Metathesis-Based de Novo Synthesis of Noviose

Article abstract of DOI:10.1002/ejoc.201301615

The rare carbohydrate L-(+)-noviose was synthesized from enantiomerically pure L-lactate. The configuration at C-4 was established by diastereoselective nucleophilic addition to an in-situ-generated lactaldehyde. The resulting homoallylic alcohol was further transformed into a set of ring-closing metathesis (RCM) precursors. These compounds were converted into noviose in few steps using RCM and RCM-allylic-oxidation sequences.

Full text of DOI:10.1002/ejoc.201301615

FULL PAPER
DOI: 10.1002/ejoc.201301615
Metathesis-Based De Novo Synthesis of Noviose
Bernd Schmidt*[a] and Sylvia Hauke[a]
Keywords: Carbohydrates / Allylic oxidation / Oxygen heterocycles / Metathesis / Ruthenium
The rare carbohydrate
enantiomerically pure
was established by diastereoselective nucleophilic addition
to an in-situ-generated lactaldehyde. The resulting homoall-
L
-(+)-noviose was synthesized from
ylic alcohol was further transformed into a set of ring-closing
metathesis (RCM) precursors. These compounds were con-
verted into noviose in few steps using RCM and RCM–allylic-
oxidation sequences.
L-lactate. The configuration at C-4
Introduction
Noviose is a rare eight-carbon sugar that is present in
glycoconjugates, e.g., the natural product novobiocin,[1]
a
clinically used coumarin antibiotic that acts through DNA-
gyrase inhibition.[2] A few years ago, it was discovered that
novobiocin also binds to the C-terminal binding site of
heat-shock protein 90 (Hsp90), which is involved in protein
folding.[3] Inhibition of the action of this protein or of chap-
erones in general has been identified as a new approach
to the chemotherapy of cancer.[4] However, the insufficient
activity of novobiocin itself, and the necessity to establish
structure–activity relationships,[5] have triggered the synthe-
sis and evaluation of several analogues,[6] of which the in-
dole derivative shown in Figure 1 was found to be particu-
larly active.[7]
Due to its scarcity, noviose is often obtained by chemical
synthesis rather than by cleavage of the glycoconjugates.
This offers the additional advantage that structural modifi-
cations of the glycosidic part of natural or unnatural glyco-
conjugates can be accomplished more conveniently. The
first synthesis of noviose was described by Spiegelberg et
al., who started from a d-glucofuranose derivative.[8,9] Al-
ternative routes rely on the modification of other common
carbohydrates[10–16] or are de novo syntheses.[17–23] Noviose
analogues have been obtained, for instance, from l-arabi-
nose by incorporation of alkyl substituents other than
methyl at the C-5 position,[24] or in de novo approaches by
the introduction of amino groups at C-3.[25,26] Although
ring-closing metathesis (RCM) was recognized early as a
method that could be used for the modification and synthe-
sis of carbohydrates,[27] we are aware of only two noviose
syntheses that use RCM as a key step. Reddy et al. used
Figure 1. Structures of noviose, novobiocin, and a noviose-contain-
ing Hsp-90 inhibitor.
RCM to convert (–)-pantolactone into a cyclopentenone,
which was then dihydroxylated and further elaborated by
Baeyer–Villiger oxidation to give a protected noviose.[21] In
contrast, Hanessian and Auzzas used a RCM step for the
synthesis of a dihydropyran, which subsequently underwent
allylic oxidation with PCC, reduction of the resulting lact-
one to the corresponding lactol, and diastereoselective Os-
catalysed dihydroxylation to give l-(+)-noviose.[22] In this
synthesis, the source of chirality was an enantioselective al-
lylation of a glyoxylate with a chiral allylborane.
In continuation of previous studies from our group on
the metathesis-based synthesis of deoxy sugars and their
derivatives,[28–34] in this paper, we report a synthesis of l-
(+)-noviose using S-ethyl lactate as a conveniently available
enantiomerically pure starting material. To the best of our
knowledge, lactic acid or its derivatives have not been used
as enantiopure starting materials for the synthesis of no-
viose or its derivatives before.
[a] Institut für Chemie, Professur für Organische Synthesechemie,
Universität Potsdam,
Karl-Liebknecht-Straße 24-25, 14476 Golm, Germany
E-mail: bernd.schmidt@uni-potsdam.de
http://www.chem.uni-potsdam.de/groups/schmidt/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301615.
Eur. J. Org. Chem. 2014, 1951–1960
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B. Schmidt, S. Hauke
FULL PAPER
Results and Discussion
The key idea behind our approach to l-(+)-noviose was
to transfer the chirality from the stereocentre of lactal-
dehyde to the adjacent carbonyl group, and subsequently to
destroy the chiral information at the original stereocentre
by oxidation and addition of a methyl Grignard reagent.
This approach resembles a chirality transfer in so far as a
new stereocentre is generated with the loss of an adjacent
stereocentre. In true chirality-transfer reactions, the genera-
tion of the new stereocentre and the loss of the inducing
stereocentre occur simultaneously, which is, of course, not
the case here. In the first step, ethyl S-lactate (1) was pro-
tected as a TBS (tert-butyldimethylsilyl) ether 2.[35] This was
reduced to the lactaldehyde, which was treated in situ with
vinylmagnesium chloride. Under these conditions, Felkin–
Anh-product 3 was obtained with a diastereomeric ratio of
9:1.[32,36] In the next step, we wanted to methylate the sec-
ondary alcohol in 3 to introduce the methoxy group at C-
4 of noviose. With NaH as the base and methyl iodide as
the alkylating agent, scrambling of the TBS group occurred
to a considerable extent, even at 0 °C, and a 3:1 mixture of
isomers 4a and 4b was formed. Migration of silyl protecting
groups is sometimes observed if a Na alkoxide is in close
proximity to a silyl ether, and it most probably proceeds
via a cyclic transition state.[37] We reasoned that this side-
reaction might be suppressed with a less nucleophilic Li alk-
Scheme 1. Synthesis of homoallylic alcohol 8 from ethyl S-lactate;
TBAF = tetrabutylammonium fluoride.
oxide, which would, however, require
a significantly
stronger methylating agent. Therefore, alcohol 3 was depro-
tonated with MeLi at –78 °C, and the resulting alkoxide was
treated with [Me3O]BF4 (Meerwein’s reagent).[38] Scram-
bling of the TBS group was indeed suppressed under these
conditions, but the conversion remained incomplete, even
after prolonged reaction times, and the desired methyl ether
(i.e., 4a) was isolated in 50% yield, together with 26% of
unreacted starting material 3. These unsatisfactory results
prompted us to protect the alcohol in 3 as a MOM (meth-
oxymethyl) ether to give 5, which was then desilylated to
give 6. Subsequent oxidation to the ketone gave 7. Addition
of MeMgCl gave carbinol 8, which served as a key interme-
diate for further transformations (Scheme 1).
Starting from homoallylic alcohol 8, two alternative
routes to the envisaged noviose precursor 11 were investi-
gated (Scheme 2). Upon treatment with acryloyl chloride,
acrylate 9 was obtained in good yield, and this compound
underwent ring-closing metathesis to give α,β-unsaturated
δ-lactone 11. Although a few examples of successful RCM
reactions involving electron-deficient double bonds cata-
lysed by first-generation catalyst A[39] have been described
in the literature,[40] such transformations usually require
more active second-generation catalysts, e.g., B.[41,42] The
initial substrate concentration is particularly important; in
most cases it should not exceed 0.01 m if synthetically useful
yields of RCM product are to be obtained.[43] Finally, a
beneficial effect of added phenol, originally described by
Scheme 2. Synthesis of lactone intermediate 11 and OH-deprotec-
tion; NaHMDS = sodium hexamethyldisilazide.
We investigated the RCM of acrylate 9 (Table 1), and
Forman et al.[44] for cross-metathesis reactions, has also identified B (5 mol-%) in toluene at 110 °C, pseudo high
been documented for other less facile metathesis reac- dilution, and phenol (0.5 equiv.) as the optimum conditions.
tions.[34,45,46]
The beneficial effect of the phenol additive (Table 1, entry 4
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Metathesis-Based De Novo Synthesis of Noviose
vs. entry 5) is clearly shown by an increased isolated yield. Table 2. Optimization of conditions for the deprotection of MOM
ether 11.
An alternative synthesis of 11 starts from allyl ether 10,
which is available from 8 by a Williamson ether synthesis.
