Synthesis of 3-deoxy glycals via tandem metathesis sequences and their use in an intermolecular heck arylation

Article abstract of DOI:10.1002/ejoc.200800824

Deoxy glycals can be synthesized from a mannitol-derived C ₂-symmetric diene diol by using the tandem RCM/isomerization approach. Incorporation of a ruthenium-catalyzed dehydrogenative silylation step into the reaction sequence is possible. Thus, an orthogonally protected 3-deoxy glycal results via a tandem RCM/hydrosilylation/isomerization sequence. All ruthenium-catalyzed steps of this tandem sequence occur under distinct conditions, allowing for the selective synthesis of the intermediates. The 3-deoxy glycals obtained via this route undergo a regio- and stereoselective Heck reaction, as exemplified by the synthesis of a C-aryl glycoside. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800824

FULL PAPER
DOI: 10.1002/ejoc.200800824
Synthesis of 3-Deoxy Glycals via Tandem Metathesis Sequences and Their Use
in an Intermolecular Heck Arylation
Bernd Schmidt*[a] and Anne Biernat[a]
Dedicated to the memory of Professor Peter Welzel
Keywords: Olefin metathesis / Isomerization / Carbohydrates / Glycals
Deoxy glycals can be synthesized from a mannitol-derived
C2-symmetric diene diol by using the tandem RCM/isomer-
ization approach. Incorporation of a ruthenium-catalyzed de-
hydrogenative silylation step into the reaction sequence is
possible. Thus, an orthogonally protected 3-deoxy glycal
results via a tandem RCM/hydrosilylation/isomerization se-
quence. All ruthenium-catalyzed steps of this tandem se-
quence occur under distinct conditions, allowing for the se-
lective synthesis of the intermediates. The 3-deoxy glycals
obtained via this route undergo a regio- and stereoselective
Heck reaction, as exemplified by the synthesis of a C-aryl
glycoside.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
described a de novo approach, starting from 2-vinylfuran
using an enantioselective dihydroxylation and subsequent
Achmatowicz rearrangement.[13] This was applied to the
synthesis of desoxygenated analogues of mannopeptimy-
cin E antibiotics.[14,15] Phthalimido derivatives of 1 and 2
were tested for antiinflammatory[16] and hypolipidemic ac-
tivity.[17] Utilization as a building block for the synthesis of
non-carbohydrate target molecules has also been reported:
examples are the amino acid vigabatrin,[18] trans-fused poly-
ether toxins,[19] and conformationally constrained C-glyco-
side amino acids.[20] Finally, TBS-protected 2 has very re-
cently been used as a chiral auxiliary in Nazarov cycliza-
tions of allenes.[21]
Introduction
The enormous importance of carbohydrates for the regu-
lation of many biological processes has been widely recog-
nized.[1] In particular, deoxygenated carbohydrates have at-
tracted considerable attention for many years, both from
the biochemical[2] and the synthetic[3] point of view. For in-
stance, deoxy carbohydrates are frequently found as con-
stituents of oligosaccharide side chains in antibiotics,[4] and
incorporation of novel substitution and deoxygenation pat-
terns might help to overcome resistance of certain patho-
genic bacteria to these antibiotics. Thus, an important goal
is the elucidation of the mechanisms used by nature to make
certain deoxygenation patterns accessible.[5] Eventually, this
could lead to deoxygenated carbohydrates with hitherto un-
known substitution patterns. This approach, proceeding via
modified biosynthetic pathways, is indeed very attractive.
However, chemical synthesis is in certain cases a useful al-
ternative due to better opportunities for generalization.[6]
Two examples for less common substitution patterns are 3-
deoxygalactose (1) and 3-deoxyglucose (2) (Figure 1). Al-
though they do not occur in nature, synthetic routes were
investigated. Most of these rely on a Ferrier rearrange-
ment[7] of acetylated galactal or glucal, followed by hydro-
genation of the C=C bond.[8–12] More recently, O’Doherty
Figure 1. 3-Deoxygalactose (1) and 3-deoxyglucose (2) and their
corresponding glycals.
