The synthesis of cis- and trans-fused bicyclic sugar amino acids

Article abstract of DOI:10.1002/ejoc.200600228

Four isomeric bicyclic sugar amino acids (SAAs) were prepared from α-acetylenic-C-glucoside 6 by employing a Petasis olefination and a ring-closing metathesis (RCM) as key steps. The applicability of the resulting SAAs in solid-phase peptide synthesis was

Full text of DOI:10.1002/ejoc.200600228

FULL PAPER
DOI: 10.1002/ejoc.200600228
The Synthesis of cis- and trans-Fused Bicyclic Sugar Amino Acids
Martijn D. P. Risseeuw,[a] Gijsbert M. Grotenbreg,[a] Martin D. Witte,[a] Adriaan W. Tuin,[a]
Michiel A. Leeuwenburgh,[a] Gijsbert A. Van der Marel,[a] Herman S. Overkleeft,[a] and
Mark Overhand*[a]
Keywords: Sugar amino acids / Ring-closing metathesis / Petasis olefination / Pyranopyran
Four isomeric bicyclic sugar amino acids (SAAs) were pre- peptide synthesis was demonstrated by the synthesis of tetra-
pared from α-acetylenic-C-glucoside 6 by employing a Pet-
asis olefination and a ring-closing metathesis (RCM) as key
steps. The applicability of the resulting SAAs in solid-phase
peptide 36.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
we previously reported the synthesis of two cis-fused, gluco-
pyranose-based pyranopyran SAAs 1 and 2, which have the
amine functionality masked as an azide group.[4b] We here
disclose full experimental detail for the synthesis of 1 and
2 (Figure 1). Further, the synthesis of the corresponding
trans-fused pyranopyran SAAs 3 and 4 and the application
of the latter in the synthesis of a hybrid peptide-SAA tetra-
mer is presented.
Introduction
In recent years sugar amino acids (SAAs) have come to
the fore as versatile building blocks in organic and bio-or-
ganic chemistry. SAAs combine the wealth of functional
and stereochemical information inherent to carbohydrates
with the ease with which oligomers can be prepared by pep-
tide bond formation. They are now explored in various di-
rections: in peptide chemistry,[1] with the aim of developing
peptidomimetics with an advantageous conformational
bias[2] and in carbohydrate chemistry, to arrive at linear and
cyclic oligosaccharide analogues (for instance as potential
receptor molecules and as templates in combinatorial li-
Results and Discussion
The synthesis of pyranopyrans 1 and 2 commenced
brary synthesis).[3] SAAs have added value for several (Scheme 1) with 3,4,6-tri-O-benzyl--glucal 5, which was
reasons, including the limited conformational freedom converted into α-C-glycoside 6 following a literature pro-
caused by the parent carbohydrate ring and the available cedure (dimethyldioxirane-mediated epoxidation of the glu-
functional groups (apart from the amine and carboxylate) cal[5] followed by treatment with lithium phenylacetylide
that are appended to the carbohydrate core. A large variety and zinc chloride).[6] Partial reduction of the triple bond
of SAA building blocks differing in structural backbone using Lindlar’s catalyst yielded the known glucoside 7 in
(ring size), stereochemistry, and functional group pattern quantitative yield. Alkylation of the hydroxy moiety with
have been described in the literature, and the list is continu- methyl bromoacetate gave compound 8 (95%),[7] which was
ously expanding.
treated with Petasis reagent[8] to provide enol ether 9. Ensu-
A recently added feature in SAA design is to introduce ing ring-closing metathesis (RCM) under the agency of the
additional conformational strain by the attachment of a second generation Grubbs ruthenium catalyst[9] gave py-
second ring onto the carbohydrate core.[4] In this context, ranopyran derivative 10 (88%). Hydrolysis of the enol ether
Figure 1. Four isomeric pyranopyran sugar amino acids.
moiety afforded ketone 11, which was treated with -se-
[a] Leiden Institute of Chemistry Gorlaeus Laboratories,
P. O. Box 9502, 2300 RA Leiden, The Netherlands
E-mail: overhand@chem.leidenuniv.nl
lectride to give alcohol 12 as an inseparable mixture
(endo/exo, 2:1).[10]
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The mixture of alcohols was converted into the corre- and applied by us in the synthesis of a series of fused oxa-
sponding mesylates 13 (40%) and 14 (25%), which at this cycles.[6]
stage could be separated. Mesylates 13 and 14 were con-
Conversion of 19 into the target SAAs went uneventfully,
verted into triols 15 and 16, respectively. Introduction of following the same sequence of reactions as outlined for the
the azide functionality was effected by treatment of the synthesis of 1 and 2. Thus, partial reduction of 19 followed
mesylates with sodium azide and 15-crown-5[11] in DMF at by alkylation, Petasis olefination, and RCM gave cyclic enol
elevated temperature with concomitant reversal of configu- ether 23. Hydrolysis, reduction, and activation of the sec-
ration. SAAs 1 and 2 were generated from compounds 17 ondary hydroxy groups gave the corresponding mesylates
and 18, respectively, through a selective TEMPO-mediated 26 and 27, which were separated on silica gel. From these,
oxidation[12] of the primary hydroxy groups to their corre- pyranopyran SAAs 3 and 4 were readily prepared by the
sponding carboxylates (1: 53%, 2: 52%). The configuration three step procedure described above. The stereochemistry
of the azide functionality at position 4 of compounds 1 and at position 4 of compounds 3 and 4 could be unmistakably
2 was unambiguously assigned on the basis of NOESY assigned using the respective coupling constants of H-4
NMR experiments.[4b]
with that of its neighboring protons.
In order to access trans-fused pyranopyran SAAs 3 and
In the next stage, the compatibility of the trans-fused py-
4 (Scheme 2) acetylenic α-glycoside 6 was epimerized into ranopyran 4 with standard solid phase peptide synthesis
its corresponding β-glycoside 19 by using a three-step meth- techniques was ascertained by the synthesis of tetrapeptide
odology originally developed by Isobe and coworkers[13] 36, as follows. The synthesis of the oligomer commenced
Scheme 1. Reagents and conditions: i) (a) dimethyldioxirane, acetone. (b) phenylacetylene, nBuLi, ZnCl2, THF, –70 °C to room temp.[6]
ii) H2, Lindlar’s catalyst, EtOAc.[6] iii) methyl bromoacetate, TBAI, NaH, DMF, 95%. iv) Cp2TiMe2, THF, 60 °C, 82 %. v) dichlorido(1,3-
dimesityl-2-imidazolidinylidene)(phenylmethylene)(tricyclohexylphosphane)ruthenium, CH2Cl2, reflux, 88%. vi) TFA, water, CH2Cl2,
92%. vii) -selectride, THF, –78 °C to room temp., (endo/exo = 2:1). viii) MsCl, Et3N, CH2Cl2, 0 °C, 13 40%, 14 25%, two steps. ix) H2,
Pd/C, EtOH, 15 quant., 16 quant. x) NaN3, DMF, 70 °C, 17 90%, 18 94%. xi) TEMPO, NaOCl, NaHCO3, MeCN, 0 °C, 1 53%, 2 52%.
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The Synthesis of cis- and trans-Fused Bicyclic Sugar Amino Acids
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Scheme 2. Reagents and conditions: i) (a) Co2(CO)8, CH2Cl2. (b) TfOH, CH2Cl2. (c) I2, THF.[6] ii) H2, Lindlar’s catalyst, EtOAc.[6] iii)
methyl bromoacetate, TBAI, NaH, DMF, 87%. iv) Cp2TiMe2, THF, 60 °C, 72 %. v) dichlorido(1,3-dimesityl-2-imidazolidinylidene)(phen-
ylmethylene)(tricyclophosphane)ruthenium, CH2Cl2, reflux, 86%. vi) TFA, water, CH2Cl2, 90%. vii) -selectride, THF, –78 °C to room
temp. viii) MsCl, Et3N, CH2Cl2, 0 °C, 26 36%, 27 43%, two steps, ix) H2, Pd/C, EtOH, 28 quant, 29 95%. x) NaN3, DMF, 70 °C, 30
70%, 31 74%. xi) TEMPO, NaOCl, NaHCO3, MeCN, 0 °C, 4 49%, 3 72%.
with Fmoc-leucine immobilized on HMPB-functionalized
Experimental Section
MBHA resin (Scheme 3). Removal of the Fmoc group un-
All reactions were performed under an inert atmosphere and at
der standard conditions and ensuing condensation with py-
ambient temperature unless stated otherwise. Reactions were moni-
ranopyran SAA 4 using PyBOP,[14] HOBt, and DIPEA as
tored by TLC analysis using DC-fertigfolien (Schleicher & Schuell,
F1500, LS254) with detection by spraying with H2SO4 in ethanol
(20%) followed by charring at Ϸ 150 °C or by spraying with a
solution of (NH4)6Mo7O24·4H2O (25 g/L) and (NH4)4Ce(SO4)4·
the condensation agents gave immobilized dipeptide 33.[15]
Staudinger reduction of the azide followed by condensation
with Fmoc-Leu gave compound 34. A second elongation
cycle using SAA 4 led to immobilized tetrapeptide 35. Re- 2H2O (10 g/L) in H2SO4 (10%) followed by charring at Ϸ 150 °C.
Column chromatography was performed on Merck silica gel
(0.040–0.063 nm), and size exclusion chromatography was per-
formed on Sephadex LH-20. Mass spectra were recorded with
a PE/Sciex API 165 instrument with a custom-built electrospray
ionization (ESI) interface and HRMS (SIM mode) were recorded
with a TSQ Quantum (Thermo Finnigan) spectrometer fitted with
an accurate mass option, interpolating between PEG calibration
peaks. 1H- and 13C-APT-NMR spectra were recorded with a
Bruker AV-400 (400/100 MHz) spectrometer equipped with a
pulsed-field gradient accessory. Chemical shifts are given in ppm
(δ) relative to tetramethylsilane as an internal standard (1H NMR)
duction of the azide followed by acid-mediated cleavage
gave the target tetrapeptide 36, which was purified to
homogeneity by reversed-phase HPLC (RP-HPLC) with an
overall yield of 24% based on 32.
