Synthesis of carbasugars from nucleophilic addition-ring closure (NARC)-derived cycloalkenes

Article abstract of DOI:10.1081/CAR-120003734

A short, enantioselective synthesis of carbasugars 4a-carba-α-L-xylofuranose 15, 4-epi-validatol 16 and their corresponding carboxylic acids 11 and 12 is reported. These compounds were prepared via a four-step sequence of nucleophilic addition, ring closu

Full text of DOI:10.1081/CAR-120003734

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SYNTHESIS OF CARBASUGARS FROM NUCLEOPHILIC
ADDITION—RING CLOSURE (NARC)—DERIVED
CYCLOALKENES
Patrick Perlmutter a & Mark Rose a
a School of Chemistry , Monash University , P.O. Box 23, Victoria, 3800, Australia
Published online: 28 Oct 2011.
To cite this article: Patrick Perlmutter & Mark Rose (2002) SYNTHESIS OF CARBASUGARS FROM NUCLEOPHILIC ADDITION—RING
CLOSURE (NARC)—DERIVED CYCLOALKENES, Journal of Carbohydrate Chemistry, 21:1-2, 1-10, DOI: 10.1081/CAR-120003734
To link to this article: http://dx.doi.org/10.1081/CAR-120003734
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J. CARBOHYDRATE CHEMISTRY, 21(1&2), 1–10 (2002)
SYNTHESIS OF CARBASUGARS FROM
NUCLEOPHILIC ADDITION—RING CLOSURE
(NARC)—DERIVED CYCLOALKENES
*
Patrick Perlmutter and Mark Rose
School of Chemistry, Monash University, P.O. Box 23, Victoria,
3800, Australia
ABSTRACT
A short, enantioselective synthesis of carbasugars 4a-carba-a-L-xylofuranose
15, 4-epi-validatol 16 and their corresponding carboxylic acids 11 and 12 is
reported. These compounds were prepared via a four-step sequence of nuc-
leophilic addition, ring closure (NARC), dihydroxylation and reduction.
INTRODUCTION
Carbasugars, including carbanucleosides, constitute a rapidly developing family of
therapeutically important carbohydrate analogues. [1–3] Their importance is largely due to
their stability in vivo. Examples include carbovir, [4] BMS200475, [5] mannostatin, [6] and
(+)-cyclophellitol. [7] We have initiated a program intended to develop new, rapid
approaches to the synthesis of enantiomerically pure compounds. One such approach
(the ‘‘NARC’’ approach) involves the combination of a Nucleophilic Addition immedi-
ately followed by a Ring Closure as the key synthetic sequence in the preparation of a
range of cyclic target molecules. [8]
In this paper we show how one such sequence, employing a syn-selective aldol
reaction followed by ring closing metathesis, [9] provides a rapid route to enantiomeri-
cally pure cycloalkenes. These were then converted into carba-a-L-xylofuranose 15, [10]
4-epi-validatol 16 [11,12] and their carboxylic acid derivatives 11 and 12. [13]
*Corresponding author. Fax: +61-3-9905-4597; E-mail: patrick.perlmutter@sci.monash.edu.au
1
Copyright D 2002 by Marcel Dekker, Inc.
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2
PERLMUTTER AND ROSE
RESULTS AND DISCUSSION
The NARC sequence used in this work involved a syn-aldol reaction for the
nucleophilic addition (NA) and ring closing metathesis for the ring closure (RC). Thus,
addition of the Z-boron enolate of acyl sultam 1[14,15] or its homologue 2, [16] to
cinnamaldehyde 3 gave syn aldol adducts 4 and 5 in 88% and 60% yields, respectively.
In each case the diastereoselectivity was excellent (dr > 95:5). Subsequent ring closing
metathesis with Grubbs’ catalyst [17] gave good yields of the highly crystalline cyclo-
alkenes 6 and 7 (83% and 74% respectively).
Dihydroxylation of 6 using potassium osmate/N-methyl morpholine oxide [18,19] in
a mixture of t-butyl alcohol and DMF gave, in 90% yield, 9 as a single diastereoisomer.
Triol 9 proved to be highly crystalline and its x-ray structure is shown in Figure 1. As is
evident from the figure, dihydroxylation occurred exclusively from the face remote to
the two ring substituents. Dihydroxylation of 7 proceeded in a similar fashion to that for
6. Again only one diastereoisomer, 10, was obtained, although in significantly lower
yield, 50%, due to incomplete reaction. The crystal structure of 10 is also shown in
Figure 1.
