Enzyme-catalyzed stereoselective synthesis of two novel carbasugar derivatives

Article abstract of DOI:10.1002/hlca.201000213

Enzymatic resolution of racemic 1,4,5,6-tetrachloro-2-(hydroxymethyl)-7,7- dimethoxybicyclo[2.2.1]hept-5-ene (rac-1) using various lipases in vinyl acetate as acetyl source was studied. The obtained enantiomerically enriched (+)-(1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl)methyl acetate ((+)-2; 94% ee), upon treatment with Na in liquid NH₃, followed by Amberlyst-15 resin in acetone, provided (-)-5-(hydroxymethyl) bicyclo[2.2.1]hept-2-en-7-one ((-)-7), which is a valuable precursor for the synthesis of carbasugar derivatives. Subsequent Baeyer-Villiger oxidation afforded a nonseparable mixture of bicyclic lactones, which was subjected to LiAlH₄ reduction and then acetylation. The resultant compounds (-)-11 and (+)-12 were submitted to a cis-hydroxylation reaction, followed by acetylation, to afford the novel carbasugar derivatives (1S,2R,3S,4S,5S)-4,5- bis(acetoxymethyl)cyclohexane-1,2,3-triyl triacetate ((-)-(13)) and (1R,3R,4R,6R)-4,6-bis(acetoxymethyl)cyclohexane-1,2,3-triyl triacetate ((-)-(14)), respectively, with pseudo-C₂-symmetric configuration. The absolute configuration of enantiomerically enriched unreacted alcohol (-)-1 (68% ee) was determined by X-ray single-crystal analysis by anchoring optically pure (R)-1-phenylethanamine. Based on the configurational correlation between (-)-1 and (+)-2, the absolute configuration of (+)-2 was determined as (1R,2R,4S).