In conclusion, we have demonstrated a flexible and pro-
ductive synthesis of four pyranopyran SAA building blocks
1, 2, 3, and 4 starting from a common intermediate, α-C-
glucoside 6. The conformational behavior of these SAAs
when incorporated in oligomeric structures such as 36 is
currently being investigated.
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Scheme 3. Reagents and conditions: i) piperidine/NMP, 1:4 v/v. ii) 4, PyBOP, HOBt, DIPEA, NMP. iii) (a) Me3P, dioxane, (b) water,
dioxane iv) FmocLeuOH, PyBOP, HOBt, DIPEA, NMP. v) TFA: CH2Cl2 1:99 v/v, 36 24% (based on 32).
or CDCl3 (13C NMR). Coupling constants are given in Hz. All
presented 13C-APT spectra are proton decoupled. The atomic num-
bering of bicyclic compounds was performed as described in Fig-
ure 1. Optical rotations were measured with a Propol automatic
polarimeter (Sodium D line, λ = 589 nm) and attenuated total re-
flectance IR (ATR-IR) spectra were recorded with a Shimadzu
FTIR-8300 spectrometer fitted with a single bounce DurasamplIR
diamond crystal ATR-element. RP-HPLC was performed with a
Gilson preparative HPLC system and a Phenomenex Gemini C18
column (150×21.2 mm).
for 48 h with the exclusion of light. The reaction mixture was
poured into light petroleum. The precipitate was removed by fil-
tration and washed with light petroleum and ether. The filtrate was
concentrated and purified by silica gel chromatography to provide
the desired enol ether.
General Procedure III: RCM of Pyrans to Pyranopyrans: To an an-
hydrous solution of the enol ether in CH2Cl2 (0.07 ),
dichlorido(1,3-dimesityl-2-imidazolidinylidene)(phenylmethylene)-
(tricyclophosphane)ruthenium (0.05 equiv.) was added. The mix-
ture was refluxed under a constant flow of argon until all starting
material had disappeared, as determined by TLC analysis. Concen-
tration of the crude mixture and purification by silica gel column
chromatography using a gradient of light petroleum and EtOAc in
toluene gave the product.
General Procedure I: Alkylation of Carbohydrate Alcohols with
Methyl Bromoacetate: To an anhydrous solution of the alcohol in
DMF (0.1 ) were added methyl bromoacetate (3.0 equiv.) and tet-
rabutylammonium iodide (0.1 equiv.). After stirring for 5 min, so-
dium hydride (5.0 equiv.) was added in portions over a period of
4 h. Stirring was continued until TLC analysis showed no further
progress of the reaction (16 h), and the mixture was partitioned
between sat. aq. NH4Cl and diethyl ether. The organic phase was
washed with saturated aq. NaHCO3 and brine, dried with MgSO4,
concentrated in vacuo, and applied to a silica column. Elution with
a gradient of ethyl acetate (EtOAc) in light petroleum ether af-
forded the methyl ester. Recovered starting material was submitted
to a second alkylation cycle as described above.
General Procedure IV: Acidic Hydrolysis of Pyranopyran Enol
Ethers to Pyranopyranones: To a solution of the enol ether in
CH2Cl2 (0.1 ⁾ was added a mixture of TFA and water (3:7 (v/v),
0.5 mL·mmol–1 enol ether). After stirring for 30 min, the mixture
was diluted twice with toluene and concentrated in vacuo.
Chromatography of the residue on a silica column using a gradient
of EtOAc in light petroleum yielded the ketone product.
General Procedure V: Conversion of Pyranopyranones to Meth-
anesulfonyl Esters: A solution of the ketone in THF (0.15 ) was
cooled to –78 °C before adding a solution of -selectride in THF
(1.0 , 2.0 equiv.) over the period of 1 h. The solution was warmed
General Procedure II: Conversion of Esters into Enol Ethers Using
Petasis Reagent: Cp2TiMe2 (1.5 equiv.) was added to a solution of
the methyl ester in THF (0.15 ). The mixture was heated at reflux
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The Synthesis of cis- and trans-Fused Bicyclic Sugar Amino Acids
FULL PAPER
to ambient temperature, and stirring was continued for 16 h. The
mixture was then quenched with saturated aq. NH4Cl and ex-
tracted with EtOAc. The combined organic phase was dried with
anhydrous MgSO4, filtered, and concentrated to afford the inter-
mediate product as an inseparable mixture of isomers, which was
directly used without further purification. A solution of the iso-
meric mixture in CH2Cl2 (0.15 ⁾ was made after thorough coevap-
oration with toluene. To this solution were added triethylamine
(3.0 equiv.) and methanesulfonyl chloride (3.0 equiv.), and the reac-
tion mixture was stirred for 4 h, until all starting material was con-
verted into two higher-running spots as determined by TLC analy-
sis. The solution was diluted with CH2Cl2, extracted with saturated
aq. NaHCO3 and brine. The organic layer was dried with MgSO4
and concentrated in vacuo. Purification and separation of the epi-
meric methanesulfonyl esters could be effected by silica gel
chromatography using a gradient of light petroleum and ethyl ace-
tate.
10.7 Hz, 1 H, CH2Bn), 4.45 (d, J = 12.2 Hz, 1 H, CH2Bn), 4.19 (d,
J = 16.3 Hz, 1 H, CH2C=O), 4.12 (d, J = 16.3 Hz, 1 H, CH2C=O),
3.97 (dd, J3Ј,2Ј = J3Ј,4Ј = 8.9 Hz, 1 H, H3Ј), 3.72 (m, 2 H, H2Ј, H4Ј),
3.68 (m, 2 H, H5Ј, H6Јa), 3.58 (s, 3 H, OMe), 3.46 (dd, J6Јb,5Ј
=
3.5 Hz, J6Јb,6Јa = 12.3 Hz, 1 H, H6Јb) ppm. 13C NMR (100 MHz,
CDCl3): δ = 170.3 (C=O), 138.6, 138.2, 137.9 (Cq Bn), 137.4
(=CH–Ph), 135.9 (Cq Ph), 129.5, 128.4, 128.3, 128.1, 127.9, 127.7,
127.6 (CHarom. Bn, Ph), 124.4 (=CH–C1Ј), 83.8 (C3Ј), 81.3 (C2Ј),
78.2 (C4Ј), 75.5, 75.0, 73.4 (3×CH2 Bn), 72.3 (C5Ј), 69.8 (C1Ј), 68.7
(C6Ј), 68.5 (OCH C=O), 51.7 (OCH ) ppm. ATR-IR (thin film): ν
˜
2
3
= 2862.2, 1755.1, 1496.7, 1452.3, 1436.9, 1361.7, 1211.2, 1137.9,
1095.5, 1028.0, 736.8, 698.2 cm–1. [α]2D3 = +145.6 (c = 1.00, CHCl3).
MS (ESI): m/z = 631.4 [M+Na]+. HRMS: calcd. for C38H40O7H
609.2852, found 609.2852.
α-D-Glucopyranosyl Derivative 9: Methyl ester 8 (2.31 g, 3.8 mmol)
was treated according to General Procedure II to yield the title
compound (1.89 g, 3.12 mmol, 82%) as a colorless oil. Silica gel
chromatography: petroleum Ǟ petroleum/EtOAc v/v, 19:1. 1H
NMR (400 MHz, CDCl3): δ = 7.53–7.14 (m, 20 H, CHarom. Bn,
Ph), 6.86 (d, J = 11.8 Hz, 1 H, Ph-CH), 6.06 (dd, J = 11.8, 11.8 Hz,
1 H, =CH–C1Ј), 5.00 (d, J = 10.8 Hz, 1 H, CH2Bn), 4.86 (m, 1 H,
H1), 4.83 (d, J = 10.8 Hz, 1 H, CH2Bn), 4.81 (d, J = 10.8 Hz, 1 H,
CH2Bn), 4.63 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.50 (d, J = 10.8 Hz,
1 H, CH2Bn), 4.44 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.07 (m, 1 H,
=CH2), 4.01 (d, J = 12.5 Hz, 1 H, OCH2C=), 3.96–3.76 (m, 3 H,
H3Ј, OCH2C=, =CH2), 3.79 (m, 1 H, H2Ј), 3.75 (m, 1 H, H4Ј), 3.69
(m, 2 H, H5Ј, H6Јa), 3.50 (dd, J6Јb,5 = 3.5 Hz, J6Јb,6Јa = 12.3 Hz, 1
H, H6Јb), 3.30 (s, 3 H, OMe) ppm. 13C NMR (100 MHz, CDCl3):
δ = 159.9 (C=O), 138.8, 138.3, 137.9 (Cq Bn), 137.1 (=CH–Ph),
136.0 (Cq Ph), 129.4, 128.3, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6,
127.5 (CHarom. Bn, Ph), 125.0 (=CH–C1Ј), 84.0 (=CH2), 82.7 (C3Ј),
80.4 (C2Ј), 78.1 (C4Ј), 75.5, 75.0, 73.3 (3×CH2 Bn), 72.2 (C5Ј), 71.5
(OCH2C=O), 69.7 (C1Ј), 68.8 (C6Ј), 54.6 (OCH3) ppm. ATR-IR
General Procedure VI: Cleavage of Benzyl Ether Protecting Groups
by Catalytic Reduction: To a solution of the benzylated methanesul-
fonyl ester in ethanol (0.1 ⁾ was added a catalytic amount of 10%
Pd/C. The reaction mixture was stirred under a constant stream of
H2(g) for 4 h, filtered through a path of diatomaceous earth, and
concentrated to give the deprotected product.
