chimie, Universite´ Catholique de Louvain, Baˆtiment Lavoisier, Place Louis Pasteur 1,
B-1348 Louvain-la-Neuve, Belgium
marko@chim.ucl.ac.be
Received May 3, 2002
A novel methodology based upon the allylmetalation step followed by an Intramolecular Sakurai
Cyclization (IMSC) provides an efficient access to a variety of tetrahydropyran derivatives. This
new strategy nicely complements our initial protocol that embodied a tandem ene reaction/IMSC
sequence. Both mono- and dihydroxy-tetrahydropyrans could be easily assembled with complete
stereocontrol at the various chiral centers.
In tr od u ction
to be associated with the ability of the polyene side chain
to perturb plasmic membranes. It is also interesting to
note that amphidinols also possess, embedded in their
complex architectural framework, two or three dihy-
droxylated tetrahydropyran subunits. These substruc-
tures constitute ubiquitous fragments of many other
natural products from marine or terrestrial origin. It is
therefore not surprising that a large number of inventive
and reliable strategies have been designed for the
construction of stereodefined tetrahydropyrans.6 Our
laboratory has also been active in this area and several
novel and concise methodologies for the rapid assembly
of such interesting heterocycles have been reported over
the years. More recently, we have disclosed a new
multicomponent condensation strategy, embodying an
ene reaction and an Intramolecular Sakurai Cyclization
(IMSC), for the stereocontrolled synthesis of polysubsti-
tuted tetrahydropyran derivatives (Scheme 1).7
Numerous natural products from marine microorgan-
isms possess a fascinating and synthetically challenging
structural framework. Their diversity, paucity, and often
remarkable biological properties have spurred the inter-
est of the synthetic community, resulting over the years
in the development of many elegant approaches toward
their total synthesis.1 The microorganisms responsible
for the biosynthesis of such architecturally complex
molecular skeletons are varied, but the genus amphidium
appears to be especially productive.2 In particular, am-
phidinium klebsii was found to produce amphidinol 1,
whose structure has been revealed recently.3 Amphidinol
1 was the first member of a new family of closely related
polyhydroxy-polyenes encompassing nowadays eight de-
rivatives (amphidinols 1-8).4 Unfortunately, the minute
quantity of material isolated from natural sources has
plagued the determination of the relative and absolute
configuration of the various stereocenters present on the
amphidinol backbone and only the “flat” structure could
be deduced from numerous spectroscopic experiments.
Recently, a tridimensionnal structure has been proposed
for amphidinol 3, one of the simplest members of this
family (Figure 1).5
Our approach involves an initial ene reaction between
an aldehyde and the allylsilane 1, promoted by Et2AlCl,
leading efficiently to the (Z)-homoallylic alcohol 2 with
complete control of the geometry of the double bond.
Subsequent condensation of 2 with another aldehyde
(6) For excellent reviews, see: (a) Boivin, T. L. B. Tetrahedron 1987,
43, 3309. (b) Elliott, M. C. J . Chem. Soc., Perkin Trans. 1 2000, 1291
and references therein.
Amphidinols exhibit promising antifungal, hemolytic,
cytotoxic, ichtyologic, and surfactant properties, believed
(7) (a) Marko´, I. E.; Bayston, D. J . Tetrahedron Lett. 1993, 34, 6595.
(b) Marko´, I. E.; Plancher, J .-M. Tetrahedron Lett. 1999, 40, 5259. For
similar strategies based upon the capture of an oxonium cation
intermediate by allyl- or vinylsilanes, see: (a) J ohnson, W. S. Acc. Chem.
Res. 1968, 1, 1. (b) Chow, H.-F.; Fleming, I. J . Chem. Soc., Perkin
Trans. 1 1984, 1815. (c) Coppi, L.; Ricci, A.; Taddei, M. J . Org. Chem.
1988, 53, 911. (d) Wei, Z. Y.; Wang, D.; Li, J . S.; Chan, T. H. J . Org.
Chem. 1989, 54, 5768. (e) Mohr, P. Tetrahedron Lett. 1995, 36, 2453.
(f) Semeyn, C.; Blaauw, R. H.; Hiemstra, H.; Speckamp, W. N. J . Org.
Chem. 1997, 62, 3426. (g) Suginome, M.; Iwanami, T.; Ito, Y. J . Org.
Chem. 1998, 63, 6096. (h) Yang, J .; Viswanathan, G. S.; Li, C. J .
Tetrahedron Lett. 1999, 40, 1627. (i) Viswanathan, G. S.; Yang, J .; Li,
C.-J . Org. Lett. 1999, 1, 993. (j) Yadav, J . S.; Subba Reddy, B. V.;
Mahesh Kumar, G.; Murthy, C. V. S. R. Tetrahedron Lett. 2001, 42,
89. (k) Marko´, I. E.; Mekhalfia, A.; Bayston, D. J .; Adams, H. J . Org.
Chem. 1992, 57, 2211. (l) Marko´, I. E.; Bayston, D. J . Synthesis 1996,
297. (m) Marko´, I. E.; Chelle´, F. Tetrahedron Lett. 1997, 38, 2895.
* Address correspondence to this author. Fax: (+32) 10 47 27 88.
(1) (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897. (b)
Shimizu, Y. Chem. Rev. 1993, 93, 1685.
(2) (a) Kobayashi, J .; Ishibashi, M. Chem. Rev. 1993, 93, 1753. (b)
Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.; Huang, S. Tetra-
hedron Lett. 1995, 36, 991. (c) Kobayashi, J .; Yamagushi, N.; Ishibashi,
M. Tetrahedron Lett. 1994, 35, 7049.
(3) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J .
Am. Chem. Soc. 1991, 113, 9859.
(4) (a) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K.
Tetrahedron Lett. 1995, 36, 6279. (b) Paul, G. K.; Matsumori, M.;
Konoki, K.; Murata, M.; Tachibana, K. J . Mar. Biotechnol. 1997, 5,
124.
(5) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Ta-
chibana, K. J . Am. Chem. Soc. 1999, 121, 870.
10.1021/jo025899c CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/15/2002
8744
J . Org. Chem. 2002, 67, 8744-8752

Synthesis of Polysubstituted Tetrahydropyrans
F IGURE 1. Structure and absolute configuration of amphidinol 3.
SCHEME 1. En e-IMSC Str a tegy
SCHEME 2. Retr osyn th etic An a lysis
SCHEME 3. Syn th esis of Allylca r ba m a te 13
Resu lts a n d Discu ssion 9
Ster eoselective Allyltita n a tion of Ald eh yd es. Car-
bamate substituents are known to facilitate the formation
of stable allylic anions and to favor stereoselective
reactions of these intermediates with various electro-
philes.10 The synthesis of allylsilane 13, bearing a diiso-
propylcarbamate directing group, was thus initiated.
Deprotonation of allylic alcohol 12 (prepared according
to the literature11) by sodium hydride, followed by treat-
ment of the resulting alkoxide with diisopropylcarbamoyl
chloride provided an efficient access to 13 (Scheme 3).