[a] Universität Potsdam, Institut für Chemie, Organische Synthese-
chemie,
Particularly useful building blocks for the introduction
of glycosyl moieties are glycals,[22] 1,2-unsaturated deriva-
tives of carbohydrates. In this particular case, the corre-
sponding glycals 3 and 4 have been obtained by Pd-cata-
lysed allylic reduction of the corresponding galactal or glu-
cal, albeit in moderate to low yields.[23] More recently, the
Karl-Liebknecht-Straße 24–25, Haus 25, 14476 Golm, Ger-
many
Fax: +49-331-977-5059
E-mail: bernd.schmidt@uni-potsdam.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Synthesis of 3-Deoxy Glycals by Tandem Metathesis Sequences
cyclization of alkynols,[24] reductive Ferrier rearrangement is, however, irrelevant for our purposes: in a subsequent
followed by rhodium-catalyzed isomerization,[25] and the re- step, the alcohol was allylated to give allyl ether 8[50] using
ductive elimination of 2-deoxy-2-iodothio glycosides have either a Pd-catalysed reaction or a conventional Williamson
been devised as alternatives.[26] Several synthetic applica- ether synthesis at 0 °C. Under these basic conditions low
tions of protected glycals 3 and 4 have been described in temperatures (and consequently longer reaction times) are
the literature: hexose nucleic acids have been synthesized required to prevent undesired epoxide rearrangement reac-
using 2,3-dideoxy glycals,[27] upon treatment of the glycals tions.[51] 8 was then (as a mixture of diastereomers) sub-
with nucleic acids a ring contraction occurs, leading to cy- jected to an acid-catalyzed hydrolysis of the epoxide, re-
clopropanated analogues of deoxy nucleosides as potential sulting in diol 9 as a mixture of diastereomers. In the fol-
antiviral agents,[28,29] and the formation of 1-azides[30] and lowing step the vic-diol was oxidatively cleaved with per-
2-iodo-1-azides[31] has also been investigated. A synthesis of iodate, followed by reductive work-up. After this step, the
3-deoxy-3-azido glycals from TBS-protected 2 was reported metathesis precursor 10 required for the -3-deoxygalactose
by Kirschning et al. with a view to 3-deoxy-3-amino gly- pattern was obtained as a single isomer in quantitative
cals.[32]
yield. Occasionally, difficulties arising from undesired trans-
We have recently embarked on a project directed at the fer hydrogenation reactions were observed when conducting
utilization of the tandem RCM[33–35]/isomerization se- tandem RCM/isomerization reactions with unprotected
quence, developed by Snapper et al.[36] and by us,[37–39] for alcohols.[52] Therefore, 10 was protected as a benzyl ether
the synthesis of deoxy glycals.[40–42] We describe our method 11 (Scheme 2).
as catalysis at the interface of Ru-carbene and Ru-hydride
chemistry,[43,44] as it relies on the in situ conversion of the
metathesis-active carbene to an isomerization-active Ru-hy-
dride species, which is induced by additives. A major advan-
tage of the method is that the drawbacks of enol ether me-
tathesis, such as the necessity for high dilution conditions
and low reactivity can be avoided. In this contribution we
describe a new synthesis of 3-deoxygalactal using the tan-
dem RCM/isomerization approach.
Results and Discussion
It has previously been reported that chiral C2-symmetric
(R,R)-hexa-1,5-diene-3,4-diol [(R,R)-5][45–47] is conveniently
available from -mannitol in few steps. Interestingly, the
Scheme 2. Access to RCM and tandem RCM/isomerization precur-
sors.