General Procedure VII: Substitution of Methanesulfonyl Esters
Using Sodium Azide: The mesylate was coevaporated twice with dry
toluene before being dissolved in DMF (0.1 ). The solution was
placed under an inert atmosphere, and sodium azide (5.0 equiv.)
and 15-crown-5 (catalytic) were added. The mixture was stirred for
7 days at 70 °C. The mixture was concentrated under reduced pres-
sure, redissolved in MeOH/CH2Cl2 (1:1 v/v), filtered, and concen-
trated before being applied to a Dowex-Na+ column in order to
remove 15-crown-5. Further purification was performed by silica
gel column chromatography using a gradient of methanol in
EtOAc.
(thin film) ν = 2910.4, 1629.7, 1494.7, 1452.3, 1359.7, 1299.9,
˜
1257.5, 1155.3, 1074.3, 1043.4, 1028.0, 810.0, 732.9, 694.3 cm–1.
General Procedure VIII: TEMPO Oxidation of the Primary Hy-
droxy Groups to Carboxylates: First, three solutions were prepared.
Solution A: KBr in saturated aq. NaHCO3 (5.0 mg·mL–1). Solution
B: 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (TEMPO) in
acetonitrile (1.0 mg·mL–1). Solution C: a mixture of saturated aq.
NaHCO3, aq. NaOCl (15% w/w), and saturated aq. NaCl (5:8:9
v/v/v).
[α]2D3
= +188.4 (c = 1.00, CHCl3) MS (ESI): m/z = 629.6
[M+Na]+. HRMS: calcd. for C39H42O6Na 629.2879, found
629.2872.
(1R,6R,8S,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-4-meth-
oxy-2,7-dioxabicyclo[4.4.0]dec-4-ene (10): Enol ether 9 (0.66 g,
1.1 mmol) was treated according to General Procedure III to yield
the title compound (0.49 g, 0.97 mmol, 88%) as a clear oil. Silica
gel chromatography: petroleum/toluene, 1:1 Ǟ petroleum/EtOAc,
1:1. 1H NMR (400 MHz, CDCl3): δ = 7.37–7.18 (m, 15 H, CHarom.
Bn), 4.86 (d, J = 11.3 Hz, 1 H, CH2Bn), 4.80 (d, J = 10.6 Hz, 1 H,
CH2Bn), 4.77 (d, J = 11.3 Hz, 1 H, CH2Bn), 4.69 (m, 1 H, H5),
4.66 (m, 1 H, H6), 4.59 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.50 (d, J =
12.1 Hz, 2 H, 2×CH2Bn), 3.99–3.88 (m, 3 H, H1, H3, H10), 3.77–
3.64 (m, 4 H, H8, H9, H11), 3.55 (s, 3 H, OMe) ppm. 13C NMR
(100 MHz, CDCl3): δ = 156.4 (C4), 138.5, 138.1 (Cq Bn), 128.3,
128.0, 127.8, 127.7, 127.6, (CHarom. Bn), 92.2 (C5), 78.8, 76.6, 75.9,
72.6 (C1, C8, C9, C10) 74.6, 73.6, 73.4 (3× CH2 Bn), 69.5 (C11), 67.5
To a solution of the alcohol in saturated aq. NaHCO3 (0.07 ⁾ were
added solution A and B (2.6 mL·mmol–1 each). Solution C was
added dropwise, causing the color of the mixture to oscillate be-
tween yellowish and colorless. When TLC analysis revealed com-
pletion of the reaction, addition of solution C was terminated, and
the reaction was quenched with MeOH, acidified to pH 7 with HCl
(1.0 ⁾ and extracted with CH2Cl2. Concentration of the aqueous
layer yielded a crude product contaminated with inorganic salts,
which were removed to a large extent by precipitation from MeOH.
Removal of residual salts by HW-40 column chromatography
yielded the acid.
(C6), 61.4 (C3), 54.4 (OCH ) ppm. ATR-IR (thin film) ν = 2910.6,
˜
3
α-D-Glucopyranosyl Derivative 8: 2-(3Ј,4Ј,6Ј-Tri-O-benzyl-α--
1672.2, 1496.7, 1452.3, 1355.9, 1224.7, 1174.6, 1093.6, 1072.3,
1026.1, 1004.8, 939.0, 846.7, 734.8, 696.3 cm–1. [α]2D3 = +80.8 (c =
1.00, CHCl3). MS (ESI): m/z = 526.6 [M+Na]+, 541.4 [M+K]+.
HRMS: calcd. For C31H34O6H 503.2434, found 503.2437.
glucopyranosyl)-(Z)-styrene 7[6b] (12.9 g, 23 mmol) was treated ac-
cording to General Procedure I to yield the title compound (13.2 g,
21.7 mmol, 95%) as a pale yellow oil. Silica gel chromatography:
petroleum Ǟ petroleum/EtOAc, 1:1 v/v. 1H NMR (400 MHz,
CDCl3): δ = 7.55–7.13 (m, 20 H, CHarom. Bn, Ph), 6.86 (d, J =
11.9 Hz, 1 H, Ph-CH,), 6.01 (dd, J = 7.9, 11.9 Hz, 1 H, =CH–C1Ј),
5.04 (ddd, J = 1.3, 7.9, 7.3 Hz, 1 H, H1Ј), 4.99 (d, J = 10.9 Hz , 1 H,
(1R,6R,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-di-
oxabicyclo[4.4.0]decane-4-one (11): Enol ether 10 (0.97 g,
1.95 mmol) was treated according to General Procedure IV to yield
CH2Bn), 4.87 (d, J = 10.9 Hz, 1 H, CH2Bn), 4.85 (d, J = 10.7 Hz, 1 the title compound (0.872 g, 1.79 mmol, 92%) as a colorless oil.
H, CH2Bn), 4.62 (d, J = 12.2 Hz, 1 H, CH2Bn), 4.51 (d, J = Silica gel chromatography: petroleum/EtOAc, 9:1 Ǟ petroleum/
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EtOAc, 3:2 v/v. 1H NMR (400 MHz, CDCl3): δ = 7.35–7.24 (m, 15 ate 13 (301 mg, 0.53 mmol) was treated according to General Pro-
FULL PAPER
H, CHarom. Bn), 4.82 (d, J = 11.2 Hz, 1 H, CH2Bn), 4.80 (d, J =
11.6 Hz, 1 H, CH2Bn), 4.75 (d, J = 11.6 Hz, 1 H, CH2Bn), 4.53–
cedure VI to yield the title compound (158 mg, 0.53 mmol, quanti-
tative) as a colorless oil that solidified upon standing. 1H NMR
4.47 (m, 3 H, H6, 2×CH2Bn), 4.39 (d, J = 12.1 Hz, 1 H, CH2Bn), (400 MHz, CD3OD/CDCl3): δ = 4.73 (m, 1 H, H4), 4.15 (m, 1 H,
4.13 (d, J = 17.2 Hz, 1 H, H3a), 3.95–3.85 (m, 3 H, H1, H3b, H10), H6), 4.02 (dd, J10,1 = J10,9 = 8.1 Hz, 1 H, H10), 3.85 (dd, J3eq,4
=
3.84–3.78 (m, 2 H, H8, H9), 3.62 (dd, J11a,8 = 3.6 Hz, J11a,11b
=
4.3 Hz, J3eq,3ax = 11.9 Hz, 1 H, H3eq), 3.79 (d, J = 3.9 Hz, 2 H,
10.5 Hz, 1 H, H11a), 3.57 (dd, J11b,8 = 2.6 Hz, J11b,11a = 10.5 Hz, 1
H, H11b), 2.70 (d, J = 5.3 Hz, 2 H, H5) ppm. 13C NMR (100 MHz,
H11), 3.72 (dd, J3ax,4 = 8.3 Hz, J3ax,3eq = 11.9 Hz, 1 H, H3ax), 3.65
(m, 1 H, H1), 3.59 (m, 1 H, H8), 3.43 (dd, J9,8 = J9,10 = 8.1 Hz, 1
CDCl3): δ = 207.7 (C4), 138.0 (Cq Bn), 128.4, 128.1, 127.9, 127.8, H, H9), 3.11 (s, 3 H, SO3CH3), 2.24 (m, 2 H, H5) ppm. 13C NMR
127.7, 127.6 (CHarom. Bn), 79.1, 77.7 (C1, C10), 75.4, 74.1 (C8, C9), (100 MHz, CD3OD/CDCl3): δ = 74.5 (C1, C8), 73.2 (C4), 70.0 (C9),
74.1, 73.5, 73.2 (3×CH2 Bn), 71.1 (C3), 69.5 (C11), 68.2 (C6), 41.6 67.3 (C10), 67.0 (C6), 63.2 (C3), 61.2 (C11), 38.0 (SO3CH3), 30.5
(C5) ppm. ATR-IR (thin film) ν = 2866.0, 1735.8, 1496.7, 1454.2,
(C5) ppm. ATR-IR (thin film) ν = 3332.8, 2937.4, 1346.2, 1272.9,
˜
˜
1363.6, 1207.4, 1089.7, 1028.0, 912.3, 736.8, 696.3 cm–1. [α]2D3
=
1172.6, 1083.9, 1035.7, 960.5, 896.8, 831.3 cm–1. [α]2D3 = +47.6 (c =
1.00, 1/1 v/v MeOH/CHCl3). MS (ESI): m/z = 298.9 [M+ H]+,
320.9 [M + Na]+. HRMS: calcd. For C10H18O8SNH4 316.1066,
found 316.1044.
+32.2 (c = 1.00, CHCl3), MS (ESI): m/z = 511.4 [M+Na]+. HRMS:
calcd. for C30H32O6H 489.2277, found 489.2276.
(1R,4S,6R,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-
dioxabicyclo[4.4.0]decane-4-yl Methanesulfonate (13) and
(1R,4R,6R,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-
dioxabicyclo[4.4.0]decane-4-yl Methanesulfonate (14): Pyranopyr-
anic ketone 11 (654 mg, 1.34 mmol) was treated according to Gene-
ral Procedure V to yield compounds 13 (301 mg, 0.53 mmol, 40%)
and 14 (191 mg, 0.34 mmol, 25%) as transparent oils. Silica gel
chromatography: petroleum Ǟ petroleum/EtOAc, 2:1 v/v.