Precursor 10 was subjected to the conditions of a tandem
RCM–allylic-oxidation sequence, which was recently de-
scribed by us[47] and shortly afterwards by Arisawa et al.[48]
In this transformation, the metathesis catalyst is converted
into an allylic oxidation catalyst in situ by the addition of
tert-butyl hydroperoxide, which also serves as an oxidant.
Although the yield for the reaction of 10 to 11 is consider-
ably lower than the direct conversion of 9 to 11 by RCM,
it proceeds with the cheaper first-generation catalyst A, and
does not require high- or pseudo high-dilution conditions.
Entry Reaction conditions
Yield of 12a
Yield of 12b
1[a]
CeCl3·7H2O (0.5 equiv.),
methanol/CH3CN (1:1),
65 °C, 48 h
42%
n.d.
2
HCl (2 m)/THF (1:1),
20 °C, 16 h, then 40 °C,
5 h
CF3CO2H (1.0 equiv.),
CH2Cl2, 20 °C, 24 h, then
CF3CO2H (1.0 equiv.),
40 °C, 6 h
82%
54%
14%
n.d.
3[b]
4
5
CF3CO2H/CH2Cl2 (1:4),
20 °C, 16 h
BF3·OEt2 (1.6 equiv.),
Et3SiH (1.6 equiv.),
CH3CN, –45 °C, 0.5 h,
20 °C, 16 h
Ͼ98%
n.d.
95% combined yield
(12a/12b = 2:1)
Table 1. Optimization of conditions for RCM of acrylate 9.
Entry Phenol [equiv.]
c0 [m][a]
T [°C]
Yield of 11 [%][b]
1
2
3
4
5
0.5
0.5
0.5
none
0.5
0.01
0.01
80
65
79
74
67
89
[a] Starting material 11 was partially recovered (41%). [b] Starting
material 11 was partially recovered (10%); n.d.: not determined.
110
110
110
110
0.005
[c]
–
–
[c]
80 °C resulted in the formation of hydrogenated product
13b (Table 3, entry 3). Most probably, a contamination of
the starting material (i.e., 12a) with trace amounts of Ru
originating from the metathesis reaction is responsible for
the concomitant hydrogenation. The Ru residues are pre-
sumably converted into Ru hydrides, which then catalyse
the addition of hydrogen to the double bond. We have pre-
viously made similar observations for other metathesis reac-
tions.[52] A successful methylation of the C-4 hydroxy group
was eventually accomplished by replacing the strongly basic
reagent NaH by silver oxide. This method has previously
been used for the alkylation of base-sensitive sub-
strates[29,53,54] or sterically encumbered alcohols.[22,55] Dif-
fering from literature precedent, we carried out the methyl-
ation in the absence of any solvent, and we isolated methyl
ether 13a as the sole product in quantitative yield (Table 3,
entry 4).
[a] Initial substrate concentration. [b] Yield of isolated product.
[c] Pseudo high-dilution conditions were used.
The next steps involved cleavage of the MOM group and
methylation of the OH group at C-4. When a substoichio-
metric amount of CeCl3·7H2O was used in a methanol/
acetonitrile solvent mixture,[49] the deprotection remained
incomplete, and only 42% of 12a was isolated, along with
41% of 11 (Table 2, entry 1). In contrast, when MOM ether
11 was dissolved in a 1:1 mixture of HCl (2 m aq.) and THF,
the complete consumption of the starting material was ob-
served, but this also led to a partial rearrangement of 12a
into butenolide 12b (Table 2, entry 2). Under less acidic
conditions, using trifluoroacetic acid (2 equiv.) in dichloro-
methane (Table 2, entry 3), this ring contraction was sup-
pressed, but the conversion of the starting material was
again incomplete, and the isolated yield of 12a remained
unsatisfactory. A quantitative yield of 12a was eventually
achieved by using CF3CO2H as a cosolvent at ambient tem-
perature.[50] Under these conditions, neither unreacted
starting material nor ring-contracted lactone 12b was de-
tected (Table 2, entry 4). Inspired by Mitchell and Bode’s
report on the synthesis of dialkyl ethers from MOM
ethers[51] we considered a synthesis of methyl ether 13a di-
rectly from 11 (Table 2, entry 5). We thought that a combi-
nation of the strong Lewis acid BF3·OEt2 and triethylsilane
as a hydride source might result in the substitution of the
methoxy part of the MOM group by hydride, which would
eventually yield the desired methyl ether (i.e., 13a). Unfor-
tunately, we could only isolate the deprotected product (i.e.,
12a) and its ring-contracted isomer (i.e., 12b) in a ratio of
2:1 and a combined yield of 95%.
Table 3. Optimization of conditions for the methylation of 12a.
Entry Conditions
Time [h] Product[a] Yield [%]
1
NaH (1.2 equiv.),
MeI (2.0 equiv.),
THF, 65 °C
NaH (1.2 equiv.),
MeI (2.0 equiv.),
DMF, 0 °C
NaH (1.2 equiv.),
MeI (2.0 equiv.),
DMF, 80 °C
16
16
16
48
n.r.
13a
13b
13a
–
2
traces
20
3
4[b]
Ag2O (1.1 equiv.),
MeI (1.5 equiv.),
40 °C
Ͼ98
[a] n.r.: no reaction. [b] Reaction was run in the dark.
The apparently straightforward methylation of 12a was
Compound 13a was a key intermediate in the synthesis
also associated with some unexpected difficulties. Under the of noviose by Hanessian and Auzzas,[22] but they obtained
standard conditions of Williamson etherification (Table 3, it by a different route. All the spectroscopic data we ob-
entry 1), alkylated product 13a was not observed. In DMF served for this compound match those reported in the lit-
at 0 °C (Table 3, entry 2), only trace amounts of the methyl erature perfectly, apart from the value for the specific rota-
ether were obtained, whereas increasing the temperature to tion, for which our observed value was slightly higher. The
Eur. J. Org. Chem. 2014, 1951–1960
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1953

B. Schmidt, S. Hauke
FULL PAPER
final steps to noviose were a cis-dihydroxylation of the the hydrolysis of the intermediate osmate)[56] were added
double bond and a reduction of the lactone to the lactol. immediately. l-(+)-Noviose was isolated in 63% yield over
Hanessian and Auzzas mentioned that the Os-catalysed di- the two steps as a mixture of α and β anomers in a ratio of
hydroxylation of lactone 13a was not feasible because the 1:2. The α and β configurations were assigned based on a
1
isolated yields of the diol were low under various condi- comparison of H and 13C NMR spectroscopic data with
tions. We checked this statement, and we can confirm the the values previously reported by Pankau and Kreiser.[18]
observation. This prompted us to revert to the order of For this anomeric mixture, we observed a specific rotation
steps proposed by Hanessian and Auzzas, i.e., reduction to of [α]2D5 = +29.7 [c = 0.30, ethanol/water (1:1)], which
the lactol prior to dihydroxylation. Thus, lactone 13a was matches previously reported values well. For example, Han-
treated with DIBAl-H (diisobutylaluminium hydride) at essian and Auzzas obtained two slightly different values for
–78 °C, and the reaction was quenched at this temperature l-(+)-noviose, depending on the starting material they used:
by the addition of methanol (Scheme 3). The 1H NMR [α]D25 = +33.6 [c = 0.2, ethanol/water (1:1)], and [α]D25
=
spectrum of the crude reaction mixture showed that four +27.4 [c = 0.2, ethanol/water (1:1)].[22] Pankau and Kreiser
products were formed. Notably, two doublets at δ Ͼ synthesized d-(–)-noviose, and they reported a specific rota-
9.5 ppm indicate the presence of two aldehydes, and a mul- tion of [α]2D5 = –29.2 [c = 1.0, ethanol/water (1:1)].[18]
tiplet at δ = 5.33 can be attributed to a lactol. Our interpret-
Two intermediates en route to noviose, i.e., ketone 7 and
ation of the NMR spectrum is that the crude reduction RCM precursor 10, offer additional opportunities for the
product consists of both anomers of lactol 14, which are in synthesis of noviose derivatives. Ring-closing metathesis of
equilibrium with δ-hydroxy aldehyde Z-15. The third prod- 10 gave MOM-protected dihydropyran 16, which was sub-
uct was identified as E-configured enal E-15, based on a sequently dihydroxylated under the same conditions as for
large 3J2-H,3-H value of 15.8 Hz; a 3J2-H,3-H value of 11.6 Hz the dihydroxylation of lactol 14. Dihydroxylation proceeded
was observed for the Z isomer. After the NMR sample of trans to the MOM group, as expected, to give tetrahydropy-
the crude reduction mixture had been stored for two weeks, ran 17 as the only product. Subjecting diene 10 to RCM–
only the signals of E-15 were detected in the NMR spec- isomerization conditions[57–59] gave glycal 18 (Scheme 4).
trum, which indicates a slow and irreversible Z/E isomeriza-
tion. In contrast to our observations, Hanessian and Auzzas
report the presence of two epimeric lactols 14, but they do
not mention the presence of any δ-hydroxy aldehydes. A
comparison of the NMR spectra obtained by us with those
provided in the Supporting Information of the previous re-
port[22] shows that they are identical, apart from the pres-
ence of a certain amount of E-enal E-15 in our spectra.
