Ring-closing metathesis of α-ester-substituted enol ethers: Application to the shortest synthesis of KDO

Article abstract of DOI:10.1016/S0040-4020(03)00819-6

Ring-closing metathesis reactions of α-ester-substituted enol ethers are described. In the case of unsubstituted terminal olefins, isomerization prior to cyclization was observed as an undesired side reaction, which could not be completely inhibited. Furt

Full text of DOI:10.1016/S0040-4020(03)00819-6

Tetrahedron 59 (2003) 6751–6758
Ring-closing metathesis of a-ester-substituted enol ethers:
application to the shortest synthesis of KDO
*
Koen F. W. Hekking, Floris L. van Delft and Floris P. J. T. Rutjes
Department of Organic Chemistry, NSRIM, University of Nijmegen, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands
Received 2 April 2003; revised 10 April 2003; accepted 10 April 2003
This paper is dedicated to our inspirator Professor K. C. Nicolaou
Abstract—Ring-closing metathesis reactions of a-ester-substituted enol ethers are described. In the case of unsubstituted terminal olefins,
isomerization prior to cyclization was observed as an undesired side reaction, which could not be completely inhibited. Furthermore, this
methodology was applied to a formal synthesis of KDO, which now represents the shortest synthetic pathway to KDO and its deoxy
analogue. Interestingly, in this route olefin isomerization was not observed, presumably due to the increased steric environment of the double
bond. Finally, an efficient two-step conversion to transform an alcohol into an a-alkoxy acrylate is also described.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
might eventually provide practical pathways to biologically
relevant natural products such as the ulosonic acids KDO (4,
3-deoxy-D-manno-2-octulosonic acid) and 2-deoxy KDO
(5),9 and the sialic acids KDN (6, 3-deoxy-D-glycero-D-
galacto-2-nonulosonic acid) and N-acetylneuraminic acid
(Neu5Ac (7), 5-acetamido-3,5-dideoxy-D-glycero-D-
galacto-2-nonulosonic acid).10,11
In the past decade, ring-closing metathesis (RCM) has
emerged as a powerful tool for the synthetic organic
chemist.1 During this period, the scope of this type of
reaction has been continuously increased starting from
regular terminal olefins to olefins that are substituted with
very different electron-withdrawing or electron-donating
substituents. Many examples nowadays exist where
electron-poor olefins have been cyclized in high yields,2
including results from our own group.3 On the other hand,
RCM of electron-rich olefins—substituted with heteroatoms
such as oxygen or nitrogen—is also encountered. Early
examples of electron-rich olefins involve Ti-mediated
cyclization reactions of enol ethers,4 followed by other
examples where either Mo-catalysts5 or Ru-catalysts have
been used.6 In addition, our group was the first to
demonstrate that electron-rich enamide double bonds
could be efficiently cyclized into their cyclic counterparts,7
which was later also shown by others in the synthesis of
indoles.8 Considering these reactions, we realized that there
are virtually no RCM examples of olefins substituted with
both electron-withdrawing and electron-donating sub-
stituents (e.g. olefin 2, Scheme 1). Notwithstanding, we
anticipated that such a transformation would hold a
considerable potential since cyclic ethers 1 are formed,
which may be synthetically useful building blocks. We also
envisaged that if such cyclizations are successful, more
elaborated cyclic ethers 3 could be synthesized, which
2. RCM of ester-substituted enol ethers
Initially, we set out to investigate the potential of the RCM
reaction for the generation of unsaturated oxygen hetero-
cycles 1 as shown in Scheme 1. We thereby focused on the
generation of small six- and seven-membered ring systems
as well as on a twelve-membered ring oxacycle.
Keywords: a-alkoxy acrylate; ring-closing metathesis; cross-metathesis.
*
Corresponding author. Tel.: þ31-24-365-3202; fax: þ31-24-365-3393;
e-mail: rutjes@sci.kun.nl
Scheme 1. RCM of a-ester-substituted enol ethers.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00819-6

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K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
the products showed the presence of an almost equal amount
of the five-membered heterocycle 12d together with the
anticipated six-membered ring 12a (entry 3), both of which
could not be separated by column chromatography.
Isomerization of the terminal double bond to the more
stable internal one prior to the cyclization reaction must be
the reason for this observation. This undesired side reaction
has very recently also been reported in a number of other
publications.7,13 In most cases, the isomerization has been
attributed to the presence of a ruthenium-hydride species,
although the exact nature and source of this catalyst
impurity is still unknown. More specifically, Grubbs has
reported that a Fischer–carbene complex, resulting from
reaction of the Ru-catalyst with a vinyl ether moiety, could
be converted into a Ru-H species upon prolonged heating.14
However, in the proposed mechanism it is the a-vinyl ether
hydrogen, which is effectively transferred to the Ru.15 This
can obviously not occur with compounds 11a–c, which all
lack such a hydrogen atom.
Scheme 2. Synthesis of the RCM precursors; phen¼1,10-phenanthroline.
2.1. Synthesis of the precursors
The precursors 11a–c for the formation of six-, seven- and
twelve-membered rings, respectively, were prepared from
the corresponding unsaturated alcohols 8 as shown in
Scheme 2. First, the alcohol functions were efficiently
vinylated in good yields according to a recently reported
procedure, using a Pd(OAc)2/phenanthroline catalyst and
ethyl vinyl ether.12 Next, the resulting vinyl ethers 9 were
lithiated using tert-butyllithium, followed by reaction with
CO2 at low temperature, resulting in the corresponding
lithium carboxylate salts 10. Subsequent addition of an
excess of benzyl bromide produced the desired benzyl esters
11 in moderate yields.