(S,S)-enantiomer of this compound is also available in few
steps from -tartrate.[48] A major advantage of a route start-
ing from 5 would be the opportunity for independent access
As expected, 11 smoothly undergoes RCM with the first
to both - and -3-deoxy glycals via an identical sequence
generation ruthenium catalyst A,[53] giving the dihydropy-
of steps (Scheme 1).
ran 12. Tandem RCM/isomerization of 11 was achieved
using the 2-propanol/NaOH protocol developed by us.[38]
Thus, after completion of the metathesis step, transforma-
tion of the metathesis catalyst to a Ru-hydride species was
induced with 2-propanol in the presence of hydroxide. Un-
der these conditions, dibenzylated -3-deoxygalactal 13 was
obtained in 61% yield after column chromatography on sil-
ica. NMR spectroscopy of the crude reaction mixture re-
veals that the RCM/isomerization sequence is selective, con-
firming that the reduced yield can be attributed to loss of
material during purification. As a representative example
Scheme 1. Ex-chiral pool starting materials for - and -3-deoxy
for stereo- and regioselective functionalization, 13 was used
glycals.
for the synthesis of a C-aryl glycoside. Characteristic struc-
Our route starts with a selective monobenzylation of 5 tural feature of these compounds is an aromatic moiety di-
via a stannylene acetal. Formation of benzyl ether 6 has rectly attached to a carbohydrate via a C–C rather than a
previously been described in the literature.[47,49] Vanadium- C–O bond. C-aryl glycosides are frequently found in the
catalysed epoxidation of 6 was investigated in different con- aglycon part of various antitumor antibiotics[54] and as nat-
text by us.[50] The reaction yields epoxide 7[50] in good yield ural products originating from various plants.[55] Conse-
and perfect regioselectivity within short periods of time. quently, many syntheses have been published and the sub-
The only drawback is a diastereomeric ratio of 2:1, which ject of C-aryl glycoside synthesis has been extensively re-
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B. Schmidt, A. Biernat
FULL PAPER
viewed.[56–59] A classical method for obtaining C-aryl glyco- alcohols or carboxylic acids[73] can be achieved with silanes
sides involves an O-glycosylation of phenols with glycosyl in a dehydrogenative manner, using either Lewis acids[74]
fluorides, followed by a Fries-type OǞC rearrangement.[60] or transition metal catalysts.[75] The combination of these
Palladium-mediated couplings of a 3-pyranoid glycal with observations initiated a project directed at the synthesis of
aryl iodides (Heck reaction)[61] or an organomercury com- mono-protected or orthogonally diprotected dihydropyrans
pound leading to a C-aryl glycoside have been reported by and glycals from a single precursor, the alcohol 10: while
Daves and co-workers.[62] A major obstacle in these inter- RCM of 10 in dichloromethane gave the expected dihy-
molecular Heck arylations of cyclic enol ethers is the occa- dropyran 16 at ambient temperature, addition of 1 equiva-
sionally low reactivity, resulting in long reaction times at lent of Et3SiH to the reaction mixture and heating to reflux
elevated temperatures, high catalyst loadings and the neces- inititated the dehydrogenative silylation, resulting in the for-
sity to use one coupling partner in excess. In addition, un- mation of orthogonally diprotected dihydropyran 17. This
desired double bond migrations may occur, leading to mix- reaction can be described as a tandem RCM/dehydro-
tures of isomers. We have previously shown that arene dia- genative silylation sequence. Notably, under these condi-
zonium salts[63] are highly reactive electrophiles in the inter- tions (refluxing CH2Cl2) no isomerized product was de-
molecular Heck reaction with cyclic enol ethers[64] and that tected. If, however, toluene is used as a solvent and the mix-
the problems mentioned above can be avoided with these ture is heated to reflux for several hours, subsequent isom-
arylating agents.[65,66] Thus, 13 was treated with the elec- erization occurs and glycal 18 is obtained in quantitative
tron-rich arene diazonium salt 14 in the presence of yield. The formation of 18 is an example of a tandem RCM/
2.5 mol-% Pd2(dba)3·CHCl3. Gratifyingly, the C-aryl glyco- dehydrogenative silylation/isomerization sequence, where
side 15 was obtained as a single α-isomer in good yield, and three ruthenium-catalyzed transformations occur under dis-
no undesired double bond migration was observed tinct conditions in a defined order of events (Scheme 4).
(Scheme 3).
Scheme 4. RCM and RCM/isomerization coupled with dehydro-
genative silylation of alcohols.
Conclusions
Scheme 3. RCM and tandem RCM/isomerization of precursor 11
and formation of a C-aryl glycoside.
