Enantiospecific synthesis of a protected equivalent of APTO, the β-amino acid fragment of microsclerodermins C and D, by aziridino-γ-lactone methodology

Article abstract of DOI:10.1002/ejoc.200801000

The efficient synthesis of a protected form of (2S,3R,4S,5S,7E)-3-amino-8- phenyl-2,4,5-trihydroxyoct-7-enoic acid (APTO), the α-hydroxy β-amino acid component of microsclerodermins C and D, 23-membered cyclic peptides isolated from lithistid sponges, is

Full text of DOI:10.1002/ejoc.200801000

FULL PAPER
DOI: 10.1002/ejoc.200801000
Enantiospecific Synthesis of a Protected Equivalent of APTO, the β-Amino
Acid Fragment of Microsclerodermins C and D, by Aziridino-γ-lactone
Methodology
Aurélie Tarrade-Matha,[a] Marcelo Siqueira Valle,[a] Pierre Tercinier,[a] Philippe Dauban,*[a]
and Robert H. Dodd*[a]
Dedicated to the memory of Christian Marazano[†]
Keywords: Microsclerodermins / Amino acids / Aziridines / Synthesis design / Nucleophilic ring-opening
The efficient synthesis of
a
protected form of
the terminal phenyl group, provides lactone 48. This, a lac-
(2S,3R,4S,5S,7E)-3-amino-8-phenyl-2,4,5-trihydroxyoct-7-en- tonized form of APTO, can be considered an activated build-
oic acid (APTO), the α-hydroxy β-amino acid component of
microsclerodermins C and D, 23-membered cyclic peptides
isolated from lithistid sponges, is described. The strategy is
based on the preparation of the aziridino-γ-lactone 46 from
ing block for the synthesis of microsclerodermins C and D or
their analogues, as demonstrated by its subsequent reaction
with a benzylamine to give the carboxamide 51. This repre-
sents the first example of the use of an aziridino-γ-lactone for
the stereoselective synthesis of an α-substituted β-amino acid
derivative.
L-gulose by a procedure previously developed in our labora-
tory for simpler substrates. Regioselective opening of the az-
iridine at C-2 by acetate anion, an intrinsic reactivity pattern
of aziridino-γ-lactones, followed by a Heck reaction to install
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
an aryl moiety. The last of these has been identified as
(2S,3R,4S,5S,7E)-3-amino-2,4,5-trihydroxy-8-phenyloct-7-
enoic acid (APTO, 3) in the case of microsclerodermins C
and D (Figure 1, 1 and 2, respectively).
The structural complexity of the microsclerodermins, as
well as their significant antifungal and cytotoxic activities,
have spurred efforts to develop synthetic routes to these
molecules. So far, only one total synthesis, that of micro-
sclerodermin E, has been reported.[3] In that study, Zhu and
Ma prepared a protected and reduced (terminal hydroxy
group) form of (2S,3R,4S,5S,7E,9E)-3-amino-10-(4-ethoxy-
phenyl)-2,4,5-trihydroxydeca-7,9-dienoic acid (AETD, 4) in
16 steps and 10% overall yield starting from γ-gluconolac-
tone.
Shioiri and co-workers[4] have synthesized four constitu-
ent building blocks of microsclerodermins A and B, one of
which was the protected trihydroxy β-amino acid
(2S,3R,4S,5S,6S,11E)-3-amino-2,4,5-trihydroxy-12-(4-meth-
oxyphenyl)-6-methyldodec-11-enoic acid (AMMTD, 5) pre-
pared in over 30 steps starting from methyl (R)-3-O-
TBDPS-2-methylpropionate. These authors have not re-
ported the assembly of these fragments into microsclero-
dermins A and B. Chandrasekhar and Sultana[5] have also
described the synthesis of a reduced form of protected
AMMTD in 27 steps starting from (–)-(S)-citronellol, in
which the hydroxy groups were introduced by iterative ster-
Introduction
Lithistid sponges, found mainly in the waters of New
Caledonia and the Philippines, are a source of a wide array
of well-known bioactive metabolites, such as discodermol-
ide, acetogenins, and swinholide.[1] Another family of me-
tabolites, the microsclerodermins, has been isolated from
these sponges by Faulkner and co-workers and is receiving
increasing attention. The nine members of this family
(microsclerodermins A–I) each contain a 23-membered cy-
clic peptide structure composed of six different amino ac-
ids.[2] Common to all the microsclerodermins so far iden-
tified are the amino acids glycine, N-methylglycine, and
(3R)-4-amino-3-hydroxybutyric acid (GABOB). Structural
differences originate from the presence of variously substi-
tuted tryptophan and 3-aminopyrrolidone derivatives, as
well as a complex 3-amino-2,4,5-trihydroxy acid unit at-
tached to an unsaturated hydrocarbon chain terminating in
[a] Institut de Chimie des Substances Naturelles, CNRS,
Avenue de la Terrasse, Bât. 27, 91198 Gif-sur-Yvette Cedex,
France
Fax: +33-1-69077247
E-mail: philippe.dauban@icsn.cnrs-gif.fr
robert.dodd@icsn.cnrs-gif.fr
[†] Our friend and colleague and a great admirer of marine natural
products.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 673–686
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
673

A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
FULL PAPER
Figure 1. Microsclerodermins C and D and β-amino acid components.
eoselective dihydroxylations. Preparations of both protected electron-withdrawing group.[8] A key feature of this strategy
APTO and AETD in 12 steps were recently reported by is the diastereoselectivity of the addition, which is governed
McLeod and co-workers,[6] in this case with the use of suc- by the chirality at C-4. The usefulness of aziridino-γ-lac-
cessive aminohydroxylation and dihydroxylation reactions tones for the preparation of naturally occurring non-pro-
to introduce these functional groups with the correct stereo- teinogenic α-amino acid derivatives is attested by our recent
chemistry. Finally, Aitken and co-workers have developed a syntheses of (2S,3S,4S)-dihydroxyglutamic acid (DHGA, 7)
[9]
five-step synthesis of APTO and AETD by a two-carbon
and (–)-polyoxamic acid (8).[10] These syntheses were
homologation of chiral sulfinimines derived from 2-deoxy- made possible by the propensity of aziridino-γ-lactones to
-ribose acetonide.[7]
react with hard nucleophiles (i.e., alcohols) exclusively at C-
Here we wish to report the use of aziridino-γ-lactones 3. In contrast, soft nucleophiles such as thiols and acetate
for the enantiospecific synthesis of a protected lactone form react regioselectively at C-2, thereby giving access to 2-sub-
of APTO that can be used directly for subsequent peptide stituted 3-aminobutyrolactones 9.[11] Such compounds can
synthesis. We have previously demonstrated that stereo- be regarded (after lactone hydrolysis) as protected and acti-
chemically pure and synthetically useful aziridino-γ-lac- vated forms of α-substituted β-amino acids (10, R1 = OH).
tones (6, Scheme 1) can be easily and efficiently prepared in Alternatively, opening of the lactone by the amine function
three steps starting from 5-O-protected ribonolactones by of an amino acid or a peptide would give access to the cor-
triflation of the diol, followed by Michael-type addition of responding α-substituted β-amino carboxamides (10, R1 =
a benzylamine and replacement of the benzyl moiety by an NHR2). We thus decided to exploit this property of azirid-
Scheme 1. Previous results.
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Eur. J. Org. Chem. 2009, 673–686

Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
ino-γ-lactones to synthesize an optically pure α-substituted
β-amino acid derivative for the first time. In particular, the
preparation of a protected and activated form of APTO
suitable for eventual use in the total synthesis of micro-
sclerodermins C and D was targeted.
Results and Discussion
We first envisaged that APTO (3) should be accessible
from an aziridino-γ-lactone of general structure 11 by re-
gioselective opening of the aziridine at C-2 by acetate, lac-
tone hydrolysis, and deprotection (Scheme 2). Aziridino-γ-
lactone 11 should in turn be preparable by our chemistry
from the starting protected dihydroxybutyrolactone 12 (the
stereochemistry at C-2 and C-3 being unimportant) incor-
porating the required 1-hydroxy-4-phenylprop-3-enyl chain
at C-4. This chain should be introducible by opening of the
C-5–C-6 epoxide 13 by a vinylmetal reagent, followed by
Heck arylation. From this analysis, commercially available
-gulonolactone (14) appeared to be an appropriate starting
material for the preparation of epoxide 13 with the correct
configuration at C-4 and C-5.
Scheme 3. Preparation and reactivity of epoxide 17. Reagents and
conditions: (a) 2,2-dimethoxypropane, TsOH, acetone, room temp.,
36 h; (b) AcOH/H2O (7:1), 30 °C, 16 h; (c) CBr4, PPh3, THF, 0 °C,
2 h then room temp., 10 h; (d) CsF, acetone, reflux, 5 h; (e) allyl-
magnesium bromide, LiCuCl4 (0.3 equiv.), THF, –35 °C, 30 min,
then addition of 17 at –78 °C, 10 min; (f) MeLi, CuI (0.5 equiv.),
Et2O, 0 °C, 15 min, then addition of 17 in THF, 0 °C, 1 h.
Because selective epoxide opening of 17 by an organo-
cuprate seemed compromised at this point, we decided to
avoid this competitive lactone opening by using -gulose as
starting material, at the expense of additional protection/
deprotection/oxidation steps at the anomeric center. -Gu-
lose diacetonide 20 was thus prepared,[15] and the product
was converted into the p-methoxybenzyl (PMB) glycoside
21 (Scheme 4). Selective deprotection of the 5,6-diol with
aqueous acetic acid gave 22, which was transformed first
into the C-6 bromide 23 and then into the epoxide 24 under
the same conditions as previously. The epoxide 24 now
cleanly reacted with the cuprate generated in situ from vi-
nylmagnesium bromide and catalytic copper iodide to give
the epoxide-opening product 25 regioselectively and in 70%
Scheme 2. First synthetic strategy.
In our initial approach, the key C-5–C-6 epoxide 17 was yield. The resulting secondary hydroxy function was pro-
prepared by first protecting the hydroxy groups of -gulon- tected with a tert-butyldiphenylsilyl group to give 26. Treat-
olactone (14) as the diacetonide, followed by selective de- ment of glycoside 26 with DDQ in dichloromethane/water
protection of the C-5 and C-6 hydroxy groups with aqueous (10:1) at room temperature efficiently removed the PMB
acetic acid to give the monoacetonide 15 (Scheme 3).[12] group,[16,17] and the resulting compound 27 was oxidized
Treatment of 15 with carbon tetrabromide and tri- with TPAP in acetonitrile in the presence of NMO[11b–11d,18]
phenylphosphane in THF provided the C-6 bromo deriva- to give lactone 28 in 95% yield.
tive 16 in 50% yield, and this was cyclized to provide the
With lactone 28 to hand, several options were open to
epoxide 17 by use of cesium fluoride in acetone at reflux.[13] us for the subsequent synthetic route to APTO, notably
In their synthetic route to (–)-muracaticin, Depezay and co- with respect to the order of introduction of the terminal
workers[14] had reported the preparation of the 2,3-dideoxy phenyl moiety and the C-2 acetate (through opening of the
analogue of epoxide 17 and the regioselective opening of 2,3-aziridino-γ-lactone prepared by our methodology). We
the epoxide ring with excess cuprate generated from undec- first explored the viability of initially introducing the phenyl
anylmagnesium chloride and LiCuCl4.
group. As shown in Scheme 5, Heck coupling[19] between
In model experiments, epoxide 17 was then treated in iodobenzene and the olefinic lactone 28 was found to pro-
THF at –78 °C with the cuprate generated from allylmagne- ceed reasonably well, the expected product 29 being isolated
sium bromide and LiCuCl4. However, in contrast to the re- in 55% yield. From this compound, preparation of the azir-
sult obtained with the 2,3-dideoxy analogue, only the prod- idino-γ-lactone 31 was achieved by first removing the 2,3-
uct of lactone opening, compound 18, was obtained. Simi- di-O-isopropylidene group. This proved to be particularly
larly, use of CuI to generate the cuprate of methyllithium delicate, because all the classical hydrolytic conditions[20]
led to opening both of the epoxide and of the lactone to gave only very low yields of the desired diol, sometimes
give the oxo diol 19, though in low yield (22%), with no with, but more often without, recovery of starting material.
trace of the product only of epoxide opening.
Finally, the most satisfactory conditions found required
Eur. J. Org. Chem. 2009, 673–686
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675

A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
FULL PAPER
Scheme 5. Preparation of aziridino-γ-lactone 11. Reagents and con-
ditions: (a) Pd(OAc)2 (0.05 equiv.), PPh3 (0.1 equiv.), Et3N
(1.3 equiv.), PhI (1.3 equiv.), DMF, 110 °C, 20 h; (b) AcOH/H2O
(4:1), Dean–Stark, 85 °C, 24 h; (c) Tf2O, pyridine, CH2Cl2, –78 °C
to 0 °C, 4 h; (d) DMB-NH2, DMF, –60 °C, 30 min; (e) DDQ,
CH2Cl2/H2O (10:1), room temp., 24 h, then Boc2O (5 equiv.),
DMAP (0.2 equiv.), Et3N (10 equiv.), CH3CN, room temp., 48 h;
(f) CAN, CH3CN/H2O (5:1), room temp., 2 h; (g) Boc2O (5 equiv.),
DMAP (0.2 equiv.), Et3N (10 equiv.), CH3CN, room temp., 1.5 h.