After thorough experimentation, it was found that depro-
tonation of 13 with sec-BuLi, followed by transmetalation
of the resulting allyllithium species by titanium tetrai-
sopropoxide and addition of an aldehyde gave the desired
homoallylic alcohol 16 as the single (E)-isomer (Scheme
4). This selectivity is believed to result from the prefer-
affords the polysubstituted exo-methylene tetrahydropy-
ran 4 in good yields and with total stereocontrol. The
second reaction is believed to proceed through the forma-
tion of the oxonium cation 3 that undergoes an intramo-
lecular addition of the allylsilane moiety via a chairlike
transition state, in agreement with the exclusive equato-
rial disposition of the substituents in the final product.
Subsequent ozonolysis of the exocyclic double bond of 4,
followed by stereocontrolled reduction of the correspond-
ing ketone gives access to the two stereocomplementary
dihydroxy-tetrahydropyrans 5 and 6.
As part of our efforts toward the preparation of various
analogues of the tetrahydropyran fragments of amphi-
dinols and in order to unambiguously establish the
relative and absolute stereochemistry of these subunits,
a concise and flexible access to the diastereomeric diols
7 and 8 (Scheme 2) proved mandatory. According to our
previous approach, these two diols could be obtained by
oxidation of the exocyclic double bond of tetrahydropyran
9, followed by a stereoselective reduction of the corre-
sponding ketone. Heterocycle 9 could in turn be prepared
by an IMSC cyclization starting from the homoallylic
alcohol 10. Unfortunately, the previously employed ene
reaction gives selective access to the (Z)-olefin and is
therefore not suitable for preparing the desired (E)-
homoallylic alcohol 10. Therefore, we envisaged the use
of allylmetal intermediate 11 for the selective synthesis
of 10.8
(8) For excellent reviews on allylmetal species bearing R-alkoxy
substituents, see: (a) Yamamoto, Y. Heteroatom-stabilized allylic
anions. In Trost, B. M.; Fleming, I., Eds. Comprehensive Organic
Synthesis; Pergamon Press: Oxford, UK, 1991; Vol. 2, p 55. (b)
Katritzky, A. R.; Piffl, M.; Lang, H.; Anders, E. Chem. Rev. 1999, 99,
665.
(9) Some results have been previously reported in a communication:
Marko´, I. E.; Leroy, B. Tetrahedron Lett. 2000, 41, 7225.
(10) (a) Hoppe, D.; Hanko, R.; Bro¨nneke, A.; Lichtenberg, A. Angew.
Chem., Int. Ed. Engl. 1981, 20, 1024. (b) Hoppe, D. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 932. (c) Hoppe, D.; Kra¨mer, T. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 160. (d) Zschage, O.; Hoppe, D. Tetrahedron
1992, 48, 5657. (e) Paulsen, H.; Graeve, C.; Hoppe, D. Synthesis 1996,
141. (f) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. Engl. 1997, 36,
2283.
(11) Trost, B. M.; Chan, D. M. T.; Nanninga, T. N. Org. Synth. 1984,
62, 58.
J . Org. Chem, Vol. 67, No. 25, 2002 8745

Leroy and Marko´
SCHEME 5. Syn th esis a n d Ster eoch em istr y of
SCHEME 4. Syn th esis of (E)-En olca r ba m a tes
Tetr a h yd r op yr a n s
ential axial position of the carbamate group in the
transition state 15, allowing a more efficient coordination
of the metal center. Among the numerous experimental
conditions used to achieve this transformation, diethyl
ether proved to be the solvent of choice, and sec-BuLi was
found to give slightly better results than n-BuLi. While
the deprotonation and the transmetalation steps are
effected at low temperature (-78°C), it is crucial to
increase the temperature rapidly to 0°C after the addition
of the aldehyde in order to maximize the yields and to
minimize the formation of byproducts such as the iso-
meric olefins 17 and 18. These compounds probably
originate from the protonation of the unreacted alkyl-
titanium intermediate 14.
tetrahydropyran 29 bearing a silyloxy group in the
equatorial position.7l
This reaction tolerates a wide range of homoallylic
alcohols and aldehydes, as exemplified in Table 2. Alkyl
groups on both reactants may be simple (entries 1 and
2) or hindered (entry 3). Unsaturated substituents are
tolerated as well (entry 4), giving access, for example, to
trienic tetrahydropyran 33. Finally, the brominated
derivative 24 affords the interesting heterocycle 34 in
good yield (entry 5).
This methodology proved to be general and applicable
to a wide range of aldehydes, as illustrated in Table 1.
Primary, secondary, and tertiary aliphatic aldehydes
reacted smoothly (entries 1-3), and so did unsaturated
aldehydes (entries 4 and 5). In some cases, complete
diastereoselectivity was observed, as exemplified by the
condensation of 13 with bromovaleraldehyde, affording
the anti-adduct 24 as the only product (entry 6). In
contrast, R-hydroxy- or R,â-dihydroxyaldehydes formed
the desired adducts with only modest stereocontrol
(entries 7 and 8). This low selectivity might be due to a
competition between chelated and nonchelated transition
states.12 It is noteworthy that, in all cases, only the (E)-
geometric isomer of the enolcarbamate double bond is
observed.
In tr a m olecu la r Sa k u r a i Cycliza tion (IMSC). Hav-
ing developed a ready access to the desired (E)-enolcar-
bamates, we next turned our attention to the crucial
Intramolecular Sakurai Cyclization. It was rapidly found
that BF3‚Et2O smoothly promotes this transformation,
generating efficiently the expected tetrahydropyrans 28
with exquisite diastereocontrol (Scheme 5). We were
delighted to find that the carbamate substituent adopted,
in every case, an axial disposition, in agreement with the
geometry of the starting olefin 16 and the proposed
chairlike transition state 27. The stereochemistry of the
carbamate substituent was clearly established by com-
paring the values of the coupling constants between the
newly formed heterocyle 30 and the previously prepared
The case of the propargyl-substituted allylcarbamate
23 is slightly different. Indeed, the condensation of this
substrate with cinnamaldehyde led to a mixture of the
two epimeric tetrahydropyrans 35 and 36 (Scheme 6).
Though still largely in favor of the all-syn product, this
reaction constitutes the first example of a nonstereo-
selective IMSC cyclization. The reasons for this discrep-
ancy are not yet clear, but other reports in the literature
on the particular behavior of acetylenic derivatives tend
to suggest a predominant role of electronic interactions.
The use of R-hydroxyaldehydes such as 37 in the IMSC
reaction proved to be problematic. Instead of the expected
tetrahydropyran 40, only the homoallylic alcohol 38,
resulting from a direct Sakurai allylation, was obtained
(Scheme 7). This particular behavior of R-hydroxyalde-
hydes originates probably from the difficulty in generat-
ing the oxonium intermediate 39 due to the presence of
the electron-withdrawing oxygen substituent at the
R-position. The cyclization pathway would consequently
be disfavored and the direct allylation process takes
place.13 It is noteworthy that 38 is obtained as a single
diastereoisomer, of yet unknown relative stereochemis-
try.