Scheme 4. Synthesis of noviose derivatives from metathesis precur-
sor 10.
Some 5,5-dialkylnoviose derivatives have been reported
to show improved antibiotic activity when conjugated to
the coumarin aglycon part,[24,60] which prompted us to in-
Scheme 3. Reduction and reduction/dihydroxylation of lactone 13a. vestigate the possibility of synthesizing such derivatives by
a modification of our sequence. For this purpose, ketone
As the configurational integrity of the lactol (or δ- 7 (Scheme 1) was identified as a suitable intermediate, as
hydroxy aldehyde) is essential for the correct relative configu- outlined for one example in Scheme 5. Treatment of 7 with
ration of the C-2,C-3 diol moiety, we conducted the dihy- phenylmagnesium chloride gave tertiary alcohol 19 with a
droxylation immediately after quenching the reduction of diastereomeric ratio of 12:1 in favour of the Cram-type che-
the lactone. Thus, the crude reaction mixture obtained after late product. The RCM precursor, allyl ether 20, was syn-
aqueous work-up of the reduction of lactone 13a was redis- thesized from 19 in high yield, and was subjected to the
solved in the solvent mixture required for the Sharpless di- same RCM–isomerization conditions previously used for
hydroxylation without delay. Then the precatalyst K2Os- glycal 18. This gave the expected 5-methyl-5-phenyl-substi-
(OH)6, the oxidant N-methylmorpholine N-oxide (NMO), tuted glycal (i.e., 21) as a single diastereoisomer in syntheti-
and methanesulfonamide (a rate-accelerating reagent for cally useful yield (Scheme 5).
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Metathesis-Based De Novo Synthesis of Noviose
quid. [α]2D4 = –26.4 (c = 0.24, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 4.30 (q, J = 6.7 Hz, 1 H), 4.33–4.11 (m, 2 H), 1.38 (d,
J = 6.7 Hz, 3 H), 1.27 (t, J = 7.1 Hz, 3 H), 0.90 (s, 9 H), 0.09 (s, 3
H), 0.06 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 174.1 (0),
68.5 (1), 60.7 (2), 25.8 (3), 21.3 (3), 18.3 (0), 14.2 (3), –5.0 (3), –5.3
(3) ppm. IR (neat): ν = 2930 (w), 2858 (w), 1753 (m), 1473 (w),
˜
1252 (m), 1141 (s), 830 (s), 776 (s) cm–1. MS (EI): m/z (%) = 255
(8) [M + Na]+, 251 (26), 217 (100), 197 (20), 189 (100), 161 (32),
155 (18), 119 (12), 105 (11). HRMS (ESI): calcd. for C11H24O3NaSi
[M + Na]+ 255.1392; found 255.1379. C11H24O3Si (232.39): calcd.
C 56.9, H 10.4; found C 56.5, H 10.9.
(3R,4S)-4-(tert-Butyldimethylsilyloxy)pent-1-ene-3-ol (3):[32,36]
A
solution of 2 (4.30 g, 18.5 mmol) in dry CH2Cl2 (100 mL) was
cooled to –90 °C. DIBAl-H (1.1 m in cyclohexane; 25.2 mL,
27.8 mmol) was slowly added at this temperature. Conversion of
ester 2 was monitored by TLC, and after it had been completely
consumed, vinylmagnesium chloride (1.7 m in THF; 21.8 mL,
37.0 mmol) was added slowly. The reaction mixture was warmed
to ambient temperature over 12 h, and then it was poured into a
mixture of water and diethyl ether. A saturated solution of tartaric
acid was added to solubilize the inorganic precipitates, the organic
phase was separated, and the aqueous phase was extracted with
diethyl ether. The combined organic phases were dried with MgSO4
and filtered, and the solvents were evaporated. The residue was
purified by column chromatography on silica to give 3 (2.52 g,
11.6 mmol, 63%) as a colourless liquid. [α]2D5 = +13.9 (c = 0.26,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 5.81 (ddd, J = 17.1,
10.5, 6.2 Hz, 1 H), 5.28 (ddd, J = 17.3, 1.6, 1.5 Hz, 1 H), 5.17 (ddd,
J = 10.6, 1.5, 1.5 Hz, 1 H), 4.02 (m, 1 H), 3.85 (qd, J = 6.3, 3.6 Hz,
1 H), 2.29 (br. d, J = 3.4 Hz, 1 H), 1.08 (d, J = 6.3 Hz, 3 H), 0.90
(s, 9 H), 0.08 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.6 (1), 116.5 (2), 76.7 (1), 71.3 (1), 25.8 (3), 18.1
Scheme 5. Synthesis of noviose derivative 21 from ketone 7.
Conclusions
In summary, we report the synthesis of l-(+)-noviose
from l-lactate as a chiral pool starting material. The se-
quence involves the transfer of chirality from the enantio-
pure starting compound to an adjacent prochiral centre, a
ring-closing metathesis or a ring-closing metathesis/allylic
oxidation sequence for the construction of the six-mem-
bered ring, and a reduction of the lactone followed by di-
hydroxylation to establish the cis-C-2,C-3 diol motif. A
modification of the sequence to make unnatural noviose de-
rivatives available has been exemplified for the synthesis of
a polyhydroxylated tetrahydropyran and two 3-deoxy glyc-
als. Further syntheses of unnatural noviose derivatives and
their conjugation to novobiocin aglycons are currently un-
der investigation in our laboratory.
(0), 17.6 (3), –4.5 (3), –4.8 (3) ppm. IR (neat): ν = 2930 (w), 2857
˜
(w), 1472 (w), 1253 (m), 1087 (m), 832 (s), 774 (m) cm–1. MS (EI):
m/z (%) = 239 (17) [M + Na]+, 213 (100), 199 (60), 197 (34), 155
(34), 133 (12), 115 (26). HRMS (ESI): calcd. for C11H24O2NaSi [M
+ Na]+ 239.1443; found 239.1452.
Experimental Section
tert-Butyl-[(2S,3R)-3-methoxypent-4-ene-2-yloxy]dimethylsilane
(4a) and tert-Butyl-[(3R,4S)-4-methoxypent-1-ene-3-yloxy]dimethyl-
silane (4b)
General Remarks: All experiments were carried out in dry reaction
vessels under an atmosphere of dry nitrogen. Solvents were purified
by standard procedures. 1H NMR spectra were obtained at
300 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as an internal stan-
dard, or in CD3OD with CHD2OD (δ = 3.31 ppm) as an internal
standard. Coupling constants (J) are given in Hz. 13C NMR spec-
tra were recorded at 75 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm)
as an internal standard, or in CD3OD with CD3OD (δ = 49.2 ppm)
as an internal standard. The number of coupled protons was ana-
lysed by DEPT or APT experiments, and is denoted by a number
in parantheses after the chemical shift value. IR spectra were re-
Attempted Synthesis of 4a by Methylation of the Na Alkoxide of 3:
NaH (60 wt.-% dispersion in mineral oil; 222 mg, 5.6 mmol) and
CH3I (0.27 mL, 4.3 mmol) were added to a solution of 3 (400 mg,
1.9 mmol) in dry, degassed THF (20 mL) at 0 °C. The mixture was
warmed to ambient temperature and stirred for 12 h. The reaction
was quenched by the careful addition of water and MTBE (methyl
tert-butyl ether). The organic layer was separated, and the aqueous
layer was extracted with MTBE. The combined organic extracts
were dried with MgSO4 and filtered, and the solvents were evapo-
rated. NMR spectroscopy of the crude reaction mixture revealed
the presence of two isomeric products 4a and 4b in a ratio of 2.7:1,
which could be partially separated by column chromatography to
give 4a,b (345 mg, 1.5 mmol, 79% combined yield).
corded neat. Wavenumbers (ν) are given in cm–1. The peak inten-
˜
sities are defined as strong (s), medium (m), or weak (w). Mass
spectra were obtained at 70 eV.