Scheme 4. Preparation of lactone 28. Reagents and conditions: (a)
2,2-dimethoxypropane, TsOH, acetone, room temp., 36 h; (b)
PMBCl, NaH, DMF, room temp., 2.5 h; (c) AcOH/H2O (4:1),
30 °C, 18 h; (d) CBr4, PPh3, THF, 0 °C to room temp., 10 h; (e)
CsF, acetone, reflux, 6 h; (f) vinylmagnesium bromide, CuI
(0.3 equiv.), THF, –25 °C to room temp., 2 h; (g) TBDPSCl, imid-
azole, DMF, 0 °C to room temp., 22 h; (h) DDQ, CH2Cl2/H2O
(10:1), room temp., 20 h; (i) TPAP, NMO, CH3CN, room temp.,
3 h.
amine were then added to the reaction mixture, together
with a catalytic amount of DMAP. After 48 h at room tem-
perature, the expected N-Boc aziridine 11 was obtained, but
in only 20% yield and accompanied by many unidentified
by-products, with no starting material remaining. Because
heating of a solution of 29 in 80% acetic acid at 85 °C for modification of the reaction conditions had no beneficial
24 h with continual removal of water by use of a Dean– effects on the yield of 11, we decided to isolate the interme-
Stark apparatus. This afforded diol 12 in 60% yield and diate deprotected amine in order to determine which step
recovery of 20% of the starting acetonide. Longer reaction posed a problem. Treatment of the N-DMB derivative 31
times resulted in lower yields both of the diol and of reco- with DDQ under the same conditions as before allowed iso-
vered starting material. Diol 12 was next transformed into lation of amine 32 in less than 20% yield, but the product
the monotriflate 30 in 90% yield by treatment, first at was very difficult to purify. On the other hand, use of ceric
–78 °C and then at 0 °C, with 2.7 equiv. of triflic anhydride ammonium nitrate (CAN)[17,24] instead of DDQ for the oxi-
in the presence of pyridine in dichloromethane.[8,10] Treat- dative cleavage facilitated isolation of the product by
ment of triflate 30 with a very slight excess of 3,4-dimeth- chromatography on silica gel, although the yield of N-de-
oxybenzylamine[8,10] at –60 °C for 30 min provided azirid- protected aziridine 32 was again in the 20% range. Because
ino-γ-lactone 31 in only 36% yield, although 40% of the the free NH function of aziridine 32 could subsequently be
starting material was recovered and could be recycled. transformed to give the N-Boc derivative 11 in high yield
Attempts to drive the reaction to completion (i.e., by in- (73%), we concluded that inefficient removal of the DMB
creasing reaction times, temperature, or equivalents of group was responsible for the low overall yield of the two-
DMB-amine) led in all cases to concomitant and irrevers- step process.
ible opening of the lactone ring by the amine (vide infra).
As a result, and suspecting that the styrene moiety of
1
The H NMR spectrum of compound 31 displayed reso- compound 31 may interfere with the intermediates formed
nances for 3-H and 2-H at δ = 2.54 and 2.63 ppm, respec- during the cleavage of the DMB group with DDQ or CAN,
tively, characteristic of N-alkylaziridino-γ-lactones.[8]
we decided to investigate our second synthetic option: that
As demonstrated previously, efficient and regioselective is, installation of the phenyl moiety after formation and
opening of the aziridine ring of an aziridino-γ-lactone is opening of the aziridine. The acetonide protecting group of
best achieved when the aziridine nitrogen atom is protected compound 28 was thus removed with acetic acid/water as
by an electron-withdrawing group.[11] We thus proceeded to before to afford diol 33 in 55% yield (Scheme 6). Treatment
convert the N-DMB derivative 31 into its N-Boc analogue of this with 2.2 equiv. of triflic anhydride and pyridine in
11 by our previously described one-pot procedure.[10,23] dichloromethane provided the expected monotriflate 34 in
Compound 31 was first treated with 1 equiv. of DDQ at 94% yield, and this was then treated with DMB-amine in
room temperature in a dichloromethane/water (10:1) mix- DMF at –60 °C to give aziridino-γ-lactone 35 in 41% yield,
ture over 24 h.[10,17,24] Excess Boc anhydride and triethyl- with 38% of the starting material being recovered after
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Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
Scheme 6. Preparation and reactivity of aziridino-γ-lactone 36. Reagents and conditions: (a) AcOH/H2O (4:1), Dean–Stark, 85 °C, 24 h;
(b) Tf2O, pyridine, CH2Cl2, –78 °C to –25 °C, 3 h; (c) DMB-NH2, DMF, –60 °C, 30 min; (d) DDQ, CH2Cl2/H2O (10:1), room temp.,
24 h, then Boc2O, DMAP, Et3N, room temp., 24 h.
chromatography of the reaction mixture. The DMB group respectively, by treatment with DDQ, followed in the same
of 35 was then removed with DDQ in dichloromethane/ pot with the appropriate acylating or sulfonylating agent
water (10:1), and the resulting free amine was immediately (Scheme 7).
protected by addition of Boc anhydride, triethylamine, and
Each of these four aziridino-γ-lactones was then treated
a catalytic amount of DMAP directly to the reaction mix- with different sources of acetate anion. In the case of N-
ture. The N-Boc-aziridino-γ-lactone 36 was thus obtained Boc derivative 39, treatment with excess acetic acid in chlo-
with an excellent yield of 92% from 35, thereby corroborat- roform in the presence of boron trifluoride–diethyl ether
ing the hypothesis that the poor yields of 11 obtained from at room temperature gave no ring-opened product (Table 1,
derivative 31 by the same series of operations (Scheme 5) Entry 1), whereas heating of the reaction mixture at 50 °C
were indeed due to the presence of the terminal phenyl for 24 h led only to degradation products (Entry 2). The
1
group in 31. In its H NMR spectrum, compound 36 dis- same observations were made when potassium acetate or
played a downfield shift of the 2-H and 3-H resonances to cesium acetate in DMF were used to effect aziridine ring
δ = 3.30 and 3.25 ppm relative to the N-alkylaziridine-γ- opening (Entries 3 and 4). These results obtained with the
lactones, again typical of their N-carbamoyl analogues.[11]
model N-Boc-protected aziridino-γ-lactone 39 are thus sim-
We then investigated the critical opening of the aziridine ilar to those seen with the APTO precursor 36. Although
ring of 36 with an acetate anion source, which from our the N-acetyl derivative 40 also proved to be unsatisfactory
previous work with analogous but simpler systems was ex- with cesium acetate (Entry 5), better results were obtained
pected to occur regioselectively at C-2 to give 37.[11b] How- with the N-Cbz derivative 41. In this case, both acetic acid
ever, treatment of 36 with acetic acid, potassium acetate, in the presence of boron trifluoride–diethyl ether at 50 °C
or cesium acetate in a variety of solvents and at various and cesium acetate in DMF, also at 50 °C, gave the desired
temperatures led only to degradation of the starting mate- C-2 acetate derivative 43 in 48% and 42% yields, respec-
rial and formation of a multitude of products that were not tively (Entries 6 and 7). Finally, the best results were ob-
identified.
tained with N-tosylaziridine 42. In this case, efficient azirid-
It thus seemed advisable at this point to optimize the ine opening could be achieved at room temperature with
aziridine ring-opening on a model aziridino-γ-lactone, in cesium acetate in DMF to give 44 in 49% yield (Entry 8).
which the N-protecting/activating group could be easily var- The expected regioselective opening of the aziridine ring by
ied. For this purpose, the 5-O-TBDPS-aziridino-γ-lactone acetate at C-2 was clearly indicated by the COSY and
38, the preparation of which we have previously re- HMBC NMR spectra of 44.[25] Interestingly, with a pro-
ported,[10,23] seemed particularly suitable, this substrate dif- cedure recently described by Fan and Hou,[26] treatment of
fering from 35 only by the absence of the terminal allyl 42 with tri-n-butylphosphane and acetic anhydride led both
group. Compound 38 was thus easily transformed into the to regioselective opening of the aziridine ring and to acety-
N-Boc, N-acetyl, N-Cbz,[10] and N-tosyl derivatives 39–42, lation of the amine, providing 45 in 58% yield (Entry 9).
Scheme 7. Preparation and reactivity of aziridino-γ-lactones 39–42.
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A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
Table 1. Nucleophilic opening of aziridino-γ-lactones 39–42 by a variety of acetate anion sources.
FULL PAPER
Entry
Compound
Conditions
Results[a]
[b]
1
2
3
4
5
6
7
8
9
39
39
39
39
40
41
41
42
42
42
AcOH (5 equiv.), CHCl3, BF3·OEt2, room temp.,15 h
AcOH/CHCl3 (1:1), BF3·OEt2, 50 °C, 24 h
AcOK, DMF, room temp. to 90 °C
–
[c]
–
[c]
–
[c]
AcOCs (5 equiv.), DMF, 50 °C
–
[c]
AcOCs, DMF, 50 °C, 2 h
–
AcOH/CHCl3, BF3·OEt2, 50 °C, 20 h
43 (48%)
43 (42%)
44 (49%)
45 (58%)
45 (72%)
AcOCs, DMF, 50 °C, 2 h
AcOCs, DMF, room temp., 2 h
PBu3 (0.2 equiv.), Ac2O (3 equiv.), toluene, 110 °C, 2 h
PBu3 (0.2 equiv.), Ac2O (3 equiv.), microwaves, toluene, 130 °C, 30 min
10
[a] Values in parentheses are for isolated yields. [b] No reaction. [c] Degradation of starting materials.
When the same reaction was performed under microwave hydroxy groups. Treatment of the mixture with acetic anhy-
irradiation conditions, compound 45 was obtained in an dride in pyridine then gave the diacetate 51 in 60% yield
optimal yield of 72% (Entry 10).
over the two steps. This thus represents the synthesis of a
Because the N-tosylaziridine derivative 42 had given the protected form of APTO that can be employed directly for
best results in these model studies, the N-tosylaziridino-γ- the subsequent total synthesis of microsclerodermins C and
lactone 46 was prepared by sequential treatment of the N- D.
DMB precursor 35 with DDQ and tosyl chloride
(Scheme 8). Treatment of 46 with 20 mol-% tri-n-butylphos-
phane and excess acetic anhydride in toluene under micro-
wave irradiation conditions then afforded the 2-O-acetyl-3-
N-acetyl-3-N-tosyl derivative 47 in 79% yield. Regioselec-
tive opening of the aziridine at C-2 was clearly indicated by
the COSY H NMR spectra of 47 (see Supporting Infor-
mation).
Conclusions
Here we report the first use of an aziridino-γ-lactone for
the enantiospecific synthesis of an α-substituted β-amino
acid derivative. From the gulonolactone derivative 33, easily
obtained from -gulose by standard chemical transforma-
tions, the aziridino-γ-lactone 46 was efficiently prepared by
a methodology previously developed by us for simpler sub-
strates. From the known reactivity of aziridino-γ-lactones,
conditions that allowed chemo- and regioselective opening
of the aziridine at C-2 with acetate anion were found. The
final product, lactone 48, is a protected form of APTO, the
α-hydroxy β-amino acid component of microsclero-
dermins C and D. As shown by its reaction with benzyl-
amine to give APTO benzylamide, lactone 48 can be re-
garded as a convenient, activated building block for the
eventual synthesis of microsclerodermins C and D or their
analogues. This objective is presently being pursued by us.
1
Scheme 8. Preparation of the protected equivalent of APTO 51.
Reagents and conditions: (a) DDQ, CH2Cl2/H2O (10:1), room
temp., 20 h, then TsCl, pyridine, room temp., 2 h; (b) PBu3
(0.2 equiv.), Ac2O (3 equiv.), microwaves, toluene, 90 °C, 2 h; (c)
Pd(OAc)2 (0.1 equiv.), PPh3 (0.2 equiv.), Et3N (5 equiv.), PhI
(1.3 equiv.), DMF, 110 °C, 24 h; (d) BnNH2, THF, room temp., 2 h;
(e) Ac2O, pyridine, 0 °C to room temp., 18 h.
Experimental Section
General Remarks: Melting points, measured in capillary tubes and
recorded with a Büchi B-540 melting point apparatus, are uncor-
rected. IR spectra were recorded with a Perkin–Elmer Spectrum
BX FT-IR spectrometer. Optical rotations were determined with a
JASCO P-1010 polarimeter. 1H and 13C NMR spectra were re-
Finally, installation of the terminal phenyl moiety on
compound 47 by means of a Heck reaction was studied.
Whereas use of iodobenzene with 1 equiv. of triethylamine corded with Bruker spectrometers, namely Avance 300 and 500 (300
and 500 MHz, respectively). Chemical shifts (δ) are reported in
parts per million (ppm) with reference to tetramethylsilane (TMS)
as internal standard. NMR experiments were carried out in deuter-
iochloroform (CDCl3) or in deuteriobenzene (C6D6). The following
afforded the desired styrene derivative as a mixture of N-
acetylated and N-deacetylated products, use of excess trieth-
ylamine (5 equiv.) ensured complete removal of the N-acetyl
group to give lactone 48 in 74% yield. Compound 48 is a
protected form of APTO that can be used directly for the
formation of a carboxamide (e.g., peptide) bond as sug-
gested by the following result. Treatment of 48 with ben-
zylamine in THF at room temperature over 2 h provided a
mixture of N-benzylcarboxamides 49 and 50 resulting from
1
abbreviations are used for the H multiplicities: s: singlet, d: doub-
let, t: triplet, q: quartet, m: multiplet. Coupling constants (J) are
reported in Hertz (Hz). Mass spectra were obtained with an LCT
(Micromass) instrument by electrospray ionization and with a time-
of-flight analyzer (ESI-MS) for high-resolution mass spectra
(HRMS). Thin-layer chromatography was performed on silica gel
scrambling of the acetate group between the C-2 and C-4 60 plates with a fluorescent indicator and visualized under a UVP
678 Eur. J. Org. Chem. 2009, 673–686
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
Mineralight UVGL-58 lamp (254 nm) and with a solution of phos-
phomolybdic acid in ethanol (7%). Flash chromatography was per-
formed with silica gel 60 (40–63 µm, 230–400 mesh ASTM) at me-
dium pressure (200 mbar). All solvents were distilled and stored
over molecular sieves (4 Å) before use. All reagents were obtained
from commercial suppliers, unless otherwise stated. Organic ex-
tracts were, in general, dried with magnesium sulfate (MgSO4) or
sodium sulfate (Na2SO4). Elemental analyses were performed at
the ICSN, CNRS, Gif-sur-Yvette, France.
and filtered, and the solvents were evaporated to dryness under
vacuum. The crude product was purified by flash chromatography
on silica gel (heptane/EtOAc, 4:1) to furnish 19 (20 mg, 0.09 mmol,
22%) as a pale yellow oil; Rf = 0.40 (EtOAc/heptane, 2:1). 1H
NMR (CDCl3, 300 MHz): δ = 1.01 (t, J7,6 = 7.4 Hz, 3 H, 7-H),
1.42, 1.44 [2ϫs, 6 H, C(CH3)2], 1.57 (m, 2 H, 6-H, 6Ј-H), 3.38 (m,
1 H, 5-H), 3.85 [s, 3 H, C(O)CH3], 4.10 (dd, J4,5 = 2.9, J4,3
=
7.7 Hz, 1 H, 4-H), 4.24 (dd, J3,2 = 4.2, J3,4 = 7.7 Hz, 1 H, 3-H),
4.37 (m, 1 H, 2-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 10.2 (C-
7), 27.0, 27.3 [C(CH3)2], 27.6 (C-6), 52.8 (COCH3), 71.1 (C-2), 71.8
(C-5), 78.4 (C-3), 79.3 (C-4), 109.9 [C(CH3)2], 172.5 (C=O, lactone)
5,6-Anhydro-2,3-O-isopropylidene-L-gulono-γ-lactone (17): Cesium
fluoride (1.3 g, 8.54 mmol, 3 equiv., dried beforehand at 150 °C in
vacuo overnight) was added to a solution of 16 (0.8 g, 2.85 mmol)
in dry acetone (13 mL). The reaction mixture was heated at reflux
for 5 h, active charcoal was added, the mixture was filtered, and
the filtrate was concentrated to dryness under vacuum. The crude
product was dissolved in hot chloroform. Active charcoal was again
added, the mixture was filtered, and the solvent was evaporated in
vacuo to give epoxide 17 (0.42 g, 2.1 mmol, 74%) as a white solid;
ppm. FTIR: ν = 3445 (OH), 2931, 1742 (C=O, ketone), 1215,
˜
1074 cm–1. ESI-MS: m/z = 255 [M + Na]+, 271 [M + K]+, 287 [M
+ Na + MeOH]+.