In conclusion, a route to enantiopure protected 3-deoxy
glycals and isomeric dihydropyrans was developed that
makes use of conventional ring closing metathesis or the
tandem RCM/isomerization sequence. We showed that in-
corporation of a dehydrogenative alcohol silylation into the
sequence is possible, and that the ruthenium catalyzed steps
occur at distinct temperatures. Regio- and stereoselective
Heck arylation with an arene diazonium salt opens up a
route to C-aryl gycosides. Further applications of 3-deoxy
glycals and their isomeric dihydropyrans is currently un-
derway.
Selective deprotection of the hydroxy groups in 12, 13 or
products derived from one of these two can sometimes be
challenging.[67,68] We thought that our metathesis precursor
10 would be well suited to access dihydropyrans or glycals
with two orthogonal protecting groups at C4 and C6 posi-
tion, for instance one benzyl ether and one silyl ether. While
conventional silylation of 10 with a silyl halide or triflate
would be an obvious solution, we pursued an alternative
route that relies on the ability of ruthenium carbenes to
activate Si–H bonds: for instance, Grubbs’ catalysts are
known to catalyze the hydrosilylation of alkynes[69–71] or the
hydrogenation of alkenes with silanes.[72] In addition, we
had previously reported that triethylsilane is also a suitable
additive to promote the double bond migration step of the
Experimental Section
General Remarks: All experiments were conducted in dry reaction
tandem RCM/isomerization sequence.[39] Silylation of vessels under an atmosphere of dry argon. Solvents were purified
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Synthesis of 3-Deoxy Glycals by Tandem Metathesis Sequences
by standard procedures. 1H NMR spectra were obtained at
300 MHz, 400 MHz or 500 MHz in CDCl3 with CHCl3 (δ =
7.26 ppm) as an internal standard or in C6D6 with C6D5H (δ =
7.18 ppm) as an internal standard. Coupling constants are given in
Hz. Signal assignments are based on H,H-correlation spectroscopy.
(2R,3R)-2-(Allyloxy)-1,3-bis(benzyloxy)pent-4-ene (11): To a solu-
tion of 10 (360 mg, 1.40 mmol) in THF (40 mL) was added NaH
(60% dispersion in mineral oil, 120 mg, 3.00 mmol) and the mix-
ture was heated to reflux for 30 min. Benzyl bromide (0.36 mL,
3.00 mmol) was added, and the mixture was again heated to reflux
13C NMR spectra were recorded at 75 MHz, 100 MHz, or at for 30 min. Aqueous workup, followed by flash chromatography on
1
125 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm) as an internal stan-
dard or in C6D6 with C6D6 (δ = 128.0 ppm) as an internal standard.
The number of coupled protons was analyzed by DEPT- or APT-
experiments and is denoted by a number in parantheses following
the chemical shift value. NMR-peak assignment for cyclic products
refers to carbohydrate numbering (i.e. positions –OCH2CH = in
compounds 12, 16, 17 and –OCH=CH– in compounds 13 and 18
are numbered H1 or C1, respectively). IR spectra were recorded as
films on NaCl or KBr plates. The peak intensities are defined as
silica, yielded 11 (350 mg, 74%). H NMR (CDCl3, 300 MHz): δ =
7.48–7.18 (10 H, Ph), 6.00–5.80 (2 H, -CH=CH2), 5.35–5.21 (3 H,
=CH2), 5.14 (dm, J = 10.4 Hz, 1 H, =CH2), 4.64 (d, J = 12.1 Hz,
1 H, -CH2Ph) 4.49 (s, 2 H, -CH2Ph) 4.41 (d, J = 12.1 Hz, 1 H,
-CH2Ph), 4.22 (dddd, J = 12.9, 5.2, 1.3, 1.3 Hz, 1 H, -CH2CH=),
4.16 (dddd, J = 12.9, 5.2, 1.3, 1.3 Hz, 1 H, -CH2CH=), 3.98 (dd, J
= 7.5, 4.9 Hz, 1 H, -CHOBn) 3.71–3.48 (3 H, -CH2OBn, -CHOAll)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 138.4, 138.4 (0, ipso-C, Ph),
135.4, 135.3 (1, -CH=CH2), 128.3, 128.2, 127.8, 127.6, 127.5, 127.4
strong (s), medium (m) or weak (w). Mass spectra were obtained (1, Ph), 118.3, 116.7 (2, -CH=CH2), 80.4, 80.3 (1, -CHO-), 73.4,
at 70 eV. Optical purities were determined by HPLC using a HP-
LC-1050 system equipped with a Daicel Chiralcel OD column. The
following compounds have been prepared following procedures de-
scribed in the literature: 6,[47,49] 7,[50] 8,[50] 14.[76]
72.5, 70.8, 70.4 (2, -CH2O-) ppm. [α]2D5 = –7.5 (c = 0.83, CH2Cl2).