Syn th esis of syn -Diol. To prepare the stereocomple-
mentary syn- and anti-diols 7 and 8, we envisioned
(12) For the effect of oxygenated substituents on stereoselectivity
in allyltitanation of aldehydes, see: Martin, S. F.; Li, W. J . Org. Chem.
1989, 54, 6129.
8746 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Polysubstituted Tetrahydropyrans
TABLE 1. Selective Syn th esis of F u n ction n a lyzed (E)-En olca r ba m a tesa
a
b
All reactions were carried out according to the general procedure described in Scheme 4. All yields refer to pure, isolated products.
c d.e. values were measured by 1H NMR spectroscopy.
SCHEME 6 Cycliza tion of Acetylen ic Der iva tive 23
SCHEME 7. Sa k u r a i Rea ction w ith
r-Hyd r oxya ld eh yd e 37
oxidatively cleaving the exocyclic double bond of tetra-
hydropyran 30 and reducing the resulting ketone 41
under appropriate conditions. Gratifyingly, ozonolysis of
30, followed by reductive treatment with dimethyl sulfide
afforded quantitatively ketone 41. This compound was
not isolated, but directly submitted to various reductive
conditions in order to obtain the syn- or the anti-
dihydroxylated compounds 42 and 43, corresponding
respectively to an axial and an equatorial approach of
the reducing agent (Scheme 8).14As illustrated in Table
3, the selectivity of this reduction is, in every case, in
favor of the syn product 42. This is the expected selectiv-
(13) Similar results have been obtained in our attempts to condense
homoallylic alcohols such as
2 with R-hydroxyaldehydes or R,â-
dihydroxyaldehydes. In these cases, however, degradation is observed
instead of the Sakurai addition product. A modified strategy, based
upon the use of allylstannane derivatives, allows the introduction of
such aldehydes: (a) Leroy, B.; Marko´, I. E. Tetrahedron Lett. 2001, 42,
8685. (b) Leroy, B.; Marko´, I. E. Org. Lett. 2002, 4, 47.
J . Org. Chem, Vol. 67, No. 25, 2002 8747

Leroy and Marko´
TABLE 2. In tr a m olecu la r Sa k u r a i Cycliza tion of En olca r ba m a tesa
a
b
All reactions were carried out according to the general procedure described in Scheme 5. All yields refer to pure, isolated products.
TABLE 3. Red u ction of k eton e 41
SCHEME 8. Syn th esis of syn -Diol 44
entry
conditions
42/43a
yield,b %
1
2
3
4
5
6
7
8
9
NaBH4, EtOH
90/10
69/31
83/17
67/33
90/10
62/38
71/29
>99/1
80/20
58/42
86
86
77
66
54
91
70
74
70
35
0
BH3‚Me2S, Et2O, rt
BH3‚Me2S, Et2O, -78 °C to rt
AlH3, Et2O
Zn(BH4)2, Et2O
DIBAL-H, CH2Cl2
DIBAL-H, toluene
L-Selectride, THF
tBuMgCl, MAD, toluene
NaBH4, CeCl3‚7H2O, THF/MeOH
H2, PtO2 cat., MeOH
10
11
a
Ratios were determined by 1H NMR spectroscopy of the crude
b
reaction mixture. Combined yields after separation of the two
diastereoisomers by column chromatography. Selected J values
for H4: 42 (ddd, J ) 11.8, 5.0, 3.1 Hz); 43 (q, J ) 3.0 Hz).
to prevent axial reduction by using a bulky coordinating
Lewis acid, such as MAD15 (entry 9) or cerium trichloride
(entry 10), met with little success. Though the amount
of anti product increased, the selectivity still remained
in favor of the syn compound. Finally, hydrogenation
proved to be completely ineffective (entry 11). Although
none of the conditions tested provided a selective route
to the anti-hydroxycarbamate 43, the syn isomer 42 could
be prepared in good overall yield. To complete our
sequence and ultimately reach syn-diol 44, the deprotec-
tion of the carbamate function had to be accomplished.
This transformation was smoothly realized by treatment
of 42 with LAH, affording finally the desired syn-diol 44
in quantitative yield. In an even more efficient procedure,
ity for a small hydride donor such as NaBH4 (entry 1),
BH3 (entries 2 and 3), or AlH3 (entry 4). However, the
carbamate function appears unable to direct the reduc-
tion in the presence of a chelating hydride donor such as
Zn(BH4)2 (entry 5). A more sterically hindered reducing
agent are normally expected to deliver a hydride from
an equatorial approach in the case of configurationally
blocked cyclohexanones. However, the use of Dibal-H did
not improve the proportion of anti product (entries 6 and
7) and a complete axial selectivity is observed with the
bulky L-Selectride (entry 8). The axial, voluminous car-
bamate group therefore appears to prevent the equatorial
approach of the reducing agent. This repulsive steric
interaction is believed to be particularly unfavorable in
the case of large reagents such as L-Selectride. Attempts
(15) Maruoka, K.; Itoh, T.; Sakurai, M.; Nonoshita, K.; Yamamoto,
H. J . Am. Chem. Soc. 1988, 110, 3588.
(14) Gung, B. W. Tetrahedron 1996, 52, 5263.
8748 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Polysubstituted Tetrahydropyrans
SCHEME 9. Attem p ted P a th w a ys tow a r d
a n ti-Diol 48
SCHEME 10. Syn th esis of th e a n ti-Diol 48
F IGURE 2. Stereochemistry of dihydroxylated tetrahydro-
pyrans.
SCHEME 11. P r ep a r a tion of Mod ified Ca r ba m a te
54
it was possible to treat ketone 41 directly with an excess
of reducing agent to obtain 44 with excellent yield and
selectivity.
Syn th esis of a n ti-Diol. As mentioned earlier, no
reductive conditions were found to prepare selectively the
tetrahydropyran 43 possessing an anti-diol functionality.
Therefore, several strategies to access diol 48 from syn
compound 42 were explored (Scheme 9). Attempts to
invert the alcohol function of compound 42 under Mit-
sunobu conditions or by displacement of the correspond-
ing mesylate 45 with cesium carbonate or superoxide ion
proved to be ineffective. Ozonolysis of tetrahydropyran
46 was attempted to explore the possibility of a directed
reduction of the resulting hydroxyketone 47 into 48.
However, ozonolysis of 46 resulted in complete degrada-
tion, possibly due to interaction of the axial alcohol with
the ozonide intermediate (in stark contrast, the analogous
compound with an equatorial alcohol can be ozonolyzed
in good yield).16 These unsuccessful approaches prompted
us to focus on an alternative strategy involving cyclic
sulfate 49. According to the protocol described by Sharp-
less, the efficient transformation of the previously ob-
tained syn-diol 44 into the corresponding cyclic sulfate
49 was performed in 90% yield.17 This activated inter-
mediate was then reacted with ammonium benzoate, in
DMF, affording the hydroxyester 50, which was not
isolated but directly hydrolyzed to the desired anti-diol
48 by treatment with sodium hydroxide in methanol
(Scheme 10). The opening of the cyclic sulfate was
completely axial selective, no trace of the possible syn-
hydroxyester contaminant being detected. The stereo-
chemistry of the syn- and anti-diols 44 and 48 was
confirmed by comparison of the proton NMR data with
those of the stereocomplementary tetrahydropyrans 51
and 52 (Figure 2).