Full text of DOI:10.1002/hlca.201000213

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Enzyme-Catalyzed Stereoselective Synthesis of Two Novel Carbasugar
Derivatives
by Ays¸egꢀl Gꢀmꢀs¸ and Cihangir Tanyeli*
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
(phone: þ 90-312-2103222; fax: þ 90-312-2103200; e-mail:tanyeli@metu.edu.tr)
Enzymatic resolution of racemic 1,4,5,6-tetrachloro-2-(hydroxymethyl)-7,7-dimethoxybicyclo[2.2.1]-
hept-5-ene (rac-1) using various lipases in vinyl acetate as acetyl source was studied. The obtained
enantiomerically enriched (þ)-(1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl)methyl
acetate ((þ)-2; 94% ee), upon treatment with Na in liquid NH3, followed by Amberlyst-15 resin in
acetone, provided (ꢀ)-5-(hydroxymethyl)bicyclo[2.2.1]hept-2-en-7-one ((ꢀ)-7), which is a valuable
precursor for the synthesis of carbasugar derivatives. Subsequent Baeyer– Villiger oxidation afforded a
nonseparable mixture of bicyclic lactones, which was subjected to LiAlH4 reduction and then acetylation.
The resultant compounds (ꢀ)-11 and (þ)-12 were submitted to a cis-hydroxylation reaction, followed by
acetylation, to afford the novel carbasugar derivatives (1S,2R,3S,4S,5S)-4,5-bis(acetoxymethyl)cyclo-
hexane-1,2,3-triyl triacetate ((ꢀ)-(13)) and (1R,3R,4R,6R)-4,6-bis(acetoxymethyl)cyclohexane-1,2,3-
triyl triacetate ((ꢀ)-(14)), respectively, with pseudo-C2-symmetric configuration. The absolute config-
uration of enantiomerically enriched unreacted alcohol (ꢀ)-1 (68% ee) was determined by X-ray single-
crystal analysis by anchoring optically pure (R)-1-phenylethanamine. Based on the configurational
correlation between (ꢀ)-1 and (þ)-2, the absolute configuration of (þ)-2 was determined as (1R,2R,4S).
1. Introduction. – Polyhydroxylated cyclohexanoids are widespread in the nature,
and they usually possess a wide range of important biological activities [1]. In view of
their potential as therapeutic agents for the treatment of a variety of carbohydrate-
mediated diseases like diabetes, AIDS, viral infections, and cancers, many structural
variants of conduritol and carbasugar have been synthesized [2]. A novel approach for
the synthesis of several carbasugars emanating from norbornyl systems has been
developed by Mehta et al. [3].
The increasing demand for the synthesis of enantiomerically pure compounds has
led to the investigation of different approaches for obtaining chiral cyclitol derivatives.
One of the most promising methods is the use of a microbial enzyme, Pseudomonas
putida [4], to convert achiral aromatic compounds to the optically active key
compounds of cyclitol derivatives [5].
The pursuit for novel approaches in enantiomerically pure compound (EPC)
syntheses is a major topic in modern organic synthesis [6]. The chemo-enzymatic
approach for asymmetric synthesis has been increasingly included in synthetic
strategies, while the use of biocatalysts as routine chiral catalysts has already found
widespread application in preparative organic chemistry over the last decade [7].
Lipases can catalyze asymmetric hydrolysis [8] as well as esterification [9]. This
property has attracted a great deal of attention from synthetic chemists, since lipases do
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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not require cofactors, and are readily available and easily handled. Polychlorinated
norbornene adducts can be given as an interesting example of the extensive application
area of lipases. In the literature, there are only a few examples of enzymatic resolution
of hexa- and tetrachlorinated norbornene and norbornadiene derivatives [10].
Recently, we reported the enzymatic resolution of various hydroxymethyl-substituted
hexachlorinated norbornene and norbornadiene derivatives [11]. In connection with
these biotransformations, we turned our attention to the enzymatic resolution of
rac-1,4,5,6-tetrachloro-2-endo-(hydroxymethyl)-7,7-dimethoxybicyclo[2.2.1]hept-5-ene,
which involves versatile structural benefits. High endo selectivity can be obtained
during the Diels – Alder reactions of 1,2,3,4-tetrachloro-5,5-dimetoxycyclopentadiene
because of the steric repulsion of its MeO groups at C(5). Moreover, it is well
documented by Mehta et al. [3] that the dimethoxy-substituted bridge C-atom of
similar cycloadducts may serve as a precursor of OH and HOCH2 groups in the
synthesis of carbasugar derivatives. On the basis of the versatility of 2-endo-
(acetoxymethyl)-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-ene (2), here,
we report the resolution of rac-1 and the highly efficient enantioselective conversion
of the resulting enantiomerically enriched acetate (þ)-2 to carbasugar derivatives
(1S,2R,3S,4S,5S)-4,5-bis(acetoxymethyl)cyclohexane-1,2,3-triyl triacetate ((ꢀ)-13) and
pseudo-C2-symmetric
(1R,3R,4R,6R)-4,6-bis(acetoxymethyl)cyclohexane-1,2,3-triyl
triacetate ((ꢀ)-14). To the best of our knowledge, this is the first stereoselective
synthesis of novel carbasugar derivatives.
2. Results and Discussion. – 2.1. Synthesis and Enzymatic Resolution of rac-1. The
key substrate rac-1 was synthesized, in its pure endo-form, through a Diels – Alder
reaction by heating a mixture of 1,2,3,4-tetrachloro-5,5-dimethoxycyclopentadiene and
allyl alcohol (1:1.2 molar ratio) to 1508 for 50 h in a sealed tube [12]. Then, various
lipases were tested with rac-1 in the presence of vinyl acetate as acetyl source
(Scheme 1).
Scheme 1
The first bioconversion was performed using porcine pancrease lipase (PPL)
according to the following procedure (Table 1). To a stirred solution of rac-1 (500 mg)
in vinyl acetate (5 ml) was added PPL (50 mg) in one portion, and the mixture was
shaken at 258. The conversion was monitored by TLC, and 38% conversion was
achieved after 45 h. The products were separated by flash column chromatography, and
(þ)-2 was isolated in 45% yield with 64% ee (Entry 1). The next attempts involved the
resolutions achieved by Candida rugosa lipase (CRL; 50 mg) and Novazyme 435