2,3:5,6-Di-O-isopropylidene-1-O-(4-methoxybenzyl)-L-gulose (21): A
solution of lactol 20 (3.08 g, 11.8 mmol) in DMF (30 mL) was
added at room temperature under argon to a suspension of NaH
(0.94 mg, 23.7 mmol) in anhydrous DMF (30 mL). After 3 h of stir-
ring, the reaction was quenched by slow addition of water. The
mixture was extracted with CH2Cl2 (3ϫ25 mL), the organic ex-
tracts were combined and dried with MgSO4, and the solvents were
evaporated to dryness under vacuum. The crude product was puri-
fied by flash chromatography on silica gel (heptane/EtOAc, 5:1) to
afford compound 21 (3.01 g, 7.9 mmol, 67%) as a pasty white solid;
1
Rf = 0.54 (EtOAc/heptane, 2:1). [α]2D0 = +74 (c = 1.4, CHCl3). H
NMR (CDCl3, 250 MHz): δ = 1.41 (s, 3 H, CH3), 1.52 (s, 3 H,
CH3), 2.74 (dd, J6,5 = 2.6, J6,6 = 4.5 Hz, 1 H, 6-H), 2.96 (t, J6Ј,6
=
J6Ј,5 = 4.5 Hz, 6Ј-H), 3.35 (m, 1 H, 5-H), 4.04 (m, 1 H, 4-H), 4.84
(m, 2 H, 2-H, 3-H) ppm. 13C NMR (CDCl3, 75 MHz): δ = 25.7,
26.6 [C(CH3)2], 43.0 (C-6), 49.6 (C-5), 75.8, 76.3 (C-2, C-3), 80.9
(C-4), 114.7 [C(CH ) ], 173.1 (C=O, lactone) ppm. FTIR: ν = 2987,
˜
1
Rf = 0.70 (EtOAc/heptane 1:1). [α]2D0 = +52 (c = 1.0, CHCl3). H
3 2
1786 (C=O, lactone), 1379, 1197, 1114 cm–1. HRMS (ESI+): calcd.
NMR (CDCl3, 300 MHz): δ = 1.27, 1.41, 1.45, 1.48 [s, 12 H,
2ϫC(CH3)2], 3.72 (m, 1 H, 6-H), 3.80 (s, 3 H, OCH3), 3.99 (dd,
J4,3 = 3.2, J4,5 = 8.4 Hz, 1 H, 4-H), 4.22 (m, 1 H, 6Ј-H), 4.40 (m,
1 H, 5-H), 4.45 (d, J = 11.7 Hz, 1 H, OCH2Ar), 4.64 (m, 2 H, 2-
H, 3-H), 4.69 (d, J = 11.7 Hz, 1 H, OCH2Ar), 5.17 (s, 1 H, 1-H),
6.87 (d, 2 H, 2Ј-H, 6Ј-H), 7.25 (d, J = 7.4 Hz, 2-H, 3Ј-H, 5Ј-H)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 24.7, 25.4, 25.9, 26.8
[C(CH3)2], 55.2 (OCH3), 66.0 (C-6), 68.8 (OCH2Ar), 75.6 (C-5),
79.8 (C-3), 82.1 (C-4), 85.1 (C-2), 105.4 (C-1), 109.7, 112.8
[C(CH3)2], 113.8 (C-2Ј, C-6Ј), 129.4 (C-1Ј), 129.7 (C-3Ј, C-5Ј), 159.3
for [C9H12O5Na + MeOH]+ 255.0845; found 255.0846.
Compound 18: Allylmagnesium bromide (0.58 mL, 1.16 mmol of a
2  solution in THF) was added dropwise at –35 °C under argon
to a solution of LiCuCl4 [1.9 mL, 0.19 mmol of a 0.1  solution in
THF, prepared from a mixture of CuCl2 (1 mol) and LiCl (2 mol)].
After 30 min of stirring at –35 °C, the reaction mixture was cooled
to –78 °C, and a solution of epoxide 17 (77 mg, 0.39 mmol) in THF
(5 mL) was added. The mixture was stirred at –78 °C for 10 min,
quenched with saturated aqueous NH4OAc, and extracted with di-
ethyl ether (4ϫ5 mL). The organic extracts were combined, washed
with saturated aqueous NaCl, and dried with MgSO4, and the sol-
vents were evaporated under vacuum. The crude product was puri-
fied by flash chromatography on silica gel (heptane/EtOAc, 8:1) to
furnish compound 18 (43 mg, 0.18 mmol, 46%) as a white solid;
Rf = 0.5 (EtOAc/heptane, 4:3); m.p. 85–87 °C. [α]2D0 = –26 (c = 1.11,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 1.33 (s, 3 H, CH3), 1.51
(s, 3 H, CH3), 2.50 (dd, J7,8 = 8.8, J7,7Ј = 13.9 Hz, 1 H, 7-H), 2.64
(dd, J1,2 = 2.7, J1,1Ј = 4.6 Hz, 1 H, 1-H), 2.72 (dd, J7,8 = 5.8, J7,7Ј
= 13.9 Hz, 1 H, 7Ј-H), 2.90 (t, J1Ј,1 = J1Ј,2 = 4.6 Hz, 1 H, 1Ј-H),
3.23 (m, 1 H, 2-H), 3.58 (dd, J3,4 = 3.9, J3,2 = 7.3 Hz, 1 H, 3-H),
4.48 (d, J5,4 = 5.8 Hz, 1 H, 5-H), 4.81 (dd, J4,3 = 3.9, J4,5 = 5.8 Hz,
1 H, 4-H), 5.24 (m, 2 H, 9-H, 9Ј-H), 5.95 (m, 1 H, 8-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 24.6, 25.9 [C(CH3)2], 39.6 (C-7), 43.6
(C-1), 49.8 (C-2), 81.0, 81.4 (C-3, C-4), 85.1 (C-5), 112.8
[C(CH3)2], 120.4 (C-9), 131.7 (C-8), 199.0 (C=O, ketone) ppm.
(C-4Ј) ppm. FTIR: ν = 2987, 2937, 1613 (C=C), 1514, 1374, 1249,
˜
1084, 1011, 848 cm–1. ESI-MS: m/z = 403 [M + Na]+. C20H28O7
(380.18): calcd. C 63.14, H 7.42; found C 62.77, H 7.54.
2,3-O-Isopropylidene-1-O-(4-methoxybenzyl)-L-gulose (22): Com-
pound 21 (2.99 g, 7.9 mmol) was dissolved in a mixture of acetic
acid/H2O (4:1, 20 mL), and the mixture was stirred at 30 °C for
18 h. The solution was concentrated to dryness under vacuum. To
remove traces of acetic acid, the resulting oil was dissolved in n-
butanol (35 mL) and toluene (35 mL), and the solvents were again
removed in vacuo to furnish diol 22 (2.61 g, 7.7 mmol, 98%) as a
white solid, homogeneous by TLC. For analytical purposes, an ali-
quot of the crude product was purified by flash chromatography
on silica gel (heptane/EtOAc, 1:1); Rf = 0.10 (EtOAc/heptane, 1:1);
m.p. 119–125 °C (decomp.). [α]2D0 = +80 (c = 1.11, CHCl3). 1H
NMR (CDCl3, 300 MHz): δ = 1.29, 1.46 [s, 6 H, 2ϫC(CH3)2], 2.08
(t, J = 6.3 Hz, 1 H, OH), 3.64 (t, J = 6.3 Hz, 1 H, OH), 3.74 (d,
J6,5 = J6Ј,5 = 4.8 Hz, 2 H, 6-H, 6Ј-H), 3.79 (s, 3 H, OCH3), 4.00
(dd, J4,3 = 3.6, J4,5 = 5.3 Hz, 1 H, 4-H), 4.12 (m, 1 H, 5-H), 4.51
(2ϫd, J = 11.5 Hz, 2 H, OCH2Ar), 4.30 (d, J2,3 = 5.9 Hz, 1 H, 2-
H), 4.76 (dd, J3,4 = 3.6, J3,2 = 5.9 Hz, 1 H, 3-H), 5.13 (s, 1 H, 1-
H), 6.87 (d, J = 8.0 Hz, 2 H, H arom), 7.24 (d, J = 8.0 Hz, 2 H, H
FTIR: ν = 3412 (OH), 1735 (C=O, ketone), 1641 (C=C), 1376,
˜
1211, 1101 cm–1. ESI-MS: m/z = 225 [M + H – H2O]+, 243 [M +
H]+, 265 [M + Na]+, 281 [M + K]+.
Compound 19: MeLi (1.5 mL, 2.4 mmol, from a 1.6  solution in
diethyl ether) was added under argon at 0 °C to a suspension of
CuI (229 mg, 1.2 mmol) in diethyl ether (1 mL). After the mixture
had been stirred at 0 °C for 15 min, a solution of epoxide 17
(80 mg, 0.4 mmol) in THF (7 mL) was added dropwise, and stirring
was continued at 0 °C for 1 h. The reaction was quenched with
saturated aqueous NH4Cl and the mixture extracted with diethyl
ether (3ϫ10 mL). The organic extracts were dried with MgSO4
arom) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 24.3, 25.8
[C(CH3)2], 55.2 (OCH3), 63.5 (C-6), 68.8 (OCH2Ar), 70.6 (C-5),
79.1 (C-4), 80.3 (C-3), 85.3 (C-2), 104.9 (C-1), 112.7 [C(CH3)2],
113.8 (C-2Ј, C-6Ј), 129.2 (C-1Ј), 129.7 (C-3Ј, C-5Ј), 159.3 (C-4Ј)
ppm. FTIR: ν = 3500, 3350 (OH), 2931, 1612 (C=C), 1514, 1376,
˜
1249, 1081, 1009, 820 cm–1. ESI-MS: m/z = 363 [M + Na]+, 379
Eur. J. Org. Chem. 2009, 673–686
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
679

A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
FULL PAPER
[M + K]+. C17H24O7 (340.15): calcd. C 59.99, H 7.11, O 32.90;
found C 59.82, H 7.27, O 33.18.
CH2Cl2, 1:99) to afford the alcohol 25 (1.03 g, 2.95 mmol, 70%) as
a white solid; Rf = 0.40 (EtOAc/CH2Cl2, 2:98); m.p. 39–40 °C.