Dep r otection of th e Ca r ba m a te Moiety. While the
routes depicted above afforded an efficient and concise
access to diols 44 and 48, it was also desirable to prepare
the corresponding exo-methylene tetrahydropyran 46,
bearing an axially oriented alcohol function, by depro-
tection of the carbamate functionnality of 30. Unfortu-
nately, none of the classical conditions for deprotection
of carbamate (basic, acidic, or reductive) were successful
in this case. To circumvent this problem, we turned our
attention toward the use of a modified carbamate group
described by Hoppe et al.18 Carbamoyl chloride 53 was
prepared, according to the literature, from ethanolamine.
Condensation of 53 with alcohol 12 afforded allylcarbam-
ate 54 in good yield (Scheme 11).
Initial attempts at allyltitanation of butyraldehyde
with carbamate 54 proceeded less efficiently than with
the diisopropyl analogue 13. However, the choice of the
base proved to be of crucial importance, as sec-BuLi gave
the expected homoallylic alcohol 55 in only 13% yield.
(16) For interactions of free alcohols with intermediate ozonides, see:
J ung, M. E.; Davidov, P. Org. Lett. 2001, 3, 627.
(17) Gao, Y.; Sharpless, K. B. J . Am. Chem. Soc. 1988, 110, 7538.
(18) Derwing, C.; Hoppe, D. Synthesis 1996, 149.
J . Org. Chem, Vol. 67, No. 25, 2002 8749

Leroy and Marko´
SCHEME 12. Syn th esis of Hyd r oxyla ted
Tetr a h yd r op yr a n 46
Con clu sion s
In summary, we have developed an efficient access
toward new tetrahydropyran units, based upon an allyl-
metalation protocol followed by an Intramolecular Saku-
rai Cyclization. This novel strategy nicely complements
our initial protocol involving an ene/IMSC sequence.
Furthermore, we have demonstrated that mono- and
dihydroxylated tetrahydropyrans could be prepared in a
highly stereoselective manner. These heterocycles are
interesting fragments ubiquitously present in a range of
biologically active natural products. Current efforts are
now directed toward exploring the application of this
novel methodology to the total synthesis of interesting
biomolecules, including the amphidinols, and delineating
an enantioselective version of this connective strategy.
Exp er im en ta l Section
Most of the commercially available reagents were used
without further purification. Titanium tetraisopropoxide was
distilled prior to use. Methylene chloride, acetonitrile, and
TMEDA were distilled over calcium hydride. Diethyl ether and
THF were distilled over sodium and benzophenone. All glass-
ware was flame dried prior to use and the reactions were
carried out under argon atmosphere.
SCHEME 13. Alter n a tive Syn th esis of a n ti-Diol 48
2-Tr im eth ylsilylm eth ylallyl-diisopr opylcar bam ate (13).
To a suspension of NaH (60% in mineral oil, 833 mg, 20.8
mmol) in diethyl ether (12 mL) at 0 °C was added a solution
of alcohol 12 (2 g, 13.9 mmol) in diethyl ether (12 mL). After
the mixture was stirred for 30 min at 0 °C, a solution of
diisopropylcarbamoyl chloride (4.55 g, 27.8 mmol) in diethyl
ether (12 mL) was added and the solution was stirred at room
temperature for 18 h. The mixture was poured onto saturated
aqueous NH4Cl (30 mL) and extracted with dichloromethane.
The organic layer was dried over MgSO4, filtered, and con-
centrated in vacuo. The residue was purified by column
chromatography over silica gel (petroleum ether/ethyl acetate
30/1) to give 13 as a colorless oil (3.48 g, 93%). IR (neat) 1699,
We assumed that sec-BuLi was a base strong enough to
competitively abstract protons next to the nitrogen of the
carbamate moiety, leading to degradation.19 In contrast,
the use of a slightly weaker base such as n-BuLi provided
adduct 55 in a much improved yield of 51% (Scheme 12).
The allylic alcohol 55 thus obtained was then subjected
to the IMSC reaction with butyraldehyde, affording in
excellent yield tetrahydropyran 56, which was easily
deprotected by treatment with lithium hydroxide, allow-
ing for the first time an easy access to hydroxylated
heterocycles such as 46. Moreover, axial carbamate 56
also proved to be an interesting intermediate in the
preparation of anti-diol 48. Thus, ozonolysis of 56 fol-
lowed by fluoride-mediated deprotection afforded hydrox-
yketone 57 in excellent yield (Scheme 13). At this stage,
we speculated that hydroxyl-directed reduction of the
ketone function would produce the desired anti-hydroxy-
carbamate 58. Although such an intramolecularly as-
sisted hydride delivery bears marginal chances of success,
it was nevertheless attempted with use of triacetoxy-
borohydride.20 Gratifyingly, anti-hydroxycarbamate 58
was obtained as a single diastereoisomer, albeit in rather
modest yield. Simple treatment of 58 with NaH removed
the protecting group, affording anti-diol 48, identical in
all respects with a sample prepared by the cyclic sulfate
opening protocol.
1
1645 cm-1; H NMR (200 MHz, CDCl3) δ 4.85 (1H, q, J ) 1.6
Hz), 4.66 (1H, br s), 4.43 (2H, s), 3.61-4.19 (2H, m), 1.52 (2H,
s), 1.18 (12H, d, J ) 6.2 Hz), 0.02 (9H, s); 13C NMR (50 MHz,
CDCl3) δ 155.93, 143.45, 109.21, 68.64, 46.56, 24.35, 21.70,
-0.75; mass spectrum (EI) m/z 271.2 (M•+, 82). Anal. Calcd
for C14H29NO2Si: C, 61.94; H, 10.77; N, 5.16. Found: C, 61.97;
H, 10.88; N, 5.10.