(1R,4R,6R,8R,9S,10S)-9,10-Dihydroxy-8-hydroxymethyl-2,7-dioxa-
bicyclo[4.4.0]decane-4-yl Methanesulfonate (16): Benzylated mesyl-
ate 14 (191 mg, 0.34 mmol) was treated according to General Pro-
cedure VI to yield the title compound (101 mg, 0.34 mmol, quanti-
tative) as a colorless oil that solidified upon standing. 1H NMR
(400 MHz, CD3OD/CDCl3): δ = 4.90 (m, 1 H, H4), 4.19 (m, 1 H,
H6), 3.85 (dd, J3ax,4 = 2.8 Hz, J3ax,3eq = 12.4 Hz, 1 H, H3ax), 3.82
(dd, J10,1 = J10,9 = 7.6 Hz, 1 H, H10), 3.66–3.61 (m, 2 H, H11), 3.53
(dd, J3eq,4 = 4.7 Hz, J3eq,3ax = 12.4 Hz, 1 H, H3eq), 3.51 (m, 1 H,
H1), 3.47 (m, 1 H, H8), 3.26 (dd, J9,8 = J9,10 = 7.6 Hz, 1 H, H9),
1
Compound 13: H NMR (400 MHz, CDCl3): δ = 7.37–7.16 (m, 15
H, CHarom. Bn), 4.81 (d, J = 11.4 Hz, 1 H, CH2Bn), 4.79 (d, J =
10.9 Hz, 1 H, CH2Bn), 4.75 (d, J = 11.4 Hz, 1 H, CH2Bn), 4.69
(m, 1 H, H4), 4.58 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.50 (d, J =
10.9 Hz, 1 H, CH2Bn), 4.49 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.13
(m, 1 H, H6), 3.98 (dd, J10,1 = J10,9 = 7.6 Hz, 1 H, H10), 3.86 (dd,
3.02 (s, 3 H, SO3CH3), 2.27 (m, 1 H, H5ax), 1.91 (m, 1 H, H5eq
)
ppm. 13C NMR (100 MHz, CD3OD/CDCl3): δ = 77.2 (C1), 77.0
(C4, C8), 71.3 (C9), 69.3 (C10), 66.8 (C6), 65.5 (C3), 62.4 (C11), 38.4
(SO CH ), 31.4 (C5) ppm. ATR-IR (thin film) ν = 3271.0, 2933.5,
J1,6 = 5.1 Hz, J1,10 = 7.6 Hz, 1 H, H1), 3.78–3.74 (m, 2 H, H3eq
,
˜
3
3
1326.9, 1234.4, 1170.7, 1083.9, 1029.9, 933.5, 894.9, 875.6, 813.9,
771.5 cm–1. [α]2D3 = +22.0 (c = 1.00, 1:1 v/v MeOH/CHCl3). MS
(ESI): m/z = 298.9 [M+H]+, 320.9 [M+Na]+ 619.1 [2M+Na]+.
HRMS: calcd. for C10H18O8SNH4 316.1066, found 316.1087.
H8), 3.69–3.63 (m, 3 H, H9, H11), 3.54 (dd, J3ax,4 = 7.8 Hz, J3ax,3eq
= 12.1 Hz, 1 H, H3ax), 2.98 (s, 3 H, SO3CH3), 2.20–2.14 (m, 2 H,
H5) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.0, 137.9, 137.8
(Cq Bn), 128.3, 128.1, 127.9, 127.8, 127.7, 127.6 (CHarom. Bn), 77.2
(C9), 77.1 (C10), 75.3 (C1), 74.4, 73.5, 73.4 (3×CH2 Bn), 72.9 (C4),
72.4 (C8), 69.1 (C11), 67.5 (C6), 64.1 (C3), 38.7 (SO3CH3), 31.0 (C5)
(1R,4R,6R,8R,9S,10S)-4-Azido-9,10-dihydroxy-8-hydroxymethyl-
2,7-dioxabicyclo[4.4.0]decane (17): Mesylate 15 (56 mg, 0.19 mmol)
was treated according to General Procedure VII to yield the title
compound (42 mg, 0.17 mmol, 90%) as a pale yellow oil. Silica
gel chromatography: EtOAc Ǟ EtOAc/MeOH, 4:1 v/v. 1H NMR
(400 MHz, CD3OD/CDCl3): δ = 4.27 (m, 1 H, H6), 3.99 (dd,
J3ax,3eq = 11.2 Hz, J3ax,4 = 1.0 Hz, 1 H, H3ax) 3.70–3.96 (m, 3 H,
H4, H11a, H10), 3.74–3.80 (m, 2 H, H11b, H8), 3.54 (dd, J1,6 = 2.9 Hz
J1,10 = 5.5 Hz, 1 H, H1), 3.51 (dd, J9,8 = J9,10 = 5.1 Hz, 1 H, H9),
3.34 (dd, J3eq,4 = 7.3 Hz, J3ax,3eq = 11.2 Hz, 1 H, H3eq), 2.30 (m, 1
H, H5a), 1.71 (m, 1 H, H5b) ppm. 13C NMR (100 MHz, CD3OD/
CDCl3): δ = 77.0 (C8), 75.8 (C1), 69.2 (C9), 67.6 (C10), 66.9 (C3),
64.1 (C6), 61.4 (C11), 53.8 (C4), 31.4 (C5) ppm. ATR-IR (thin film)
ppm. ATR-IR (thin film) ν = 2871.8, 1496.7, 1454.2, 1355.9,
˜
1209.3, 1174.6, 1093.6, 1070.4, 1028.0, 958.6, 937.3, 889.1, 864.1,
829.3, 738.7, 698.2 cm–1. [α]2D3 = +62.6 (c = 1.00, CHCl3). MS (ESI):
m/z = 569.2 [M + H]+, 591.2 [M + Na]+. HRMS: calcd. for
C31H36O8SH 569.2209, found 569.2192.
1
Compound 14: H NMR (400 MHz, CDCl3): δ = 7.34–7.20 (m, 15
H, CHarom. Bn), 4.96 (m, 1 H, H4), 4.75 (d, J = 11.4 Hz, 1 H,
CH2Bn), 4.69 (d, J = 11.6 Hz, 1 H, CH2Bn), 4.62 (d, J = 11.6 Hz,
1 H, CH2Bn), 4.56 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.53 (d, J =
11.4 Hz, 1 H, CH2Bn), 4.48 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.22
(m, 1 H, H6), 3.90 (dd, J3ax,4 = 3.1 Hz, J3ax,3eq = 11.9, 1 H, H3ax),
3.80 (m, 2 H, H8, H10), 3.73–3.66 (m, 3 H, H1, H9, H11a), 3.60 (dd,
ν = 3340.5, 2931.6, 2360.7, 2106.1, 2052.1, 1651.0, 1211.2, 1080.1,
˜
1033.8, 879.5 cm–1. [α]2D3 66.5 (c = 1.00, CHCl3) MS: m/z = 268.1
[M+Na]+, 513.2 (2M+Na)+ HRMS: calcd. For C9H15N3O5Na
268.09094, found 268.09022
J11b,8 = 3.2 Hz, J11b,11a = 10.4 Hz, 1 H, H11b), 3.47 (dd, J3eq,4
=
7.2 Hz, J3eq,3ax = 11.9 Hz, 1 H, H3eq), 3.02 (s, 3 H, SO3CH3), 2.32
(m, 1 H, H5ax), 1.90 (m, 1 H, H5eq) ppm. 13C NMR (100 MHz,
CDCl3): δ = 138.0, 137.9, 137.8 (Cq Bn), 128.4, 128.3, 127.9, 127.8,
127.7, 127.6 (CHarom. Bn), 77.9 (C10), 76.1 (C1), 74.5 (C9), 73.7
(CH2 Bn), 73.5, 73.4 (C4, C8), 73.3, 72.7 (2×CH2 Bn), 68.8 (C11),
66.5 (C3), 65.9 (C6), 38.4 (SO3CH3), 32.3 (C5) ppm. ATR-IR (thin
(1R,4S,6R,8R,9S,10S)-4-Azido-9,10-dihydroxy-8-hydroxymethyl-
2,7-dioxabicyclo[4.4.0]decane (18): Mesylate 16 (171 mg,
0.57 mmol) was treated according to General Procedure VII to
yield the title compound (133 mg, 0.54 mmol, 94%) as an oil. Silica
gel chromatography: EtOAc Ǟ EtOAc/MeOH, 4:1 v/v. 1H NMR
(400 MHz, CD3OD/CDCl3): δ = 4.11 (m, 1 H, H6), 4.00 (dd, J10,1
film) ν = 2864.1, 1496.7, 1454.2, 1355.9, 1209.3, 1174.6, 1093.6,
˜
1028.0, 1001.0, 958.6, 935.4, 891.1, 854.4, 738.7, 698.2 cm–1. [α]2D3
= +44.6 (c = 1.00, CHCl3). MS (ESI): m/z = 569.2 [M+H]+, 591.2
[M + Na]+. HRMS: calcd. for C31H36O8S 569.2209, found
569.2207.