IR (film, KBr plates): ν = 3064 (w), 3029 (w), 2863 (m), 1645 (w),
˜
1453 (m). LRMS (EI 361 (M+ + Na, 100%)m/z HRMS (ESI):
+
calcd. for C22H27O3 (M+ + H) 339.1955, found 339.1945.
(2R,3R)-3-(Benzyloxy)-2-(benzyloxymethyl)-3,6-dihydro-2H-pyran
(12): To a solution of 11 (100 mg, 0.30 mmol) in dry DCM (10 mL)
was added ruthenium catalyst A (12 mg, 5 mol-%). The solution
was stirred at ambient temperature, until the starting material was
fully consumed as indicated by TLC. All volatiles were evaporated,
and the residue was purified by flash chromatography to give 12
(2RS,3R,4R)-3-Allyloxy-4-(benzyloxy)hex-5-ene-1,2-diol (9): To a
solution of 8 (780 mg, 3.00 mmol, mixture of diastereomers) in a
1:1 mixture of THF (20 mL) and water (20 mL) was added a cata-
lytic amount of H2SO4. After complete conversion the solution was
neutralized with saturated solution of sodium hydrogen carbonate
and the aqueous layer was extracted with diethyl ether. The organic
layers were dried with MgSO4 and the solvent was removed in
vacuo. After filtration through a short pad of silica, 9 (720 mg,
86%) was obtained as an inseparable mixture of diastereomers.
Diol 9 was used without further purification. 1H NMR (300 MHz,
CDCl3): δ = 7.40–7.28 (5 H), 6.02–5.81 (2 H), 5.45–5.33 (2 H),
5.30–5.12 (2 H), 4.70–4.63 (1 H), 4.42–3.97 (4 H), 3.85–3.40 (4 H),
3.15 (br. d, J = 4.4 Hz, 0.5 H), 2.65 (br. d, J = 6.1 Hz, 0.5 H), 2.33
(br. dd, J = 6.3 Hz, 0.5 H), 2.29 (br. dd, J = 6.0 Hz, 0.5 H) ppm.
13C NMR (75 MHz, CDCl3): δ = (ipso-C not observed) 134.8,
134.5, 134.4, 134.2 (1), 128.5, 128.4, 127.9, 127.8, 127.7 (1), 119.4,
119.3, 117.6, 117.5 (2), 81.2, 80.9, 80.4, 80.1 (1), 73.6, 73.1, 70.8,
70.7 (2), 71.1 (1), 64.1, 63.4 (2) ppm.
1
(60 mg, 65%). H NMR (CDCl3, 300 MHz): δ = 7.40–7.27 (10 H,
Ph), 6.10–5.96 (2 H, H2, H3), 4.68 (d, J = 12.0 Hz, 1 H, -OCH2Ph),
4.66 (d, J = 12.0 Hz, 1 H, -OCH2Ph), 4.57 (d, J = 12.0 Hz, 1 H,
-OCH2Ph), 4.56 (d, J = 12.0 Hz, 1 H, -OCH2Ph), 4.36 (dm, J =
16.6 Hz, 1 H, H1), 4.19 (dm, J = 16.6 Hz, 1 H, H1Ј), 3.86–3.73 (4
H, H4, H5, H6, H6Ј) ppm. 13C NMR (CDCl3, 75 MHz): δ = 138.7,
138.2 (0, ipso-C, Ph), 131.4, 128.3, 128.2, 127.7, 127.6, 127.5, 127.4,
123.5 (1, Ph, C2, C3), 76.7, 68.5 (1, C4, C5), 73.5, 70.6, 69.9, 65.8
(2, -OCH2Ph, C1, C6) ppm. [α]2D5 = –178.6 (c = 0.69, CH2Cl2). IR
(film, KBr plates): ν 3030 (w), 2861 (m), 1496 (m), 1453 (m). LRMS
˜
+
(EI): m/z 311 (M+ + H, 100%). HRMS (ESI): calcd. C20H23O3
(M+ + H) 311.1642, found 311.1633.