1
[α]2D0 = +73 (c = 1.54, CHCl3). H NMR (CDCl3, 300 MHz): δ =
6-Bromo-6-deoxy-2,3-O-isopropylidene-1-O-(4-methoxybenzyl)-L-gu-
1.31, 1.48 [s, 6 H, 2ϫC(CH3)2], 2.44 (m, 2 H, 6-H, 6Ј-H), 3.01 (s,
1 H, OH), 3.81 (s, 3 H, OCH3), 3.90 (m, 1 H, 4-H), 4.11 (m, 1 H,
5-H), 4.51 (d, J = 11.3 Hz, 2 H, OCH2Ar), 4.64 (d, J2,3 = 5.9 Hz,
1 H, 2-H), 4.75 (dd, J3,2 = 5.9, J3,4 = 3.5 Hz, 1 H, 3-H), 5.15 (m,
3 H, 1-H, 8-H, 8Ј-H), 5.90 (m, 1 H, 7-H), 6.82 (d, J = 8.0 Hz, 2 H,
H arom), 7.28 (d, J = 8.0 Hz, 2 H, H arom) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 24.4, 25.8 [C(CH3)2], 37.9 (C-6), 55.2
(OCH3), 68.7 (OCH2Ar), 69.2 (C-5), 80.5, 80.7 (C-3, C-4), 85.5 (C-
2), 104.7 (C-1), 112.7 [C(CH3)2], 113.9 (C-2Ј, C-6Ј), 117.6 (C-8),
129.2 (C-1Ј), 129.8 (C-3Ј, C-5Ј), 134.4 (C-7), 159.4 (C-4Ј) ppm.
lose (23): Triphenylphosphane (2.53 g, 9.9 mmol) and carbon tetra-
bromide (2.52 g, 7.6 mmol) were added at 0 °C under argon to a
solution of diol 22 (2.58 g, 7.6 mmol) in THF (25 mL). The reac-
tion mixture was allowed to come to room temperature over 2 h,
and stirring was continued for 10 h. The mixture was diluted with
diethyl ether (25 mL) and filtered, and the solvents were evaporated
to dryness. The crude product was purified by flash chromatog-
raphy on silica gel (heptane/EtOAc, 5:1) to afford the product 23
(1.9 g, 2.2 mmol, 62%) as a colorless oil; Rf = 0.60 (EtOAc/heptane
1:1). [α]2D0 = +63 (c = 0.9, CHCl3). 1H NMR (CDCl3, 250 MHz): δ
= 1.30, 1.47 [s, 6 H, 2ϫC(CH3)2], 3.22 (d, JOH,5 = 2.7 Hz, 1 H,
OH), 3.62 (d, J6,5 = J6Ј,5 = 5.0 Hz, 2 H, 6-H, 6Ј-H), 3.82 (s, 3 H,
OCH3), 4.17 (m, 1 H, 4-H), 4.22 (m, 1 H, 5-H), 4.53 (2ϫd, J =
11.3 Hz, 2 H, OCH2Ar), 4.64 (d, J2,3 = 6.0 Hz, 1 H, 2-H), 4.80 (dd,
J3,4 = 3.6, J3,2 = 5.8 Hz, 1 H, 3-H), 5.15 (s, 1 H, 1-H), 6.90 (d, J =
8.0 Hz, 2 H, H arom), 7.27 (d, J = 8.0 Hz, 2 H, H arom) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 24.3, 25.8 [C(CH3)2], 34.3 (C-6), 55.2
(OCH3), 68.8 (OCH2Ar), 69.9 (C-5), 79.5 (C-4), 80.1 (C-3), 85.4
(C-2), 104.7 (C-1), 112.9 [C(CH3)2], 113.9 (C-2Ј, C-6Ј), 129.1 (C-
FTIR: ν = 3456 (OH), 2937, 1613, 1376, 1249, 1081, 1022,
˜
854 cm–1. HRMS (ESI)+: calcd. for [C19H26O6Na]+ 373.1627;
found 373.1606.
4-Methoxybenzyl 5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-
6,7,8-trideoxy-β-L-gulo-oct-7-enofuranoside (26): Imidazole
(354 mg, 5.2 mmol) and tert-butyldiphenylsilyl chloride (0.67 mL,
2.6 mmol) were added under argon at 0 °C to a solution of alcohol
25 (0.92 g, 2.6 mmol) in DMF (6.7 mL). The reaction mixture was
allowed to come to room temperature, and, after 20 h of stirring,
the mixture was diluted with water (10 mL) and EtOAc (10 mL).
The organic phase was separated, and the aqueous phase was ex-
tracted with EtOAc (2ϫ10 mL). The organic phases were com-
bined, washed with water (2ϫ10 mL), dried with MgSO4, and fil-
tered, and the solvents were evaporated to dryness under vacuum.
The crude product was purified by flash chromatography on silica
gel (heptane/EtOAc, 8:1) to furnish the silylated compound 26
(1.18 g, 2.01 mmol, 77%) as a colorless oil; Rf = 0.70 (EtOAc/hep-
tane, 3:5). [α]2D0 = +55 (c = 1.7, CHCl3). 1H NMR (CDCl3,
300 MHz): δ = 1.08 [s, 9 H, SiC(CH3)3], 1.13, 1.20 [s, 6 H,
2ϫC(CH3)2], 2.32 (m, 2 H, 6-H, 6Ј-H), 3.81 (s, 3 H, OCH3), 4.03
(m, 1 H, 4-H), 4.21 (m, 2 H, 5-H, OCHHAr), 4.46 (d, J = 11.5 Hz,
1 H, OCHHAr), 4.53 (m, 1 H, 2-H), 4.59 (m, 1 H, 3-H), 4.86 (s, 1
H, 1-H), 5.05 (m, 2 H, 8-H, 8Ј-H), 6.08 (m, 1 H, 7-H), 6.84 (d, J
= 8.0 Hz, 2 H, H arom), 7.25 (d, J = 8.0 Hz, 2 H, H arom), 7.30–
7.40 (m, 6 H, H arom), 7.70–7.85 (m, 4 H, H arom) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 19.6 [SiC(CH3)3], 25.3, 26.0
[C(CH3)2], 27.1 [SiC(CH3)3], 37.9 (C-6), 55.3 (OCH3), 68.0
(OCH2Ar), 71.5 (C-5), 79.5 (C-3), 82.9 (C-4), 85.6 (C-2), 104.3 (C-
1), 112.2 [C(CH3)2], 113.8 (C-2Ј, C-6Ј), 117.1 (C-8), 127.2, 127.3,
127.7, 129.2 (C arom), 129.5 (C-1Ј), 129.8 (C-3Ј, C-5Ј), 134.3 (C-
1Ј), 129.8 (C-3Ј, C-5Ј), 159.4 (C-4Ј) ppm. FTIR: ν = 3474 (OH),
˜
2989, 2934, 1613, 1514, 1377, 1250, 1081, 1024, 821 cm–1. HRMS
(ESI+): calcd. for [C17H23BrO6Na]+ 425.0576; found 425.0563.
5,6-Anhydro-2,3-O-isopropylidene-1-O-(4-methoxybenzyl)-L-gulose
(24): Cesium fluoride (2.8 g, 18.4 mmol, dried beforehand at 150 °C
in vacuo overnight) was added to a solution of 23 (1.86 g,
4.6 mmol) in dry acetone (25 mL). The reaction mixture was heated
at reflux for 6 h, active charcoal was added, the mixture was fil-
tered, and the filtrate was concentrated to dryness under vacuum.
The crude product was dissolved in hot chloroform, active charcoal
was again added, and, after filtration, the solvent was evaporated
in vacuo to give epoxide 24 (1.41 g, 4.4 mmol, 95%) as a white
solid; Rf = 0.60 (EtOAc/CH2Cl2 2:98); m.p. 87–89 °C. [α]2D0 = +74
1
(c = 1.4, CHCl3). H NMR (CDCl3, 250 MHz): δ = 1.32, 1.49 [s,
6 H, C(CH3)2], 2.43 (dd, J6,6Ј = 2.7, J6,5 = 4.8 Hz, 1 H, 6-H), 2.89
(t, J6Ј,6 = J6Ј,5 = 4.5 Hz, 1 H, 6Ј-H), 3.26 (m, 1 H, 5-H), 3.54 (dd,
J4,3 = 3.7, J4,5 = 7.0 Hz, 1 H, 4-H), 3.75 (s, 3 H, OCH3), 4.52 (2ϫd,
J = 11.9 Hz, 2 H, OCH2Ar), 4.64 (d, J2,3 = 5.7 Hz, 1 H, 2-H), 4.74
(dd, J3,2 = 5.9, J3,4 = 3.8 Hz, 1 H, 3-H), 5.14 (s, 1 H, 1-H), 6.85 (d,
J = 8.0 Hz, 2 H, H arom), 7.25 (d, J = 8.0 Hz, 2 H, H arom) ppm.
13C NMR (CDCl3, 75 MHz): δ = 24.7, 26.0 [C(CH3)2], 43.6 (C-6),
50.0 (C-5), 55.3 (OCH3), 68.6 (OCH2Ar), 80.6 (C-4), 82.4 (C-3),
85.1 (C-2), 105.2 (C-1), 112.8 [C(CH3)2], 113.9 (C-2Ј, C-6Ј), 129.1
7), 134.4, 134.7, 135.2 (C arom), 159.3 (C-4Ј) ppm. FTIR: ν = 3071,
˜
2934, 2857, 1613, 1514, 1428, 1250, 1110, 1082, 822, 703 cm–1. ESI-
MS: m/z = 611 [M + Na]+. C35H44O6Si·0.1C7H16 (598.30): calcd.
C 71.63, H 7.62; found C 72.01, H 7.65.
(C-1Ј), 129.8 (C-3Ј, C-5Ј), 159.4 (C-4Ј) ppm. FTIR: ν = 2991, 2937,
˜
1613 (C=C), 1515, 1376, 1250, 1081, 1020, 856, 821 cm–1. ESI-MS:
m/z = 345 [M + Na]+, 361 [M + K]+. C17H22O6 (322.14): calcd. C
63.34, H 6.88, O 29.78; found C 63.57, H 6.97, O 29.91.
5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-6,7,8-trideoxy-β-L-
gulo-oct-7-enofuranose (27): DDQ (613 mg, 2.7 mmol) was added
in small portions to a solution of 26 (1.12 g, 1.8 mmol) in CH2Cl2/
H2O (10:1, 19.8 mL). The dark green solution was stirred at room
temperature for 20 h. The resulting reddish-brown mixture was di-
luted with saturated aqueous NaHCO3 (20 mL) and CH2Cl2
(20 mL). The organic phase was separated, and the aqueous phase
was extracted with CH2Cl2 (2ϫ20 mL). The organic phases were
combined, dried with MgSO4, and filtered, and the solvents were
evaporated to dryness under vacuum. The crude product was puri-
fied by flash chromatography on silica gel (heptane/EtOAc, 10:1)
to furnish lactol 27 (0.53 g, 1.1 mmol, 63%) as a colorless oil; Rf
= 0.20 (AcOEt/heptane, 1:5). [α]2D0 = +40 (c = 1.40, CHCl3). 1H
NMR (CDCl3, 250 MHz): δ = 1.05 [s, 9 H, SiC(CH3)3], 1.11, 1.20
4Ј-Methoxybenzyl 2,3-O-Isopropylidene-6,7,8-trideoxy-β-L-gulo-oct-
7-enofuranoside (25): Vinylmagnesium bromide (12.7 mL of a 1 
solution in THF) was added at –25 °C under argon to a solution
of copper iodide (240 mg, 1.26 mmol) in THF (20 mL). After the
mixture had been stirred for 15 min, a solution of epoxide 24
(1.36 g, 4.2 mmol) in THF (10 mL) was added dropwise. The reac-
tion mixture was allowed to come to room temperature, and stir-
ring was continued for 1.5 h. The reaction was quenched with satu-
rated aqueous NH4OAc, and the mixture was extracted with diethyl
ether (3ϫ30 mL). The organic phases were combined, washed with
saturated aqueous NaCl, dried with MgSO4, and filtered, and the
solvents were evaporated to dryness under vacuum. The crude
product was purified by flash chromatography on silica gel (EtOAc/
[s, 6 H, 2ϫC(CH3)2], 2.35 (m, 2 H, 6-H, 6Ј-H), 4.01 (dd, J4,3
=
3.2, J4,5 = 8.7 Hz, 1 H, 4-H), 4.16 (m, 2 H, 5-H, OH), 4.43 (d, J2,3
680
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 673–686

Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
= 5.8 Hz, 1 H, 2-H), 4.58 (dd, J3,4 = 3.3, J3,2 = 5.8 Hz, 1 H, 3-H), (7E)-5-O-tert-Butyldiphenylsilyl-8-phenyl-6,7,8-trideoxy-β-
L
-gulo-
4.99 (s, 1 H, 1-H), 5.04 (m, 2 H, 8-H, 8Ј-H), 6.08 (m, 1 H, 7-H), oct-7-eno-1,4-lactone (12): A solution of acetonide 29 (486 mg,
7.30–7.76 (m, 10 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): 0.9 mmol) in aqueous AcOH (80%, 4 mL) was stirred at 90 °C in
δ = 19.4 [SiC(CH3)3], 25.2, 25.8 [C(CH3)2], 26.9 [SiC(CH3)3], 37.7
(C-6), 71.6 (C-5), 79.4 (C-3), 82.9 (C-4), 85.7 (C-2), 100.4 (C-1),
112.2 [C(CH3)2], 116.9 (C-8), 126.7, 127.0, 128.9, 129.0 (C arom),
a Dean–Stark apparatus for 24 h. The reaction mixture was con-
centrated to dryness under vacuum, the residue was dissolved in
EtOAc (10 mL), and the solution was neutralized with saturated
aqueous NaHCO3 (10 mL). The organic phase was separated, and
the aqueous phase was extracted with EtOAc (2ϫ10 mL). The or-
ganic phases were combined, washed with water (2ϫ10 mL), dried
with MgSO4, and filtered, and the solvents were evaporated to dry-
ness under vacuum. The crude product was purified by flash
chromatography on silica gel (heptane/EtOAc, 2:1) to furnish the
diol 12 (271 mg, 0.54 mmol, 60%) as a pasty white solid; Rf = 0.20
(EtOAc/heptane, 3:4). [α]2D0 = +39 (c = 1.26, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 1.12 [s, 9 H, SiC(CH3)3], 2.44 (m, 2 H, 6-
H, 6Ј-H), 4.18 (m, 1 H, 5-H), 4.33–4.47 (m, 3 H, 2-H, 3-H, 4-H),
6.17–6.34 (d, J8,7 = 16.0 Hz, 2 H, 7-H, 8-H), 7.19–7.79 (m, 15 H,
H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.3 [SiC(CH3)3],
26.8 [SiC(CH3)3], 36.2 (C-6), 68.8, 71.0, 71.6 (C-2, C-3, C-5), 82.5
(C-4), 124.6 (C-7), 125.9, 127.2, 127.4, 128.4, 129.6, 129.7 (C arom),
132.9 (C-8), 135.8, 136.0, 136.29, 136.8 (C arom), 175.1 (C=O)
134.4 (C-7), 135.7, 135.9 (C arom) ppm. FTIR: ν = 3411 (OH),
˜
3072, 2934, 1428, 1109, 1085, 703 cm–1. ESI-MS: m/z = 453 [M –
CH3]+. C27H36O5Si (468.23): calcd. C 69.20, H 7.74; found C 69.49,
H 8.11.