Ethyl (S)-2-(tert-butyldimethylsilyloxy)propanoate (2):[32,35] Imid-
azole (4.32 g, 63.5 mmol) and TBSCl (7.65 g, 51.0 mmol) were
added to a solution of l-ethyl lactate (5.00 g, 42.3 mmol) in dry
Attempted Synthesis of 4a by Methylation of the Li Alkoxide of 3:
A solution of 3 (150 mg, 0.69 mmol) in dry, degassed diethyl ether
CH2Cl2 (100 mL) at 0 °C. The mixture was warmed to ambient (3.5 mL) was cooled to –78 °C. MeLi (1.6 m in diethyl ether;
temperature and stirred for 12 h. The reaction was quenched by
the addition of water, and the aqueous layer extracted with diethyl
ether. The combined organic extracts were washed with HCl (1 m
aq.) and brine, dried with MgSO4 and filtered, and the solvents
were evaporated. The residue was distilled (b.p. 90–92 °C at
14 mbar) to give 2 (9.83 g, 42.3 mmol, quant.) as a colourless li-
0.40 mL, 0.69 mmol) was added, and the mixture was stirred for
0.5 h. Then Meerwein’s reagent [Et3O]BF4 (154 mg, 1.04 mmol)
was added. Stirring was continued for 2 h at –78 °C, and then the
mixture was warmed to ambient temperature over 12 h. A saturated
aqueous solution of NH4Cl was added, the aqueous layer was sepa-
rated and extracted with diethyl ether. The combined organic layers
Eur. J. Org. Chem. 2014, 1951–1960
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1955

B. Schmidt, S. Hauke
FULL PAPER
were dried with MgSO4 and filtered, and the solvents were evapo-
rated. The residue was purified by chromatography on silica to give
4a (80 mg, 0.35 mmol, 50%) as a colourless liquid, along with unre-
acted starting material 3 (40 mg, 0.18 mmol, 26%).
13C NMR (75 MHz, CDCl3): δ = 134.0 (1), 119.9 (2), 94.3 (2), 81.9
(1), 69.3 (1), 55.5 (3), 17.8 (3) ppm. IR (neat): ν = 3445 (w), 2889
˜
(w), 1152 (m), 1096 (s), 1026 (s), 919 (s) cm–1. MS (EI): m/z (%) =
147 (39) [M + H]+, 141 (33), 115 (42), 99 (100). HRMS (ESI):
calcd. for C7H15O3 [M + H]+ 147.1021; found 147.1033. C7H14O3
(146.18): calcd. C 57.5, H 9.7; found C 57.5, H 9.8.
1
Analytical data for 4a: [α]2D4 = –12.2 (c = 0.63, CH2Cl2). H NMR
(300 MHz, CDCl3): δ = 5.71 (ddd, J = 17.3, 10.5, 7.6 Hz, 1 H),
5.28–5.18 (m, 2 H), 3.77 (qd, J = 6.2, 5.0 Hz, 1 H), 3.34 (ddm, J
= 7.5, 5.0 Hz, 1 H), 3.30 (s, 3 H), 1.14 (d, J = 6.2 Hz, 3 H), 0.85
(s, 9 H), 0.04 (s, 3 H), 0.03 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.2, 118.3, 87.8, 70.8, 56.8, 25.9, 19.9, 18.1, –4.5,
(R)-3-(Methoxymethoxy)pent-4-en-2-one (7): Dess–Martin
periodinane (3.82 g, 9.0 mmol) was added to a solution of 6 (1.32 g,
9.0 mmol) in dry, degassed CH2Cl2 (30 mL) at 0 °C. The mixture
was warmed to ambient temperature and stirred for 1 h. Then it
was diluted with CH2Cl2 and washed repeatedly with a saturated
aqueous solution of NaHCO3 and Na2S2O3·5H2O (250 g/L). The
aqueous layer was separated and extracted with CH2Cl2, the com-
bined organic extracts were dried with MgSO4 and filtered, and
the solvents were evaporated. The residue was purified by column
chromatography to give ketone 7 (1.23 g, 8.6 mmol, 95 %) as a
colourless liquid. [α]2D2 = –35.6 (c = 0.56, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 5.77 (ddd, J = 17.0, 10.4, 6.5 Hz, 1 H),
5.46 (ddd, J = 17.2, 1.3, 1.3 Hz, 1 H), 5.36 (ddd, J = 10.4, 1.3,
1.3 Hz, 1 H), 4.71 (d, J = 6.7 Hz, 1 H), 4.62 (d, J = 6.7 Hz, 1 H),
4.51 (ddd, J = 6.5, 1.3, 1.3 Hz, 1 H), 3.37 (s, 3 H), 2.18 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 206.3 (0), 132.4 (1), 119.9
–4.6 ppm. IR (neat): ν = 2929 (m), 2856 (m), 1252 (m), 1116 (s),
˜
924 (s), 830 (s), 777 (s) cm–1. MS (EI): m/z (%) = 231 (37)
[M + H]+, 227 (57), 213 (93), 199 (100), 99 (8). HRMS (ESI): calcd.
for C12H27O2Si [M + H]+ 231.1780; found 231.1784. C12H26O2Si
(230.42): calcd. C 62.6, H 11.4; found C 62.5, H 11.8.
Analytical data for 4b: [α]2D2 = –1.5 (c = 0.68, CH2Cl2). H NMR
1
(300 MHz, CDCl3): δ = 5.86 (ddd, J = 17.2, 10.5, 5.8 Hz, 1 H),
5.24 (ddd, J = 17.2, 1.7, 1.7 Hz, 1 H), 5.14 (ddd, J = 10.4, 1.9,
1.4 Hz, 1 H), 4.07 (dddd, J = 5.7, 4.2, 1.4, 1.4 Hz, 1 H), 3.36 (s, 3
H), 3.22 (qd, J = 6.3, 4.2 Hz, 1 H), 1.09 (d, J = 6.3 Hz, 3 H), 0.91
(s, 9 H), 0.07 (s, 3 H), 0.03 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 138.6, 115.4, 80.9, 76.2, 57.1, 25.9, 18.2, 14.9, –4.5,
(2), 94.9 (2), 83.1 (1), 55.9 (3), 25.6 (3) ppm. IR (neat): ν = 2893
˜
–4.7 ppm. IR (neat): ν = 2929 (m), 2857 (m), 1252 (m), 1102 (s),
˜
(w), 1719 (s), 1152 (s), 1036 (s), 919 (s) cm–1. MS (EI): m/z (%) =
167 (5) [M + Na]+, 143 (58), 121 (20), 113 (100), 99 (8). HRMS
(ESI): calcd. for C7H12O3Na [M + Na]+ 167.0684; found 167.0697.
1031 (m), 834 (s), 775 (s) cm–1. MS (EI): m/z (%) = 231 (26) [M +
H]+, 227 (33), 213 (100), 199 (17), 113 (20), 99 (35). HRMS (ESI):
calcd. for C12H28O2Si [M + H]+ 231.1780; found 231.1799.
C12H27O2Si (230.42): calcd. C 62.6, H 11.4; found C 62.7, H 11.1.
(R)-3-(Methoxymethoxy)-2-methylpent-4-ene-2-ol (8): A solution of
7 (1.01 g, 7.0 mmol) in dry, degassed CH2Cl2 (30 mL) was cooled
to 0 °C. MeMgCl (3 m in THF; 4.7 mL, 14.0 mmol) was slowly
added by syringe, and the reaction mixture was stirred at 0 °C for
1 h. The reaction mixture was poured into a stirred water/diethyl
ether mixture, and a saturated aqueous solution of tartaric acid
was added. The organic layer was separated, the aqueous layer was
extracted with diethyl ether, and the combined organic layers were
washed with brine and then dried with MgSO4. The residue was
purified by column chromatography on silica to give 8 (937 mg,
5.9 mmol, 84%) as a colourless liquid. [α]2D2 = –78.5 (c = 0.98,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 5.72 (ddd, J = 17.2,
10.5, 8.2 Hz, 1 H), 5.35–5.24 (m, 2 H), 4.72 (d, J = 6.7 Hz, 1 H),
4.57 (d, J = 6.7 Hz, 1 H), 3.77 (d, J = 8.2 Hz, 1 H), 3.39 (s, 3 H),
2.44 (s, 1 H), 1.20 (s, 3 H), 1.16 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 134.5 (1), 120.2 (2), 94.2 (2), 84.8 (1), 71.8 (0), 55.7
(2S,3R)-2-(tert-Butyldimethylsilyloxy)-3-(methoxymethoxy)pent-4-
ene (5): A solution of 3 (2.00 g, 9.2 mmol) in dry, degassed CH2Cl2
(100 mL) was cooled to 0 °C. MOM bromide (90 wt.-%; 1.7 mL,
18.7 mmol) and NEt(iPr)2 (4.7 mL, 33.8 mmol) were added, and
the reaction mixture was heated to reflux for 12 h. The reaction
was quenched by the addition of water, then the aqueous layer was
separated and extracted with MTBE. The combined organic ex-
tracts were dried with MgSO4 and filtered, and the solvents were
evaporated. The residue was purified by column chromatography
on silica to give 5 (2.35 g, 9.0 mmol, 98%) as a colourless liquid.