(2R,3R)-3-(Benzyloxy)-2-(benzyloxymethyl)-3,4-dihydro-2H-pyran
(13): To a solution of 11 (100 mg, 0.30 mmol) in toluene (20 mL)
was added ruthenium catalyst A (12 mg, 5 mol-%). The solution
was stirred at ambient temperature, until the starting material was
fully consumed as indicated by TLC. 2-Propanol (300 µL) and solid
NaOH (10 mg) were added, and the mixture was heated to reflux
for 30 min. After this time, the intermediate RCM product was
completely converted to 13, as indicated by TLC. The solution was
washed with water, and all volatiles were evaporated. The residue
was purified by flash chromatography to yield 13 (57 mg, 61%).
1H NMR (CDCl3, 300 MHz): δ = 7.40–7.27 (10 H, Ph), 6.41 (ddd,
J = 6.4, 1.9, 1.9 Hz, 1 H, H1), 4.67 (d, J = 11.3 Hz, 1 H, -CH2Ph),
4.66 (m, 1 H, H2), 4.58 (d, J = 11.3 Hz, 1 H, -CH2Ph), 4.50 (d, J
= 11.3 Hz, 1 H, -CH2Ph), 4.49 (d, J = 11.3 Hz, 1 H, -CH2Ph), 4.13
(ddm, J = 7.1, 5.3 Hz, 1 H, H5), 3.86 (m, 1 H, H4), 3.74 (dd, J =
9.5, 7.1 Hz, 1 H, H6), 3.66 (dd, J = 9.5, 5.3 Hz, 1 H, H6Ј), 2.28–
2.06 (2 H, H3, H3Ј) ppm. 13C NMR (CDCl3, 75 MHz): δ = 143.0
(1, C1), 138.3, 138.1 (0, ipso-C, Ph), 128.3, 128.3, 127.8, 127.7,
127.6, 127.6 (1, Ph), 97.7 (1, C2), 75.2, 69.9 (1, C4, C5), 73.4, 71.1,
68.7 (2, -CH2Ph, C6), 24.6 (2, C3) ppm. [α]2D5 = –7.0 (c = 0.80,
(2R,3R)-2-(Allyloxy)-3-(benzyloxy)pent-4-en-1-ol (10): To a solu-
tion of 9 (180 mg, 0.70 mmol) in MeOH (40 mL) and H2O (6 mL)
was added NaIO4 (1.39 g, 6.50 mmol) and the reaction mixture was
stirred for 12 h. Excess NaIO4 was destroyed by adding ethylene
glycol, and the mixture was stirred for 2 h and filtered through
silica. The solvent was removed, and the residue was dissolved in
dry DCM and cooled to –50 °C. NaBH4 (490 mg, 12.90 mmol) was
added and the reaction mixture was stirred for 3 h. After aqueous
workup, the organic layer was extracted with diethyl ether, dried
with MgSO4 and the solvent was evaporated. After column
chromatography on silica, 10 (160 mg, quant.) was obtained.