= 9.2 Hz, J10,9 = 8.5 Hz, 1 H, H10) 3.70–3.80 (m, 2 H, H11 H3eq),
,
3.67 (dd, J1,6 = 5.6 Hz J1,10 = 9.2 Hz, 1 H, H1) 3.57 (m, 2 H, H4
,
H8), 3.49 (dd, J3ax,4 = 9.7 Hz, J3ax,3eq = 11.2 Hz, 1 H, H3ax), 3.38
(dd, J9,8 = J9,10 = 8.5 Hz, 1 H, H9), 2.13 (m, 1 H, H5eq), 2.00 (m,
1 H, H5ax) ppm. 13C NMR (100 MHz, CD3OD/CDCl3): δ = 74.4
(1R,4S,6R,8R,9S,10S)-9,10-Dihydroxy-8-hydroxymethyl-2,7-dioxa-
bicyclo[4.4.0]decane-4-yl Methanesulfonate (15): Benzylated mesyl-
3882
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3877–3886

The Synthesis of cis- and trans-Fused Bicyclic Sugar Amino Acids
FULL PAPER
(C1), 74.0 (C8), 70.2 (C9), 67.8 (C6), 67.1 (C10), 62.8 (C3), 61.1(C11),
the title compound (4.57 g, 7.5 mmol, 72%). Silica gel chromatog-
raphy: petroleum Ǟ petroleum/EtOAc v/v, 19:1. 1H NMR
(400 MHz, CDCl3): δ = 7.47–7.13 (m, 20 H, Harom), 6.80–6.77 (d,
J’ = 11.6 Hz, 1 H, =CH–C1’), 5.75–5.70 (dd, J = 11.6 Hz, J =
9.2 Hz, 1 H, =CH–Ph), 5.02–5.00 (d, J = 10.8 Hz, 1 H, CH2Bn),
4.84–4.83 (d, J = 3.9 Hz, 1 H, CH2Bn), 4.81–4.80 (d, J = 3.9 Hz,
1 H, CH2Bn), 4.60–4.57 (d, J = 12.5 Hz, 1 H, CH2Bn), 4.54–4.51(d,
J = 10.8 Hz, 1 H, CH2Bn), 4.50–4.47 (d, J = 12.5 Hz, 1 H, CH2Bn),
4.23–4.18 (dd, J1, =CH–C1’ = J1’,2’ = 9.2 Hz, 1 H, H1’), 4.18 (s, 2 H,
CH2C=), 4.15–4.14 (dd, J = 2.2 Hz, 1 H, =CH2), 4.01–4.00 (dd, J
= 2.2 Hz, 1 H, =CH2), 3.71–3.64 (m, 4 H, H3’, H4’, H6’), 3.45 (s, 3
H, OMe), 3.50–3.39 (m, 2 H, H2’, H5’) ppm. 13C NMR (100 MHz,
CDCl3): δ = 160.1 [=C(OMe)], 138.8, 138.2, 138.1 (CqBn), 136.2
(CqPh), 134. (=CH–C1’), 129.0–127.3 (CHarom = CH–Ph), 86.4
(C3’), 83.8 (=CH2),82.8, (C2’), 78.3, 78.0 (C4’,C5’), 75.4, 74.8
(2×CH2Bn), 74.8 (C1’), 73.4 (CH2 Bn), 73.1 (C1’’), 69.1 (C6) 54.6
54.7 (C4), 29.1 (C5) ppm. ATR-IR (thin film) ν = 3255.6, 2931.6,
˜
2360.7, 1350.1, 1249.8, 1087.8, 1010.6, 925.8, 848.6 cm–1. [α]2D3
=
+116 (c = 1.00, MeOH) MS: m/z = 268.1 [M + Na]+, 513.2
(2M+Na)+
(1R,4R,6R,8S,9S,10S)-4-Azido-9,10-dihydroxy-2,7-dioxabicyclo-
[4.4.0]decane-8-carboxylic Acid (1): Compound 17 (42 mg,
0.17 mmol) was treated according to General Procedure VIII to
yield the title compound (23 mg, 0.09 mmol, 53%) as an oil. 1H
NMR (400 MHz, D2O): δ = 4.49 (m, 1 H, H6), 4.09 (d, J8,9
=
5.3 Hz, 1 H, H8), 4.05 (dd, J10,9 = 5.5 Hz, J10,1 = 5.9 Hz, 1 H, H10),
4.02 (m, 2 H, H3ax, H4), 3.89 (dd, J9,8 = 5.3 Hz, J9,10 = 5.5 Hz, 1
H, H9), 3.65 (dd, J1,6 = 3.5 Hz, J1,10 = 5.9 Hz, 1 H, H1), 3.45 (ddd,
J3eq 5eq = 1.7 Hz, J3eq,4
= 7.8 Hz, J3eq,3ax = 12.4 Hz, 1 H, H3eq),
,
2.37 (m, 1 H, H5ax), 1.86 (m, 1 H, H5eq) ppm. 13C NMR (100 MHz,
D2O): δ = 177.3 (C=O), 76.8 (C8) 75.2 (C1), 70.9 (C9), 67.6 (C10),
66.7 (C3), 66.0 (C6), 54.9 (C4), 30.7 (C5) ppm. ATR-IR (thin film):
(OMe) ppm. ATR-IR (thin film): ν = 1496.7, 1452.3, 1361.7,
˜
1299.9, 1257.5, 1207.4, 1056.9, 1028.0, 1001.0, 950.8, 910.3, 810.0,
775.3, 732.9, 694.3, 650.0, 619.1 cm–1. [α]2D3 = +73.6 (c = 1.00,
CHCl3). HRMS: calcd. For C39H46O6N1 624.33251, found
624.33869.
ν = 3398.1, 2920.0, 2120.1, 1605.6, 1454.5, 1385.0, 1315.5, 1247.7,
˜
1096.9, 1076.7, 1062.2, 1001.4, 947.7, 923.1, 879.9, 811.4 cm–1
.
[α]2D3 = +39.0 (c = 1.00, CHCl3) MS (ESI): m/z = 260.0 [M+H]+,
282.1 [M + Na]+ , 541.1 [2 M + Na]+ . HRMS: calcd. For
C9H13N3O6Na 282.07020, found 282.06943
(1R,6S,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-4-meth-
oxy-2,7-dioxabicyclo[4.4.0]dec-4-ene (23): Compound 22 (172 mg,
0.28 mmol) was treated according to General Procedure III to yield
the title compound (121 mg, 0.24 mmol, 86%) as an oil. Silica gel
chromatography: petroleum/toluene, 1:1 Ǟ petroleum/EtOAc, 1:1.
1H NMR (400 MHz, CDCl3): δ = 7.39–7.10 (m, 15 H, Harom),
5.00–4.97 (d, J = 11.5 Hz, 1 H, CH2Bn), 4.87 (m, 1 H, H5), 4.87–
4.85 (d, J = 10.8 Hz, 1 H, CH2Bn), 4.78–4.75 (d, J = 11.5 Hz, 1 H,
CH2Bn), 4.61–4.58 (d, J = 12.3 Hz, 1 H, CH2Bn), 4.54–4.51 (d, J
= 12.3 Hz, 1 H, CH2Bn), 4.48–4.45 (d, J = 10.8 Hz, 1 H, CH2Bn),
4.16–4.13 (dt, J = 15.1 Hz, J = 2.1 Hz, 1 H, H3), 4.07–4.03 (dt, J
= 15.1 Hz, 1 H, H3), 3.92–3.90 (dd, J = 8.7 Hz, J = 2.1 Hz, 1 H,
H6), 3.74–3.58 (m, H8, H9, H10, H11), 3.56 (s, 3 H, OMe), 3.31–
3.26 (t, J = 9.1 Hz, 1 H, H1) ppm. 13C NMR (100 MHz, CDCl3):
δ = 155.6 (C4), 138.8, 138.1, 138.0 (Cq Bn), 128.3–127.5
(CHaromBn), 93.6 (C5), 83.6 (OCH), 80.1 (C1), 79.3, 78.1 (2×
OCH), 75.1, 74.7 (2× CH2 Bn), 73.4 (CH2 Bn), 72.8 (C6), 69.2
(1R,4S,6R,8S,9S,10S)-4-Azido-9,10-dihydroxy-2,7-dioxabicyclo-
[4.4.0]decane-8-carboxylic Acid (2): Compound 18 (133 mg,
0.54 mmol) was treated according to General Procedure VIII to
yield the title compound (73 mg, 0.28 mmol, 52%) as an oil. 1H
NMR (400 MHz, D2O): δ = 4.31 (m, 1 H, H6), 4.10 (d, J8,9
=
5.8 Hz, 1 H, H8), 4.07 (dd, J10,9 = 6.1 Hz, J10,1 = 6.3 Hz, 1 H, H10),
3.83 (dd, J9,8 = 5.8 Hz, J9,10 = 6.1 Hz, 1 H, H9), 3.78 (m, 3 H, H3,
H4), 3.70 (dd, J1,6 = 3.8 Hz, J1,10 = 6.3 Hz, 1 H, H1), 2.15 (m, 2 H,
H5) ppm. 13C NMR (100 MHz, D2O): δ = 177.4 (C=O), 76.7 (C8)
75.6 (C1), 71.5 (C9), 68.2 (C10), 66.8 (C3, C6), 55.2 (C4), 30.3 (C5)
ppm. ATR-IR (thin film): ν = 3353.3, 2955.6, 2955.6, 2924.6,
˜
2853.7, 2102.1, 1606.7, 1370.7, 1271.5, 1246.9, 1116.3, 1077.8,
1008.8. 967.4, 941.3 cm–1 [α]2D3 = +68.0 (c = 1.00, CHCl3). MS
(ESI): m/z = 260.0 [M+H]+, 282.1 [M+Na]+.