[α]2D2 = –56.0 (c = 0.53, CH2Cl2). H NMR (300 MHz, CDCl3): δ
1
= 5.73 (ddd, J = 16.9, 10.8, 7.4 Hz, 1 H), 5.29–5.19 (m, 2 H), 4.70
(d, J = 6.6 Hz, 1 H), 4.58 (d, J = 6.6 Hz, 1 H), 3.87–3.77 (m, 2 H),
3.37 (s, 3 H), 1.15 (d, J = 6.1 Hz, 3 H), 0.88 (s, 9 H), 0.06 (s, 3 H),
0.05 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 135.6 (1),
118.6 (2), 94.0 (2), 81.7 (1), 70.8 (1), 55.4 (3), 25.8 (3), 19.6 (3), 18.1
(3), 26.1 (3), 24.6 (3) ppm. IR (neat): ν = 3465 (w), 2976 (w), 1372
˜
(w), 1146 (m), 1030 (s), 919 (s) cm–1. MS (EI): m/z (%) = 161 (55)
[M + H]+, 139 (24), 129 (73), 113 (44), 99 (23), 91 (100). HRMS
(ESI): calcd. for C8H17O3 [M + H]+ 161.1178; found 161.1182.
C8H16O3 (160.21): calcd. C 60.0, H 10.1; found C 60.2, H 9.9.
(0), –4.6 (3), –4.7 (3) ppm. IR (neat): ν = 2929 (w), 2857 (w), 1252
˜
(m), 1100 (m), 1034 (s), 830 (s), 774 (s) cm–1. MS (EI): m/z (%) =
283 (4) [M + Na]+, 265 (19), 227 (100), 213 (82), 199 (33), 159 (33),
147 (21), 133 (28), 115 (49). HRMS (ESI): calcd. for C13H28O3NaSi
[M + Na]+ 283.1705; found 283.1719. C13H28O3Si (260.45): calcd.
C 60.0, H 10.8; found C 60.0, H 11.0.
(R)-3-[(Methoxymethoxy)-2-methylpent-4-en-2-yl]acrylate (9):
NEt(iPr)2 (1.00 mL, 12.6 mmol) and acryloyl chloride (2.7 mL,
15.7 mmol) were added to a solution of 8 (1.00 g, 6.3 mmol) in dry,
degassed CH2Cl2 (20 mL). The mixture was heated to reflux for
8 h, and then it was stirred at ambient temperature for 10 h. The
reaction was quenched by the addition of aqueous NaHCO3 solu-
tion, and the mixture was extracted with MTBE. The organic layer
was separated, dried with MgSO4 and filtered, and the solvents
were evaporated. The residue was purified by column chromatog-
raphy on silica to give 9 (1.20 g, 5.5 mmol, 87%) as a colourless
liquid. [α]2D5 = –64.0 (c = 0.84, CH2Cl2). 1H NMR (300 MHz,
CDCl3): δ = 6.31 (dd, J = 17.3, 1.4 Hz, 1 H), 6.05 (dd, J = 17.3,
(2S,3R)-3-(Methoxymethoxy)pent-4-ene-2-ol (6): Compound 5
(2.30 g, 8.8 mmol) and TBAF·3H2O (4.62 g, 17.7 mmol) were dis-
solved in THF (100 mL), and the mixture was stirred for 16 h at
ambient temperature. The mixture was diluted with diethyl ether
and washed with brine. The organic layer was separated, dried with
MgSO4, and filtered, and the solvents were evaporated. The residue
was purified by column chromatography on silica using pentane/
diethyl ether (5:1) as eluent, to give 6 (1.19 g, 8.2 mmol, 93%) as a
colourless liquid. [α]2D1 = –111.6 (c = 0.68, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 5.76 (ddd, J = 17.4, 10.6, 7.6 Hz, 1 H),
5.37–5.25 (m, 2 H), 4.71 (d, J = 6.7 Hz, 1 H), 4.60 (d, J = 6.7 Hz, 10.3 Hz, 1 H), 5.82–5.68 (m, 2 H), 5.36–5.28 (m, 2 H), 4.70 (d, J
1 H), 3.93 (dd, J = 7.6, 3.8 Hz, 1 H), 3.87 (qd, J = 6.3, 3.8 Hz, 1
H), 3.38 (s, 3 H), 2.28 (br. s, 1 H), 1.14 (d, J = 6.4 Hz, 3 H) ppm.
= 6.7 Hz, 1 H), 4.56 (d, J = 6.7 Hz, 1 H), 4.36 (d, J = 7.8 Hz, 1
H), 3.37 (s, 3 H), 1.51 (s, 3 H), 1.53 (s, 3 H) ppm. 13C NMR
1956
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1951–1960

Metathesis-Based De Novo Synthesis of Noviose
(75 MHz, CDCl3): δ = 165.5 (0), 133.8 (1), 130.1 (1), 129.7 (2),
120.3 (2), 94.3 (2), 83.5 (0), 81.5 (1), 55.8 (3), 22.4 (3), 22.3 (3) ppm.
1034 (s), 969 (m) cm–1. MS (EI): m/z (%) = 128 (38), 99 (4), 83 (4),
55 (7), 45 (100), 43 (22). HRMS (EI): calcd. for C9H14O4 [M]+
IR (neat): ν = 2986 (w), 1721 (s), 1403 (m), 1206 (s), 1032 (s), 919 186.0892; found 186.0909. C9H14O4 (186.21): calcd. C 58.1, H 7.6;
˜
(m) cm–1. MS (EI): m/z (%) = 215 (3) [M + H]+, 115 (16), 75 (23),
73 (46), 55 (62), 45 (62), 41 (100). HRMS (ESI): calcd. for
C11H18O4Na [M + Na]+ 237.1103; found 237.1113. C11H18O4
(214.26): calcd. C 61.7, H 8.5; found C 61.5, H 8.5.
found C 57.8, H 7.4.
(R)-5-Hydroxy-6,6-dimethyl-3,4-dihydropyran-2-one (12a) and (R)-
5-(2-Hydroxypropan-2-yl)furan-2(5H)-one (12b)
Method 1: MOM-protected lactone 11 (433 mg, 2.34 mmol) was
dissolved in a mixture of CH2Cl2 (8 mL) and CF3CO2H (2 mL).
The solution was stirred at ambient temperature for 16 h. All the
volatiles were evaporated under reduced pressure. The residue was
dissolved in MTBE, and the solution was washed with Na2CO3
(aq.). The aqueous layer was separated and extracted with MTBE.
The organic extracts were dried with MgSO4 and filtered, and the
solvents were evaporated. The residue was purified by chromatog-
raphy on silica to give 12a (324 mg, 2.31 mmol, quant.) as a colour-
less oil.
(R)-4-(Allyloxy)-3-(methoxymethoxy)-4-methylpent-1-ene (10):
NaHMDS (1.5 m in THF; 3.4 mL, 5.0 mmol) was added to a solu-
tion of 8 (400 mg, 2.5 mmol) in dry, degassed THF (20 mL). The
solution was stirred at ambient temperature for 1 h, and then allyl
bromide (0.9 mL, 10.0 mmol) was added. The reaction mixture was
heated to reflux for 16 h. After cooling to ambient temperature, the
reaction was quenched by the addition of water. The aqueous layer
was extracted with MTBE. The combined organic layers were
washed with brine, dried with MgSO4 and filtered, and the solvents
were evaporated. The residue was purified by column chromatog-
raphy to give 10 (377 mg, 1.9 mmol, 75%) as a colourless liquid.
Method 2: Compound 11 (193 mg, 1.00 mmol) was dissolved in
THF (5 mL), and HCl (2 m aq.; 5 mL) was added. The mixture was
stirred for 16 h at ambient temperature, and then for 5 h at 40 °C.
A saturated aqueous solution of Na2CO3 was carefully added, and
the aqueous layer was separated and extracted with MTBE. The
combined organic extracts were dried with MgSO4 and filtered, and
the solvents were evaporated. The residue was purified by
chromatography on silica to give 12a (120 mg, 0.80 mmol, 82%)
and 12b (27 mg, 0.10 mmol, 14%) as colourless oils.