1H NMR (CDCl3, 300 MHz): δ = 7.37–7.27 (5 H, Ph), 6.00–5.75
(2 H, -CH=CH2), 5.35–5.27 (2 H, =CH2), 5.26 (dddd, J = 17.3,
1.7, 1.7, 1.7 Hz, 1 H, =CH2), 5.17 (dm, J = 10.5 Hz, 1 H, =CH2),
4.64 (d, J = 11.8 Hz, 1 H, -CH2Ph), 4.40 (d, J = 11.8 Hz, 1 H,
-CH2Ph), 4.25 (ddt, J = 12.6, 5.6, 1.5 Hz, 1 H, -CH2CH=), 4.13
(ddt, J = 12.6, 6.0, 1.3 Hz, 1 H, -CH2CH=), 3.97 (dd, J = 6.6,
5.9 Hz, 1 H, -CHOBn), 3.76–3.44 (3 H, -CH2OH, -CHOAll), 1.74
(br. s, 1 H, -OH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 138.2 (0,
ipso-C, Ph), 134.9, 134.6 (1, -CH=CH2), 128.4, 127.8, 127.6 (1, Ph),
119.1, 117.1 (2, -CH=CH2), 81.2, 80.9 (1, -CHO-), 72.4, 70.6, 62.1
(2, -OCH2-) ppm. [α]2D4 = –7.0 (c = 0.88, CH2Cl2). IR (film, KBr
CH Cl ). IR (film, KBr plates): ν 3062 (w), 3029 (w), 2865 (w),
˜
2
2
1654 (m), 1496 (m). LRMS (EI): m/z 311 [M+ + H, 100%]. HRMS
(ESI): calcd. for C20H23O3 (M+ + H) 311.1642, found 311.1664.
+
plates): ν = 3454 (br., w), 3065 (w), 2868 (m), 1736 (w), 1454 (m).
˜
LRMS (EI): m/z (%) = 249 (M+ + H, 60%) 117 (100). HRMS
(2R,3R,6S)-3-(Benzyloxy)-2-(benzyloxymethyl)-6-(4-methoxyphen-
yl)-3,6-dihydro-2H-pyran (15): 13 (120 mg, 0.80 mmol) was dis-
(ESI): calcd. for C15H21O3 (M+ + H) 249.1485, found 249.1492.
+
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5767

B. Schmidt, A. Biernat
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solved in dry acetonitrile (5 mL) and [Pd2(dba)3·CHCl3] (10 mg,
2.5 mol-%) was added. Diazonium salt 14 (106 mg, 0.50 mmol) was
subsequently added over a period of 20 minutes. After complete
conversion, the solvent was evaporated. After column chromatog-
raphy on silica (cyclohexane/MTBE), 15 (276 mg, 83%) was ob-
tained. 1H NMR (300 MHz, CDCl3): δ = 7.48–7.20 (12 H, Ph, Ar),
6.89 (d, J = 8.8 Hz, 2 H, p-OMe-Ph), 6.26 (dd, J = 10.5, 3.1 Hz, 1
H, H2), 6.14 (ddd, J = 10.3, 4.5, 1.8 Hz, 1 H, H3), 5.33 (br. s, 1 H,
H1), 4.72 (d, J = 11.9 Hz, 1 H, -CH2Ph), 4.64 (d, J = 11.9 Hz, 1 H-
CH2Ph), 4.54 (d, J = 11.8 Hz, 1 H, -CH2Ph), 4.49 (d, J = 11.8 Hz, 1
H, -CH2Ph), 3.97 (ddd, J = 6.6, 6.0, 2.9 Hz, 1 H, H5), 3.89 (dd, J
= 4.2, 3.0 Hz, 1 H, H4), 3.81 (s, 3 H, -OMe), 3.81 (signal not re-
solved due to overlap with singlet at 3.81, 1 H, H6), 3.72 (dd, J =
10.1, 6.8 Hz, 1 H, H6Ј) ppm. 13C NMR (75 MHz, CDCl3): δ =
159.3 (0, C-OMe), 138.7, 138.4 (0, ipso-C, Ph), 132.4 (1, C2/3),
131.2 (0, ipso-C, p-OMe-Ph), 129.3, 128.3, 128.2, 127.8, 127.6,
127.5, 127.4, 125.0 (1, Ph, C2/3), 113.7 (1, p-OMe-Ph), 73.4, 70.8,
69.1 (2, C6, -CH2Ph), 73.2, 70.9, 68.3 (1, C1, C4, C5), 55.2 (3,