Figure 1. Different RCM catalysts.
Column chromatographic purification of catalyst B
immediately before use, as suggested by Snapper and
co-workers,16 significantly decreased the amount of
isomerization (entry 4). In contrast, the addition of
tricyclohexylphosphine oxide was reported by Nolan and
co-workers to slow down the catalysis and thereby inhibit
isomerization.13a Unfortunately, we found this not to be the
case for compound 11a. A slower reaction was indeed
observed, but this only resulted in formation of a substantial
amount of the homodimeric cross-metathesis product 13a
(entry 5). The use of catalysts C and D did not improve the
2.2. Ring-closing metathesis
Subjection of compound 11a to the first generation Grubbs’
catalyst A (Figure 1) at either 708C or 958C in toluene did
not result in any cyclization, but instead in the slow
formation of the homodimeric cross-metathesis product 13a
(Table 1, entries 1 and 2). The more reactive catalyst B, on
the other hand, showed cyclic products with a conversion of
85% at 708C within 2 h. Surprisingly, GC–MS analysis of
Table 1. RCM results of 11a using catalysts A–D
Entry
Catalyst (mol%)/additive (mol%)
Temperature (8C)
Solvent
Time (h)
12aa
12db
13aa
11aa
1
2
3
4
5
6
7
8
9
10
A (20)
A (20)
B (10)
70
95
70
70
Toluene
Toluene
Toluene
Toluene
Toluene
(ClCH2)2
Toluene
Toluene
Toluene
Toluene
40
18
2
–
–
–
–
56b
65b
–
–
23
–
9
–
59b
47
n.d.
n.d.
15
21
9
39
27
4
45
51
40
32
42
40
–
40
28
28
29
22
56
–
B (10)c
B (10)/Cy3PO (10)
B (10)
2
60
20
48
48
3
3
2
40–60
50
85
50
85
C (10)
C (10)
D (15)
D (15)
n.d.
39
12
2
Reactions were performed under a nitrogen atmosphere, in approximately 0.03 M solutions. n.d.¼not determined.
a
GC yields, unless noted otherwise.
Isolated yield.
Catalyst was purified by column chromatography directly before use.
b
c

K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
6753
Scheme 3. Ring-closing metathesis of 11b.
outcome of the reaction either. The Hoveyda catalyst C
produced results similar to those obtained with B (entries 7
and 8), whereas the Schrock catalyst D hardly yielded any
cyclized product (entries 9 and 10). In conclusion, only
catalysts B and C were able to readily react in the desired
fashion with the acrylic double bond of 11a. The optimal
temperature for the RCM reaction was approximately 708C,
since higher temperatures appeared to promote isomeriza-
tion and lower temperatures resulted in significant amounts
of the cross-metathesis product.
syntheses of KDO have already been reported, including
enzymatic approaches,17 de novo syntheses18 and routes
using carbohydrates as starting materials.19
Our approach to the synthesis of KDO involves the RCM
methodology discussed in the previous section as the key
step (Scheme 5), which may result in the olefin 14, a known
intermediate in the synthesis of KDO,20 and more
importantly, a crucial starting point for the synthesis of
derivatives of KDO.21 The required precursor would then be
the sugar-derived enol ester 15, which might be accessible
from readily available di-O-isopropylidene-protected
D-mannose (16).22
When the homologue 11b was reacted under the optimized
conditions with catalyst B, a similar double bond migration
prior to RCM was observed (Scheme 3). Besides the
expected seven-membered ring 12b, the corresponding six-
and five-membered ring systems 12a and 12d were
encountered in comparable yields. Especially the formation
of the latter product is remarkable, since the terminal double
bond must have isomerized twice before cyclization to the
five-membered ring can take place.
Finally, we did not succeed in generating a twelve-
membered ring. Reaction of 11c with catalyst B at 708C
gave exclusively the dimer 13c, resulting from cross-
metathesis of the starting material, in 56% isolated yield
(Scheme 4). Despite these somewhat disappointing results,
it is obvious that ester-substituted enol ethers indeed can
undergo RCM, although isomerization could never be
completely suppressed. Because of these isomerization
problems, we decided to abandon the model systems and
look into applications of this approach involving substituted
olefins, where the substituents as a result of steric hindrance
might efficiently retard such isomerization processes.16
Scheme 5. Retrosynthetic approach towards KDO and 2-deoxy KDO.
Scheme 4. Reaction of 11c with catalyst B.
3. Synthesis of KDO
The monosaccharide 3-deoxy-D-manno-2-octulosonic acid
(4, KDO) is an important component of lipopolysaccharides
(LPS) that are present in the outer membrane in Gram-
negative bacteria.9 For this reason, KDO-containing oligo-
saccharides present promising lead compounds for the
development of vaccines. Moreover, KDO has been used as
a lead molecule for potentially new antibiotics, because of
its likely involvement in the growth of bacteria. As a
consequence, the development of efficient synthetic routes
to KDO and analogues thereof has been an important
subject of investigation over the past decades. Several
Scheme 6. Unsuccessful routes; (a) Ph3PCH2Br, nBuLi, THF, rt;
(b) [Ir(cod)Cl2, vinyl acetate, Na2CO3, toluene, 1008C, 24 h; (c) BrCH2-
CO2Me, NaH, THF, rt, 17 h.