Although 9 and 10 are relatively polar compounds it was found that they could be
manipulated in a straightforward fashion. Due to the hydrophobic nature of the auxiliary
it proved possible to efficiently recover each triol from water by extraction with organic
solvents. In addition both were amenable to chromatography on silica.
Some attempts were made to reverse the stereoselectivity of the dihydroxylations.
Reaction of 6 with either of the Sharpless ADa or ADb ligand catalyst mixtures [21,22]
yielded only 9. No evidence for the production of 8 was found. This strongly suggests
that the ring substituents control the selectivity in these dihydroxylations, overriding any
reagent control that the AD mixes normally provide.
Reduction of 9 and 10 with NaBH4 gave the carbasugars, 4a-carba-a-L-xylofur-
anose 15 and 4-epi-validatol 16 in 52% and 95% yields, respectively. Both compounds
were obtained as oils. These highly polar compounds were purified by a sequence of (i)
evaporation of the crude aqueous extracts of the reaction mixture, (ii) extraction of the
residue into ethanol and chromatography on silica gel or celite.
Hydrolysis of 9 and 10 provided the highly polar, water-soluble trihydroxy acids
11 and 12 in good yield. The cyclohexane derivative 12 was characterized as its methyl
ester 14 after treatment of the crude hydrolysate with acidic methanol. Unlike 12, 11
resisted all attempts at esterification. To our surprise it was unreactive to diazomethane
or acidic methanol. This may be due to strong intramolecular hydrogen bonding. For
Figure 1. X-ray crystal structures of 9 and 10.

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SYNTHESIS OF CARBASUGARS
3
Scheme. (i) (a) 1 or 2, Et2BOTf, (iPr)2NEt, CH2Cl2 (b) 3; (ii) RuCl2(=CHPh)(PCy3)2, CH2Cl2;
(iii) K2OsO4.2H2O, tBuOH, DMF, NMO; (iv) LiOH, H2O2, H2O, THF; (v) Ac2O, H2SO4; (vi)
MeOH, H2SO4; (vii) NaBH4, EtOH.

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4
PERLMUTTER AND ROSE
this reason 11 was isolated and characterized as its triacetate, 13, obtained in 41%
overall yield from 9.
In summary, we have prepared four carbasugar derivatives using a highly stereo-
selective NARC sequence followed by a completely diastereoselective dihydroxylation.
Noteworthy also is that this approach obviated the need for any hydroxy group protection
during the synthesis.
EXPERIMENTAL
General Procedures. 1H NMR spectra are assigned according to the type of
proton e.g. CH3, CHN, CH = CH2 or according to numbering as shown in the text. 13C
NMR spectra are assigned in a similar fashion with the exception of the sultam carbons
which are numbered 10–100. Dichloromethane, tetrahydrofuran (THF) and toluene were
dried and distilled before use. Solvents used for metathesis reactions were degassed by
bubbling a stream of argon through them for at least 20 min prior to use. Grubbs’ catalyst
was purchased from Aldrich Chemical Company. Compounds characterized without
elemental analyses were found to be pure by nmr spectroscopy.
For the x-ray structure determination of 9 and 10 a suitable single crystal was
mounted on a glass fibre and data collected on a Nonius Kappa CCD area detector. The
structures were solved by direct methods and refined by the full matrix least-squares
method: for 9 the programs used were—Texan: Crystal Structure Analysis Package, Mole-
cular Structure Corporation (1992), and for 10 ShelocS-97 and ShelocL-97: G.M.Shel-
¨
¨
drick, Universitat Gottingon, 1997. All nonhydrogen atoms were refined anisotropically.
The hydrogens were put into theoretical positions and refined using the riding model.