1
[α]2D2 = –77.3 (c = 0.77, CH2Cl2). H NMR (300 MHz, CDCl3): δ
= 5.91 (ddd, J = 17.2, 10.4, 5.2 Hz, 1 H), 5.81 (ddd, J = 17.2, 10.5,
7.7 Hz, 1 H), 5.32–5.19 (m, 3 H), 5.08 (ddd, J = 10.4, 3.4, 1.5 Hz,
1 H), 4.70 (d, J = 6.7 Hz, 1 H), 4.66 (d, J = 6.7 Hz, 1 H), 4.00
(dddd, J = 5.2, 4.2, 1.6, 1.6 Hz, 2 H), 3.94 (dm, J = 7.6 Hz, 1 H),
3.38 (s, 3 H), 1.22 (s, 3 H), 1.20 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 136.1 (1), 134.8 (1), 119.1 (2), 115.3 (2), 94.2 (2), 82.6
(1), 65.8 (0), 63.2 (2), 55.7 (3), 22.8 (3), 21.9 (3) ppm. IR (neat): ν
˜
= 2980 (w), 1381 (w), 1146 (m), 1033 (s), 917 (s) cm–1. MS (EI):
m/z (%) = 223 (100) [M + Na]+, 214 (51), 197 (30), 169 (36), 139
(7). HRMS (ESI): calcd. for C11H20O3Na [M + Na]+ 223.1310;
found 223.1325. C11H20O3 (200.27): calcd. C 66.0, H 10.1; found
C 65.9, H 10.0.
Analytical data for 12a: [α]2D1 = –62.4, (c = 0.53, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 6.81, (dd, J = 9.8, 4.0 Hz, 1 H), 6.00, (dd,
J = 9.9, 1.4 Hz, 1 H), 4.18, (d, J = 3.0 Hz, 1 H), 3.34, (br. s, 1 H),
1.44, (s, 3 H), 1.43, (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 163.4, (0), 146.1, (1), 121.1, (1), 83.6, (0), 68.3, (1), 26.3, (3), 21.7,
(3) ppm. MS (EI): m/z = 84, (100), 55, (47), 43, (25), 39, (12).
HRMS (EI): calcd. for C7H10O3 [M]+ 142.0630; found 142.0633.
(R)-5-(Methoxymethoxy)-6,6-dimethyl-3,4-dihydropyran-2-one (11)
By RCM of Acrylate 9: Phenol (44 mg, 0.47 mmol) was dissolved
in toluene (30 mL) in a three-necked round-bottomed flask
equipped with two dropping funnels and a reflux condenser, and
the solution was heated to reflux. Solutions of acrylate 9 (200 mg,
0.94 mmol) in toluene (30 mL) and precatalyst B (40 mg, 5 mol-%)
in toluene (30 mL) were simultaneously added dropwise using the
two dropping funnels at 110 °C. After the addition of both solu-
tions was complete, the heating to reflux was continued for a fur-
ther 2 h. Then the mixture was cooled to ambient temperature and
evaporated, and the residue was purified by column chromatog-
raphy on silica to give 11 (156 mg, 0.84 mmol, 89%) as a colourless
oil.
Analytical data for 12b: [α]2D1 = +1.9 (c = 0.58, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.51 (dd, J = 5.8, 1.5 Hz, 1 H), 6.18 (dd,
J = 5.8, 2.0 Hz, 1 H), 4.87 (d, J = 2.0, 1.5 Hz, 1 H), 2.55 (s, 3 H),
1.27 (s, 3 H), 1.26 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
173.3 (0), 153.9 (1), 122.7 (1), 89.5 (1), 71.6 (0), 28.6 (3), 25.3 (3)
ppm. IR (neat): ν = 3416 (s), 2980 (m), 1740 (s), 1172 (m), 1096
˜
(m), 827 (m) cm–1. HRMS (EI): C7H10O3Na [M + Na]+ 165.0528;
found 165.0531.
(R)-5-Methoxy-6,6-dimethyltetrahydro-2H-pyran-2-one (13b): NaH
(60 wt.-% dispersion in mineral oil; 31 mg, 0.77 mmol) and MeI
(0.08 mL, 1.28 mmol) were added to a solution of 12a (90 mg,
0.64 mmol) in DMF (5 mL), and the mixture was heated at 80 °C
for 16 h. The mixture was cooled to ambient temperature, then the
reaction was quenched by the careful addition of water, and the
mixture was extracted twice with MTBE. The combined organic
extracts were dried with MgSO4 and filtered, and the solvents were
evaporated. The residue was purified by chromatography on silica
to give hydrogenated product 13b (20 mg, 0.13 mmol, 20%) as a
colourless oil. 1H NMR (300 MHz, CDCl3): δ = 3.67 (s, 3 H), 3.60
(m, 1 H), 2.89–2.85 (m, 2 H), 2.68–2.63 (m, 2 H), 1.40 (s, 3 H),
1.40 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 173.0 (0), 76.3
(0), 51.8 (3), 30.5 (2), 27.8 (2), 26.6 (3), 26.6 (3) ppm.
By RCM/Allylic Oxidation: A solution of 10 (300 mg, 1.51 mmol)
in dry, degassed benzene (15 mL) was heated to 40 °C. First genera-
tion Grubbs’ catalyst A (62 mg, 5 mol-%) was added, and the mix-
ture was stirred at 40 °C until the starting material had been fully
consumed, as indicated by TLC (approx. 2 h). tBuOOH (5.5 m in
decane; 1.10 mL, 6.04 mmol) was added over a period of 20 min
using a syringe pump, and the stirring at 40 °C was continued for
3 h. The mixture was cooled to ambient temperature, then it was
diluted with MTBE and filtered through a short pad of silica. All
the volatiles were evaporated, and the residue was purified by
chromatography on silica to give 11 (145 mg, 0.77 mmol, 51%) as
a colourless oil. [α]2D4 = –91.7 (c = 0.60, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 6.80 (dd, J = 9.9, 3.4 Hz, 1 H), 6.04 (dd,
J = 9.9, 1.4 Hz, 1 H), 4.76 (d, J = 7.0 Hz, 1 H), 4.69 (d, J = 7.0 Hz,
(R)-5-Methoxy-6,6-dimethyl-5,6-dihydropyran-2-one (13a): Ag2O
(105 mg, 0.45 mmol) was added to a solution of 12a (58 mg,
0.41 mmol) in MeI (0.6 mL). The reaction mixture was stirred in
1 H), 4.13 (dd, J = 3.4, 1.4 Hz, 1 H), 3.40 (s, 3 H), 1.46 (s, 3 H), the dark for 2 d at reflux temperature. After cooling to ambient
1.42 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.6 (0), temperature, the mixture was diluted with CH2Cl2, and filtered
144.7 (1), 121.4 (1), 96.6 (2), 82.6 (0), 74.2 (1), 55.9 (3), 26.6 (3),
through a short pad of Celite, which was subsequently washed with
21.9 (3) ppm. IR (neat): ν = 2940 (w), 1715 (s), 1292 (m), 1108 (s), MTBE. All the volatiles were evaporated, and the residue was puri-
˜
Eur. J. Org. Chem. 2014, 1951–1960
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1957

B. Schmidt, S. Hauke
FULL PAPER
fied by chromatography on silica to give 13a (64 mg, 0.41 mmol,
and K2Os(OH)6 (8.1 mg, 0.022 mmol, 4.6 mol-%) were added to
the solution, and the resulting mixture was stirred at ambient tem-
quant.) as a colourless oil. [α]2D3 = –124.7 (c = 0.33, CHCl3). 1H
NMR (300 MHz, CDCl3): δ = 6.80 (dd, J = 10.0, 3.0 Hz, 1 H), perature for 16 h. MgSO4 was added to the mixture, which was
6.03 (dd, J = 10.0, 1.5 Hz, 1 H), 3.82 (dd, J = 2.9, 1.6 Hz, 1 H),
3.45 (s, 3 H), 1.45 (s, 3 H), 1.36 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 162.7 (0), 143.6 (1), 121.4 (1), 82.9 (0), 77.9 (1), 57.9
then filtered, and the filter cake was thoroughly washed with ethyl
acetate. All the volatiles were evaporated from the filtrate, and the
residue was purified by column chromatography on silica (ethyl
acetate and then ethyl acetate/methanol, 9:1) to give l-(+)-noviose
(3), 26.9 (3), 21.3 (3) ppm. IR (neat): ν = 2986 (w), 2939 (w), 2830
˜
(w), 1715 (s), 1275 (m), 1110 (s), 973 (m) cm–1. MS (EI): m/z (%) (58 mg, 0.30 mmol, 63%) as a mixture of α and β anomers (1:2
= 125 (11), 98 (71), 43 (100), 41 (27). HRMS (ESI): calcd. for
C8H12O3Na [M + Na]+ 179.0684; found 179.0691. C8H12O3
(156.18): calcd. C 61.5, H 7.7; found C 61.4, H 8.1.