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K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
Thus, compound 16 was reacted with the appropriate Wittig
reagent under literature conditions to give the olefin 17.23
The approach that was used to prepare the enol ester
fragments in model compounds 11a–c proved not to be
successful for the preparation of compound 15 (Scheme 6)
The palladium-catalyzed vinylation method gave no con-
version at all, while a different recently reported method,
using [Ir(cod)Cl]2 as the catalyst,24 yielded only a small
amount (13%) of the desired vinyl ether 18. In a different
approach, alcohol 17 was first reacted with an a-bromo ester
resulting in the formation of 19. Unfortunately, attempts to
react 19 with Eschenmoser’s salt to introduce the double
bond, were also unsuccessful.
refluxing acetonitrile led to the formation of the quaternary
ammonium salt, followed by elimination and iodide-
induced decarboxylation to produce the desired RCM-
precursor 15 in 73% yield.
In addition to this route, which consists of essentially known
conversions, we also discovered a shorter route to prepare
the a-alkoxy acrylate fragment of 15. For this purpose,
bromide 21 was prepared by reacting commercially
available 2,3-dibromopropionic acid methyl ester (20)
with pyrrolidine and Et3N in toluene at 08C for 30 min.
This reaction, which probably proceeds via an elimination/
conjugate addition mechanism, was directly used for the
next step without further purification (Scheme 7). Treatment
of alcohol 17 with bromide 21 in the presence of NaH led to
a clean conversion into ester 24 in 75% yield. Reaction of 24
with MeI and Na2CO3 in refluxing methanol resulted in
methylation of the pyrrolidine-nitrogen and subsequent
base-induced elimination to give the desired precursor 15 in
good yield. Hence, an efficient procedure has been
developed to convert alcohols into the corresponding
a-enol esters in good yields. Further investigation of the
synthetic potential of this sequence is currently being
carried out.
A route that finally led to success is shown in Scheme 8.
Following a procedure of Ganem,25 alcohol 17 was reacted
with dimethyl diazomalonate26 in the presence of a catalytic
amount of Rh2(OAc)4 to give the corresponding product 22
in 63% yield. Reaction with Eschenmoser’s salt under
mildly basic conditions then gave compound 23 in good
yield. Treatment with an excess of methyl iodide in
Gratifyingly, subjection of precursor 15 to catalyst B under
the optimized conditions led at 708C to a smooth conversion
to give the functionalized oxacycle 14 in 84% isolated yield
within 1 h. Indeed, no isomerization of the mono-substituted
double bond was observed, which sharply contrasts with the
results obtained with the model systems 11a–c. This
underlines the assumption that the observed double bond
isomerization is strongly dependent on steric hindrance.
Scheme 7. Synthesis of pyrrolidine-substituted a-bromo ester 21.
Reduction of the double bond,20a followed by oxidation
with MoOPH and deprotection20b have been previously
reported to give KDO in three steps from 14. More
significant, however, is the fact that 14 is an important
and useful building block for the preparation of oligo-
saccharides containing KDO fragments.21 Thus, we
efficiently prepared 14 in only four steps from readily
available starting materials in an overall yield of 45%. To
the best of our knowledge, this sequence now represents the
shortest synthesis of KDO and its crucial intermediate 14.
4. Conclusions
In summary, application of RCM on ester-substituted enol-
ethers showed that the six- and seven-membered oxygen
heterocycles could be efficiently generated by this method.
A drawback, however, was that isomerization of the
unhindered terminal olefin occurred as an undesired side-
reaction, which could not be completely inhibited. None-
theless, this methodology was applied in a formal synthesis
of KDO, where due to the increased steric environment of
the terminal olefin, isomerization was not observed. Finally,
preliminary results were described involving a novel two-
step transformation to efficiently convert an alcohol into the
corresponding a-alkoxy acrylate function. Implementation
of this novel reaction allowed us to carry out a formal
synthesis of KDO in only seven steps starting from
protected D-mannose.
Scheme 8. Reagents and conditions: (a) dimethyl diazomalonate,
Rh2(OAc)4, benzene, 558C, 3 h; (b) CH2vNMe2I, Et3N, CH2Cl2, 408C,
48 h; (c) MeI, MeCN, reflux, 48 h; (d) 21, NaH, THF/DMF, 08C!rt, 18 h;
(e) MeI, Na2CO3, MeOH, reflux, 16 h; (f) B, toluene, 708C, 1 h.

K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
6755
5. Experimental
5.3. General procedure for preparation of the enol esters
5.1. General
To a solution of the vinyl ether in THF (0.35 M) was added a
t
1.7 M pentane solution of BuLi (1.7 equiv.) at 2788C.
All reactions were performed under a nitrogen atmosphere,
unless stated otherwise. Nitrogen was dried over SICA-
PENTw (Merck), CaCl2 and KOH. CH2Cl2 was distilled
over CaH2. THF was distilled over Na. Acetonitrile was
distilled and stored on molecular sieves (4A). Benzene was
˚
dried on molecular sieves (4A). Toluene was deoxygenated
After stirring for 1 h, the cold bath was removed and the
mixture was stirred for 1 h at room temperature. Next, the
reaction was cooled again to 2788C and during 30 min a
stream of CO2 was led through the solution, followed by
stirring for another hour upon gradually warming to room
temperature. Benzyl bromide (1.7 equiv.) and DMF were
then added and the reaction was stirred overnight at 508C.
After cooling to room temperature, H2O was added and the
resulting mixture was extracted three times with pentane.
The organic layers were concentrated and the product
purified by column chromatography (EtOAc/hexane/Et3N
2:100:1).