Further details of data collection: Diffractometer; Nonius Kappa CCD; Radiation:
˚
l =0.71069 A (MX–Ka) with graphite monochromator;
9: crystal size: 0.24ꢀ0.14ꢀ0.14 mm; formula: C16H25NO6S; formula weight: 359.44;
temperature: 123(2)K; crystal system: orthorhombic; space group P212121; unit cell
˚
ꢁ3
˚
˚
˚
dimensions: a = 8.0585(1)A, b= 13.8941(3)A, c=14.5160(3)A; volume: 1625.29(4)A
;
z=4; density (Calcd): 1.469 Mg/m3; absorption coefficient: 0.233 mmꢁ1; F(000):768;
Max q value for data collection: 30.0 °C ; index ranges: ꢁ11ꢂ h ꢂ 11, ꢁ19 ꢂ k< 19,
ꢁ20 ꢂ l ꢂ 20; reflections collected: 24155; independent; 2734; R(int) 0.034; completeness
to q= 27.5 °C, 99.7%; data/restraints/parameters: 2067/0/217; goodness-of-fit on F: 2.19;
final R indicies [I >3s(I)]: R1 =0.040, Rw =0.033; absolute structures parameter: 0.03(3);
3
˚
longest diff. peak and hole: 0.45 and ꢁ0.44 e/A .
10: crystal size: 0.20ꢀ0.16ꢀ0.19 mm; formula: C35H60N2O14S2; formula weight:
796.97; temperature: 123(2)K; crystal system: orthorhombic; space group P212121; unit cell
˚
ꢁ3
˚
˚
˚
dimensions: a = 28.1405(9)A, b= 11.0610(3)A, c=11.9020(3)A; volume: 3704.6(2)A
;
z=4; density (Calcd): 1.429 Mg/m3; absorption coefficient: 0.216 mmꢁ1; F(000):1712;
Max q value for data collection: 30.0 °C ; index ranges: ꢁ39ꢂ h ꢂ 39, ꢁ15 ꢂ k< 15,
ꢁ15 ꢂ lꢂ 15; reflections collected: 34181; independent; 10280; R(int) 0.072; complete-
ness to q =27.5 °C, 96.3%; data/restraints/parameters: 10280/2/429; goodness-of-fit on F2:
1.028; final R indicies [I> 2s(I)]: R1 = 0.060, wR2 =0.103; absolute structures parameter:
3
˚
0.04(7); longest diff. peak and hole: 0.42 and ꢁ0.43 e/A . Crystallographic data for the
structures reported in this paper have been deposited with the Cambridge Crystallo-
graphic data Centre as supplementary publication nos. CCDC-172515 and 172516.

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SYNTHESIS OF CARBASUGARS
5
Copies of the data can be obtained free of charge an application to The Director. CCDC,
12 Union Road, Cambridge CB2 1EZ, UK (fax: Int.code + (1223) 336-033; e-mail:
deposit@ccdc.cam.ac.uk).
(2R)-N-[(2R)-2-((1S,2E)-1-Hydroxy-3-phenyl-2-propen-1-yl)-4-penten-1-oyl]-
bornane-10,2-sultam (4). A solution of diethylboron triflate was generated by drop-
wise addition of freshly distilled triflic acid (340 mL, 3.8 mmol) to triethylborane (1 M in
hexane, 3.8 mL, 3.8 mmol). The solution was stirred at rt for 20 min. (Note: if not
homogeneous warm at approx. 40 °C for 20 min.) The above solution was cooled to
ꢁ5 °C and a solution of 1 (530 mg, 1.8 mmol) in dichloromethane (5 mL), followed
by a solution of N,N-diisopropylethylamine (1 M in dichloromethane, 4 mL, 4.0 mmol)
were added. After stirring at ꢁ5 °C for 20 min the solution was cooled to ꢁ78 °C and
a solution of 3 (0.5 mL, 4.0 mmol) in dichloromethane (1 mL) was added. After
stirring for 2 h the reaction was quenched by addition of 0.5 M pH 7 phosphate buffer
(8 mL) and left to warm to rt. The mixture was then taken up in ether (30 mL), the
aqueous layer separated and the organic layer washed with satd aq NH4Cl (2ꢀ50 mL).
After drying (MgSO4) and removal of solvent in vacuo (at ambient temperature), 4
was purified by column chromatography (hexane/ethyl acetate, 4:1). The aldol adduct
25
4 (680 mg, 88%) was obtained as a colorless foam. [a]D ꢁ86 °C (c 0.8, CH2Cl2). Rf
(0.27) in hexane/ethyl acetate (3:1). IR (nujol/CH2Cl2): 3539, 2923, 2853, 1671, 1461,
1
1377, 1339, 1271, 1241, 1217, 1163, 1134, 1065, 970, 922, 721 cmꢁ1. H NMR (300
mHz, CDCl3) d 0.97 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.32–1.45 (m, 2H, CH2), 1.92–
1.97 (m, 3H, CH2 and CH), 2.02–2.04 (m, 2H, CH2), 2.44–2.60 (m, 2H, 2ꢀH-3), 3.42
(m, 1H, H-2), 3.47 and 3.53 (AB quartet, 2H, J =13.9 Hz, CH2SO2), 3.93 (t, 1H, J =
6.3 Hz, CHN), 4.70 (m, 1H, H-1), 5.02 (m, 2H, CH = CH2), 5.82 (m, 1H, CH = CH2),
6.23 (dd, 1H, J =5.8, 16.0 Hz, CH = CHPh), 6.69 (d, 1H, J = 16.0 Hz, CH = CHPh),
7.20–7.44 (m, 5H, Ph). 13C NMR (75 mHz, CDCl3) d 20.0(C-80), 20.9(C-90), 26.4(C-50).