ratio). [α]2D5 = +29.7 (c = 0.30, EtOH/H2O, 1:1). 1H NMR
(500 MHz, [D4]methanol): δ = 5.00 (d, J = 3.4 Hz, 1 H, α, minor),
4.86 (d, J = 0.8 Hz, 1 H, β, major), 3.99 (dd, J = 8.3, 3.4 Hz, 1 H,
minor), 3.77 (dd, J = 3.2, 1.1 Hz, 1 H, major), 3.70 (dd, J = 3.4,
3.4 Hz, 1 H, minor), 3.66 (dd, J = 10.0, 3.4 Hz, 1 H, major), 3.57
(s, 3 H, major), 3.53 (s, 3 H, minor), 3.21 (d, J = 8.3 Hz, 1 H,
minor), 3.17 (d, J = 10.0 Hz, 1 H, major), 1.31 (s, 3 H, minor),
1.28 (s, 3 H, major), 1.27 (s, 3 H, minor), 1.14 (s, 3 H, major) ppm.
13C NMR (125 MHz, [D4]methanol): δ = 95.6, 91.0, 85.8, 85.2,
78.1, 75.1, 73.8, 73.3, 72.5, 69.7, 62.2, 61.5, 29.0, 28.5, 25.1,
(4R,E)-5-Hydroxy-4-methoxy-5-methylhex-2-enal (E-15): A solu-
tion of 13a (100 mg, 0.64 mmol) in CH2Cl2 (6.4 mL) was cooled to
–78 °C, and DIBAl-H (1.1 m in cyclohexane; 1.75 mL, 1.92 mmol)
was added. The mixture was stirred at this temperature until the
starting material had been fully consumed (TLC, approx. 0.25 h).
Then the reaction was quenched by the addition of methanol
(2.2 mL). The reaction mixture was warmed to ambient tempera-
ture, a saturated aqueous solution of sodium potassium tartrate
was added, and the resulting mixture was stirred for 1 h. The aque-
ous layer was separated and extracted with diethyl ether, the com-
bined organic extracts were dried with MgSO4 and filtered, and the
solvents were evaporated. NMR spectroscopy of the crude reaction
mixture revealed the presence of Z-15, a minor amount of E-15,
and anomeric lactols 14.
Selected spectroscopic data of Z-15 obtained from the mixture: 1H
NMR (300 MHz, CDCl3): δ = 10.08 (d, J = 7.5 Hz, 1 H), 6.44 (dd,
J = 11.6, 9.4 Hz, 1 H), 6.23 (dd, J = 11.6, 7.5 Hz, 1 H), 4.29 (d, J
= 9.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.9 (1),
147.5 (1), 133.8 (1), 83.1 (1) ppm.
Selected spectroscopic data of the anomers of 14: 1H NMR
(300 MHz, CDCl3): δ = 6.05–5.93 (m, 1 H), 5.87–5.80 (m, 1 H),
5.38–5.30 (br. m, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 128.5
(1, major anomer), 128.3 (1, minor anomer), 127.8 (1, major an-
omer), 127.7 (1, minor anomer), 89.0 (1, major anomer), 88.8 (1,
minor anomer) 79.2 (1, minor anomer), 78.4 (1, major anomer)
ppm.
18.6 ppm. IR (neat): ν = 3392 (s), 2933 (w), 1595 (w), 1329 (m),
˜
1102 (s), 1023 (s), 774 (s) cm–1. HRMS (ESI): calcd. for
C8H16O5Na [M + Na]+ 215.0895; found 215.0892.
(R)-3-(Methoxymethoxy)-2,2-dimethyl-3,6-dihydro-2H-pyran (16):
First generation Grubbs’ catalyst A (52 mg, 5 mol-%) was added
to a solution of 10 (250 mg, 1.3 mmol) in dry, degassed CH2Cl2
(12.5 mL), and the solution was heated to reflux for 1 h. After cool-
ing to ambient temperature, the solvent was evaporated, and the
residue was purified by chromatography on silica to give 16
(163 mg, 1.0 mmol, 75%) as a colourless oil. [α]2D1 = –72.1 (c = 0.86,
CH2Cl2). 1H NMR (300 MHz, CDCl3): δ = 5.86–5.77 (m, 2 H),
4.77 (d, J = 6.8 Hz, 1 H), 4.65 (d, J = 6.9 Hz, 1 H), 4.20–4.03 (m,
2 H), 3.77 (m, 1 H), 3.39 (s, 3 H), 1.26 (s, 3 H), 1.21 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 127.9 (1), 125.1 (1), 96.1 (2), 75.4
(1), 72.7 (0), 61.1 (2), 55.6 (3), 25.3 (3), 20.5 (3) ppm. IR (neat): ν
˜
= 2933 (w), 1727 (w), 1144 (m), 1035 (s), 917 (m) cm–1. HRMS
(ESI): calcd. for C9H17O3 [M + H]+ 173.1178; found 173.1190.
(3S,4S,5R)-5-(Methoxymethoxy)-6,6-dimethyltetrahydro-2H-
pyran-3,4-diol (17): Dihydropyran 16 (172 mg, 1.0 mmol) was dis-
solved in a mixture of acetone (3 mL), water (1 mL), and tert-but-
anol (1 mL). N-Methylmorpholine N-oxide (352 mg, 3.0 mmol),
methane sulfonamide (95 mg, 1.0 mmol), and K2Os(OH)6
(17.0 mg, 0.046 mmol, 4.6 mol-%) were added to this solution, and
the resulting mixture was stirred at ambient temperature for 4 h. A
saturated aqueous solution of Na2S2O3 was added, and the mixture
was stirred for 1 h. The aqueous layer was separated and extracted
with ethyl acetate, the combined organic layers were dried with
MgSO4 and filtered, and the solvents were evaporated. The residue
was purified by chromatography on silica (hexane/ethyl acetate, 1:7)
to give diol 17 (151 mg, 0.73 mmol, 73%) as a colourless solid, m.p.
The crude mixture was purified by column chromatography on sil-
ica to give aldehyde E-15 (102 mg, 0.64 mmol, quant.) as a colour-
less oil. [α]2D4 = –66.3 (c = 0.40, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 9.61 (d, J = 7.8 Hz, 1 H), 6.74 (dd, J = 15.9, 6.7 Hz,
1 H), 6.29 (ddd, J = 15.9, 7.8, 0.8 Hz, 1 H), 3.63 (d, J = 6.2 Hz, 1
H), 3.36 (s, 3 H), 2.51 (br. s, 1 H), 1.21 (s, 3 H), 1.15 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 192.9 (1), 152.7 (1), 134.8 (1),
87.8 (1), 72.4 (0), 58.1 (3), 25.8 (3), 24.8 (3) ppm. IR (neat): ν =
˜
3442 (m), 2935 (m), 1688 (s), 1100 (s), 981 (m) cm–1. MS (EI): m/z
(%) = 149 (73), 141 (77), 100 (86), 71 (100), 59 (72), 45 (74). HRMS
(ESI): calcd. for C8H13O3 [M + H]+ 157.0865; found 157.0854.
1
63–64 °C. [α]2D5 = +53.1 (c = 0.30, CH3CN). H NMR (300 MHz,
L-(+)-Noviose: A solution of 13a (75 mg, 0.48 mmol) in dry, de-
[D4]methanol): δ = 4.87 (d, J = 6.6 Hz, 1 H), 4.85 (br. s, 2 H), 4.68
(d, J = 6.6 Hz, 1 H), 3.82 (m, 1 H), 3.72 (dd, J = 12.8, 1.5 Hz, 1
H), 3.67 (dd, J = 9.4, 3.5 Hz, 1 H), 3.63 (dd, J = 12.8, 2.3 Hz, 1
H), 3.47 (d, J = 9.5 Hz, 3 H), 3.41 (s, 3 H), 1.29 (s, 3 H), 1.16 (s,
3 H) ppm. 13C NMR (75 MHz, [D4]methanol): δ = 99.8, 83.6, 77.1,
gassed CH2Cl2 was cooled to –78 °C. DIBAl-H (1.1 m in cyclohex-
ane; 1.31 mL, 1.44 mmol) was added, and the resulting solution
was stirred until the starting material had been fully consumed, as
indicated by TLC (approx. 0.25 h). The reaction was quenched by
the addition of methanol (2 mL), then the mixture was warmed
to ambient temperature, a saturated aqueous solution of sodium
potassium tartrate was added, and the mixture was stirred for 1 h.