˚
using the freeze-pump-thaw method. Et3N was distilled and
stored over KOH. All other chemicals were purchased and
1
used without further purification. H and 13C NMR spectra
were recorded on a Bruker DPX 200 or a Bruker DMX 300
spectrometer. IR measurements were performed on an ATI
Mattson Genesis Series FTIP spectrometer. Mass spectra
were measured on a Fisons (VG) Micromass 7070E
apparatus or a Finnigan MAT 900S apparatus. Optical
rotations were determined with a Perkin–Elmer 241
polarimeter.
1
5.3.1. Benzyl 2-(4-pentenyloxy)acrylate (11a). H NMR
(C6D6, 200 MHz): d 7.06 (m, 5H, Ar-H), 5.69–5.52 (m, 1H,
CH2vCH), 5.44 (d, J¼2.2 Hz, 1H, OCvCH2), 5.04 (s, 2H,
OCH2Ph), 4.92 (m, 2H, CHvCH2), 4.26 (d, J¼2.2 Hz, 1H,
OCvCH2), 3.30 (t, J¼6.4 Hz, 2H, OCH2CH2), 1.99 (m, 2H,
CH2vCHCH2), 1.54 (m, 2H, CH2vCHCH2CH2). 13C
NMR (CDCl3, 75 MHz): d 162.7, 151.0, 137.4, 135.5,
128.3, 128.0, 127.9, 115.1, 94.1, 67.8, 66.9, 30.2, 27.9. IR
(film) 3066, 3034, 2946, 1734, 1618, 1165 cm21. HRMS:
calcd for (C15H18O3)þ: 246.1256, found: 246.1250.
5.2. General procedure for preparation of vinyl ethers
To a solution of the alcohol in ethyl vinyl ether (0.3 M)
was added a solution of Pd(OAc)2 (5 mol%) and 1,10-
phenanthroline (5.5 mol%) in a small amount of CH2Cl2.
The mixture was stirred in air for 4–6 days, filtered over
Celite and carefully concentrated in vacuo. The resulting
crude product was filtered over a short silica gel
column (100% pentane) to remove any starting alcohol.
The vinyl ethers were further purified by column
chromatography (100% pentane) or directly used in the
next steps.
1
5.3.2. Benzyl 2-(5-hexenyloxy)acrylate (11b). H NMR
(C6D6, 300 MHz): d 7.05 (m, 5H, Ar-H), 5.74–5.60 (m, 1H,
CH2vCH), 5.45 (d, J¼2.1 Hz, 1H, OCvCH2), 5.05 (s, 2H,
OCH2Ph), 4.97 (m, 2H, CHvCH2), 4.29 (d, J¼2.3 Hz, 1H,
OCvCH2), 3.33 (t, J¼6.0 Hz, 2H, OCH2CH2), 1.89 (m, 2H,
CH2vCHCH2), 1.50 (m, 2H, CH2vCHCH2CH2), 1.34 (m,
2H, CH2CH2O). 13C NMR (CDCl3, 75 MHz): d 162.7,
151.0, 138.1, 135.5, 128.3, 128.0, 127.9, 114.6, 93.9, 68.4,
66.8, 33.5, 28.1, 25.4. IR (film) 3066, 3033, 2959, 1735,
5.2.1. 5-Vinyloxypent-1-ene27 (9a). 1H NMR (CDCl3,
300 MHz): d 6.45 (dd, J¼6.6, 14.3 Hz, 1H, OCHvCH2),
5.81 (m, 1H, CH2CHvCH2), 5.03 (m, 2H, CH2CHvCH2),
4.16 (dd, J¼1.8, 14.3 Hz, 1H, OCHvCH2), 3.96 (dd,
J¼1.8, 6.9 Hz, 1H, OCHvCH2), 3.68 (t, J¼6.4 Hz, 2H,
CH2CH2O), 2.15 (m, CH2vCHCH2), 1.74 (m, CH2CH2O).
13C NMR (CDCl3, 75 MHz): d 151.6, 137.6, 114.9, 86.2,
67.3, 30.3, 28.4.
1618, 1166 cm21
.
260.1412, found: 246.1414.
HRMS: calcd for (C16H20O3)þ:
5.3.3. Benzyl 2-(10-undecenyloxy)acrylate (11c). 1H
NMR (CDCl3, 200 MHz): d 7.36 (m, 5H, Ar-H), 5.91–
5.71 (m, 1H, CH2vCH), 5.34 (d, J¼2.2 Hz, 1H,
OCvCH2), 5.24 (s, 2H, OCH2Ph), 4.96 (m, 2H,
CHvCH2), 4.60 (d, J¼2.3 Hz, 1H, OCvCH2), 3.73 (t,
J¼6.7 Hz, 2H, OCH2CH2), 2.03 (m, 2H, CH2vCHCH2),
1.75 (m, 2H, CH2vCHCH2CH2), 1.28 (m, 12H, 6£CH2).
13C NMR (CDCl3, 50 MHz): d 160.8, 151.2, 139.2, 128.6,
128.5, 128.2, 128.1, 114.1, 94.0, 68.6, 66.8, 33.8, 29.5, 29.4,
29.3, 29.1, 28.9, 28.5, 25.9. IR (film) 3066, 3033, 2924,
1734, 1617, 1166 cm21. HRMS: calcd for (C21H30O3)þ:
330.2195, found: 330.2191.
5.2.2. 6-Vinyloxyhex-1-ene (9b). 1H NMR (CDCl3,
200 MHz): d 6.46 (dd, J¼6.7, 14.5 Hz, 1H, OCHvCH2),
5.80 (m, 1H, CH2CHvCH2), 4.99 (m, 2H, CH2CHvCH2),
4.15 (dd, J¼2.0, 14.3 Hz, 1H, OCHvCH2), 3.96
(dd, J¼2.0, 6.7 Hz, 1H, OCHvCH2), 3.67 (t, J¼6.3 Hz,
2H, CH2CH2O), 2.08 (m, 2H, CH2vCHCH2), 1.70–
1.43 (m, 4H, CH2CH2CH2O). 13C NMR (CDCl3,
75 MHz): d 151.6, 138.2, 114.4, 86.1, 67.9, 33.6, 28.7,
25.5.