Gen er a l P r oced u r e for th e P r ep a r a tion of Hom oa l-
lylic Alcoh ols. 4-Hyd r oxy-2-tr im eth ylsilylm eth yl-h ep t-
1-en yl-d iisop r op ylca r ba m a te (19). To a solution of TMEDA
(1.12 mL, 7.38 mmol) in diethyl ether (15 mL) at -78°C was
added sec-BuLi (1.3 M solution in hexane, 5.68 mL, 7.38 mmol)
and the resulting solution was stirred 30 min at -78 °C. A
solution of allylcarbamate 13 (1 g, 3.69 mmol) in diethyl ether
(15 mL) was added dropwise and the solution was stirred 30
min at -78 °C. Titanium tetraisopropoxide (3.27 mL, 11.07
mmol) was added in one portion and the solution was stirred
for 30 min at -78 °C. A solution of butyraldehyde (499 µL,
5.54 mmol) in diethyl ether (15 mL) was quickly added and
the temperature was allowed to warm rapidly to 0 °C by
changing the dry ice/acetone bath with an ice bath immediatly
after the addition of the aldehyde. After stirring 15 min at
0°C, the reaction mixture was poured onto 1 N HCl (50 mL)
and extracted with diethyl ether (2 × 50 mL). The organic layer
was washed with saturated NaHCO3 (40 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography over silica gel (petroleum
ether/ethyl acetate 8/1) to give 19 as a colorless oil (901 mg,
1
71%). IR (neat) 3474, 1700 cm-1; H NMR (200 MHz, CDCl3)
δ 6.79 (1H, s), 3.75-3.94 (3H, m), 2.36 (1H, dd, J ) 13.2, 9.3
Hz), 2.09 (1H, dd, J ) 13.4, 3.8 Hz), 1.78 (1H, br s), 1.01-1.51
(6H, m), 1.23 (12H, d, J ) 6.5 Hz), 0.92 (3H, t, J ) 6.1 Hz),
0.04 (9H, s); 13C NMR (50 MHz, CDCl3) δ 153.94, 132.61,
(19) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J . J . Am. Chem. Soc. 1994,
116, 3231.
(20) Evans, D. A.; Chapman, K. T.; Carreira, E. M. J . Am. Chem.
Soc. 1988, 110, 3560.
8750 J . Org. Chem., Vol. 67, No. 25, 2002

Synthesis of Polysubstituted Tetrahydropyrans
119.00, 69.92, 46.92, 40.21, 39.31, 21.72, 21.42-21.84, 19.58,
14.82, -0.49; mass spectrum (EI) m/z 343.3 (M•+, 8). Anal.
Calcd for C18H37NO3Si: C, 62.93; H, 10.85; N, 4.08. Found: C,
62.95; H, 10.89; N, 4.07.
perature and was then stirred for 18 h. The mixture was
evaporated in vacuo to afford crude ketone 41, which was used
in the next step without further purification. To a solution of
crude ketone 41 (100 mg, 0.284 mmol) in THF (5 mL) at -78
°C was added a 1 M solution of L-Selectride (341 µL, 0.341
mmol) in THF. The temperature was allowed to warm to 0 °C
over 3 h. The reaction mixture was diluted with diethyl ether
(20 mL) and poured onto saturated NH4Cl (20 mL), and the
aqueous layer was extracted with diethyl ether (2 × 20 mL).
The combined organic layers were dried (MgSO4), filtered, and
evaporated in vacuo. The residue was purified by column
chromatography (silica gel, petroleum ether/ethyl acetate 3/1)
to give tetrahydropyran 42 as a colorless oil (69 mg, 74%). IR
Gen er a l P r oced u r e for th e P r ep a r a tion of Tetr a h y-
d r op yr a n s. 4-Meth ylen e-2,6-d ip r op yl-tetr a h yd r op yr a n -
3-yl-d iisop r op ylca r ba m a te (30). To a solution of alcohol 19
(855 mg, 2.49 mmol) and butyraldehyde (198 mg, 2.74 mmol)
in dichloromethane (25 mL) at -78 °C was added slowly
BF3.Et2O (338 µL, 2.74 mmol). The temperature was allowed
to warm to 0 °C over 3 h. The reaction mixture was poured
onto saturated NaHCO3 (25 mL) and the aqueous layer was
extracted with dichloromethane (2 × 25 mL). The combined
organic layers were dried (MgSO4), filtered, and evaporated
in vacuo. The residue was purified by column chromatography
(silica gel, petroleum ether/ethyl acetate 25/1) to give the
tetrahydropyran 30 as a colorless oil (737 mg, 91%). IR (neat)
1693, 1657 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.08 (2H, br s),
4.89 (1H, t, J ) 1.6 Hz), 3.90-4.23 (1H, m), 3.59-3.72 (1H,
m), 3.34 (1H, ddd, J ) 8.2, 4.5, 1.4 Hz), 3.24-3.32 (1H, m),
2.18 (1H, tt, J ) 13.2, 1.6 Hz), 2.11 (1H, dd, J ) 13.4, 3.5 Hz),
1.38-1.66 (8H, m), 1.19 (12H, d, J ) 6.8 Hz), 0.91 (3H, t, J )
7.1 Hz), 0.89 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3) δ
155.20, 143.23, 113.20, 79.99, 78.43, 74.12, 46.10 (br), 38.42,
37.52, 33.73, 21.20 (br), 18.89, 18.72, 14.03; mass spectrum
(EI) m/z 325.2 (M•+, 11). Anal. Calcd for C19H35NO3: C, 70.11;
H, 10.84; N, 4.30. Found: C, 70.00; H, 10.81; N, 4.36.
1
(neat) 3447, 1670, 1442 cm-1; H NMR (300 MHz, CDCl3) δ
4.93 (1H, d, J ) 3.0 Hz), 3.90-4.04 (2H, m), 3.90 (1H, ddd, J
) 11.8, 5.0, 3.1 Hz), 3.36 (1H, dd, J ) 7.2, 4.7 Hz), 3.25-3.36
(1H, m), 1.78 (1H, dddd, J ) 12.6, 5.0, 2.0; 1.2 Hz), 1.32-1.72
(9H, m), 1.21-1.29 (12H, m), 0.92 (3H, t, J ) 7.0 Hz), 0.91
(3H, t, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 155.01, 76.87,
75.63, 72.92, 70.42, 46.04-46.48, 38.08, 35.50, 33.86, 20.63-
21.52, 18.91, 18.77, 14.00, 13.95; mass spectrum (EI) m/z 329.2
(M•+, 22). Anal. Calcd for C18H35NO4: C, 65.62; H, 10.71; N,
4.25. Found: C, 65.42; H, 10.66; N, 4.23.
a n ti-4-Hyd r oxy-2,6-d ip r op yl-tetr a h yd r op yr a n -3-yl-d i-
isop r op ylca r ba m a te (43). IR (neat) 3439, 1668 cm-1 1H
;
NMR (300 MHz, CDCl3) δ 4.54 (1H, dd, J ) 3.0, 1.2 Hz), 4.04
(1H, q, J ) 3.0 Hz), 3.82 (1H, ddd, J ) 8.4, 4.5, 1.3 Hz), 3.80-
4.05 (2H, m), 3.25-3.36 (1H, m), 3.66-3.75 (1H, m), 2.60 (1H,
m), 1.30-1.64 (10H, m), 1.21 (12H, d, J ) 6.6 Hz), 0.90 (3H, t,
J ) 6.8 Hz), 0.89 (3H, t, J ) 7.2 Hz); 13C NMR (75 MHz, CDCl3)
δ 155.10, 73.12, 72.16, 71.33, 65.71, 45.50-46.48, 38.38, 34.42,
33.63, 20.52-21.51, 18.92, 18.75, 14.13, 14.06; mass spectrum
(CI) m/z 330.2 (M + H+, 100).