32.6(C-60), 32.9(C-3), 38.4(C-30), 44.7(C-40), 47.7(C-70), 48.2(C-10), 49.6(C-2), 53.2(C-
100), 65.3(C-20), 71.6(C-1), 117.4(CH2 = C), 126.5(Ph), 127.4(C = HC), 128.3 (C = HC
and Ph), 131.4(Ph), 134.8(CH = C), 136.5(Ph), 174.5(CO). [M + Na+] m/z 452.2 (100%),
[MꢁOH]m/z 412.2 (50%).
Anal. Calcd for C24H31NO4S: C, 67.10; H, 7.27; N, 3.26: Found: C, 67.44; H, 7.17;
N, 3.14.
(2R)-N-[(2R)-2-((1S,2E)-1-Hydroxy-3-phenyl-2-propen-1-yl)-5-hexen-1-oyl]-
bornane-10,2-sultam (5). A solution of diethylboron triflate was generated from triflic
acid (240 mL, 2.7 mmol) and triethylborane (1 M in hexane, 2.7 mL, 2.7 mmol). To this
solution was added, at ꢁ5 °C, 2 (398 mg, 1.3 mmol) in dichloromethane (5 mL), followed
by a solution of N,N-diisopropylethylamine (1 M in dichloromethane, 3 mL, 3.0 mmol).
After cooling to ꢁ78 °C, a solution of 3 (2.65 mmol) in dichloromethane (1 mL) was
added. The reaction was quenched by addition of 0.5 M pH 7 phosphate buffer (5.4 mL),
taken up in ether (30 mL) and the aqueous layer separated. The organic layer was washed
with satd aq NH4Cl (2ꢀ50 mL), dried (MgSO4) and concentrated in vacuo (at ambient
temperature). The resulting mixture was purified by column chromatography (hexane/
25
ethyl acetate, 4:1) to yield the aldol adduct 5 (340 mg, 60%) as an oil. [a]D ꢁ 89 °C (c
0.9, CH2Cl2). Rf (0.31) in hexane/ethyl acetate (3:1). IR (nujol/CH2Cl2): 3502, 2924,
2854, 1684, 1461, 1378, 1338, 1264, 1237, 1214, 1165, 1135, 1066, 9687, 744 cmꢁ1. 1H

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PERLMUTTER AND ROSE
NMR (200 mHz, CDCl3) d 0.99 (s, 3H,CH3), 1.18 (s, 3H, CH3), 1.40 (m, 2H, CH2), 1.60
(m, 2H, CH2), 1.80–2.20 (m, 8H, 3ꢀCH2, CH and OH), 3.33 (pent, 1H, J =4.1 Hz, H-2),
3.49 and 3.56 (AB quartet, 2H, J =13.8 Hz, CH2SO2), 3.95 (t, 1H, J = 6.3 Hz, CHN), 4.65
(m, 1H, H-1), 4.90 (m, 2H, CH = CH2), 5.70 (m, 1H, CH = CH2), 6.25 (dd, 1H, J = 5.8,
16.0 Hz, CH = CHPh), 6.68 (d, 1H, J =16.0 Hz, CH = CHPh), 7.20–7.50 (m, 5H, Ph). 13
C
NMR (75 mHz, CDCl3) d 19.6(C-80), 20.9(C-90), 26.4(C-50), 27.5(C-3), 31.3(C-4), 33.0(C-
60), 38.6(C-30), 44.7(C-40), 47.8(C-70), 48.2(C-10), 50.1(C-2), 53.2(C-100), 65.4(C-20),
71.9(C-1), 115.0(CH2 = C), 126.5(Ph), 127.4(CH = C), 128.3(Ph), 128.5(Ph),
131.2(CH = C), 136.6(Ph), 137.5(CHC), 174.9(CO). Exact mass m/z calcd for
C25H32NSO3 (MꢁOH) 426.2103, found 426.2083.