5.2.3. 11-Vinyloxyundec-1-ene (9c). 1H NMR (CDCl3,
5.4. General procedure for the ring-closing metathesis
reactions of compounds 11a–c
300 MHz):
d
6.45 (dd, J¼6.9, 14.3 Hz, 1H,
OCHvCH2), 5.80 (m, 1H, CH2CHvCH2), 4.95 (m,
2H, 2H, CH2CHvCH2), 4.16 (dd, J¼1.9, 14.4 Hz, 1H,
OCHvCH2), 3.95 (dd, J¼1.9, 6.8 Hz, 1H, OCHvCH2),
3.66 (t, J¼6.6 Hz, 2H, CH2CH2O), 2.03 (m, 2H,
CH2vCHCH2), 1.64 (m, 2H, CH2vCHCH2CH2), 0.86
(m, 12H, 6£CH2). 13C NMR (CDCl3, 75 MHz): d
151.7, 138.9, 114.0, 86.1, 68.1, 34.0, 29.7, 29.6, 29.5,
29.3, 29.2. 29.1, 26.2.
A solution of the enol ester (0.03 M) and the catalyst in
toluene was stirred and monitored by TLC or GC. When no
further conversion was observed, the mixture was concen-
trated and the products isolated by column chromatography.
The different products could not be separated by this
method, but GC–MS allowed us to determine the nature and
ratio of the compounds. With this knowledge we were able

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K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
to assign the 1H NMR-signals of compounds 12a, b, d (data
are shown below).
(dd, J¼6.4, 14.0 Hz, 1H, OCHvCH2), 6.02–5.84 (m, 1H,
CCHvCH2), 5.33 (m, 2H, CCHvCH2), 4.66 (t, J¼7.3 Hz,
1H, CHCHvCH2), 4.41–4.17 (m, 3H, OCHvCH2 and
CHCHCHvCH2), 4.01 (m, 3H, CH2O and CHCH2O), 3.79
(dd, J¼2.2, 4.9 Hz, 1H, CHOH), 1.52 (s, 3H, CCH3), 1.38
(s, 3H, CCH3), 1.36 (s, 3H, CCH3), 1.33 (s, 3H, CCH3).
5.4.1. Benzyl 3,4-dihydro-2H-6-pyrancarboxylate (12a).
1H NMR (C6D6, 200 MHz): d 7.20–7.03 (m, 5H, Ar-H),
5.71 (t, J¼3.2 Hz, 1H, CHvC), 5.03 (s, 2H, OCH2Ph), 3.91
(t, J¼9.9 Hz, 2H, CH2CHO), 1.98 (dt, J¼3.2, 9.8 Hz, 2H,
CH2CHvC), 1.21 (m, 2H, CH2CH2O). LRMS: m/z 218
(Mþ).
5.5.3. Methyl 2-((R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-
4-yl]-1-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-
yl]methyloxy)acetate (19). A solution of 17 (402 mg,
1.56 mmol) in THF (20 mL) was cooled to 08C and NaH
(60% dispersion in mineral oil, 154 mg, 3.84 mmol) was
added. The resulting suspension was stirred at room
temperature for 1 h, before it was cooled again to 08C.
Next, methyl 2-bromoacetate (644 mg, 4.21 mmol) was
added and the reaction was stirred overnight upon warming
to room temperature. Finally, H2O (20 mL) was added and
the mixture was extracted with CH2Cl2 (3£30 mL). The
combined organic layers were dried (MgSO4) and concen-
trated, after which the product was purified by column
chromatography (EtOAc/heptane, 1:3). The yield was
5.4.2. Benzyl 4,5,6,7-tetrahydro-2-oxepinecarboxylate
1
(12b). H NMR (C6D6, 300 MHz): d 7.20–7.03 (m, 5H,
Ar-H), 6.44 (t, J¼6.0 Hz, 1H, CHvC), 5.06 (s, 2H,
OCH2Ph), 3.68 (m, 2H, CH2CHO), 1.84 (m, 2H, CH2-
CHvC), 1.47 (m, 2H, CH2CH2CH2O), 1.31 (m, 2H,
CH2CH2O). LRMS: m/z 232 (Mþ).
1
5.4.3. Benzyl 4,5-dihydro-2-furancarboxylate (12d). H
NMR (C6D6, 200 MHz): d 7.20–7.03 (m, 5H, Ar-H), 6.06
(t, J¼4.1 Hz, 1H, CHvC), 5.08 (s, 2H, OCH2Ph), 3.60 (dd,
J¼4.8, 5.1 Hz, 2H, CH2CHO), 1.56 (m, 2H, CH2CHvC).
LRMS: m/z 204 (Mþ).
1
475 mg (92%). H NMR (CDCl3, 300 MHz): d 5.96 (m,
1H, CHvCH2), 5.30 (m, 2H, CHvCH2), 4.57 (dd, J¼6.6,
7.3 Hz, 1H, CHCHvCH2), 4.42–4.03 (m, 6H, CH2CO2Me
and CH2O and CHCH2O and CHCHCHvCH2), 3.72 (s, 3H,
OCH3), 3.63 (m, 1H, CHOCH2CO2Me), 1.51 (s, 3H,
CCH3), 1.37 (s, 3H, CCH3), 1.34 (s, 3H, CCH3), 1.31 (s,
3H, CCH3). 13C NMR (CDCl3, 75 MHz): d 170.2, 134.3,
118.6, 109.0, 108.6, 79.5, 78.9, 78.0, 76.9, 69.1, 66.1, 51.7,
27.4, 26.3, 25.9, 25.3.