6-[(ter t-Bu tyl-d im eth yl-silyl)-eth yn yl]-4-m eth ylen e-2-
styr yl-tetr a h yd r op yr a n -3-yl-d iisop r op ylca r ba m a te (35).
IR (neat) 1689, 1439 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.18-
7.35 (5H, m), 6.68 (1H, d, J ) 15.8 Hz), 6.23 (1H, dd, J ) 15.8,
5.3 Hz), 5.26 (1H, s), 5.24 (1H, s, H-9a), 5.06 (1H, s), 4.26 (1H,
dd, J ) 11.5, 2.9 Hz), 4.15 (1H, d, J ) 5.3 Hz), 3.92-4.18 (1H,
m), 3.58-3.86 (1H, m), 2.71 (1H, bt, J ) 13.4 Hz), 2.46 (1H,
dd, J ) 13.4, 2.9 Hz), 1.06-1.30 (12H, s), 0.95 (9H, s), 0.13
(3H, s), 0.12 (3H, s); 13C NMR (50 MHz, CDCl3) δ 154.84,
140.86, 136.88, 131.91, 128.39, 127.50, 126.53, 125.81, 114.92,
104.52, 88.26, 80.65, 73.71, 68.98, 45.94 (br), 38.21, 26.02,
syn -2,6-Dip r op yl-tetr a h yd r op yr a n -3,4-d iol (44). F r om
ca r ba m a te 42: To a solution of carbamate 42 (19 mg, 0.058
mmol) in THF (4 mL) was added a 1 M solution of LiAlH4 (230
µL, 0.230 mmol) in diethyl ether. The reaction mixture was
refluxed for 2 h, then diluted with dichloromethane (20 mL)
and poured onto water (20 mL). The aqueous layer was
extracted with dichloromethane (2 × 20 mL). The combined
organic layers were dried (MgSO4), filtered, and evaporated
in vacuo. The residue was purified by column chromatography
(silica gel, petroleum ether/ethyl acetate 1/2) to give diol 44
21.01 (br), 16.53, -4.75; mass spectrum (EI) m/z 481.4 (M•+
,
2); HRMS calcd for C29H43NO3Si (EI, M•+) 481.3012, found
481.3002.
6-[(ter t-Bu tyl-d im eth yl-silyl)-eth yn yl]-4-m eth ylen e-2-
styr yl-tetr a h yd r op yr a n -3-yl-d iisop r op ylca r ba m a te (36).
IR (neat) 1691, 1469 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.17-
7.35 (5H, m), 6.65 (1H, d, J ) 16.1 Hz), 6.22 (1H, dd, J ) 16.1,
5.2 Hz), 5.35 (1H, d, J ) 1.7 Hz), 5.29 (1H, s), 5.01 (1H, s),
4.96 (1H, dd, J ) 5.7, 1.9 Hz), 4.74 (1H, dd, J ) 5.2, 1.8 Hz),
3.59-4.15 (2H, m), 2.89 (1H, dd, J ) 13.7, 5.7 Hz), 2.28 (1H,
dd, J ) 13.2, 1.7 Hz), 1.13-1.28 (12H, m), 0.94 (9H, s), 0.11
(6H, s); 13C NMR (75 MHz, CDCl3) δ 154.79, 138.56, 136.93,
131.71, 128.39, 127.44, 126.43, 125.82, 115.61, 103.04, 90.72,
74.98, 73.99, 66.07, 46.00 (br), 39.94, 26.03, 20.05 (br), 16.44,
-4.66; mass spectrum (EI) m/z 481.2 (M•+, 8). Anal. Calcd for
1
as a white solid (13 mg, 99%). IR (KBr) 3355 cm-1; H NMR
(300 MHz, CDCl3) δ 3.66 (1H, ddd J ) 11.5, 5.2, 3.1 Hz), 3.61
(1H, d J ) 3.2 Hz), 3.21-3.30 (2H, m), 2.07 (2H, br s), 1.81
(1H, dddd, J ) 12.9, 5.2, 2.1, 0.9 Hz), 1.24-1.76 (9H, m), 0.93
(3H, t, J ) 7.2 Hz), 0.90 (3H, t, J ) 7.2 Hz); 13C NMR (75
MHz, CDCl3) δ 77.99, 75.65, 70.26, 69.93, 37.91, 35.69, 33.35,
18.87, 13.96; mass spectrum (CI) m/z 203.1 (M + H+, 13). Anal.
Calcd for C11H22O3: C, 65.31; H, 10.96. Found: C, 65.28; H,
10.86. F r om tetr a h yd r op yr a n 30: Ozonolysis of 30 was
performed as described above. To a solution of crude ketone
41 (50 mg, 0.122 mmol) in THF (8 mL) at 0 °C was added a 1
M solution of LiAlH4 (488 µL, 0.480 mmol) in THF. The
reaction mixture was stirred 10 min at 0 °C, refluxed 2 h, then
diluted with diethyl ether (20 mL) and finally poured onto
saturated NH4Cl (20 mL). The aqueous layer was extracted
with diethyl ether (2 × 20 mL). The combined organic layers
were dried (MgSO4), filtered, and evaporated in vacuo. The
residue was purified by column chromatography (silica gel,
petroleum ether/ethyl acetate 1/2) to give diol 44 as a white
solid (24 mg, 98%).
4,6-Dipr opyl-tetr ah ydr o-[1,3,2]dioxath iolo[4,5-c]pyr an -
2,2-d ioxid e (49). To a solution of diol 44 (273 mg, 1.349 mmol)
in CCl4 (25 mL) was added thionyl chloride (118 µL, 1.619
mmol) and the reaction mixture was refluxed for 1 h. After
cooling at 0 °C, the solution was diluted with acetonitrile (25
mL). RuCl3‚xH2O (6 mg, 0.027 mmol), NaIO4 (433 mg, 2.024
mmol), and water (37 mL) were successively added and the
solution was stirred at room temperature for 18 h. The reaction
mixture was diluted with diethyl ether (50 mL) and water (20
mL). The organic layer was separated, washed with saturated
NaHCO3 (40 mL) and saturated NaCl (40 mL), dried (MgSO4),
filtered, and evaporated in vacuo to give cyclic sulfate 49 as a
C
29H43NO3Si: C, 72.30; H, 9.00; N, 2.91. Found: C, 71.98; H,
9.05; N, 2.83.