(2R)-N-[(1R,2S)-2-Hydroxy-3-cyclopenten-1-oyl]bornane-10,2-sultam (6). The
aldol adduct 4 (680 mg, 1.6 mmol) was dissolved in degassed dichloromethane (60 mL)
under argon. A solution of Grubbs’ catalyst (130 mg, 0.16 mmol) in dichloromethane (5
mL) was added and the reaction stirred overnight. Evaporation of the solvent, followed
by chromatography (hexane/ethyl acetate, 2:1), gave 6 (415 mg, 83%) as colorless
crystals, mp 141–143 °C. [a]D25 + 13 °C (c 1.0, CH2Cl2). Rf (0.13) in hexane/ethyl
acetate (4:1). IR (nujol/CH2Cl2): 3514, 2924, 2854,1686, 1458, 1378, 1360, 1321, 1274,
1249, 1208, 1166, 1134, 1119, 1059, 1040, 1001, 964, 802, 788, 721 cmꢁ1. 1H NMR (200
mHz, CDCl3) d 0.98 (s, 3H,CH3), 1.17 (s, 3H,CH3), 1.30–1.45 (m, 2H, CH2), 1.70–2.10
(m, 8H, 3ꢀCH2, CH and OH), 2.55 (m, 1H, H-5), 2.90 (m, 1H, H-5), 3.51 and 3.53 (AB
quartet, 2H, J =13.9 Hz, CH2SO2), 3.85 (m, 1H, H-1), 3.96 (dd, 1H, J =5.3, 5.3 Hz,
CHN), 5.20 (m, 1H, H-2), 5.75 (m, 1H, H-4), 5.95 (m, 1H, H-3). 13C NMR (50 mHz,
CDCl3) d 20.0(C-80), 21.1(C-90), 26.5(C-50), 32.9(C-60), 36.0(C-5), 38.8(C-30), 44.7(C-
40), 47.1(C-1), 47.9(C-70), 48.4(C-10), 53.3(C-100), 65.7(C-20), 78.2(C-2), 131.7(C-4),
133.7(C-3), 171.7(CO). Exact mass m/z Calcd for C16H23NSO4Na (M +Na+) 348.1245,
found 348.1231.
(2R)-N-[(1R,2S)-2-Hydroxy-3-cyclohexen-1-oyl]bornane-10,2-sultam (7). The
aldol adduct 5 (690 mg, 1.5 mmol) was dissolved in degassed dichloromethane (55 mL)
under argon. A solution of Grubbs’ catalyst (125 mg, 0.15 mmol) in dichloromethane (10
mL) was added and the reaction stirred overnight. Evaporation of the solvent, followed
by chromatography (hexane/ethyl acetate, 2:1), gave 7 (393 mg, 74%) as colorless
25
crystals, mp 176–178 °C. [a]D ꢁ 58 °C (c 1.6, CH2Cl2). Rf (0.25) in hexane/ethyl
acetate (4:1). IR (nujol/CH2Cl2): 3424, 2924, 2854, 1689, 1665, 1461, 1377, 1330, 1264,
1237, 1213, 1166, 1131, 1051, 1000, 939, 829, 743 cmꢁ1. 1H NMR (200 mHz, CDCl3) d
0.98 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.20–1.60 (m, 5H, 2ꢀCH2 and CH), 1.70–2.20 (m,
7H, 3ꢀCH2, and OH), 3.10 (m, 1H, H-1), 3.49 and 3.50 (AB quartet, 2H, J = 13.9 Hz,
CH2SO2), 3.92 (t, 1H, J = 6.0 Hz, CHN), 4.45 (m, 1H, H-2), 5.89 (m, 2H, H-3 and H-4).
13C NMR (50 mHz, CDCl3) d 19.8(C-80), 20.7(C-90), 21.4(C-5), 25.4(C-6), 26.4(C-50),
32.7(C-60), 38.4(C-30), 44.5(C-40), 44.9(C-1), 47.8(C-70), 48.4(C-10), 53.0(C-100), 63.1(C-
2), 64.9(C-20), 127.1(C-4), 130.9(C-3), 176.3(CO). [M + 1] m/z 340.2 (100%),
[M+ 1ꢁH2O] m/z 322.2 (65%).