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(100 mg) under the same conditions as described above (Entries 2 and 3, resp.). CRL
appeared to be the best enzyme tested, since (þ)-(1,4,5,6-tetrachloro-7,7-dimethoxy-
bicyclo[2.2.1]hept-5-en-2-yl)methyl acetate ((þ)-2) was isolated in 44% yield with 94%
ee, whereas Novazyme 435 (Entry 3) showed an acceptable level of enantioselectivity
(86% ee) and appeared to be the most efficient in terms of reaction duration (20 h). All
of the enzymes afforded the acetylated derivative 2 with the same configuration. To
improve the ee value, experimental conditions were tested in detail using various co-
solvents such as (i-Pr)2O, i-PrOH, t-BuOMe, and BuOH, and changing the amount of
CRL used. No increase in the enantioselectivity was observed. In all cases, the
acetylation was interrupted after 40% conversion, since a longer reaction time and
conversion near 50% gave (þ)-2 with a lower ee value. On the other hand, this
approach caused a decrease in the ee value of the unreacted alcohol (ꢀ)-1. All ee
determinations were performed with the acetylated derivative 2, since it was effectively
resolved by HPLC. Hence, the unreacted alcohol (ꢀ)-1 was acetylated by Ac2O in
pyridine, and, then, the ee value was determined by HPLC.
Table 1. Results of the Enzyme-Catalyzed Acetylation of rac-1
Entry
Lipase
Time [h]
Esters eep [%]a)
Alcohols ees [%]b)
c [%]c)
Ed)
1
2
3
PPL
CRL
Novazyme 435
45
68
20
64
94
86
39
68
54
38
42
39
7
65
21
a) Enantiomeric excess (ee) values were determined by HPLC using Chiralcel OD-H chiral column.
b) ee was calculated after transforming to corresponding acetate. c) c ¼ ees/(ees þ eep). d) Calculated by
the method of Sih and co-workers: E ¼ ln[(1 ꢀ c)(1 ꢀ ees)]/ln[(1 ꢀ c)(1 þ ees)] [13].
2.2. Determination of Absolute Configuration of (ꢀ)-1 and (þ)-2. The absolute
configuration of (þ)-2 was not known, and its assignment was crucial since we used it as
a reference for the determination of the absolute configuration of newly generated
stereogenic centers in the target carbasugar derivatives. We decided to utilize
recovered unreacted alcohol (ꢀ)-1 with low ee (68%), which was found to be useful
and economical, since we were able to determine accurately the ee value of (ꢀ)-1. The
absolute configuration of (ꢀ)-1 was determined by X-ray single-crystal analysis. We
planned to anchor an optically pure chiral unit with a known configuration as a
reference. For this purpose, enantiomerically enriched unreacted alcohol (ꢀ)-1 was
transformed into the 1-phenylethanamine derivative 4 via first mesylation of 3 and
subsequent substitution with optically pure (R)-1-phenylethanamine (Scheme 2). We
were unable to grow single crystals of 4, but then, it was converted to its HCl salt by
passing HCl gas through the solution to afford suitable crystals of 5.
The crystal-structure analysis of 5 confirmed the compound as 1-phenyl-N-
[(1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl)methyl]ethanammoni-
um chloride (Fig. 1). There are four ion pairs (I to IV) in the asymmetric unit (triclinic
non-centrosymmetric space group P1). In the crystal, 84.1% of the cations (namely, the
cations I to III, and 36.4(3)% of the cations IV) show the (R,S,S,R)-configuration
(related to the asymmetric C-atoms at C(1), C(4), C(5), and C(17) in molecule 5), and
15.9% (namely, 63.6(3)% of the cations IV) show the (S,R,R,R)-configuration (Fig. 2).

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Scheme 2
i) MsCl, Et3N, CH2Cl2. ii) (þ)-(R)-1-Phenylethanamine. iii) HCl (gas) in Et2O.
Due to this disorder, two of the four Clꢀ ions are disordered as well. Nevertheless, each
N-atom has exactly two H-bonds by each of its bonded H-atoms to a Clꢀ ion (Table 2).
By these H-bonds, an isolated tetrameric aggregate consisting of four Clꢀ ions and four
almost coplanar NHþ2 groups is formed (Fig. 3). Due to the configurational correlation
between (ꢀ)-1 and (þ)-2, the absolute configuration of (þ)-2 was determined as
(1R,2R,4S).
Fig. 1. ORTEP [14] Plot of one cation of 5 (together with its coordinating anions showing the atomic
numbering scheme). The presumed H-bonds are indicated with dotted lines.
2.3. Stereoselective Syntheses. After successful enzymatic resolution and absolute-
configuration determination of the key compound (þ)-(1R,2R,4S)-2, we turned our
attention to the reductive dechlorination. Tetrachloro derivative (þ)-(1R,2R,4S)-2 was
successfully converted to the desired dechlorinated derivative (ꢀ)-(1S,2S,4S)-6 by
treatment of (þ)-2 with Na in liquid NH3 [15]. During the course of this reaction,
deacetylation occurred, as expected. The structure of (ꢀ)-(1S,2S,4S)-6 was assigned on
the basis of the 1H-NMR spectrum. The most distinctive features were the olefinic H-
atom resonances. The olefinic H-atoms of (ꢀ)-6 resonating at d(H) 6.18 (dd, J ¼ 3.2,
6.0 Hz) and 6.04 (dd, J ¼ 3.2, 6.0 Hz) show further splitting with adjacent bridgehead H-
atoms. Compound (ꢀ)-6 was readily and almost quantitatively deprotected by