2-(2-Hyd r oxy-p en tyl)-1-[h yd r oxy-(3-p h en yl-1,4-d ioxa -
sp ir o[4.5]d ec-2-yl)-m et h yl]-a llyl-d iisop r op ylca r b a m a t e
(38). IR (neat) 3411, 1675, 1443 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.41 (2H, d, J ) 6.9 Hz), 7.27-7.37 (3H, m), 5.27
(1H, br s), 5.10 (1H, s), 5.09 (1H, d, J ) 7.1 Hz), 5.04 (1H, s),
4.06 (1H, dd, J ) 8.2, 6.9 Hz), 3.77-4.02 (3H, m), 3.76 (1H,
dd, J ) 8.2, 2.1 Hz), 2.21 (1H, dd, J ) 13.7, 2.5 Hz), 2.10 (1H,
dd, 1H, J ) 13.8, 10.2 Hz), 1.21-1.72 (14H, m), 1.17 (12H, d,
J ) 6.6 Hz), 0.94 (3H, t, J ) 6.9 Hz); 13C NMR (50 MHz, CDCl3)
δ 154.67, 143.34, 139.87, 128.25, 127.85, 127.05, 114.97,
110.41, 82.04, 81.51, 74.50, 72.76, 67.52, 45.49-47.09, 43.13,
39.07, 36.89, 36.79, 25.11, 23.86, 20.01-21.75, 19.17, 14.14;
mass spectrum (CI) m/z 518.4 (M + H+, 7); HRMS calcd for
for C30H47NO6 (CI, M + H+) 518.3481, found 518.3477.
syn -4-H yd r oxy-2,6-d ip r op yl-t et r a h yd r op yr a n -3-yl-d i-
isop r op ylca r ba m a te (42). A solution of tetrahydropyran 30
(709 mg, 2.181 mmol) in dichloromethane (15 mL) at -78 °C
was treated with ozone until the solution turned blue. Di-
methyl sulfide (481 µL, 6.545 mmol) was then added and the
reaction mixture was allowed to warm slowly to room tem-
J . Org. Chem, Vol. 67, No. 25, 2002 8751

Leroy and Marko´
colorless oil (321 mg, 90%). IR (neat) 2962, 2936, 2875, 1386,
1210, 1096, 975, 845, 739 cm-1; 1H NMR (200 MHz, CDCl3) δ
5.00 (1H, ddd, J ) 10.9, 7.0, 4.8 Hz), 4.80 (1H, dd J ) 4.7, 1.6
Hz), 3.56 (1H, ddd, J ) 8.4, 4.1, 1.5 Hz), 3.18-3.30 (1H, m),
2.18 (1H, ddd, J ) 13.4, 7.0, 1.8 Hz), 1.90 (1H, td, J ) 13.4,
10.5 Hz), 1.23-1.87 (8H, m), 0.94 (3H, t, J ) 7.2 Hz), 0.90
(3H, t, J ) 7.2 Hz); 13C NMR (50 MHz, CDCl3) δ 80.99, 80.06,
74.83, 73.59, 37.33, 33.31, 33.04, 18.56, 18.47, 13.70, 13.58;
mass spectrum (EI) m/z 264.1 (M•+, 11). Anal. Calcd for
C11H20O5S: C, 49.98; H, 7.63; S, 12.13. Found: C, 50.18; H,
7.61; S, 11.60.
a n ti-2,6-Dip r op yl-tetr a h yd r op yr a n -3,4-d iol (48). To a
solution of cyclic sulfate 49 (164 mg, 0.619 mmol) in DMF (15
mL) was added ammonium benzoate (173 mg, 1.238 mmol)
and the reaction mixture was stirred at 130 °C for 18 h. After
cooling at room temperature, the solution was diluted with
dichloromethane (30 mL) and water (30 mL). The aqueous
layer was extracted with dichloromethane (2 × 30 mL). The
combined organic layers were dried (MgSO4), filtered, and
evaporated in vacuo to afford crude hydroxyester 50, which
was dissolved in MeOH (20 mL). NaOH (173 mg, 4.333 mmol)
was then added and the reaction mixture was stirred at room
temperature for 18 h. The solution was diluted with dichloro-
methane (30 mL) and poured onto a 1 N HCl solution (30 mL).
The aqueous layer was extracted with dichloromethane (2 ×
30 mL). The combined organic layers were dried (MgSO4),
filtered, and evaporated in vacuo. The residue was purified
by column chromatography (silica gel, petroleum ether/ethyl
acetate 1/1) to give diol 48 as a white solid (75 mg, 60%). IR
(KBr) 3412 cm-1; 1H NMR (300 MHz, CDCl3) δ 3.99 (1H, q, J
) 3.0 Hz), 3.72 (1H, dd J ) 8.5, 4.1 Hz), 3.62-3.69 (1H, m),
3.31 (1H, d, J ) 3.3 Hz), 2.55-2.95 (2H, m), 1.23-1.73 (10H,
m), 0.91 (3H, t, J ) 7.1 Hz), 0.89 (3H, t, J ) 7.1 Hz); 13C NMR
(50 MHz, CDCl3) δ 74.34, 72.25, 70.10, 68.19, 38.11, 34.17,
33.11, 18.79, 18.66, 13.95, 13.91; mass spectrum (EI) m/z 203.3
(M + H+, 7). HRMS calcd for for C11H23O3 (CI, M + H+)
203.1647, found 203.1649.
poured onto 1 N HCl (20 mL). The organic layer was separated
and washed with saturated NaHCO3 (20 mL), dried over
MgSO4, filtered, and concentrated in vacuo. The residue was
purified by column chromatography over silica gel (petroleum
ether/ethyl acetate 8/1) to give 55 as a colorless oil (58 mg,
1
51%). IR (neat) 3483, 1709 cm-1; H NMR (300 MHz, CDCl3)
δ 7.66 (4H, dd, J ) 7.5, 1.6 Hz), 7.36-7.44 (6H, m), 6.76 (1H,
s), 4.09-4.18 (1H, m), 3.66-3.77 (3H, m), 3.22-3.35 (2H, m),
2.30 (1H, dd, J ) 13.5, 8.8 Hz), 1.94-2.12 (1H, m), 1.22-1.73
(6H, m), 0.84-1.09 (9H, m), 1.05 (9H, s), 0.03 (9H, s); 13C NMR
(50 MHz, CDCl3) δ 153.63, 135.58, 133.57, 131.77, 129.72,
127.72, 118.74, 69.31, 62.75 (br), 48.14, 44.52 (br), 39.54, 36.65,
26.89, 21.04, 20.35, 19.17, 18.93, 14.07, -1.19; mass spectrum
(EI) m/z 583.4 (M•+, 2). Anal. Calcd for C33H53NO4Si2: C, 67.88;
H, 9.15; N, 2.40. Found: C, 67.84; H, 9.13; N, 2.29.
4-Meth ylen e-2,6-dipr opyl-tetr ah ydr opyr an -3-yl-[2-(ter t-
bu tyl-d ip h en yl-silyloxy)-eth yl]-isop r op ylca r ba m a te (56).