Anal. Calcd for C17H25NSO4: C, 60.15; H, 7.42; N, 4.13: Found: C, 59.90; H, 7.62;
N, 4.12.
(2R)-N-[(1R,2S,3R,4R)-2,3,4-Trihydroxycyclopentan-1-oyl]bornane-10,2-sul-
tam (9). A solution of 6 (180 mg, 0.57 mmol) in t-butyl alcohol (3 mL) and DMF (3

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SYNTHESIS OF CARBASUGARS
7
mL) was added to K2OsO4.2H2O (20 mg, 0.06 mmol) and 4-methyl morpholine N-oxide
(134 mg, 1.14 mmol) under N2. The reaction was left stirring at rt overnight, then
quenched with 20% aq. Na2S2O5 solution (1 mL) and left stirring for 30 min. The
solution was poured into water (30 mL) and extracted with ethyl acetate (3ꢀ20 mL).
Drying (MgSO4) and removal of solvent gave 9 (180 mg, 90%) as colorless crystals.
Recrystallization from ethyl acetate gave material suitable for x-ray crystallography, mp
25
187–189 °C. Rf (0.31) in ethyl acetate. [a]D ꢁ 46 °C (c 0.4, CH3OH). IR (nujol/
CH2Cl2): 3420, 3313, 2925, 2854, 1693, 1459, 1413, 1376, 1320, 1283, 1271, 1237,
1216, 1164, 1129, 1100, 1063, 1038, 1000, 882, 774 cmꢁ1. 1H NMR (300 mHz, CDCl3) d
0.98 (s, 3H, CH3), 1.14 (s, 3H, CH3), 1.35 (m, 2H, CH2), 1.80–2.20 (m, 6H, H-5, 2ꢀCH2,
CH), 2.36 (pent., 1H, J =6.5 Hz, H-5), 3.48 and 3.55 (AB quartet, 2H, J =13.7 Hz,
CH2SO2), 3.82–3.96 (m, 2H, H-1 and CHN), 4.11 (t, 1H, J =6.2 Hz, H-4), 4.29 (m, 1H,
H-2), 4.45 (t, 1H, J =7.3 Hz, H-3). 13C NMR (50 mHz, CDCl3) d 20.0(C-80), 21.1(C-90).
26.5(C-50), 33.0(C-60), 33.8(C-5), 38.7(C-30), 44.7(C-40), 44.8(C-1), 47.9(C-70), 48.4(C-
10), 53.4(C-10,), 65.7(C-20), 70.8(C-4), 77.7(C-2), 78.3(C-3), 172.9(CO). Exact mass m/z
calcd for C16H25NSO6Na (M +Na+) 382.1300, found 382.1303.
(2R)-N-[(1R,2R,3R,4R)-2,3,4-Trihydroxycyclohexan-1-oyl]bornane-10,2-sul-
tam (10). A solution of 7 (220 mg, 0.65 mmol) in t-butyl alcohol (3 mL) and DMF
(3 mL) was added to K2OsO4.2H2O (29 mg, 0.08 mmol) and 4-methylmorpholine N-
oxide (157 mg, 1.34 mmol) under N2. The reaction was left stirring at rt overnight, then
quenched with 20% aq Na2S2O5 solution (1 mL) and left stirring for 30 min. The solution
was poured into water (30 mL) and extracted with ethyl acetate (3ꢀ20 mL). Drying
(MgSO4), removal of solvent and column chromatography (eluting with 100% ethyl
acetate), gave 10 (121 mg, 50%) as colorless crystals, mp 183–185 °C. Recrystallization
from methanol/water gave material suitable for x-ray crystallography. Rf (0.65) in ethyl
25
acetate. [a]D ꢁ 91 °C (c 0.4, CH3OH). IR (CH2Cl2): 3443, 2962, 1671, 1456, 1413,
1
1394, 1334, 1267, 1237, 1217, 1166, 1135, 1066, 1001, 912, 736, 649 cmꢁ1. H NMR
(300 mHz, CDCl3) d 0.97 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.38 (m, 2H, CH2), 1.70–2.05
(m, 9H, 4ꢀCH2 and CH), 2.40 (bs, 3H, 3ꢀOH), 3.42 (m, 1H, H-1), 3.47 and 3.52 (AB
quartet, 2H, J =13.6 Hz, CH2SO2), 3.90 (t, 1H, J = 5.9 Hz, CHN), 4.05 (bs, 2H, H-2 and
H-4), 4.21 (bs, 1H, H-3). 13C NMR (75 mHz, CDCl3) d 19.9(C-80), 20.9(C-90), 22.6(C-6),
26.5(C-50), 27.3(C-5), 32.8(C-60), 38.4(C-30), 42.6(C-1), 44.6(C-40), 47.8(C-70), 48.4(C-
10), 53.0(C-100), 64.9(C-20), 67.7(C-4), 70.3(C-2), 71.1(C-3), 175.3(CO). Exact mass m/z
calcd for C17H27NSO6Na (M +Na+) 396.1457, found 396.1459.