5.4.4. Benzyl 2-[(E)-8-(1-[(benzyloxy)carbonyl]-vinyl-
oxy)-4-octenyl]oxyacrylate (13a). 1H NMR (C6D6,
300 MHz):
d 7.17–7.03 (m, 10H, Ar-H), 5.45 (t,
J¼2.1 Hz, 2H, CH2vC), 5.26 (m, 2H, CHvCH), 5.06
(m, 4H, OCH2Ph), 4.31 (t, J¼1.8 Hz, 2H, CH2vC), 3.36 (t,
J¼6.3 Hz, 4H, OCH2CH2), 2.03 (m, 4H, CHvCHCH2),
1.58 (m, 4H, OCH2CH2).
5.4.5. Benzyl 2-[(E)-20-(1-[(benzyloxy)carbonyl]-vinyl-
oxy)-10-icosenyl]oxyacrylate (13c). 1H NMR (C6D6,
300 MHz): d 7.18–7.07 (m, 10H, Ar-H), 5.61 (m, 2H,
CHvCH), 5.54 (d, J¼2.2 Hz, 2H, CH2vC), 5.13 (s, 4H,
OCH2Ph), 4.40 (d, J¼2.2 Hz, 2H, CH2vC), 3.46 (t,
J¼6.3 Hz, 4H, OCH2CH2), 2.16 (m, 4H, CHvCHCH2),
1.61 (m, 4H, OCH2CH2), 1.51–1.28 (m, 24H, 12£CH2).
5.5.4. Dimethyl 2-((R)-1-[(4R)-2,2-dimethyl-1,3-dioxo-
lan-4-yl]-1-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-
4-yl]methyloxy)malonate (22). To a solution of 17
(184 mg, 0.71 mmol) and Rh2(OAc)4 (6.5 mg, 2.1 mol%)
in benzene (4 mL) was added dimethyl diazomalonate26
(213 mg, 1.35 mmol) over a period of 10 min. The mixture
was stirred at 558C for 3 h, cooled to room temperature and
an additional 10 mL of benzene was added. The organic
layer was washed with saturated aqueous NaHCO3 (15 mL)
and H2O (2£15 mL), dried (Na2SO4) and concentrated. The
product was purified by column chromatography (EtOA-
c/heptane 1:4). The yield was 173 mg (63%). 1H NMR
(CDCl3, 300 MHz): d 5.85 (m, 1H, CHvCH2), 5.29 (m, 2H,
CHvCH2), 4.98 (s, 1H, CH(CO2Me)2), 4.56 (dd, J¼5.9,
7.0 Hz, 1H, CHCHvCH2), 4.20–4.07 (m, 4H, CH2O and
CHCH2O and CHCHCHvCH2), 3.78 (m, 7H, OCH3 and
CHOCH(CO2Me)2), 1.50 (s, 3H, CCH3), 1.38 (s, 3H,
CCH3), 1.33 (s, 3H, CCH3), 1.32 (s, 3H, CCH3). 13C NMR
(CDCl3, 75 MHz): d 166.9, 166.7, 134.2, 118.7, 109.2,
108.5, 79.8, 79.4, 79.3, 78.7, 75.8, 66.7, 52.8, 52.6, 27.8,
26.1, 25.8, 25.1. IR (film) 2986, 1747, 1214, 1155,
5.5. KDO synthesis
5.5.1. (R)[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl][(4S,5R)-
(17).
2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]methanol
This compound was prepared according to a literature
procedure.23 The yield was 2.57 g (92%). 1H NMR (CDCl3,
300 MHz): d 6.09 (m, 1H, CHvCH2), 5.37 (m, 2H,
CHvCH2), 4.69 (t, J¼7.8 Hz, 1H, CHCHvCH2), 4.38 (d,
J¼7.5 Hz, 1H, CHCHCHvCH2), 4.09–3.96 (m, 3H, CH2O
and CHCH2O), 3.45 (t, J¼7.9 Hz, 1H, CHOH), 2.19 (d,
J¼8.1 Hz, 1H, OH), 1.52 (s, 3H, CCH3), 1.40 (s, 3H,
CCH3), 1.38 (s, 3H, CCH3), 1.34 (s, 3H, CCH3). 13C NMR
(CDCl3, 75 MHz): d 134.0, 119.5, 109.2, 108.5, 79.1, 76.7,
76.0, 67.1, 27.0, 26.8, 25.5, 24.7.
1031 cm21
.
[a]2D5¼þ28.4 (c¼0.40, CH2Cl2). HRMS:
calcd for (C18H28O9)þ: 388.1733, found: 388.1724.
5.5.2. (R)-1-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-1-
[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]methyl
vinyl ether (18). To a solution of [Ir(cod)Cl]2 (3.7 mg,
2 mol%), Na2CO3 (36 mg, 1.1 mol%) and vinyl acetate
(56 mL, 0.57 mmol) in toluene (2 mL) was added 17
(81 mg, 0.31 mmol). The reaction was stirred at 1008C for
24 h, after which the mixture was concentrated in vacuo.