5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-6,7,8-trideoxy-β-L-
gulo-oct-7-eno-1,4-lactone (28): N-Methylmorpholine N-oxide
(82 mg, 0.7 mmol, dried beforehand in vacuo at 90 °C) and molecu-
lar sieves (4 Å, 240 mg, finely crushed and oven-dried) were added
successively at 20 °C under argon to a solution of lactol 27 (218 mg,
0.47 mmol) and tetrapropylammonium perruthenate (25 mg,
0.07 mmol) in acetonitrile (6 mL). After 3 h of stirring, the reaction
mixture was concentrated to dryness under vacuum. The resulting
residue was filtered through a pad of silica gel (eluent EtOAc), and
the filtrate was concentrated in vacuo to furnish lactone 28
(124 mg, 0.27 mmol, 95%) as a colorless oil; Rf = 0.16 (EtOAc/
heptane, 1:5). [α]2D0 = +36 (c = 0.96, CHCl3). 1H NMR (CDCl3,
250 MHz): δ = 1.08 [s, 9 H, SiC(CH3)3], 1.11, 1.28 [s, 6 H,
2ϫC(CH3)2], 2.29 (m, 2 H, 6-H, 6Ј-H), 4.11 (m, 1 H, 5-H), 4.41
ppm. FTIR: ν = 3432 (OH), 3071, 2929, 2856, 1781 (C=O, lactone),
˜
1427, 1190, 1109, 702 cm–1. HRMS (ESI)+: calcd. for [C30H34O5-
SiNa]+ 525.2073; found 525.2062.
(5S,6S)-6-[1-(tert-Butyldiphenylsilyloxy)-4-phenylbut-3-enyl]-3-(tri-
fluoromethylsulfonyl)furan-2(5H)-one (30): Pyridine (0.34 mL,
4.2 mmol) and trifluoromethanesulfonic anhydride (0.33 mL,
1.94 mmol) were added at –78 °C under argon to a solution of diol
12 (295 mg, 0.59 mmol) in CH2Cl2 (8 mL). After 15 min of stirring
at –78 °C, the reaction mixture was warmed to 0 °C. After 4 h of
stirring, the mixture was poured into cold diethyl ether (10 mL).
The precipitated salts were filtered, and the filtrate was concen-
trated in vacuo at 0 °C. The crude product was purified by flash
chromatography on silica gel (EtOAc/heptane, 1:4) to furnish the
triflate 30 (327 mg, 0.53 mmol, 90%) as a pale yellow oil; Rf = 0.65
(EtOAc/heptane 1:2). [α]2D0 = +22 (c = 1.00, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 1.07 [s, 9 H, SiC(CH3)3], 2.50 (m, 2 H, 7-
H, 7Ј-H), 4.09 (m, 1 H, 6-H), 5.03 (m, 1 H, 5-H), 5.98 (m, 1 H, 8-
H), 6.34 (d, J9,8 = 16.0 Hz, 1 H, 9-H), 6.78 (d, J4,5 = 1.7 Hz, 1 H,
4-H), 7.20–7.72 (m, 15 H, H arom) ppm. 13C NMR (CDCl3,
75 MHz): δ = 19.2 [SiC(CH3)3], 26.8 [SiC(CH3)3], 36.8 (C-7), 72.0
(C-6), 79.7 (C-5), 123.8 (C-7), 126.1, 127.6, 127.9, 128.1, 128.5,
130.2, 130.4, 132.5, 132.7 (C arom, CF3), 134.4 (C-9), 135.8, 135.9,
136.2, 136.3, 136.7, 137.6 (C arom, C-4), 163.6 (C=O) ppm. FTIR:
(dd, J4,3 = 3.4, J4,5 = 8.9 Hz, 1 H, 4-H), 4.59 (dd, J3,4 = 3.4, J3,2
=
5.4 Hz, 1 H, 3-H), 4.72 (d, J2,3 = 5.4 Hz, 1 H, 2-H), 5.07 (m, 2 H,
8-H, 8Ј-H), 6.05 (m, 1 H, 7-H), 7.29–7.79 (m, 10 H, H arom) ppm.
13C NMR (CDCl3, 75 MHz): δ = 19.3 [SiC(CH3)3], 26.0, 26.3
[C(CH3)2], 26.8 [SiC(CH3)3], 37.0 (C-6), 70.8 (C-5), 75.2 (C-3), 79.2
(C-2), 81.9 (C-4), 113.7 [C(CH3)2], 117.7 (C-8), 127.2, 127.3, 129.4
(C arom), 133.2 (C-7), 135.7, 136.1 (C arom), 173.2 (C=O) ppm.
FTIR: ν = 3072, 2933, 2858, 1790 (C=O), 1428, 1110, 1085,
˜
703 cm–1. ESI-MS: m/z = 489 [M + Na]+, 505 [M + K]+, 521 [M
+ Na + MeOH]+. C27H34O5Si (466.22): calcd. C 69.49, H 7.34;
found C 69.39, H, 7.48.
(7E)-5-O-tert-Butyldiphenylsilyl-2,3-O-isopropylidene-8-phenyl-
6,7,8-trideoxy-β-L-gulo-oct-7-eno-1,4-lactone (29): Pd(OAc)2 (9 mg,
0.04 mmol), triphenylphosphane (21 mg, 0.08 mmol), triethylamine
(73 µL, 0.52 mmol), and iodobenzene (58 µL, 0.52 mmol) were
added to a solution of lactone 28 (188 mg, 0.40 mmol) in DMF
(2.5 mL). After 20 h of stirring at 110 °C under argon, the mixture
was diluted with EtOAc (10 mL) and water (10 mL). The organic
phase was separated, and the aqueous phase was extracted with
EtOAc (2ϫ10 mL). The organic phases were combined, washed
with water (2ϫ10 mL), and dried with MgSO4, and the solvents
were evaporated to dryness under vacuum. The crude product was
purified by flash chromatography on silica gel (heptane/EtOAc,
10:1) to furnish the acetonide 29 (119 mg, 0.22 mmol, 55%) as a
pale yellow oil; Rf = 0.15 (EtOAc/heptane 1:5). [α]2D0 = +36 (c =
ν = 2931, 2858, 1796 (C=O), 1435 (SO ), 1220, 1138 (SO ), 1112,
˜
2
2
1108, 702 cm–1. ESI-MS: m/z = 639 [M + Na]+, 655 [M + K]+.
C31H31F3O6SSi (616.16): calcd. C 60.37, H 5.07; found C 60.14, H
5.19.
(1R,4S,5S)-4-[(1S)-1-(tert-Butyldiphenylsilyloxy)-4-phenylbut-3-
enyl]-6-(3Ј,4Ј-dimethoxybenzyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-
0.6, CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 1.11 [s, 9 H, one (31): 3,4-Dimethoxybenzylamine (88 µL, 0.58 mmol) was
SiC(CH3)3], 1.15, 1.29 [s, 6 H, 2ϫC(CH3)2], 2.49 (m, 2 H, 6-H, 6Ј-
H), 4.18 (m, 1 H, 5-H), 4.43 (dd, J4,3 = 3.3, J4,5 = 8.8 Hz, 1 H, 4-
added dropwise under argon to a solution of triflate 30 (325 mg,
0.53 mmol) in DMF (3.8 mL), maintained at –60 °C. The reaction
mixture was stirred at –60 °C for 30 min, diluted with EtOAc
(5 mL) and then with water (5 mL). The layers were separated, and
H), 4.63 (dd, J3,4 = 3.4, J3,2 = 5.3 Hz, 1 H, 3-H), 4.71 (d, J2,3
=
5.3 Hz, 1 H, 2-H), 6.35–6.41 (m, 2 H, 7-H, 8-H), 7.21–7.77 (m, 15
H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.4 [SiC- the aqueous layer was extracted with EtOAc (2ϫ5 mL). The or-
(CH3)3], 26.1, 26.5 [C(CH3)2], 27.0 [SiC(CH3)3], 36.3 (C-6), 71.5 ganic extracts were combined and dried with MgSO4, and the sol-
(C-5), 75.4 (C-3), 76.3 (C-2), 82.1 (C-4), 113.8 [C(CH3)2], 124.9 (C-
8), 125.9, 127.2, 128.4, 129.5, 129.6 (C arom), 132.7 (C-8), 134.0,
vents were evaporated to dryness under vacuum. The resulting oily
residue was purified by flash chromatography on silica gel (hep-
tane/EtOAc, 4:1) to afford aziridino-γ-lactone 31 (122 mg,
0.19 mmol, 36%) as a white solid, together with recovered starting
material (121 mg, 0.21 mmol, 40 %); Rf = 0.51 (EtOAc/heptane,
135.9, 136.2, 136.9 (C arom), 173.3 (C=O) ppm. FTIR: ν = 3072,
˜
3050, 2956, 2933, 2858, 1789 (C=O), 1428, 1186, 1110, 703 cm–1.
HRMS (ESI)+: calcd. for [C33H38O5SiNa]+ 565.2386; found
565.2385.
1
3:4). [α]2D0 = +55 (c = 1.00, CHCl3). H NMR (CDCl3, 300 MHz):
Eur. J. Org. Chem. 2009, 673–686
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
681

A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
5-O-tert-Butyldiphenylsilyl-6,7,8-trideoxy-β- -gulono-oct-7-eno-1,4-
FULL PAPER
δ = 0.96 [s, 9 H, SiC(CH3)3], 2.28 (m, 1 H, 8-H), 2.52 (m, 1 H, 8Ј-
L
H), 2.54 (d, J5,1 = 4.4 Hz, 1 H, 5-H), 2.63 (d, J1,5 = 4.4 Hz, 1 H, lactone (33): A solution of acetonide 28 (1.02 g, 2.33 mmol) in
1-H), 3.17 (d, J = 13.2 Hz, 1 H, NCH2Ar), 3.54 (d, J = 13.2 Hz, 1 aqueous AcOH (80%, 10 mL) was stirred at 90 °C in a Dean–Stark
H, NCH2Ar), 3.79 (s, 6 H, OCH3), 3.86 (m, 1 H, 7-H), 4.32 (d, J4,5 apparatus for 24 h. The mixture was concentrated to dryness under
= 2.0 Hz, 1 H, 4-H), 5.80 (m, 1 H, 9-H), 6.18 (d, J10,9 = 15.8 Hz, vacuum, the residue was dissolved in EtOAc (10 mL), and the solu-
1 H, 10-H), 6.65–7.65 (m, 18 H, H arom) ppm. 13C NMR (CDCl3,
75 MHz): δ = 19.2 [SiC(CH3)3], 26.7 [SiC(CH3)3], 36.3 (C-6), 40.1
tion was neutralized with saturated aqueous NaHCO3 (25 mL).
The organic phase was separated, and the aqueous phase was ex-
(C-5), 44.1 (C-1), 55.8 (OCH3), 60.8 (NCH2Ar), 73.0 (C-7), 80.6 tracted with EtOAc (2ϫ25 mL). The organic phases were com-
(C-4), 110.9, 111.1 (C-2Ј, C-5Ј), 120.0 (C-6Ј), 124.2 (C-9), 125.8,
bined, washed with water (2ϫ25 mL), dried with MgSO4, and fil-
127.2, 127.6, 127.8, 128.3, 129.8, 130.0 (C arom), 133.6 (C-10),
tered, and the solvents were evaporated to dryness. The crude prod-
135.7 (C arom), 149.1, 149.6 (C-3Ј, C-4Ј), 172.0 (C=O) ppm. FTIR: uct was purified by flash chromatography on silica gel (heptane/
ν = 2933, 1857, 1779 (C=O, lactone), 1516, 1427, 1112, 703 cm–1. EtOAc, 2:1) to furnish the diol 33 (516.8 mg, 1.21 mmol, 55%) as
˜
ESI-MS: m/z = 656 [M + Na]+.
a white solid; Rf = 0.40 (EtOAc/heptane, 1:1); m.p. 136–137 °C.
[α]2D0 = +13.3 (c = 1.10, CHCl3). 1H NMR (CDCl3, 300 MHz): δ =
1.11 [s, 9 H, SiC(CH3)3], 2.27 (m, 2 H, 6-H), 3.2 (br. s, 1 H, OH),
(1R,4S,5S)-4-[(1S)-1-(tert-Butyldiphenylsilyloxy)-4-phenylbut-3-
enyl)]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (32): Ceric ammonium
nitrate (188 mg, 0.34 mmol) was added at room temperature to a
solution of 31 (103 mg, 0.16 mmol) in MeCN/H2O (5:1, 2.2 mL).
After 2 h of stirring, the orange mixture was concentrated to dry-
ness under vacuum, the residue was dissolved in diethyl ether
(5 mL), and the solution was neutralized with saturated aqueous
NaHCO3. The organic phase was separated, and the aqueous phase
was extracted with diethyl ether (3ϫ5 mL). The organic phases
were combined, dried with MgSO4, filtered, and concentrated in
vacuo. The crude product was purified by flash chromatography
on silica gel (EtOAc/heptane, 1:4 + 1% Et3N) to afford aziridine
32 (15 mg, 0.032 mmol, 20%) as a colorless oil; Rf = 0.47 (EtOAc/
heptane, 3:4). 1H NMR (CDCl3, 300 MHz): δ = 1.05 [s, 9 H,
SiC(CH3)3], 2.34 (m, 1 H, 8-H), 2.48–2.65 (m, 3 H, 8Ј-H, 1-H, 5-
H), 3.95 (m, 1 H,7-H), 4.42 (s, 1 H, 4-H), 5.85 (dt, J = 7.5, J =
7.5, J = 15.8 Hz, 1 H, 9-H), 6.21 (d, J = 15.8 Hz, 1 H, 10-H), 7.13–
7.71 (m, 15 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ =
19.3 [SiC(CH3)3], 26.8 [SiC(CH3)3], 31.9 (C-8), 32.4 (C-1), 36.6 (C-
5), 73.5 (C-7), 76.6 (C-4), 126.0 (C-9), 127.5, 127.7, 128.0, 128.5,
130.3 (C arom), 133.9 (C-10), 135.8, 135.9 (C arom), 172.2 (C=O)
4.17 (br. s, 1 H, OH), 4.30 (m, 3 H, 3-H, 4-H, 5-H), 4.42 (d, J2,3
=
4.1 Hz, 1 H, 2-H), 5.02 (m, 2 H, 8-H), 5.92 (m, 1 H, 7-H), 7.3–7.9
(m, 10 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.6
[SiC(CH3)3], 27.2 [SiC(CH3)3], 37.2 (C-6), 69.1 (C-3), 70.1, 70.2 (C-
5, C-2), 83.3 (C-4), 118.4 (C-8), 127.6, 127.7, 129.8 (C arom), 133.3
(C-7), 134.3, 136.1, 136.3 (C arom), 176.1 (C=O) ppm. FTIR: ν =
˜
3415 (OH), 3071, 2931, 2856, 1773 (C=O), 1427, 1192, 1106,
702 cm–1. HRMS (ESI)+: calcd. for [C24H30O5SiNa]+ 449.1760;
found 449.1772.