(1R,2S,3R,4R)-2,3,4-Triacetoxycyclopentanoic acid (13). To a chilled solution
of 9 (456 mg, 1.3 mmol) in THF (20 mL) and water (5 mL) was added lithium hydroxide
(111 mg, 2.6 mmol) followed by 30% aqueous H2O2 solution (350 mL, 4.5 mmol). The
reaction mixture was allowed to warm to rt and stirred for a further 3 h, after which it was
acidified with 1 M HCl. The solvent was removed in vacuo, and the residue was taken up
in ethyl acetate/water (20 mL/20 mL) and the aqueous layer separated to give a solution
of 11 in water. A portion of this solution (4 mL, 0.26 mmol) was concentrated, taken up
in acetic anhydride (1 mL), treated with 3 drops of conc. H2SO4 and stirred at rt
overnight. Most of the acetic anhydride was removed in vacuo and the residue was taken
up in ethyl acetate/water (5 mL/5 mL). The organic phase was separated and dried
(MgSO4). Column chromatography (hexane/ethyl acetate,1:1, then 1:3) gave 13 (31 mg,

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8
PERLMUTTER AND ROSE
25
41%) as an oil. Rf (0.4) in hexane/ethyl acetate (1:3). [a]D ꢁ30 °C (c 1.0, CH2Cl2). IR
(CH2Cl2): 3600–2700, 1750, 1430, 1375, 1231, 1049, 938, 899, 736 cmꢁ1. 1H NMR (300
mHz, CDCl3) d 2.04 (m, 10H, 3ꢀCH3 and H-5), 2.60 (pent., 1H, J =6.7 Hz, H-5), 3.48
(m, 1H, H-1), 5.28 (dd, 1H, J = 4.7, 6.7 Hz, H-4), 5.42 (m, 1H, H-2), 5.51 (dd, 1H, J = 6.7,
8.4 Hz, H-3). 13C NMR (75 mHz, CDCl3) d 20.6(CH3), 20.8(CH3), 20.9(CH3), 30.2(C-5),
42.2(C-1), 70.4(C-4), 74.6(C-2), 75.1(C-3), 169.5(CO), 169.7(CO), 169.8(CO),
175.8(CO). Exact mass m/z calcd for C12H16O8Na (M +Na+) 311.0743 found 311.0737.
Methyl (1R,2S,3R,4R)-2,3,4-Trihydroxycyclohexanoate (14). To a chilled sol-
ution of 10 (121 mg, 0.3 mmol) in THF (4.8 mL) and water (1.2 mL) was added lithium
hydroxide (27 mg, 0.6 mmol) followed by 30% aqueous H2O2 solution (140 mL, 1.2
mmol). The reaction was allowed to warm to rt and stirred for a further 4 h, after which it
was acidified with 1 M HCl. The solvent was removed in vacuo and the residue was taken
up in ethyl acetate/water (6 mL/6 mL) and the aqueous layer separated, concentrated in
vacuo and dissolved in methanol (20 mL). A few drops of concd H2SO4 were added and
the mixture refluxed overnight. Following removal of solvent, adsorption onto silica and
chromatography (6:1 CH2Cl2, 2-propanol) 14 (45 mg, 74%) was obtained as an oil.