β-D-Glucopyranosyl Derivative 21: 2-(3Ј,4Ј,6Ј-Tri-O-benzyl-β--glu-
copyranosyl)-Z-styrene (20)[6b] (6.40 g, 11.9 mmol) was treated ac-
cording to General Procedure I to yield the title compound (6.34 g,
10.4 mmol, 87%) as a colorless oil. Silica gel chromatography: pe-
troleum Ǟ petroleum/EtOAc, 1:1 v/v 1H NMR (400 MHz, CDCl3):
δ = 7.33–7.13 (m, 20 H, Harom.), 6.83–6.80 (d,J = 11.6 Hz, 1 H,
PhCH), 5.79–5.74 (dd, J = 11.6 Hz, J = 9.1 Hz, 1 H, =CHC1Ј),
4.96–4.93(d, J = 11.1 Hz, 1 H, CH2Bn), 4.89–4.86 (d, J = 11.1 Hz,
1 H, CH2Bn), 4.82–4.79 (d, J = 11.0 Hz, 1 H, CH2Bn), 4.62–4.59
(d, J = 12.1 Hz, 1 H, CH2Bn), 4.55–4.52 (d, J = 11.0 Hz, 1 H,
CH2Bn), 4.52–4.49 (d, J = 12.1 Hz, 1 H, CH2Bn), 4.43–4.38 (d, J
= 15.6 Hz, 1 H, CH2C=O), 4.31–4.27 (d, J = 15.6 Hz, 1 H,
(C11), 65.7(C3) 54.5 (OMe) ppm. ATR-IR (thin film): ν = 3030.0,
˜
2862.2, 1728.1, 1703.0, 1668.3, 1618.2, 1496.7, 1452.3, 1357.8,
1315.4, 1271.0, 1228.6, 1207.4, 1091.6, 1076.2, 1056.9, 1026.1,
908.4, 792.7, 729.0, 696.3, 669.3, 648.0 cm–1. [α]2D3 = +20.2 (c =
1.00, CHCl3). MS (ESI): m/z = 525.2 [M+Na]+. HRMS: calcd. for
C31H34O6Na 525.2247, found 525.2255.
(1R,6S,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-di-
oxabicyclo[4.4.0]decane-4-one (24): Enol ether 23 (3.24 g,
6.45 mmol) was treated according to General Procedure IV to yield
the title compound (2.84 g, 5.8 mmol, 90%) as an oil. Silica gel
chromatography: petroleum/EtOAc, 9:1 Ǟ petroleum/EtOAc, 3:2
1
CH2C=O), 4.22 (dd, J1Ј,2Ј = 9.3 Hz, J1Ј,CHC = 9.1 Hz, 1 H, H1Ј),
1
v/v. H NMR (400 MHz, CDCl3): δ = 7.35–7.13 (m, 15 H, Harom),
3.73–3.65 (m, 2 H, OCH, 2 H, H6Ј), 3.64 (s, 3 H, OMe), 3.45 (m,
J2Ј,1Ј = 9.3 Hz, 1 H, OCH, t, J2Ј,3Ј = 8.9 Hz, 1 H, H2Ј) ppm. 13C
NMR (100 MHz, CDCl3): δ = 170.0 (C=O), 138.7, 138.1 (CqBn),
136.2 (CqPh), 135.4 (=CH–C1Ј), 129.0–127.6 (CHarom = CH–Ph),
86.3 (C2Ј), 83.7, 78.3, 77.9 (3×OCH), 75.5, 75.3 (2× CH2Bn), 74.9
(C1Ј), 73.5 (CH2Bn), 69.9 (CH2C=O), 69.1 (C6Ј) 51.7 (OMe) ppm.
4.96–4.93 (d, J = 11.5 Hz, 1 H, CH2Bn), 4.88–4.85 (d, J = 10.8 Hz,
1 H, CH2Bn), 4.80–4.77 (d, J = 11.5 Hz, 1 H, CH2Bn), 4.60–4.57
(d, J = 12.2 Hz, 1 H, CH2Bn), 4.53–4.50 (d, J = 12.2 Hz, 1 H,
CH2Bn), 4.53–4.50 (d, J = 10.8 Hz, 1 H, CH2Bn), 4.17–4.11 (dd,
J3eq,3ax = 16.2, J3eq,5eq = 1.8 Hz, 1 H, H3eq), 3.94–3.90 (d, J3ax,3eq
= 16.2 Hz, 1 H, H3ax), 3.72–3.65 (m, 4 H, 2×OCH, H11), 3.56–
3.51 (m, 2 H, H6, OCH), 3.44–3.41 (t, 1 H, H1), 3.03–2.98 (m,
J5eq,5ax = 16.6 Hz, J5eq,6 = 5.7 Hz, J5eq,3eq = 1.8 Hz, 1 H, H5eq),
2.55–2.48 (dd, J5ax,5eq = 16.6 Hz, J5ax,6 = 11.2 Hz, 1 H, H5ax) ppm.
13C NMR (100 MHz, CDCl3): δ = 204.4 (C4), 138.5, 138.0, 137.8
(CqBn), 128.5–127.6 (CHaromBn), 83.9 (OCH), 81.0 (C1), 79.1,
77.28 (2×OCH), 75.2, 75.0 (2× CH2Bn), 73.9 (C3), 73.5 (CH2Bn),
ATR-IR (thin film): ν = 3030.0, 2860.2, 1760.9, 1739.7, 1496.7,
˜
1454.2, 1436.9, 1361.7, 1209.3, 1099.3, 1056.9, 1028.0, 985.6, 912.3,
736.8, 698.2, 648.0, 621.0 cm–1. [α]2D3 = +67.2 (c = 1.00, CHCl3).
MS (ESI): m/z = 631.5 [M+Na]+. HRMS: calcd. for C38H40O7Na
631.2666, found 631.2673 [M+Na]+.
β-
D-Glucopyranosyl Derivative 22: Compound 21 (6.34 g,
10.4 mmol) was treated according to General Procedure II to yield
73.3 (C6), 68.8 (C11), 44.7 (C5) ppm. ATR-IR (thin film): ν =
˜
Eur. J. Org. Chem. 2006, 3877–3886
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3883

M. Overhand et al.
3030.0, 2866.0, 1730.0, 1496.7, 1452.3, 1363.6, 1315.4, 1272.9, H, H1), 2.39–2.35 (m, J5eq,5ax = 14.0 Hz, J5eq,6 = 5.0 Hz, J5eq,4
FULL PAPER
=
1234.4, 1207.4, 1139.9, 1095.5, 1074.3, 1058.8, 1028.0, 966.3, 935.4, J5eq,3eq = 2.3 Hz, 1 H, H5eq), 1.83–1.75 (ddd, J5ax,5eq = 14.0 Hz,
910.3, 881.4, 819.7, 734.8, 696.3, 638.4 cm–1. [α]2D3 = +15.4 (c =
1.00, CHCl3). MS (ESI): m/z = 511.3 [M+Na]+. HRMS: calcd. for
C30H32O6Na 511.2091, found 511.2122.
J5ax,6 = 11.9 Hz, J5ax,4 = 3.1 Hz, 1 H, H5ax) ppm. 13C NMR
(100 MHz, CD3OD): δ = 82.4 (C1), 82.2(OCH), 78.3(C4), 76.5
(C10), 72.1(OCH), 71.6(C6), 70.6 (C3), 62.8 (C11), 38.4 (OMs), 35.1
(C5) ppm. ATR-IR (thin film): ν = 3327.0, 2875.7, 1340.4, 1170.7,
˜
(1R,4S,6S,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-
dioxabicyclo[4.4.0]decane-4-yl Methanesulfonate (26) and
(1R,4R,6S,8R,9S,10S)-9,10-Bis(benzyloxy)-8-benzyloxymethyl-2,7-
dioxa-bicyclo[4.4.0]decane-4-yl Methanesulfonate (27): Compound
24 (2.84 g, 5.8 mmol) was treated according to General Procedure
V to yield compounds 26 (1.18 g, 2.1 mmol,36%) and 27 (1.44 g,
2.52 mmol, 43%) as transparent oils. Silica gel chromatography:
petroleum Ǟ petroleum/EtOAc, 2:1 v/v.
1132.1, 1091.6, 1045.3, 999.1, 962.4, 920.0, 894.9, 866.0, 839.0,
779.2, 630.7, 611.4 cm–1. [α]2D3 = +6.2 (c = 1.00, MeOH). MS (ESI):
m/z = 320.8 [M+Na]+. HRMS: calcd. for C10O8SNH22 316.10661,
found 316.10567.
(1R,4R,6S,8R,9S,10S)-9,10-Dihydroxy-8-hydroxymethyl-2,7-dioxa-
bicyclo[4.4.0]decane-4-yl Methanesulfonate (29): Compound 27
(1.18 g, 2.1 mmol) was treated according to General Procedure VI
to yield the title compound (0.68 g, 2.31 mmol, 95%) as a trans-
parent oil. 1H NMR [400 MHz, CD3OD/[D6]DMSO (10%)]: δ =
1
Compound 26: H NMR (400 MHz, CDCl3): δ = 7.35–7.13(m, 15
H, CH Bn), 4.99 (m, 1 H, H4), 4.97–4.95 (d, J = 11.2 Hz, 1 H,
CH2Bn), 4.86–4.84(d, J = 10.7 Hz, 1 H, CH2Bn), 4.78–4.75 (d, J
= 10.7 Hz, 1 H, CH2Bn), 4.61–4.58 (d, J = 12.2 Hz, 1 H, CH2Bn),
4.50–4.47 (d, J = 11.2 Hz, 1 H, CH2Bn), 4.53–4.50 (d, J = 12.2 Hz,
4.71–4.64 (m, 1 H, H4), 4.17–4.14 (ddd, J3eq,3ax = 10.9 Hz, J3eq,4
5.2 Hz, J3eq,5eq = 1.7 Hz, 1 H, H3eq), 3.83–3.80 (dd, 1 H, H11a),
=
3.64–3.61 (ddd, 1 H, H11b), 3.43–3.39(dd, J10,1 = 9.0 Hz, J10,9
=
8.8 Hz, 1 H, H10), 3.33–3.25 (m, 1 H, H3ax, 2 H, H8/9), 3.24–3.20
(ddd, J6,5ax = 11.5 Hz, J6,1 = 9.3 Hz, J6,5eq = 4.5 Hz, 1 H, H6), 3.13
(s, 3 H, OMs), 2.88–2.84 (dd, J1,6 = 9.3 Hz, J1,10 = 9.0 Hz, 1 H,
1 H, CH2Bn), 4.20–4.16 (ddd, J3eq,3ax = 13.3 Hz, J3eq,4 = J3eq,5eq
2.5 Hz, 1 H, H3eq), 3.72–3.66 (m, 2 H, H11, 1 H, OCH), 3.63–3.58
(m, 1 H, H3ax, 1 H, OCH), 3.54–3.49 (ddd, J6,5ax = 11.6 Hz, J6,1
=
=
H1), 2.62–2.57 (m, 1 H, H5eq), 1.74–1.65 (ddd, J5ax,5eq = J5ax,4
=
9.2 Hz, J6,5eq = 4.8 Hz, 1 H, H6, m, 1 H, OCH), 3.20–3.15 (dd, J1,6
= J1,10 = 9.2 Hz, 1 H, H1), 3.07 (s, 3 H, OMs), 2.54–2.51 (m, J5eq,5ax
= 14.1 Hz, J5eq,6 = 4.6 Hz, J5eq,4 = J5eq,3eq = 2.5 Hz, 1 H, H5eq),
1.87–1.80 (ddd, J5ax,5eq = 14.1 Hz, J5ax,6 = 11.4 Hz, J5ax,4 = 3.2 Hz,
1 H, H5ax) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.7, 138.0,
137.9 (Cq Bn), 128.3–127.5 (CH Bn), 83.8 (OCH), 82.6 (C1), 79.3
(OCH), 77.6 (OCH), 75.9(C4), 75.2, 75.1, 73.6 (3×CH2 Bn), 70.4
(C6) 69.6 (C3), 68.9 (C11), 38.9 (OMs), 364.3 (C5) ppm. ATR-IR
J5ax,6 = 11.3 Hz, 1 H, H5ax) ppm. 13C NMR [100 MHz, CD3OD/
[D6]DMSO (10%)]: δ = 82.2 (C1), 82.1(OCH), 76.3 (C10), 74.3(C4),
73.8(C6), 71.9(OCH), 69.9 (C3), 62.7 (C11), 38.3 (OMs), 36.9 (C5)
ppm. ATR-IR (thin film): ν = 1350.1, 1319.2, 1272.9, 1174.6,
˜
1122.5, 1058.8, 1041.5, 1028.0, 979.8, 956.6, 908.4, 883.3, 854.4,
759.9, 705.9 cm–1. [α]2D3 = +12.2 (c = 1.00, DMF). MS (ESI): m/z =
320.9 [M+Na]+. HRMS: calcd. for C10O8SNH22 316.10661, found
316.10567.