(5S,6S)-6-[1-(tert-Butyldiphenylsilyloxy)but-3-enyl]-3-(trifluorometh-
ylsulfonyl)furan-2(5H)-one (34): Pyridine (758 µL, 9.42 mmol) and
trifluoromethanesulfonic anhydride (734 µL, 4.33 mmol) were
added at –78 °C under argon to a solution of diol 33 (574 mg,
1.35 mmol) in CH2Cl2 (18 mL). After 15 min of stirring at –78 °C,
the reaction mixture was warmed to 0 °C. After 4 h, the mixture
was poured into cold diethyl ether (25 mL). The precipitated salts
were filtered, and the filtrate was concentrated in vacuo at 0 °C.
The crude product was purified by flash chromatography on silica
gel to furnish the triflate 34 (688 mg, 1.27 mmol, 94%) as a pale
yellow oil; Rf = 0.50 (EtOAc/heptane, 1:4). 1H NMR (CDCl3,
300 MHz): δ = 1.06 [s, 9 H, SiC(CH3)3], 2.28 (m, 1 H, 7-H), 2.45
(m, 1 H, 7Ј-H), 4.02 (m, 1 H, 6-H), 5.02 (m, 3 H, 9-H, 9Ј-H, 5-H),
5.61 (m, 1 H, 8-H), 6.79 (d, J4,5 = 1.8 Hz, 1 H, 4-H), 7.36–7.68 (m,
10 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.4
[SiC(CH3)3], 28.0 [SiC(CH3)3], 38.0 (C-7), 71.9 (C-6), 79.8 (C-5),
119.4 (C-9), 127.6, 127.7, 129.8 (C arom), 133.3 (C-8), 134.3, 136.1
ppm. FTIR: ν = 3350 (NH), 2926, 2855, 1785 (C=O, lactone),
˜
1112, 702 cm–1. ESI-MS: m/z = 484 [M + H]+.
(1R,4S,5S)-6-(tert-Butoxycarbonyl)-4-[(1S)-1-(tert-butyldiphenylsilyl-
oxy)-4-phenylbut-3-enyl]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (11):
Boc2O (45 mg, 0.21 mmol), DMAP (1 mg, 8.0 µmol), and triethyl-
amine (56 µL, 0.4 mmol) were successively added at room tempera-
ture under argon to a solution of aziridine 32 (20 mg, 0.04 mmol)
in CH3CN (1 mL). After 1.5 h of stirring, the solution was concen-
trated to dryness. The crude product was diluted with EtOAc
(5 mL), the solution was neutralized with saturated aqueous
NaHCO3, and the organic phase was separated. The aqueous phase
was extracted with EtOAc (3ϫ5 mL), and the organic phases were
combined, dried with MgSO4, filtered, and concentrated in vacuo.
The crude product was purified by flash chromatography on silica
gel (heptane/EtOAc, 6:1) to furnish compound 11 (17 mg,
0.029 mmol, 73%) as a colorless oil; Rf = 0.70 (EtOAc/heptane,
2:3). 1H NMR (CDCl3, 300 MHz): δ = 1.05 [s, 9 H, SiC(CH3)3],
(C arom), 136.3 (C-4) 176.1 (C=O, lactone) ppm. FTIR: ν = 2931,
˜
2858, 1793 (C=O, lactone), 1428, 1218, 1102, 702 cm–1. HRMS
(ESI)+: calcd. for [C25H27F3O6SSiNa]+ 563.1148; found 563.1163.
(1R,4S,5S)-4-[(1S)-1-(tert-Butyldiphenylsilyloxy)but-3-enyl]-6-
(3Ј,4Ј-dimethoxybenzyl)-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (35):
3,4-Dimethoxybenzylamine (211 µL, 1.4 mmol) was added drop-
wise under argon to a solution of triflate 34 (688 mg, 1.27 mmol)
in DMF (9.1 mL), maintained at –60 °C. The reaction mixture was
stirred at –60 °C for 30 min and was diluted with EtOAc (12 mL)
and then with water (12 mL). The layers were separated, and the
aqueous layer was extracted with EtOAc (2ϫ12 mL). The organic
1.41 [s, 9 H, OC(CH3)3], 2.33 (m, 1 H, 8-H), 2.59 (m, 1 H, 8Ј-H), extracts were combined and dried with MgSO4, and the solvents
3.28 (d, J = 3.0 Hz, 1 H, 1-H), 3.36 (d, J = 3.0 Hz, 1 H, 5-H), 3.94 were evaporated to dryness under vacuum. The resulting oily resi-
(m, 1 H, 7-H), 4.73 (d, J = 3.9 Hz, 1 H, 4-H), 5.79 (m, 1 H, 9-H), due was purified by flash chromatography on silica gel (heptane/
6.17 (d, J = 15.9 Hz, 1 H, 10-H), 7.11–7.76 (m, 15 H, H arom) EtOAc, 4:1) to afford aziridino-γ-lactone 35 (290 mg, 0.52 mmol,
ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.3 [SiC(CH3)3], 26.8
[SiC(CH3)3], 27.7 [OC(CH3)3], 34.0 (C-8), 37.8 (C-1), 42.9 (C-5),
41%) as a colorless viscous oil, together with recovered starting
material 34 (260 mg, 0.48 mmol, 38%); Rf = 0.50 (heptane/EtOAc,
73.5 (C-7), 76.6 (C-4), 83.5 [OC(CH3)3], 123.7 (C-9), 127.4, 127.8, 4:1). [α]2D0 = +10 (c = 0.9, CHCl3). 1H NMR (CDCl3, 300 MHz): δ
128.1, 128.4, 128.8, 130.3, 130.9 (C arom), 134.2 (C-10), 135.8,
135.9 (C arom), 155.9 (C=O, carbamate), 172.8 (C=O) ppm. FTIR:
= 1.04 [s, 9 H, SiC(CH3)3], 2.21 (m, 1 H, 8-H), 2.46 (m, 1 H, 8Ј-
H), 2.60 (d, J = 4.4 Hz, 1 H, 1-H), 2.66 (d, J = 4.4 Hz, 1 H, 5-H),
3.26 (d, J = 13.2 Hz, 1 H, NCH2Ar), 3.59 (d, J = 13.2 Hz, 1 H,
NCH2Ar), 3.87 (m, 7 H, 2ϫOCH3, 7-H), 4.34 (d, J7,4 = 2.5 Hz, 1
ν = 3350 (NH), 2926, 2855, 1785 (C=O lactone), 1112, 702 cm–1.
˜
ESI-MS: m/z = 606 [M + Na]+.
682
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Eur. J. Org. Chem. 2009, 673–686

Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
H, 4-H), 4.92 (m, 1 H, 10-H), 4.96 (m, 1 H, 10Ј-H), 5.53 (m, 1 H, 1727 (C=O, carbamate), 1149, 1112, 702 cm–1. ESI-MS: m/z = 468
9-H), 6.72–7.70 (m, 13 H, H arom) ppm. 13C NMR (CDCl3, [M + H]+, 490 [M + Na]+, 506 [M + K]+. C26H33NO5Si (467.21):
75 MHz): δ = 19.5 [SiC(CH3)3], 27.1 [SiC(CH3)3], 37.6 (C-8), 40.6
(C-1), 44.5 (C-5), 56.2 (OCH3), 61.2 (NHCH2Ar), 73.1 (C-7), 80.9
(C-4), 118.8 (C-10), 127.3, 128.0, 130.1, 130.3 (C arom), 133.2 (C-
9), 133.3, 136.0, 136.1, 148.3, 148.4 (C arom), 172.9 (C=O, lactone)
calcd. C 66.78, H 7.11, N 3.00; found C 66.82, H 7.24, N 2.77.
(1R,4S,5S)-6-Acetyl-4-[(tert-butyldiphenylsilyloxy)methyl]-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (40): A solution of aziridine 38
(540 mg, 1.00 mmol) and DDQ (227 mg, 1.00 mmol) in a mixture
of CH2Cl2 (60 mL) and water (6 mL) was stirred at room tempera-
ture for 24 h. Pyridine (4.0 mL, 49.4 mmol) and acetic anhydride
(0.94 mL, 10.00 mmol) were then successively added. The reaction
mixture was stirred at 5 °C for 24 h, and CH2Cl2 (10 mL) was
added, followed by aqueous HCl (10% v/v, 10 mL). The aqueous
layer was separated, and the organic layer was successively washed
with aqueous HCl (10% v/v, 10 mL), saturated aqueous NaHCO3
(10 mL), and water (10 mL). The organic phase was dried with
MgSO4 and filtered, and the solvents were evaporated to dryness
under vacuum. The resulting residue was purified by column
chromatography on silica gel (EtOAc/heptane, 1:4) to afford com-
pound 40 (327 mg, 0.8 mmol, 80%) as a colorless oil; Rf = 0.61
(EtOAc/heptane, 4:3). [α]2D0 = –22.0 (c = 1.6, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ = 0.99 [s, 9 H, C(CH3)3], 2.03 (s, 3 H, CH3),
3.49 (s, 2 H, 1-H, 5-H), 3.74 (dd, J4,7 = 1.8, J7,7Ј = 11.8 Hz, 1 H,
7-H), 3.97 (dd, J4,7Ј = 2.78, J7,7Ј = 11.8 Hz, 1 H, 7Ј-H), 4.73 (m, 1
H, 4-H), 7.2–7.6 (m, 10 H, H arom) ppm. 13C NMR (CDCl3,
75 MHz): δ = 19.9 [SiC(CH3)3], 23.1 (COCH3), 26.4 [C(CH3)3],
37.4 (C-5), 41.9 (C-1), 63.2 (C-7), 88.5 (C-4), 127.7, 127.8, 129.9,
130.0 (CH arom), 135.2, 135.4 (C arom), 168.9 (C=O, lactone),
ppm. FTIR: ν = 2931, 2854, 1774 (C=O, lactone), 1515, 1427,
˜
1111, 702 cm–1. HRMS (ESI)+: calcd. for [C33H39NO5SiNa]+
580.2495; found 580.2445.
(1R,4S,5S)-6-(tert-Butoxycarbonyl)-4-[(1S)-1-(tert-butyldiphenyl-
silyloxy)but-3-enyl]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (36): A
solution of aziridine 35 (20.7 mg, 0.038 mmol) and DDQ (8.7 mg,
0.038 mmol) in a mixture of CH2Cl2 (0.4 mL) and water (0.04 mL)
was stirred at room temperature for 24 h. Triethylamine (16 µL,
0.11 mmol), DMAP (0.2 mg, 2 µmol), and Boc2O (33.4 mg,
0.15 mmol) were then successively added. The reaction mixture was
stirred at room temperature for 24 h and was then diluted with
CH2Cl2 (0.3 mL) and water (0.5 mL). The aqueous layer was sepa-
rated, and the organic layer was successively washed with saturated
aqueous NaHCO3 (1 mL), water (1 mL), and saturated aqueous
NaCl (1 mL). The organic phase was dried with MgSO4 and fil-
tered, and the solvents were evaporated to dryness under vacuum.
The resulting residue was purified by column chromatography on
silica gel (EtOAc/heptane, 1:6) to afford compound 36 (18.1 mg,
0.036 mmol, 92%) as a colorless oil. 1H NMR (CDCl3, 300 MHz):
δ = 1.03 [s, 9 H, SiC(CH3)3], 1.43 [s, 9 H, OCO(CH3)3], 2.17 (m, 1
H, 8-H), 2.50 (m, 1 H, 8Ј-H), 3.25 (d, J = 3.2 Hz, 1 H, 1-H), 3.30
(d, J = 3.2 Hz, 1 H, 5-H), 3.84 (ddd, J = 10.2, 4.3 and 1.5 Hz, 1
H, 7-H), 4.70 (d, J = 1.5 Hz, 1 H, 2-H), 4.92 (m, 1 H, 10-H), 5.44
(m, 1 H, 9-H), 7.35–7.75 (m, 10 H, H arom) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 19.4 [SiC(CH3)3], 27.0 [SiC(CH3)3], 27.9
[OCO(CH3)3], 37.8 (C-8), 38.1 (C-5), 43.0 (C-1), 73.4 (C-7), 76.7
(C-2), 83.6 [OCO(CH3)3], 119.3 (C-10), 127.9, 128.2, 130.2, 130.5
(CH arom), 132.5 (C-9), 135.9, 136.0 (CH arom), 157.2 (C=O, car-
179.0 (C=O, amide) ppm. FTIR: ν = 3070, 2930, 1785 (C=O, lac-
˜
tone), 1710 (C=O, amide), 1427, 1112, 701 cm–1. ESI-MS: m/z =
4 1 0 [ M + H ] + , 4 3 2 [ M + N a ] + , 4 4 8 [ M + K ] +
.
C23H27NO4Si·0.4H2O (416.37): calcd. C 66.29, H 6.72, N 3.36;
found C 66.44, H 6.71, N 3.22.