Column chromatography (EtOAc/heptane, 1:5) gave the
5.5.5. Dimethyl 2-[(dimethylamino)methyl]-2-((R)-1-
[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-1-[(4S,5R)-2,2-
dimethyl-5-vinyl-1,3-dioxolan-4-yl]methyloxy)malonate
(23). To a solution of 22 (75 mg, 0.19 mmol) and
CH2vNMe2I (54 mg, 0.29 mmol) in CH2Cl2 (3 mL) was
added Et3N (45 mL, 0.32 mmol). The mixture was stirred at
reflux temperature for 48 h, cooled to room temperature and
an additional 10 mL CH2Cl2 was added. The reaction
1
product in 13% yield. H NMR (CDCl3, 200 MHz): d 6.26

K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
6757
1
mixture was washed with saturated aqueous NaHCO3
(10 mL) and the water layer was extracted with CH2Cl2
(2£10 mL). The combined organic layers were dried
(MgSO4) and concentrated, after which the product was
purified by column chromatography (EtOAc/heptane,
1:2). The yield was 70 mg (82%). 1H NMR (CDCl3,
300 MHz): d 5.97 (m, 1H, CHvCH2), 5.28 (m, 2H,
CHvCH2), 4.62 (t, J¼5.9 Hz, 1H, CHCHvCH2), 4.41
(m, 1H, CHCHCHvCH2), 4.32–4.20 (m, 3H, CH2O and
CHCH2O), 4.05 (m, 1H, CHOCH(CO2Me)2NMe2), 3.75 (s,
3H, OCH3), 3.72 (s, 3H, OCH3), 3.10 (AB, J¼14.1 Hz, 2H,
CH2NMe3), 2.25 (s, 6H, NCH3), 1.48 (s, 3H, CCH3), 1.40 (s,
3H, CCH3), 1.35 (s, 3H, CCH3), 1.33 (s, 3H, CCH3). 13C
NMR (CDCl3, 75 MHz): d 168.8, 135.1, 117.6, 109.1,
107.7, 79.4, 78.3, 77.3, 74.9, 68.2, 62.1, 52.7, 52.4, 46.7,
28.1, 26.2, 25.8, 25.3. IR (film) 2985, 2773, 1748, 1214,
1160, 1034 cm21. [a]D25¼þ52.3 (c¼0.30, CH2Cl2). HRMS:
calcd for (C21H36NO9)þ, [MþþH]: 446.2390, found:
446.2386.
Second diastereomer. H NMR (CDCl3, 300 MHz): d 5.92
(m, 1H, CHvCH2), 5.27 (m, 2H, CHvCH2), 4.64 (dd,
J¼5.2, 6.6 Hz, 1H, CHCHvCH2), 4.54 (m, 1H,
CHCHCHvCH2), 4.17 (dd, J¼5.8, 8.7 Hz, 1H,
CHCH2O), 4.05 (m, 3H, CH2O and CHOCH(CO2Me)),
3.71 (s, 3H, OCH3), 3.63 (m, 1H, OCH(CO2Me)CH2),
2.94–2.76 (m, 2H, CHCH2N), 2.58 (m, 4H, NCH2CH2),
1.71 (m, 4H, NCH2CH2), 1.49 (s, 3H, CCH3), 1.35 (s,
3H, CCH3), 1.33 (s, 3H, CCH3), 1.29 (s, 3H, CCH3). 13C
NMR (CDCl3, 75 MHz): d 172.0, 134.6, 118.4, 109.1,
108.2, 80.5, 78.9, 78.2, 77.3, 76.2, 67.4, 57.8, 54.2,
51.8, 28.2, 26.3, 25.9, 25.4, 23.7. Rf (EtOAc/heptane
4:1)¼0.07.
Mixture: IR (film) 2981, 2783, 1752, 1736, 1210, 1148,
1035 cm21. [a]D25¼þ28.2 (c¼0.30, CH2Cl2). HRMS:
calcd for (C21H34NO7)þ, [Mþ2H]: 412.2335, found:
412.2331.
5.5.8. Methyl 2-((R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-
4-yl]-1-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-
yl]methyloxy)acrylate (15). From 23. A solution of 23
(30 mg, 68 mmol) and MeI (48 mL, 0.77 mmol) in MeCN
(4 mL) was stirred at reflux temperature. After 48 h, the
reaction mixture was concentrated in vacuo and the product
was isolated by column chromatography (EtOAc/hexane
1:4). The yield was 17 mg (73%). From 24: a solution of 24
(22 mg, 53 mmol), MeI (34 mL, 0.55 mmol) and Na2CO3
(26 mg, 0.25 mmol) in MeOH (6 mL) was stirred at reflux
temperature. After 16 h, the reaction mixture was concen-
trated in vacuo and the product was isolated by column
chromatography (EtOAc/hexane 1:4). The yield was 14 mg
(78%). 1H NMR (CDCl3, 300 MHz): d 5.79 (m, 1H,
CHvCH2), 5.50 (d, J¼3.0 Hz, 1H, OCvCH2), 5.30 (m,
2H, CHvCH2), 5.87 (d, J¼2.4 Hz, 1H, OCvCH2), 4.68
(dd, J¼6.9, 7.5 Hz, 1H, CHCHvCH2), 4.34–4.19 (m, 3H,
CH2 and OCH), 4.03 (m, 2H, OCH), 3.78 (s, 3H, OCH3),
1.61 (s, 3H, CCH3), 1.39 (s, 3H, CCH3), 1.35 (s, 3H, CCH3),
1.34 (s, 3H, CCH3). 13C NMR (CDCl3, 75 MHz): d 163.2,
150.3, 133.7, 119.4, 109.6, 108.8, 96.8, 78.9, 78.5, 76.7,
75.4, 65.6, 52.3, 26.7, 26.5, 25.9, 25.6. IR (film) 2984, 2935,
1734, 1623, 1199, 1165, 1057 cm21. [a]D25¼244.7 (c¼0.30,
CH2Cl2). HRMS: calcd for (C17H26O7)þ: 342.1679, found:
342.1675.