(thin film): ν = 3031.9, 2869.9, 1450.4, 1357.8, 1172.6, 1095.5,
˜
925.8, 864.1, 740.6, 702.0 cm–1. [α]2D3 = +9 (c = 1.00, CHCl3). MS
(ESI): m/z = 591.6 [M+Na]+. HRMS: calcd. for C31H36O8SNa
591.2023, found 591.1975.
(1R,4R,6S,8R,9S,10S)-4-Azido-9,10-dihydroxy-8-hydroxymethyl-
2,7-dioxabicyclo[4.4.0]decane (30): Mesylate 28 (149 mg,
0.50 mmol) was treated according to General Procedure VII to
yield the title compound (85 mg, 0.35 mmol 70%) as a colorless
oil. Silica gel chromatography: EtOAc Ǟ EtOAc/MeOH, 4:1 v/v.
1
Compound 27: H NMR (400 MHz, CDCl3): δ = 7.35–7.11 (m, 15
H, Harom), 4.93–4.91(d, J = 11.3 Hz, 1 H, CH2Bn), 4.86–4.83 (d, J
= 10.6 Hz, 1 H, CH2Bn), 4.75–4.72 (d, J = 11.3 Hz, 1 H, CH2Bn),
4.72–4.65 (m, 1 H, H4), 4.61–4.58 (d, J = 12.2 Hz, 1 H, CH2Bn),
4.53–4.50 (d, J = 12.2 Hz, 1 H, CH2Bn), 4.49–4.47 (d, J = 10.6 Hz,
1 H, CH2Bn), 4.24–4.20 (ddd, J3eq,3ax = 10.8 Hz, J3eq,4 = 5.3 Hz,
J3eq,5eq = 1.7 Hz, 1 H, H3eq), 3.77–3.57 (m, 4 H, H11, H10, H8),
3.49–3.44 (m, 1 H, H9), 3.35–3.29 (t, J3ax,3eq = J3ax,4 = 10.8 Hz, 1
H, H3ax), 3.21–3.09 (ddd, 1 H, H6, m, 1 H, H1), 3.03 (s, 3 H, OMs),
1H NMR (400 MHz, CD3OD): δ = 3.95–3.91 (ddd, J3eq,3ax
=
10.9 Hz, J3eq,4 = 5.1 Hz, J3eq,5eq = 1.9 Hz, 1 H, H3eq), 3.78–3.74
(dd, 1 H, H11a), 3.60–3.53 (m, 2 H, H11b, H4), 3.35–3.33 (dd, J10,1
= J10,9 = 9.0 Hz, 1 H, H10), 3.24–3.21 (m, 2 H, H8, H9), 3.16–3.10
(ddd, J6,5ax = 11.4 Hz, J6,1 = 9.3 Hz, J6,5eq = 4.3 Hz, 1 H, H6),
3.07–3.02(dd, J3ax,3eq = J3ax,4 = 10.9 Hz, 1 H, H3ax), 2.78–2.74(dd,
J1,6 = 9.3 Hz, J1,10 = 9.0 Hz, 1 H, H1), 2.39–2.35 (m, J5eq,5as
=
11.4 Hz, J5eq,4 = J5eq,6 = 4.3 Hz, J5eq,3eq = 1.9 Hz, 1 H, H5eq), 1.44–
1.36 (ddd, J5ax,5eq = J5ax,6 = J5ax,4 = 11.4 Hz, 1 H, H5ax) ppm. 13C
NMR (100 MHz, CD3OD): δ = 82.3 (C1), 82.2(OCH), 76.6 (C10),
74.4(C6), 72.2(OCH), 70.6 (C3), 62.8 (C11), 56.5(C4), 35.8 (C5) ppm.
2.66–2.63 (m, J5eq,5ax = 11.2 Hz, J5eq,4 = J5eq,6 = 4.3 Hz, J5eq,3
=
=
1.7 Hz, 1 H, H5eq), 1.80–1.77 (dd, J5ax,5eq = J5ax,4 = J5ax,6
11.2 Hz, 1 H, H5ax) ppm. 13C NMR (100 MHz, CDCl3): δ = 138.6,
138.0, 137.9 (Cq Bn), 129.0–127.6 (CH Bn), 83.7 (C8/C10), 82.1
(C1), 79.4 (C9), 77.4 (C8/C10), 75.2, 75.0, 73.6 (3×CH2 Bn), 73.1
(C6) 72.6(C4), 69.0 (C3), 68.8 (C11), 38.6 (OMs), 36.0 (C5) ppm.
ATR-IR (thin film): ν = 3440.6, 2924.8, 2857.5, 2098.1, 1736.0,
˜
1459.1, 1379.3, 1311.0, 1242.6, 1125.7, 1036.1, 965.2, 904.0,
873.8 cm–1. [α]2D3 = +10.4 (c = 1.00, MeOH). MS (ESI): m/z = 267.9
[M + Na]+, 284.1 [M + K+], 513.1 [M – M + Na+], 529.2 [M –
M + K+]. HRMS: calcd. for C9O5N4H13 263.13554, found
263.13968.
ATR-IR (thin film): ν = 1357.8, 1172.6, 1080.1, 956.6, 840.9, 740.6,
˜
702.2 cm–1. [α]2D3 = +8.2 (c = 1.00, CHCl3). MS (ESI): m/z = 591.3
[M + Na]+. HRMS: calcd. for C31H36O8SNa 591.2023, found
591.1977.
(1R,4S,6S,8R,9S,10S)-9,10-Dihydroxy-8-hydroxymethyl-2,7-dioxa-
bicyclo[4.4.0]decane-4-yl Methanesulfonate (28): Compound 26
(1.18 g, 2.1 mmol) was treated according to General Procedure VI
to yield the title compound (0.63 g, 2.1 mmol, quantitative) as an
(1R,4S,6S,8R,9S,10S)-4-Azido-9,10-dihydroxy-8-hydroxymethyl-
2,7-dioxabicyclo[4.4.0]decane (31): Mesylate 29 (684 mg,
2.31 mmol) was treated according to General Procedure VII to
yield the title compound (417 mg, 1.7 mmol 70%) as a colorless
oil. 1H NMR (400 MHz, CD3OD): δ = 4.91 (m, 1 H, H4), 4.06– oil. Silica gel chromatography: EtOAc Ǟ EtOAc/MeOH, 4:1 v/v.