(1R,4S,5S)-6-(Benzyloxycarbonyl)-4-[(tert-butyldiphenylsilyloxy)-
methyl]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (41): A solution of az-
iridine 38 (1.7 g, 3.3 mmol) and DDQ (0.75 g, 3.3 mmol) in a mix-
ture of CH2Cl2 (33 mL) and water (3 mL) was stirred at room tem-
perature for 24 h. Pyridine (4.0 mL, 49.4 mmol), benzyl chloro-
formate (0.95 mL, 6.6 mmol), and DMAP (81 mg, 0.66 mmol) were
then successively added. The reaction mixture was stirred at room
temperature for 2 h, and CH2Cl2 (10 mL) was added, followed by
aqueous HCl (10% v/v, 20 mL). The aqueous layer was separated,
and the organic layer was successively washed with aqueous HCl
(10% v/v, 30 mL), saturated aqueous NaHCO3 (30 mL), and water
(30 mL). The organic phase was dried with MgSO4 and filtered,
and the solvents were evaporated to dryness under vacuum. The
resulting residue was purified by column chromatography on silica
gel (EtOAc/heptane, 1:4) to afford compound 41 (1.29 g,
2.57 mmol, 78%) as a colorless oil. Rf = 0.70 (EtOAc/heptane, 3:4).
[α]2D0 = –2.0 (c = 1.5, CHCl3). 1H NMR (CDCl3, 300 MHz): δ =
0.97 [s, 9 H, C(CH3)3], 3.45 (2ϫd, J1,5 = 3.1 Hz, 2 H, 1-H, 5-H),
3.71 (dd, J4,7 = 1.8, J7,7 = 11.8 Hz, 1 H, 7-H), 3.93 (dd, J4,7Ј = 2.7,
J7,7Ј = 11.8 Hz, 1 H, 7Ј-H), 4.62 (m, 1 H, 4-H), 5.10 (2ϫd, J =
11.9 Hz, 2 H, PhCH2), 7.2–7.7 (m, 15 H arom) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 19.2 [SiC(CH3)3], 26.7 [C(CH3)3], 37.9 (C-
5), 42.3 (C-1), 63.5 (C-7, CH2Ph), 69.3 (C-4), 128.1, 128.5, 128.7,
130.2, 131.9, 132.5 (CH arom), 134.8, 135.5, 135.7 (C arom), 158.5
bamate), 172.9 (C=O, lactone) ppm. FTIR: ν = 3070, 2929, 2856,
˜
1793 (C=O, lactone), 1730 (C=O, carbamate), 1149, 1112,
702 cm–1. HRMS (ESI)+: calcd. for [C29H37NO5SiNa]+ 530.2339;
found 530.2315.
(1R,4S,5S)-6-(tert-Butoxycarbonyl)-4-[(tert-butyldiphenylsilyloxy)-
methyl]-3-oxa-6-azabicyclo[3.1.0]hexan-2-one (39): A solution of az-
iridine 38 (870 mg, 1.65 mmol) and DDQ (382 mg, 1.65 mmol) in
a mixture of CH2Cl2 (17 mL) and water (1.7 mL) was stirred at
room temperature for 24 h. Triethylamine (0.7 mL, 5.00 mmol),
DMAP (10 mg, 0.08 mmol), and Boc2O (1.47 g, 6.7 mmol) were
then successively added. The reaction mixture was stirred at room
temperature for 24 h and was then diluted with CH2Cl2 (10 mL)
and water (20 mL). The aqueous layer was separated, and the or-
ganic layer was successively washed with saturated aqueous
NaHCO3 (30 mL), water (30 mL), and saturated aqueous NaCl.
The organic phase was dried with MgSO4 and filtered, and the
solvents were evaporated to dryness under vacuum. The resulting
residue was purified by column chromatography on silica gel
(EtOAc/heptane, 1:4) to afford compound 39 (0.66 g, 1.42 mmol,
1
85%) as a colorless oil; Rf = 0.77 (EtOAc/heptane, 3:4). H NMR
(CDCl3, 250 MHz): δ = 0.97 [s, 9 H, SiC(CH3)3], 1.40 [s, 9 H, OC-
O(CH3)3], 3.35 (2ϫd, J1,5 = 3.1 Hz, 2 H, 1-H, 5-H), 3.71 (dd, J4,7
(C=O, carbamate), 168.9 (C=O, lactone) ppm. FTIR: ν = 3070,
˜
= 1.5, J7,7Ј = 11.6 Hz, 1 H, 7-H), 3.95 (dd, J4,7Ј = 2.9, J7,7Ј
=
2930, 1792 (C=O, lactone), 1734 (C=O, carbamate), 1112,
701 cm–1. ESI-MS: m/z = 502 [M + H]+, 524 [M + Na]+, 540 [M
+ K]+. C29H31NO5Si (501.20): calcd. C 69.43, H 6.23, N 2.79;
found C 69.12, H 6.14, N 2.59.
11.6 Hz, 1 H, 7Ј-H), 4.68 (m, 1 H, 4-H), 7.2–7.6 (m, 10 H, H arom)
ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.1 [SiC(CH3)3], 26.6
[SiC(CH3)3], 27.7 [OCO(CH3)3], 38.0 (C-5), 41.1 (C-1), 63.5 (C-7),
76.3 [OCO(CH3)3], 83.5 (C-4), 127.8, 127.9, 130.1, 131.8, 132.5 (CH
arom), 135.5, 135.6 (C arom), 157.1 (C=O, carbamate), 169.2
(1R,4S,5S)-4-[(tert-Butyldiphenylsilyloxy)methyl]-6-tosyl-3-oxa-6-
azabicyclo[3.1.0]hexan-2-one (42): A solution of aziridine 38 (1.97 g,
(C=O, lactone) ppm. FTIR: ν = 3070, 2930, 1793 (C=O, lactone),
˜
Eur. J. Org. Chem. 2009, 673–686
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
683

A. Tarrade-Matha, M. S. Valle, P. Tercinier, P. Dauban, R. H. Dodd
FULL PAPER
3.8 mmol) and DDQ (866 mg, 3.8 mmol) in a mixture of CH2Cl2
(39 mL) and water (3.9 mL) was stirred at room temperature for
nish 44 (26.5 mg, 0.046 mmol, 49%) as a colorless oil; Rf = 0.5
1
(heptane/EtOAc, 3:1). [α]2D0 = +13.6 (c = 1.95, CHCl3). H NMR
24 h. Pyridine (4.6 mL, 15.3 mmol) and tosyl chloride (2.9 g, (CDCl3, 500 MHz): δ = 1.04 [s, 9 H, SiC(CH3)3], 1.93 [s, 3 H,
15.3 mmol) were then successively added. The reaction mixture was
stirred at room temperature for 2 h, and CH2Cl2 (12 mL) was
added, followed by aqueous HCl (10% v/v, 24 mL). The aqueous
layer was separated, and the organic layer was successively washed
with aqueous HCl (10% v/v, 30 mL), saturated aqueous NaHCO3
(20 mL), and water (20 mL). The organic phase was dried with
MgSO4 and filtered, and the solvents were evaporated to dryness
under vacuum. The resulting residue was purified by column
chromatography on silica gel (EtOAc/heptane, 1:4) to afford com-
pound 42 (1.52 g, 2.9 mmol, 77 %) as a white solid; Rf = 0.7
(EtOAc/heptane, 3:4); m.p. 133–134 °C. [α]2D0 = +8.0 (c = 1.01,
CH2Cl2). 1H NMR (CDCl3, 300 MHz): δ = 1.05 [s, 9 H, SiC-
(CH3)3], 2.48 (s, 3 H, PhCH3), 3.73 (d, J = 5.0 Hz, 1 H, 1-H), 3.82
(dd, J = 2.1, J = 11.7 Hz, 1 H, 7-H), 3.94 (dd, J = 3.2, J = 11.7 Hz,
1 H, 7Ј-H), 3.99 (d, J = 5.0 Hz, 1 H, 5-H), 4.56 (m, 1 H, 4-H), 7.3–
7.9 (m, 14 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.1
[SiC(CH3)3], 21.8 (PhCH3), 26.7 [SiC(CH3)3], 40.0 (C-1), 43.5 (C-
5), 63.2 (C-7), 79.7 (C-4), 128.0, 128.1, 128.1, 130.1, 130.2, 130.2,
135.5, 135.6 (CH arom), 131.7, 132.3, 133.7 (C arom), 145.8 (SO2C
OC(O)CH3], 2.44 (s, 3 H, PhCH3), 3.91 (d, J6,5 = 1.5 Hz, 2 H, 6-
H), 4.36 (m, 2 H, 4-H, 5-H), 5.55 (d, J3,4 = 9.2 Hz, 1 H, 3-H), 5.91
(d, J = 6.1 Hz, 1 H, NH), 7.20–7.75 (m, 14 H, H arom) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 19.6 [SiC(CH3)3], 20.3 [OC(O)CH3],
21.7 (PhCH3), 26.8 [SiC(CH3)3], 54.5 (C-4), 60.8 (C-6), 72.2 (C-3),
81.1 (C-5), 127.5, 127.9, 128.0, 129.8, 129.9, 130.0, 130.1 (CH
arom), 132.4, 133.0 (C arom), 134.9, 135.7, 135.9, (CH arom), 136.8
(C arom), 144.1 (SO2CArCH3), 168.6 (C=O, lactone), 170.3 (C=O,
ester) ppm. FTIR: ν = 3277 (NH), 2929, 2856, 1799 (C=O, lac-
˜
tone), 1754 (C=O, ester), 1427, 1111, 703 cm–1. HRMS (ESI)+:
calcd. for [C30H35NO7SSiNa]+ 604.1801; found 604.1806.
(3S,4R,5S)-3-Acetoxy-4-[(acetyl)(tosyl)amino]-5-[(tert-butyldiphen-
ylsilyloxy)methyl]tetrahydrofuran-2-one (45): Acetic anhydride
(91.2 µL, 0.96 mmol) and tributylphosphane (16 µL, 64 µmol) were
successively added, in a glass tube under argon, to a solution of 42
(167.7 mg, 0.32 mmol) in freshly distilled toluene (1 mL). The tube
was sealed, placed in a microwave oven, and heated at 130 °C for
30 min. The reaction mixture was diluted with water (1 mL). After
separation of the phases, the aqueous phase was extracted with
EtOAc (2ϫ1 mL). The combined organic extracts were washed
with saturated aqueous NaHCO3 (1 mL), water (1 mL), and satu-
rated aqueous NaCl. The organic phase was dried with MgSO4
and filtered, and the solvents were evaporated under vacuum. The
resulting oil was purified by column chromatography on silica gel
(heptane/EtOAc, 4:1) to furnish 45 (144.2 mg, 0.23 mmol, 72%) as
a colorless oil; Rf = 0.5 (heptane/EtOAc, 4:1). [α]2D0 = +24 (c = 1.12,
CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 1.10 [s, 9 H, SiC-
(CH3)3], 1.94 [s, 3 H, OC(O)CH3], 2.44 (s, 3 H, PhCH3), 2.51 [3 H,
NC(O)CH3], 3.80 (dd, J = 1.9, J = 11.9 Hz, 1 H, 6-H), 3.94 (dd, J
= 1.6, J = 11.9 Hz, 1 H, 6Ј-H), 4.64 (m, 1 H, 5-H), 5.27 (m, 1 H,
4-H), 5.96 (d, J3,4 = 5.4 Hz, 1 H, 3-H), 7.26–7.85 (m, 14 H, H
arom) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.4 [SiC(CH3)3],
20.4 [OC(O)CH3], 21.8 (PhCH3), 26.0 [NC(O)CH3], 26.8 [SiC-
(CH3)3], 59.3 (C-4), 62.3 (C-6), 70.3 (C-3), 80.8 (C-5), 127.8, 128.0,
130.1, 130.4 (CH arom), 132.1, 132.9, 135.5 (C arom), 135.7, 135.8
(CH arom), 146.0 (SO2CArCH3), 169.3 (C=O, ester), 170.2 (C=O,
arom), 168.2 (C=O, lactone) ppm. FTIR: ν = 3071, 2930, 1799
˜
(C=O, lactone), 1427, 1339, 1161 (SO2), 1112, 704 cm–1. ESI-MS:
m/z = 544 [M + Na]+, 576 [M + Na + MeOH]+. C28H31NO5SSi
(521.17): calcd. C 64.46, H 5.99, N 2.68, S 6.15; found C 64.51, H
5.92, N 2.69, S 5.97.
(3S,4R,5S)-3-Acetoxy-4-[(benzyloxycarbonyl)amino]-5-[(tert-butyl-
diphenylsilyloxy)methyl]tetrahydrofuran-2-one (43): BF3·Et2O
(34 µL, 0.27 mmol) was added at 0 °C under argon to a solution
of 41 (104 mg, 0.21 mmol) in a mixture of acetic acid (1 mL) and
chloroform (1 mL). The reaction mixture was stirred at 50 °C for
20 h and then diluted with EtOAc (10 mL) and neutralized with
aqueous NaHCO3 (10%, 10 mL). The aqueous layer was extracted
with EtOAc (2ϫ1 mL), the combined organic phases were dried
with MgSO4 and filtered, and the solvents were evaporated under
vacuum. The resulting residue was purified by column chromatog-
raphy on silica gel (heptane/EtOAc, 3:1) to afford 43 (58 mg,
0.10 mmol, 48%) as a colorless oil; Rf = 0.50 (EtOAc/heptane, 1:1).
1H NMR (CDCl3, 300 MHz): δ = 0.98 [s, 9 H, SiC(CH3)3], 2.11 [s,
lactone), 171.2 (C=O, carbamate) ppm. FTIR: ν = 2930, 2857, 1791
˜
3 H, OC(O)CH3], 3.78 (dd, J4,5 = 1.9, J5,5Ј = 12.1 Hz, 1 H, 5-H), (C=O, lactone), 1752 (C=O, ester), 1693 (C=O, amide), 1427, 1365,
3.91 (dd, J4,5Ј = 2.3, J5,5Ј = 12.1 Hz, 1 H, 5Ј-H), 4.37 (m, 1 H, 4-
H), 4.44 (m, 1 H, 3-H), 5.02 (m, 3 H, CH2Ph, 2-H), 5.70 (d, J =
8.4 Hz, 1 H, NH), 7.3–7.7 (m, 15 H, H arom) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 19.3 [SiC(CH3)3], 20.6 [OC(O)CH3], 26.7
[SiC(CH3)3], 53.7 (C-3), 61.8 (C-5), 67.4 (CH2Ph), 71.6 (C-2), 80.1
(C-4), 127.9, 128.3, 128.7, 130.0, 132.5, 132.8, 135.8 (CH arom),
155.7 (C=O, carbamate), 169.5 (C=O, ester), 170.3 (C=O, lactone)
1187, 1104, 926, 701 cm–1. HRMS (ESI)+: calcd. for [C32H37NO8S-
SiNa]+ 646.1907; found 646.1933.