-OMe) ppm. [α]2D8 = –135.7 (c = 1.67, CH2Cl2). IR (film, KBr
(93 mg, quant.). 1H NMR (300 MHz, CDCl3): δ = 7.38–7.25 (5 H,
Ph), 6.39 (dt, J = 6.1, 1.8 Hz, 1 H, H1), 4.68 (d, J = 12.1 Hz, 1
H, -CH2Ph), 4.63 (m, 1 H, H2), 4.55 (d, J = 12.1 Hz, 1 H, -CH2Ph),
3.99–3.87 (2 H, H4, H5), 3.87–3.82 (2 H, H6, H6Ј), 2.31–2.05 (2
H, H3, H3Ј), 0.96 [t, J = 7.9 Hz, 9 H, -Si(CH2CH3)3], 0.63 [q, J =
7.9 Hz, 6 H, -Si(CH2CH3)3] ppm. 13C NMR (75 MHz, CDCl3): δ
= 142.9 (1, C1), 138.5 (0, ipso-C, Ph), 128.3, 127.7, 127.6 (1, Ph),
97.7 (1, C2), 77.1 (1, C4/5), 71.2 (2, -OCH2Ph), 69.7 (1, C4/5), 61.2
(2, C6), 24.4 (2, C3), 6.7 [3, -Si(CH2CH3)3], 4.4 [2, -Si(CH2CH3)3]
ppm. [α]3D0 = –1.4 (c = 1.16, CH Cl ). IR (film, KBr plates): ν 3064
˜
2
2
(w), 2952 (w), 2875 (m), 1654 (m), 1455 (m). LRMS (EI): m/z 335
[M+ + Na, 100%]. HRMS (EI): calcd. for C19H31O3Si+ (M+ + H)
335.2037, found 335.2045.
Supporting Information (see also the footnote on the first page of
1
this article): Characterization data of 9 and copies of H and 13C
NMR spectra of new compounds.
Acknowledgments
plates): ν = 3030 (w), 2862 (w), 1607 (m), 1509 (s), 1453 (m).
˜
HRMS (EI): calcd. for C27H28O4 (M+) 416.1988, found 416.1949.
We thank the Deutsche Forschungsgemeinschaft (DFG) (grant no.
Schm 1095/6-1) for generous financial support, and Lanxess and
Evonik-Oxeno for generous donations of chemicals and solvents.
We thank Prof. Bernd Plietker, University of Stuttgart, Germany,
for the determination of enantiomeric ratios.
(2R,3R)-3-(Benzyloxy)-2-(hydroxymethyl)-3,6-dihydro-2H-pyran
(16): Obtained from 10 (50 mg, 0.20 mmol) following the procedure
given above for 12. After column chromatography, 16 (40 mg, 90%)
was obtained. 1H NMR (CDCl3, 300 MHz): δ = 7.37–7.27 (5 H,
Ph), 6.00–5.75 (2 H, H2, H3), 4.69 (d, J = 11.9 Hz, 1 H, -CH2Ph),
4.54 (d, J = 11.9 Hz, 1 H, -CH2Ph), 4.34 (dm, J = 17.4 Hz, 1 H,
H1), 4.26 (dm, J = 17.4 Hz, 1 H, H1Ј), 3.96 (dd, J = 11.8, 7.2 Hz,
1 H, H6), 3.83 (m, 1 H, H4), 3.75 (br. dm, J = 11.8 Hz, 1 H, H6Ј),
3.63 (ddd, J = 7.1, 4.2, 2.7 Hz, 1 H, H5), 2.29 (br. s, 1 H, -OH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 138.2 (0, ipso-C, Ph), 131.6
(1, C2/3), 128.4, 127.7, 127.7 (1, Ph), 123.2 (1, C2/3), 77.6, 68.9 (1,
C4, C5), 70.4, 65.8, 62.8 (2, -OCH2Ph, C1, C6) ppm. [α]2D4 = –15.5
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5768
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Eur. J. Org. Chem. 2000, 5764–5769
© 2000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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