To a solution of homoallylic alcohol 55 (629 mg, 1.078 mmol)
and butyraldehyde (86 mg, 1.186 mmol) in dichloromethane
(12 mL) at -78 °C was added slowly BF3‚Et2O (146 µL, 1.186
mmol). The temperature was allowed to warm to 0 °C over 3
h. The reaction mixture was poured onto saturated NaHCO3
(25 mL) and the aqueous layer was extracted with dichloro-
methane (2 × 25 mL). The combined organic layers were dried
(MgSO4), filtered, and evaporated in vacuo. The residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate 10/1) to give tetrahydropyran 56 as a
colorless oil (509 mg, 84%). IR (neat) 1700, 1657 cm-1; 1H NMR
(300 MHz, CDCl3, 50 °C) δ 7.63-7.68 (4H, m), 7.32-7.40 (6H,
m), 5.06 (1H, br s), 5.03 (1H, d, J ) 1.1 Hz), 4.86 (1H, br s),
4.03-4.23 (1H, m), 3.72-3.77 (2H, m), 3.18-3.40 (4H, m),
2.02-2.13 (2H, m), 1.29-1.58 (8H, m), 1.05-1.06 (15H, m),
0.89 (3H, t, J ) 6.5 Hz), 0.88 (3H, t, J ) 7.0 Hz); 13C NMR (75
MHz, CDCl3, 40 °C) δ 155.63, 143.24, 135.55, 133.77, 129.57,
127.64, 113.08 (br), 79.84, 78.36, 74.51, 62.90 (br), 47.88, 45.02
(br), 38.38, 37.44, 33.66, 26.67, 20.74 (br), 19.18, 18.88, 18.71,
13.94; mass spectrum (EI) m/z 565.7 (M•+, 2). Anal. Calcd for
C
34H51NO4Si: C, 72.17; H, 9.08; N, 2.48. Found: C, 72.20; H,
2-Tr im eth ylsilylm eth yl-a llyl-[2-(ter t-bu tyl-d ip h en yl-si-
lyloxy)-eth yl]-isop r op yl-ca r ba m a te (54). To a suspension
of NaH (60% in mineral oil, 1.20 g, 30.0 mmol) in diethyl ether
(20 mL) at 0 °C was added a solution of alcohol 12 (2.88 g,
20.0 mmol) in diethyl ether (20 mL). After the mixture was
stirred for 15 min at room temperature, a solution of diiso-
propylcarbamoyl chloride (8.08 g, 20.0 mmol) in diethyl ether
(20 mL) was added and the solution was stirred at rom
temperature for 18 h. The mixture was poured onto saturated
aqueous NH4Cl (40 mL) and extracted with dichloromethane
(2 × 40 mL). The organic layer was dried over MgSO4, filtered,
and concentrated in vacuo. The residue was purified by column
chromatography over silica gel (petroleum ether/ethyl acetate
40/1) to give 54 as a colorless oil (7.30 g, 71%). IR (neat) 1703,
1644 cm-1; 1H NMR (300 MHz, CDCl3, 50 °C) δ 7.66-7.70 (4H,
m), 7.26-7.45 (6H, m), 4.83 (1H, s), 4.67 (1H, s), 4.41 (2H, s),
4.19 (1H, hept, J ) 7.0 Hz), 3.77 (2H, t, J ) 7.0 Hz), 3.33 (2H,
t, J ) 7.1 Hz), 1.51 (2H, s), 1.06-1.09 (6H, m), 1.07 (9H, s),
0.04 (9H, s); 13C NMR (50 MHz, CDCl3) δ 155.70, 142.49,
135.56, 133.73, 129.64, 127.67, 108.45, 68.27, 62.75 (br), 47.85,
44.55 (br), 26.90, 23.53, 20.65 (br), 19.19, -1.42; mass spec-
trum (EI) m/z 511.3 (M•+, 8). Anal. Calcd for C29H45NO3Si2: C,
68.05; H, 8.86; N, 2.74. Found: C, 67.72; H, 8.84; N, 2.73.
2-Tr im eth ylsilylm eth yl-a llyl-[2-(ter t-bu tyl-d ip h en yl-si-
lyloxy)-eth yl]-isop r op yl-ca r ba m a te (55). To a solution of
TMEDA (59 µL, 0.392 mmol) in diethyl ether (1 mL) at -78
°C was added n-BuLi (1.6 M solution in hexane, 245 µL, 0.392
mmol) and the resulting solution was stirred for 30 min at
-78 °C. A solution of allylcarbamate 54 (100 mg, 0.196 mmol)
in diethyl ether (1 mL) was added dropwise and the solution
was stirred for 30 min at -78 °C. Titanium tetraisopropoxide
(173 µL, 0.588 mmol) was added in one portion and the solution
was stirred for 30 min at -78 °C. A solution of butyraldehyde
(22 mg, 0.294 mmol) in diethyl ether (1 mL) was quickly added
and the temperature was allowed to warm to 0 °C by changing
the dry ice/acetone bath for an ice bath immediatly after the
addition of the aldehyde. After stirring 15 min at 0 °C, the
reaction mixture was diluted with diethyl ether (20 mL) and
9.16; N, 2.48.
4-Meth ylen e-2,6-d ip r op yl-tetr a h yd r op yr a n -3-ol (46).
To a solution of carbamate 56 (150 mg, 0.265 mmol) in
methanol (6 mL) was added LiOH‚1H2O (279 mg, 6.637 mmol).
The reaction mixture was refluxed for 4 h, then diluted with
dichloromethane (25 mL) and poured onto 1 N HCl solution
(20 mL). The aqueous layer was extracted with dichloro-
methane (2 × 25 mL). The combined organic layers were dried
(MgSO4), filtered, and evaporated in vacuo. The residue was
purified by column chromatography (silica gel, petroleum
ether/ethyl acetate 8/1) to give tetrahydropyran 46 as a
colorless oil (49 mg, 94%). IR (neat) 3440, 1655 cm-1; 1H NMR
(300 MHz, CDCl3) δ 4.93 (1H, t, J ) 1.7 Hz), 4.81 (1H, t, J )
1.9 Hz), 3.84 (1H, d, J ) 7.4 Hz), 3.24-3.32 (2H, m), 2.26 (1H,
tt, J ) 13.7, 1.9 Hz), 2.18 (1H, dd, J ) 13.7, 2.7 Hz), 2.06 (1H,
d, J ) 7.6 Hz), 1.25-1.78 (8H, m), 0.94 (3H, t, J ) 7.2 Hz),
0.92 (3H, t, J ) 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 146.61,
110.52, 80.73, 78.64, 72.92, 38.22, 36.42, 33.25, 18.85, 18.76,
14.02, 13.97; mass spectrum (EI) m/z 199.0 (M + H+, 57).
Ack n ow led gm en t. Financial support of this work
by the Universite´ Catholique de Louvain, the Actions
de Recherche Concerte´es (convention 96/01-197), the
Fonds pour la Recherche dans l’Industrie et l’Agriculture
(FRIA), and the Fonds de la Recherche Fondamentale
Collective (dossier No. 2.4571.98) is gratefully acknowl-
edged. I.E.M. is thankful to Merck & Co. for its continu-
ous support and for receiving the Merck Young Inves-
tigator Award.
Su p p or tin g In for m a tion Ava ila ble: Full characteriza-
tion data for compounds 20, 21, 22, 23, 24, 25, 26, 31, 32, 33,
and 34. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O025899C
8752 J . Org. Chem., Vol. 67, No. 25, 2002