(1R,4S,5S)-4-[(1S)-1-(tert-Butyldiphenylsilyloxy)but-3-enyl]-6-tosyl-
3-oxa-6-azabicyclo[3.1.0]hexan-2-one (46): DDQ (103.4 mg,
0.46 mmol) was added at room temperature to a solution of azirid-
ino-γ-lactone 35 (254 mg, 0.46 mmol) in CH2Cl2 (4.6 mL) and H2O
(0.46 mL). After the mixture had been stirred for 24 h, pyridine
(0.55 mL, 6.83 mmol) and tosyl chloride (347.3 mg, 1.82 mmol)
were added. After 2 h, the mixture was diluted with CH2Cl2 (5 mL)
and water (5 mL). The phases were separated, and the organic
phase was washed successively with water (2ϫ10 mL) and with
saturated aqueous NaCl (10 mL), dried with MgSO4, filtered, and
concentrated in vacuo. The crude product was purified by flash
chromatography (EtOAc/heptane, 1:4) to afford compound 46
(157.1 mg, 0.28 mmol, 60%) as a viscous colorless oil; Rf = 0.60
(EtOAc/heptane, 1:4). [α]2D0 = +12 (c = 0.72, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.06 [s, 9 H, SiC(CH3)3], 2.20 (m, 1 H, 8-
H), 2.45 (m, 1 H, 8Ј-H), 2.49 (s, 3 H, PhCH3), 3.64 (d, J = 4.9 Hz,
1 H, 1-H), 3.83 (d, J = 4.9 Hz, 1 H, 5-H), 3.90 (m, 1 H, 7-H), 4.47
(d, J = 2.0 Hz, 1 H, 4-H), 4.94 (m, 1 H, 10-H), 5.00 (m, 1 H, 10Ј-
H), 5.48 (m, 1 H, 9-H), 7.35–7.86 (m, 14 H, H arom) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 19.6 [SiC(CH3)3], 21.8 (PhCH3), 27.0
ppm. FTIR: ν = 3351 (NH), 1800 (C=O, lactone), 1755 (C=O,
˜
ester), 1730 (C=O, carbamate), 1527 (C=O, carbamate), 1428,
1112, 702 cm–1. ESI-MS: m/z = 562 [M + H]+, 584 [M + Na]+, 600
[M + K]+. C31H35NO7Si·H2O (579.22): calcd. C 64.25, H 6.39;
found C 63.93, H 6.02.
(3S,4R,5S)-3-Acetoxy-5-[(tert-butyldiphenylsilyloxy)methyl]-4-(tos-
ylamino)tetrahydrofuran-2-one (44): Cesium acetate (90 mg,
0.47 mmol) was added to a solution of 42 (54.6 mg, 0.093 mmol)
in DMF (0.3 mL). The reaction mixture was stirred at room tem-
perature for 2 h and was then diluted with EtOAc (0.5 mL) and
water (0.5 mL). After separation of the phases, the organic layer
was extracted with water (2ϫ0.5 mL). The combined organic ex-
tracts were dried with MgSO4 and filtered, and the solvents were
evaporated under vacuum. The resulting residue was purified by
column chromatography on silica gel (heptane/EtOAc, 3:1) to fur-
684
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Eur. J. Org. Chem. 2009, 673–686

Synthesis of an Equivalent of the Microsclerodermin C/D Fragment APTO
[SiC(CH3)3], 37.5 (C-8), 40.3 (C-1), 43.7 (C-5), 72.8 (C-7), 80.2 (C- (C arom), 144.0 (SO2CArCH3), 168.8 (C=O, lactone), 169.9 (C=O,
4), 119.4 (C-10), 128.0, 128.3, 130.2, 130.5, 132.4 (C-9), 133.0,
133.9, 135.9, 136.0, 145.9, (SO2CArCH3), 168.4 (C=O, lactone)
acetate) ppm. FTIR: ν = 2924, 2853, 1797, 1754 (C=O), 1427, 1111,
˜
703 cm–1. HRMS (ESI)–: calcd. for [C39H43NO7SSi – H]– 696.2451;
ppm. FTIR: ν = 2928, 2856, 1792 (C=O, lactone), 1427, 1337,
found 696.2435.
˜
1159, 702 cm–1. HRMS (ESI)+: calcd. for [C31H35NO5SSiNa]+
584.1903; found 584.1921.
(2S,3R,4S,5S,7E)-2,4-Diacetoxy-N-benzyl-5-(tert-butyldiphenylsilyl-
oxy)-8-phenyl-3-(tosylamino)oct-7-enamide
(51):
Benzylamine
(3S,4R,5S)-3-Acetoxy-4-[(acetyl)(tosyl)amino]-5-[(1S)-1-(tert-butyl-
diphenylsilyloxy)but-3-enyl]tetrahydrofuran-2-one (47): Acetic anhy-
dride (29.4 µL, 0.31 mmol) and tri-n-butylphosphane (5.1 µL,
21 µmol) were added to a solution of 46 (58.3 mg, 0.1 mmol) in
toluene (340 mL), placed in a glass tube under argon. The tube was
sealed and heated at 90 °C in a microwave oven for 2 h. After cool-
ing, the reaction mixture was concentrated in vacuo, the resulting
crude product was suspended in water (0.5 mL) and stirred for
10 min, and then EtOAc (0.5 mL) was added. After separation of
the phases, the aqueous phase was extracted with EtOAc
(2ϫ0.5 mL). The organic phases were combined and washed with
saturated aqueous NaHCO3 (5 mL), water (5 mL), and saturated
aqueous NaCl, dried with MgSO4, and filtered, and the solvents
were evaporated to dryness under vacuum. The crude product was
purified by preparative TLC on silica gel (heptane/EtOAc, 2:1) to
furnish compound 47 (52.5 mg, 0.079 mmol, 79%) as a viscous col-
orless oil; Rf = 0.55 (heptane/EtOAc, 2:1). [α]2D0 = +45.8 (c = 1.0,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ = 1.07 [s, 9 H, SiC-
(CH3)3], 1.98 [s, 3 H, OC(O)CH3], 2.08 (m, 1 H, 7-H), 2.43 (m, 1
H, 7Ј-H), 2.48 (s, 3 H, PhCH3), 2.50 [s, 3 H, NC(O)CH3], 3.92
(ddd, J = 0.7, J = 3.8, J = 10.8 Hz, 1 H, 6-H), 4.56 (ddd, J = 0.7,
J = 4.8 Hz, 1 H, 5-H), 4.76 (m, 1 H, 9-H), 4.88 (m, 1 H, 9Ј-H),
5.28 (m, 1 H, 8-H), 5.33 (dd, J = 5.21, J = 4.84 Hz, 1 H, 4-H), 6.01
(d, J3,4 = 5.21 Hz, 1 H, 3-H), 7.3–7.9 (m, 14 H, H arom) ppm. 13C
NMR (CDCl3, 125 MHz): δ = 19.6 [SiC(CH3)3], 20.5 [OC(O)CH3],
21.8 (PhCH3), 26.0 [NC(O)CH3], 26.9 [SiC(CH3)3], 37.7 (C-7), 60.4
(C-4), 70.3 (C-3), 73.2 (C-6), 81.0 (C-5), 119.4 (C-9), 127.7, 127.8,
128.1, 129.9, 130.2, 130.5, 132.5, 132.6 (C arom), 133.7 (C-8),
135.9, 136.0, 145.9 (SO2CArCH3), 169.2 (C=O, acetate), 170.4
(4 µL, 32 µmol) was added at room temperature under argon to a
solution of 48 (20 mg, 29 µmol) in THF (0.2 mL). After 2 h of stir-
ring, the solvent was evaporated to dryness under vacuum. The
resulting crude product was purified by flash chromatography on
silica gel (EtOAc/heptane, 3:7) to furnish a mixture of 2-O- and 4-
O-monoacetylated derivatives 49 and 50 (18.1 mg). The mixture
was dissolved in pyridine (0.4 mL), and acetic anhydride was added
(0.4 mL). After 18 h of stirring, the reaction mixture was concen-
trated to dryness under vacuum, and the crude product was puri-
fied by preparative TLC on silica gel (EtOAc/heptane, 3:7) to fur-
nish the benzamido APTO derivative 51 (14.6 mg, 16.4 µmol, 60%)
as a colorless oil; Rf = 0.65 (EtOAc/heptane, 1:1). [α]2D0 = +45.3 (c
= 0.6, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.82 [s, 9 H,
SiC(CH3)3], 1.66, 1.70 (2ϫs, 6 H, 2 ϫCH3CO), 1.86 (m, 2 H, 6-
H), 2.10 (s, 3 H, PhCH3), 3.92 (dd, J = 5.0, J = 14.8 Hz, 1 H,
CH2Ph), 4.10 (m, 1 H, 5-H), 4.12 (dd, J = 6.3, J = 14.8 Hz, 1 H,
CH2Ph), 4.17 (m, 1 H, 3-H), 4.72 (dd, J = 3.5, J = 6.0 Hz, 1 H, 4-
H), 5.08 (d, J = 3.8 Hz, 1 H, 2-H), 5.44 (dt, J = 7.9, J = 15.8 Hz,
1 H, 7-H), 5.65 (d, 1 H, NHTs), 5.70 (d, J = 15.8 Hz, 1 H, 8-H),
5.86 (t, J = 5.4 Hz, 1 H, NHBn), 6.74–7.62 (m, 24 H, H arom)
ppm. 13C NMR (CDCl3, 125 MHz): δ = 20.6, 20.7 (2ϫCH3CO),
26.9 (PhCH3), 36.6 (C6), 43.5 (CH2Bn), 54.8 (C-3), 71.8 (C-2), 72.9
(C-4), 73.1 (C-5), 124.1 (C-7), 126.1, 127.1, 127.2, 127.4, 127.6,
127.7, 127.8, 127.9, 128.0, 128.1, 128.3, 128.7, 129.6, 129.8, 130.0,
133.0 (C arom), 133.3 (C-8), 134.0, 135.8, 135.9, 137.1, 137.2 (C
arom), 167.3, 168.9 (2ϫCH3CO), 169.8 (CONHPh) ppm. FTIR:
ν = 3282, 2924, 2854, 1745, 1683, 1598, 1522, 1495, 1426, 1370,
˜
1331, 1224, 1157, 1057, 965, 814, 740, 700, 667 cm–1. HRMS
(ESI)+: calcd. for [C48H54N2O8SSiNa]+ 869.3234; found 869.3268.
(C=O, lactone), 171.2 (C=O, amide) ppm. FTIR: ν = 2930, 2856,
˜
Supporting Information (see footnote on the first page of this arti-
cle): NMR spectra of compounds 35, 39–42, 44–46, 47, 48, 51.
1794 (C=O, lactone), 1755 (C=O, ester), 1694 (C=O, amide), 1427,
1367, 1189, 1111, 704 cm– 1 . HRMS (ESI)+ : calcd. for
[C35H41NO8SSiNa]+ 686.2211; found 686.2220.
(3S,4R,5S)-3-Acetoxy-5-[(1S,3E)-1-(tert-butyldiphenylsilyloxy)-4-
phenylbut-3-enyl]-4-(tosylamino)tetrahydrofuran-2-one (48): Palla-
dium diacetate (1.2 mg, 5.3 µmol), triphenylphosphane (2.8 mg,
10.6 µmol), triethylamine (36 µL, 265 µmol), and iodobenzene
(7.7 µL, 69 µmol) were added successively at room temperature un-
der argon to a solution of 47 (35 mg, 53 µmol) in DMF (183 µL).
The reaction mixture was heated to 110 °C and stirred for 24 h.
The mixture was then diluted with EtOAc (5 mL) and water
(5 mL). After separation of the phases, the aqueous phase was ex-
tracted with EtOAc (2ϫ5 mL). The organic phases were combined,
dried with MgSO4, filtered and concentrated in vacuo. The crude
product was purified by flash chromatography (EtOAc/heptane,
7:3) to afford 48 (27.3 mg, 39 µmol, 74%) as a colorless oil; Rf =
0.50 (EtOAc/heptane, 7:3). [α]2D0 = +54 (c = 0.75, CHCl3). 1H NMR
(CDCl3, 500 MHz): δ = 1.02 [s, 9 H, SiC(CH3)3], 1.87 [s, 3 H,
OC(O)CH3], 2.29 (m, 1 H, 7-H), 2.39 (s, 3 H, PhCH3), 2.47 (m, 1
H, 7Ј-H), 4.17 (dd, J6,7Ј = 4.6, J6,7 = 10.1 Hz, 1 H, 6-H), 4.36 (d,
J5,4 = 7.3 Hz, 1 H, 5-H), 4.48 (m, 1 H, 4-H), 5.50 (d, J3,4 = 8.9 Hz,
1 H, 3-H), 5.66 (m, 1 H, 8-H), 6.13 (d, J9,8 = 15.9 Hz, 1 H, 9-H),
7.13–7.85 (m, 19 H, H arom) ppm. 13C NMR (CDCl3, 75 MHz):
δ = 19.6 [SiC(CH3)3], 20.2 [OC(O)CH3], 21.7 (PhCH3), 27.0
[SiC(CH3)3], 37.3 (C-7), 55.4 (C-4), 71.2 (C-6), 72.4 (C-3), 81.3 (C-
5), 123.9 (C-8), 126.3, 127.4, 127.9, 128.1, 128.6, 129.9, 130.0,
130.2, 130.5, 133.1, 133.7 (C arom), 134.2 (C-9), 136.0, 136.9, 137.3
Acknowledgments
We thank the French Ministry of Education (A. T.-M., P. T.) and
the Institut de Chimie des Substances Naturelles (M. S. V.) for fel-
lowships.
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Received: October 14, 2008
Published Online: January 7, 2009
686
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 673–686