4.03 (ddd, J3eq,3ax = 13.3 Hz, J3eq,4 = J3eq,5eq = 2.3 Hz, 1 H, H3eq), 1H NMR (400 MHz, CD3OD): δ = 3.89–3.86 (ddd, J3eq,3ax
=
3.79–3.76 (dd, 1 H, H11a), 3.60–3.57 (m, 2 H, H11b, H3ax), 3.48–
3.39 (t, J10,1 = J10,9 = 9.1 Hz, 1 H, H10, ddd, J6,5ax = 11.9 Hz, J6,1
12.6 Hz, J3eq,4 = 1.8, J3eq,5eq = 2.5 Hz, 1 H, H3eq), 3.82 (m, 1 H,
H4), 3.76–3.73 (dd, 1 H, H11a), 3.56–3.52 (m, 1 H, H11b), 3.52–
= 9.3 Hz, J6,5eq = 4.7 Hz, 1 H, H6), 3.28–3.24 (m, 2 H, H8, H9), 3.40(dd, J3ax,3eq = 12.6 Hz, J3ax,4 = 1.8 Hz, 1 H, H3ax), 3.38–
3.07 (s, 3 H, OMs), 2.90–2.85 (dd, J1,6 = 9.3 Hz, J1,10 = 9.1 Hz, 1
3.36(dd, J10,1 = 9.1 Hz, J10,9 = 8.8 Hz, 1 H, H10), 3.33–3.26 (ddd,
3884
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 3877–3886

The Synthesis of cis- and trans-Fused Bicyclic Sugar Amino Acids
FULL PAPER
J6,5ax = 11.6 Hz, J6,1 = 9.2 Hz, J6,5eq = 4.5 Hz, 1 H, H6), 3.22–3.21
(m, 2 H, H8, H9), 2.83–2.78 (dd, J1,6 = 9.2 Hz, J1,10 = 9.1 Hz, 1 H,
liquid, the resin was washed 5 times with NMP (5×2 mL), the
material was taken up in dioxane (2 mL) and trimethylphosphane
(Ϸ 1 M in toluene, 200 µmol, 13 equiv.) was added. The material
was shaken mildly for 2 h during which gas evolved. After two h
the liquid was drained, and the resin was taken up in dioxane/water
H1), 2.15–2.11 (m, J5eq,5ax = 13.4 Hz, J5eq,6 = 4.5 Hz, J5eq,4
2.4 Hz, J5eq,3eq = 2.5 Hz, 1 H, H5eq), 1.70–1.63 (ddd, J5ax,5eq
=
=
13.4 Hz, J5ax,6 = 11.6 Hz, 1 H, H5ax) ppm. 13C NMR (100 MHz,
CD3OD ): δ = 82.9 (C1), 82.3(OCH), 76.7 (C10), 72.2(OCH), (9:1 v/v, 2 mL). Shaking was continued for 30 min, and the resin
72.1(C6), 69.7 (C3), 62.9 (C11), 58.5(C4), 34.0 (C5) ppm. ATR-IR
was washed 10 times with dichloromethane (2 mL). FmocLeuOH
(thin film): ν = 3369.0, 2926.1, 2870.7, 2095.7, 1726.6, 1446.5, (22 mg, 60 µmol, 5 equiv.) was condensed to the resin and depro-
˜
1312.5, 1283.7, 1239.7, 1174.9, 1128.8, 1036.5, 995.7, 961.9, 948.6, tected under standard SPPS conditions [PyBOP (1.0 equiv.), HOBt
888.3, 843.9 cm–1. [α]2D3 = +1.6 (c = 1.00, MeOH). MS (ESI): m/z =
(1.0 equiv.), DIPEA (2 equiv.), and NMP then piperidine/NMP, 1:4
268.0 [M+Na]+, 284.0 [M+K]+, 513.2 [M – M+Na]+, 529.1 [M – v/v]. A second monomer of SAA 4 (7.3 mg, 28 µmol, 2.3 equiv.)
M + K]+ HRMS: calcd. for C9O5N4H13 263.13554, found was coupled, followed by subsequent Staudinger reduction under
263.13895.
the conditions stated above. The material was cleaved from the
resin using TFA in CH2Cl2 (1%) and purified by RP-HPLC to
yield the title compound (2.3 mg, 2.9 µmol, 24% based on 32). H
NMR 500 MHz (H2O/D2O, 9:1, v/v): δ = 8.30 (d, J = 7.0 Hz, 1 H,
CONHLeuB), 8.13 (d, J = 7.5 Hz, 1 H, CONHSaaC), 8.00 (d, J =
8.0 Hz, 1 H, CONHLeuD), 4.37–4.31 (m, 1 H, HαLeuB), 4.17–4.23
(m, 1 H, HαLeuD), 4.02 (m, 1 H, H4SaaC), 3.93 (d, J = 13.5 Hz, 1
H, H3SaaA), 3.86 (d, J = 10 Hz, 1 H, H8SaaD), 3.83 (d, J = 9.5 Hz,
1 H, H8SaaA), 3.80 (d, J = 16.0 Hz, 1 H, H3SaaC), 3.70 (m, 2 H,
(1R,4R,6S,8S,9S,10S)-4-Azido-9,10-dihydroxy-2,7-dioxabicyclo-
[4.4.0]decane-8-carboxylic Acid (3): Compound 30 (85 mg,
0.35 mmol) was treated according to General Procedure VIII to
yield the title compound (65 mg, 0.25 mmol, 72%) as an oil. 1H
1
NMR (CDCl3): δ = 4.13–4.01 (ddd, J3eq,3ax = 11.1 Hz, J3eq,4
=
5.1 Hz, J3eq,5eq = 1.7 Hz, 1 H, H3eq), 3.80–3.71 (m, 1 H, H4), 3.78–
3.76 (d, J8,9 = 9.6 Hz, 1 H, H8), 3.63–3.58 (dd, J10,1 = J10,9 = 9.2 Hz,
1 H, H10), 3.55–3.50 (dd, J9,8 = 9.6 Hz, J9,10 = 9.2 Hz, 1 H, H9),
3.45–3.39 (ddd, J6,5ax = 11.6 Hz, J6,1 = 9.3 Hz, J6,5eq = 4.3 Hz, 1
H, H6), 3.35–3.25 (dd, J3ax,3eq = J3ax,4 = 11.1 Hz, 1 H, H3ax), 3.11–
3.07 (dd, J1,6 = 9.3 Hz, J1,10 = 9.2 Hz, 1 H, H1), 2.54–2.49 (m,
J5eq,5ax = 11.6 Hz, J5eq,6 = J5eq,4 = 4.3 Hz, J5eq,3eq = 1.7 Hz, 1 H,
H4SaaA, H3SaaA), 3.59–3.53 (m, 4 H, H3SaaC, H6SaaA, H10SaaA
,
H10SaaC), 3.52–3.43 (m, 3 H, H6SaaC, H9SaaA, H9SaaC), 3.08 (t, J =
9.5 Hz, 1 H, H1SaaA), 3.02 (t, J = 9.5 Hz, 1 H, H1SaaC), 2.26–2.22
(m, 1 H, H5eqSaaA), 2.11–2.08 (m, 1 H, H5eqSaaC), 1.97–1.89 (m, 1 H,
H5axSaaA), 1.75–1.70 (m, 1 H, H5axSaaC); 1.60–1.45 (6 H 2×CH2Leu
,
H5eq), 1.65–1.57 (ddd, J5ax,5eq = J5ax,6 = J5ax,4 = 11.6 Hz, 1 H, H5ax
)
2×CHLeu), 0.84–0.87 m (6 H 6×CH3Leu) ppm. 13C NMR 125 MHz
(H2O/D2O, 9:1, v/v): δ = 80.0, 81.0, 75.0, 73.0, 72.0, 70, 69.0 68,
53, 52, 48, 47, 40, 32, 30, 25, 22, 21 ppm. MS (ESI): m/z = 675.4
[M+Na]+, 697.4 [M – M+Na]+.
ppm. 13C NMR (D2O): δ = 177.1 (C11) 81.1 (C1), 80.7 (C8), 75.3
(C10), 73.5(C6), 73.4(C9), 69.9 (C3), 55.5 (C4), 34.7 (C5) ppm. ATR-
IR (thin film): ν = 3409.2, 2914.1, 2868.8, 2105.4, 1734.1, 1604.5,
˜
1425.4, 1346.0, 1309.4, 1246.9, 1129.0, 1088.1, 1042.9, 992.8, 967.4,
878.5. [α]2D3
=
–33 (c = 1.00, MeOH). MS (ESI): m/z = 282.1
[M+Na]+, 541.1 [M – M+Na]+. HRMS: calcd. for C9H13N3O6Na
Acknowledgments
282.07020, found 282.06943.
We would like to thank Nico Meeuwenoord and Hans van der Elst
for their technical assistance. Kees Erkelens and Fons Lefeber are
gratefully acknowledged for their assistance with NMR experi-
ments.
(1R,4S,6S,8S,9S,10S)-4-Azido-9,10-dihydroxy-2,7-dioxabicyclo-
[4.4.0]decane-8-carboxylic Acid (4): Compound 31 (113 mg,
0.46 mmol) was treated according to General Procedure VIII to
yield the title compound (58 mg, 0.23 mmol, 49%) as an oil. 1H
NMR (CDCl3): δ = 4.15 (m, 1 H, H4), 4.02–3.99 (ddd, J3eq,3ax
=
12.8 Hz, J3eq,4 = J3eq,5eq = 1.8 Hz, 1 H, H3eq), 3.79–3.77 (d, J =
9.7 Hz, 1H. H8), 3.73–3.69(dd, J3ax,3eq = 12.8 Hz, J3ax,4 = 1.8 Hz,
1 H, H3ax), 3.66–3.61 (dd, J10,9 = 9.0 Hz, J10,1 = 9.2 Hz, 1 H, H10),
3.61–3.56 (ddd, J6,5ax = 11.7 Hz, J6,1 = 9.4 Hz, J6,5eq = 4.4 Hz, 1
H, H6), 3.53–3.47 (dd, J9,8 = 9.7 Hz, J9,10 = 9.0 Hz, 1 H, H9), 3.18–
3.13 (dd, J1,6 = 9.4 Hz, J1,10 = 9.2 Hz, 1 H, H1), 2.34–2.31 (m,
J5eq,5ax = 13.3 Hz, J5eq,6 = 4.4 Hz, J5eq,4 = 0.9, J5eq,3eq = 1.8 Hz, 1
H, H5eq), 1.91–1.84 (ddd, J5ax,5eq = 13.3 Hz, J5ax,6 = 11.7 Hz, J5ax,4
= 3.6 Hz, 1 H, H5ax) ppm. 13C NMR (D2O): δ = 177.1 (C11) 81.8
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32.7 (C5) ppm. ATR-IR (thin film): ν = 3353.3, 2880.5, 2105.0,
˜
1609.2, 1421.0, 1299.5, 1241.3, 1127.3, 1083.3, 1037.2, 963.6. [α]2D3
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Eur. J. Org. Chem. 2006, 3877–3886
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3885

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Received: March 15, 2006
Published Online: June 28, 2006
[7] During the reaction a considerable amount of trans-cyclopro-
pane-1,2,3-tricarboxylic acid trimethylester was formed. This
side product could be removed by means of size exclusion
chromatography (Sephadex LH-20).
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Eur. J. Org. Chem. 2006, 3877–3886