5.5.6. Methyl 2-bromo-3-pyrrolidin-1-ylpropanoate (21).
A solution of methyl 2,3-dibromopropanoate 20 (853 mg,
3.47 mmol) in toluene (50 mL) was cooled to 08C and
pyrrolidine (0.28 mL, 3.39 mmol) and Et3N (0.48 mL,
3.46 mmol) were added. After stirring at 08C for 30 min,
the resulting suspension was filtered over Celite, washed
with H2O (25 mL) and concentrated. The resulting crude
product was .95% pure according to NMR and therefore
directly used in the next step. The yield was 747 mg (91%).
1H NMR (CDCl3, 200 MHz): d 4.33 (dd, J¼6.0, 9.2 Hz, 1H,
CHBr), 3.88 (s, H, OCH3), 3.30 (dd, J¼9.2, 12.9 Hz, 1H,
CHCH2N), 2.95 (dd, J¼6.0, 12.9 Hz, 1H, CHCH2N), 2.72
(m, 4H, NCH2CH2), 1.84 (m, 4H, NCH2CH2). 13C NMR
(CDCl3, 300 MHz): d 169.5, 59.3, 58.2, 54.1, 43.0, 23.6.
5.5.7. Methyl 2-((R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-
4-yl]-1-[(4S,5R)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-
yl]methyloxy)-3-pyrrolidin-1-ylpropanoate
(24).
A
solution of 17 (66 mg, 0.26 mmol) in THF (6 mL) and
DMF (2 mL) was cooled to 08C and NaH (60% dispersion in
mineral oil, 22 mg, 0.55 mmol) was added. The resulting
suspension was stirred at room temperature for 1 h, before it
was cooled again to 08C. Next, 21 (200 mg, 0.84 mmol) was
added and, upon warming to room temperature, the mixture
was stirred for 18 h, followed by quenching with H2O
(5 mL). The mixture was extracted with pentane (4£15 mL)
and the organic layers were dried (MgSO4) and concen-
trated. Purification by column chromatography (EtOAc/
heptane/Et3N 66:33:1) yielded 80 mg (75%) of the desired
product. Using the eluent above, both diastereomers could
be separated.
5.5.9. Methyl (3aS,4R,7aR)-4-[(4R)-2,2-dimethyl-1,3-
dioxolan-4-yl]-2,2-dimethyl-3a,7a-dihydro-4H-[1,3]di-
oxolo[4,5-c]pyran-6-carboxylate (14).20a A solution of 15
(24.1 mg, 70 mmol) and B (6.2 mg, 10.4 mol%) in toluene
(4 mL) was stirred at 708C. After 1 h, TLC indicated that the
reaction was complete and the mixture was concentrated in
vacuo. After purification by column chromatography
(EtOAc/heptane 1:4) the product was obtained in a yield
First diastereomer. 1H NMR (CDCl3, 300 MHz): d 6.03 (m,
1H, CHvCH2), 5.28 (m, 2H, CHvCH2), 4.51 (dd, J¼6.1,
7.1 Hz, 1H, CHCHvCH2), 4.34 (m, 1H, CHCHCHvCH2),
4.09 (m, 4H, CH2O and CHCH2O and CHOCH(CO2Me)),
3.77 (m, 1H, OCH(CO2Me)CH2), 3.70 (s, 3H, OCH3),
2.82–2.67 (m, 2H, CHCH2N), 2.52 (m, 4H, NCH2CH2),
1.71 (m, 4H, NCH2CH2), 1.47 (s, 3H, CCH3), 1.39 (s, 3H,
CCH3), 1.31 (s, 3H, CCH3), 1.30 (s, 3H, CCH3). 13C NMR
(CDCl3, 75 MHz): d 171.9, 134.5, 118.7, 108.9, 108.4, 79.9,
79.6, 78.9, 78.8, 76.1, 66.4, 58.9, 54.6, 51.6, 27.9, 26.3,
25.9, 25.0, 23.9. Rf (EtOAc/heptane 4:1)¼0.12.
1
of 17.5 mg (84%). H NMR (CDCl3, 300 MHz): d 5.99
(dd, J¼1.5, 3.3 Hz, 1H, CHvC), 4.78 (dd, J¼3.3, 6.0 Hz,
1H, CHCHvC), 4.45 (m, 2H, CHCH2 and CHCHCHvC),
4.19 (m, 2H, CH2), 3.82 (m, 1H, CHCHCH2), 3.79 (s, 3H,
OCH3), 1.46 (s, 1H, CCH3), 1.41 (s, 9H, CCH3). 13C NMR
(CDCl3, 75 MHz): d 162.2, 143.7, 110.9, 110.3, 109.5,
76.4, 73.8, 71.2, 68.8, 66.8, 52.4, 28.2, 27.1, 26.9, 25.5.
[a]2D5¼þ31.9 (c¼0.30, CH2Cl2). The data in all
respect were congruent to those that were previously
reported.20a

6758
K. F. W. Hekking et al. / Tetrahedron 59 (2003) 6751–6758
(b) Boons, G. J.; Demchenko, A. V. Chem. Rev. 2000, 100,
4539–4565.
Acknowledgements
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This research has been financially supported (in part) by the
Council for Chemical Sciences of the Netherlands
Organization for Scientific Research (CW-NWO).
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