The aqueous layer was separated and extracted with diethyl ether,
the combined organic extracts were dried with MgSO4 and filtered,
and the solvents were evaporated. The crude product was redis-
solved without delay in a mixture of acetone (1.5 mL), water
(0.5 mL), and tert-butanol (0.5 mL). N-Methylmorpholine N-oxide
71.8, 71.0, 65.3, 56.3, 28.4, 18.0 ppm. IR (neat): ν = 3412 (s), 2935
˜
(m), 1097 (s), 1036 (s), 767 (m) cm–1. MS (EI): m/z (%) = 180 (20),
117 (23), 85 (62), 82 (97), 45 (61). HRMS (ESI): calcd. for C9H19O5
[M + H]+ 207.1232; found 207.1239. C9H18O5 (206.24): calcd. C
52.4, H 8.8; found C 52.3, H 8.8.
(R)-3-(Methoxymethoxy)-2,2-dimethyl-3,4-dihydro-2H-pyran (18):
First generation Grubbs’ catalyst A (47.5 mg, 5 mol-%) was added
(167 mg, 1.42 mmol), methane sulfonamide (46 mg, 0.48 mmol), to a solution of 10 (230 mg, 1.2 mmol) in dry, degassed toluene
1958 Eur. J. Org. Chem. 2014, 1951–1960
www.eurjoc.org
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Metathesis-Based De Novo Synthesis of Noviose
(12 mL), and the mixture was heated to 80 °C until the starting
material had been fully consumed (approx. 0.5 h). 2-Propanol
(3 mL) and NaOH (solid, 23 mg, 0.06 mmol) were added, and the
mixture was heated to reflux until the intermediate RCM product
had been fully converted (TLC, approx. 4 h). The mixture was co-
oled to ambient temperature, and water and MTBE were added.
The aqueous layer was separated and extracted with MTBE, the
combined organic extracts were dried with MgSO4 and filtered, and
the solvents were evaporated. The residue was purified by
chromatography on silica to give 18 (125 mg, 0.8 mmol, 68%) as a
colourless oil. [α]2D2 = –24.0 (c = 0.58, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 6.24 (ddd, J = 6.1, 1.9, 1.9 Hz, 1 H), 4.75
(d, J = 6.9 Hz, 1 H), 4.64 (d, J = 6.9 Hz, 1 H), 4.59 (ddd, J = 6.1,
4.0, 4.0 Hz, 1 H), 3.56 (dd, J = 6.9, 5.4 Hz, 1 H), 3.39 (s, 3 H), 2.29
(dddd, J = 17.1, 5.5, 4.2, 1.8 Hz, 1 H), 2.02 (dddd, J = 17.1, 6.9,
3.3, 2.1 Hz, 1 H), 1.29 (s, 3 H), 1.23 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 141.7 (1), 96.8 (1), 95.6 (2), 75.6 (0), 75.3
ppm. 13C NMR (75 MHz, CDCl3): δ = 142.4 (0), 135.7 (1), 134.4
(1), 127.8 (1), 127.3 (1), 127.1 (1), 118.6 (2), 115.0 (2), 94.7 (2), 83.8
(1), 81.6 (0), 63.8 (2), 55.4 (3), 18.8 (3) ppm. IR (neat): ν = 2984
˜
(m), 2888 (m), 1446 (m), 1027 (s), 918 (s), 701 (s) cm–1. HRMS
(ESI): calcd. for C16H23O3 [M + H]+ 263.1647; found 263.1660.
(2R,3R)-3-(Methoxymethoxy)-2-methyl-2-phenyl-3,4-dihydro-2H-
pyran (21): First generation Grubbs’ catalyst A (9.1 mg, 5 mol-%)
was added to a solution of ether 20 (58 mg, 0.22 mmol) in dry,
degassed toluene (2.2 mL). The solution was heated to 80 °C until
the starting material had been fully converted (TLC, approx. 2 h).
2-Propanol (0.46 mL) and NaOH (solid, 4.4 mg, 0.11 mmol) were
added, and the mixture was heated to reflux until the intermediate
RCM product had been fully converted (TLC, approx. 3 h). The
mixture was cooled to ambient temperature, and water and MTBE
were added. The aqueous layer was separated and extracted with
MTBE, the combined organic extracts were dried with MgSO4 and
filtered, and the solvents were evaporated. The residue was purified
by chromatography on silica to give 21 (40 mg, 0.17 mmol, 77%)
as a colourless oil. [α]2D2 = –34.1 (c = 0.20, CH2Cl2). 1H NMR
(300 MHz, CDCl3): δ = 7.53 (dm, J = 7.3 Hz, 2 H), 7.33 (ddm, J
= 7.8, 7.1 Hz, 2 H), 7.24 (m, 1 H), 6.50 (ddd, J = 6.2, 1.8, 1.7 Hz,
1 H), 4.67 (m, 1 H), 4.59 (d, J = 7.1 Hz, 1 H), 4.32 (d, J = 7.1 Hz,
1 H), 3.97 (dd, J = 4.6, 4.6 Hz, 1 H), 2.97 (s, 3 H) 2.35 (dddd, J =
17.4, 4.7, 3.2, 2.3 Hz, 1 H), 2.02 (dddd, J = 17.3, 4.6, 4.3, 1.6 Hz,
1 H), 1.56 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.8,
142.0, 127.9, 126.7, 125.5, 97.3, 95.2, 79.0, 75.4, 55.3, 25.4,
(1), 55.6 (3), 25.4 (3), 24.3 (2), 20.6 (3) ppm. IR (neat): ν = 3063
˜
(m), 2934 (m), 1652 (s), 1247 (s), 1041 (s) cm–1. MS (EI): m/z (%)
= 172, (2) [M]+, 116 (5), 110 (33), 95 (32), 85 (11), 71 (18), 57 (23),
45 (100), 43 (40). HRMS (EI): calcd. for C9H16O3 [M]+ 172.1099;
found 172.1084. C9H16O3 (172.22): calcd. C 62.8, H 9.4; found C
62.4, H 9.0.
(2R,3R)-3-(Methoxymethoxy)-2-phenylpent-4-ene-2-ol (19): A solu-
tion of ketone 7 (300 mg, 2.1 mmol) in dry, degassed CH2Cl2
(20 mL) was cooled to 0 °C. Phenylmagnesium chloride (25 wt.-%
solution in THF; 1.5 mL, 2.7 mmol) was added slowly, and the
reaction mixture was stirred for 1 h at 0 °C. It was then poured
into water/diethyl ether (1:1), and a saturated aqueous solution of
tartaric acid was added. The aqueous layer was separated and ex-
tracted with diethyl ether, the combined organic layers were washed
with brine, dried with MgSO4, and filtered, and the solvents were
evaporated. The residue was purified by column chromatography
on silica to give alcohol 19 (334 mg, 1.5 mmol, 72%) as a colourless
liquid. [α]2D3 = –42.1 (c = 0.44, CHCl3). 1H NMR (300 MHz,
CDCl3): δ = 7.58–7.19 (m, 5 H), 5.78 (ddd, J = 17.3, 10.4, 8.0 Hz,
1 H), 5.36 (ddd, J = 10.4, 1.8, 0.6 Hz, 1 H), 5.26 (ddd, J = 17.3,
1.7, 0.8 Hz, 1 H), 4.64 (d, J = 6.8 Hz, 1 H), 4.39 (d, J = 6.8 Hz, 1
H), 4.19 (d, J = 8.1 Hz, 1 H), 2.94 (s, 3 H), 1.46 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 133.8 (1), 131.4 (0), 127.9 (1), 126.7
(1), 125.5 (1), 120.5 (2), 93.9 (2), 84.1 (1), 75.8 (0), 55.4 (3), 25.4
24.2 ppm. IR (neat): ν = 2931 (m), 1653 (m), 1244 (m), 1150 (m),
˜
1038 (s), 764 (m), 700 (m) cm–1. HRMS (ESI): calcd. for C14H19O3
[M + H]+ 235.1334; found 235.1332.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra for all products.
Acknowledgments
This work was generously supported by the Deutsche Forschungs-
gemeinschaft (DFG) (grant number Schm 1095/6-2). The authors
thank Evonik Oxeno for generous donations of solvents.
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Eur. J. Org. Chem. 2014, 1951–1960
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1959

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Received: October 28, 2013
Published Online: January 17, 2014
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