Rf(0.66) in CH2Cl2/2-propanol (3:1). [a]D25+5 °C (c 1.0, CH3OH). IR (neat): 3500–
1
3000, 2951, 2840, 1720, 1650, 1452, 1223, 1113, 1063, 1026, 775 cmꢁ1. H NMR (300
mHz, CD3OD) d 1.60–1.90 (m, 4H, H-5 and H-6), 2.75 (dq, 1H, J = 2.9, 11.3 Hz, H-1),
3.68 (s, 3H, CH3), 3.85 (m, 2H, H-2 and H-3), 4.21 (t, 1H, J =3.2 Hz, H-4). 13C NMR (75
mHz, CD3OD) d 21.4(C-6), 28.0(C-5), 43.3(CH3), 52.1(C-1), 68.7(C-4), 72.6(C-2),
73.4(C-3), 176.1(CO). Exact mass m/z calcd for C8H14O5Na (M+ Na+) 213.0739, found
213.0736.
(1R,2R,3R,4S)-4-Hydroxymethyl-1,2,3-trihydroxycyclopentane or 4a-carba-a-
L-xylofuranose (15). To a solution of 9 (50 mg, 0.14 mmol) in ethanol (4 mL) was
added NaBH4 (50 mg, 1.3 mmol). After stirring at rt for 1 hour the reaction was acidified
to pH 4 by dropwise addition of 2 M H2SO4. Following removal of solvent in vacuo, the
residue was taken up in water/ethyl acetate (5 mL/5 mL) and the aqueous layer was
separated and concentrated. The residue was extracted by stirring in methanol (10 mL)
for 20 min and the solution was filtered through Celite. Removal of solvent, adsorption
onto silica and chromatography (CH2Cl2/2-propanol, 1:1) gave 15 (11 mg, 52%) as an
25
oil. [a]D ꢁ15 °C (c 1.0, CH3OH). IR (neat): 3419, 2941, 2137, 1652, 1416, 1337, 111,
1
1037, 979 cmꢁ1. H NMR (300 mHz, CD3OD) d 1.75 (m, 2H, 2ꢀH-5), 2.44 (m, 1H, H-
4), 3.56 (dd, 1H, J =6.5, 10.9 Hz, HCHOH), 3.68 (dd, 1H, J = 6.5, 10.9 Hz, HCHOH),
3.80 (t, 1H, J =4.4 Hz, H-1), 4.14 (m, 2H, H-2 and H-3). 13C NMR (75 mHz, CD3OD)
d 34.0(C-5), 41.8(C-4), 63.3(CH2OH), 72.3(C-1), 78.1(C-3), 80.3(C-2) Exact mass m/z
calcd for C6H12O4Na (M+ Na+) 171.0633, found 171.0629.
(1R,2R,3R,4S)-4-Hydroxymethyl-1,2,3-trihydroxycyclohexane or 4-epi-validi-
tol (16). To a solution of 10 (46 mg, 0.12 mmol) in ethanol (4 mL) was added NaBH4
(45 mg, 1.2 mmol). After stirring at rt for 2 h the reaction was acidified to pH 4 by
dropwise addition of 2 M H2SO4. Following removal of solvent in vacuo, the residue was
taken up in water/ethyl acetate (5 mL/5 mL) and the aqueous layer was separated and
concentrated. The residue was extracted by stirring in 2-propanol (10 mL) for 20 min and

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SYNTHESIS OF CARBASUGARS
9
the solution was successively filtered through silica and Celite. Evaporation of solvent
gave 16 (19 mg, 95%) as an oil. [a]D25 + 16 °C (c 1.0, CH3OH). IR (neat): 3386, 2948,
1648, 1560, 1458, 1114, 1019 cmꢁ1. 1H NMR (300 mHz, CD3OD) d 1.32–1.72 (m, 4H,
2ꢀH-5 and 2ꢀH-6), 1.85 (m, 1H, H-4), 3.50 (dd, 1H, J = 6.7, 10.7 Hz, HCHOH), 3.62
(dd, 1H, J =6.7, 10.7 Hz, HCHOH), 3.78 (t, 1H, J = 3.4 Hz, H-1), 3.85 (m, 1H, H-3), 3.95
(t, 1H, J =3.4 Hz, H-2). 13C NMR (75 mHz, CD3OD) d 22.3 (C-5), 28.6 (C-6), 39.0 (C-
4), 64.7 (CH2OH), 69.4 (C-1), 72.4 (C-3), 73.8 (C-2). Exact mass m/z calcd for
C7H14O4Na (M + Na+) 185.0790, found 185.0783.
ACKNOWLEDGMENTS
P. P. and M. R. are grateful to the Australian Research Council for financial
support. We also thank Dr Gary D. Fallon for solving the x-ray structures of 9
and 10.
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Received May 8, 2001
Accepted November 20, 2001