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Fig. 2. ORTEP [14] plot of the disordered cation IV of 5. The atoms are drawn with arbitrary radii. The
cation with the (S,R,R,R)-configuration (site occupation factors of 0.636(3)) is drawn with full bonds, the
cation with the (R,S,S,R)-configuration (site occupation factors of 0.364(3)) is drawn with open bonds.
Amberlyst-15 resin in acetone to afford the ketone (ꢀ)-(1S,2S,4S)-7 in 99% yield [16].
In particular, the 13C-NMR spectrum consisting of a characteristic ketone resonance
signal at d(C) 204.6 was a good evidence for the structure of (ꢀ)-(1S,2S,4S)-7. So far,
since only the CꢀCl bonds were cleaved, and subsequently the ketal group was
transferred to the corresponding oxo group in these reactions, the configuration at all
C-atoms were preserved (Scheme 3).
In our synthetic design, the norbornen-7-one ((ꢀ)-7) is an ideal substrate for the
synthesis of carbasugar derivatives. We planned to use the oxo group as the source of
HOCH2 and OH groups. The OH group of compound (ꢀ)-7 was protected by the Ac
group prior to the Baeyer – Villiger oxidation to avoid possible side-reactions. The
reaction of acetyl derivative (ꢀ)-8 with m-CPBA resulted in the formation of a mixture
of two lactone isomers, 9 and 10, in 75% total yield. Although many attempts were
made to separate the mixture 9/10, we did not obtain satisfactory results and decided to
proceed to the next step, in which the mixture 9/10 was subjected to LiAlH4 reduction
in dry THF. After acetylation of the mixture with Ac2O in pyridine, the products (ꢀ)-11
and (þ)-12 were isolated in 36 and 45% yields, respectively. The structures of (ꢀ)-11
and (þ)-12 were assigned on the basis of the 1H-NMR spectra. The most characteristic
features of (ꢀ)-11 and (þ)-12 are the resonances of the AcO-bearing CH groups. The

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Table 2. H-Bonds of 5. The NꢀH distances were restrained to 0.92 ꢂ. The atoms Cl(93), Cl(94), N(7),
H(701), and H(702) have site occupation factors of 0.636(3), the corresponding atoms Cl(95), Cl(96),
N(9), H(901), and H(902) have site occupation factors of 0.364(3).
DꢀH ··· A
d(H ··· A) [ꢂ]
d(D ··· A) [ꢂ]
< (DHA) [8]
N(1)ꢀH(102) ··· Cl(91)
N(1)ꢀH(101) ··· Cl(93)a)
N(1)ꢀH(101) ··· Cl(95)a)
N(3)ꢀH(301) ··· Cl(91)b)
N(3)ꢀH(302) ··· Cl(93)
N(3)ꢀH(302) ··· Cl(95)
N(5)ꢀH(501) ··· Cl(92)
N(5)ꢀH(502) ··· Cl(91)c)
N(7)ꢀH(702) ··· Cl(93)
N(7)ꢀH(701) ··· Cl(94)
N(9)ꢀH(902) ··· Cl(95)
N(9)ꢀH(901) ··· Cl(96)
2.36
2.40
2.25
2.39
2.39
2.07
2.19
2.32
2.29
2.24
2.32
2.08
3.232(4)
3.291(6)
3.117(9)
3.271(4)
3.274(6)
2.919(8)
3.082(3)
3.221(3)
3.179(7)
3.072(6)
3.126(13)
2.997(14)
158.0
162.5
156.1
160.6
161.6
152.2
163.8
167.0
161.3
150.2
146.5
171.1
Symmetry transformations used to generate equivalent atoms: a) x, y, z ꢀ 1. b) x, y, z þ 1. c) x, y þ 1, z.
Fig. 3. Stereoscopic ORTEP [14] plot of the H-bonded aggregate of 5. The probability ellipsoids are
drawn at the 50% probability level, the C- and H-atoms bonded to N-atoms are drawn with arbitrary
radii, the other H-atoms as well as the atoms with site occupation factors less than 0.5 are omitted for
clarity. The presumed H-bonds are drawn with dotted lines.
CH H-atom, Ha, of (ꢀ)-11 resonates at d(H) 5.17 (J ¼ 3.6 Hz) as a quartet, whereas Ha
of (þ)-12 gives rise to a signal at d(H) 5.09 (J ¼ 5.0, 1.6 Hz) as a dd. The positions of the
AcO groups in (ꢀ)-11 and (þ)-12 were determined with the help of the COSY spectra:
Ha of (ꢀ)-11 shows cross-peaks with the neighboring diastereotopic CH2 H-atoms, Hb

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Scheme 3
i) Na, NH3 (liq.). ii) Amberlyst-15 resin. iii) AcCl, pyridine, CH2Cl2. iv) m-CPBA, CH2Cl2. v) LiAlH4,
THF. vi) AcCl, pyridine, CH2Cl2. vii) OsO4-NMO (N-methylmorpholine N-oxide) and then Ac2O,
pyridine.
and Hc, resonating at d(H) 1.82 (J ¼ 14.1 and 3.5 Hz) as a dt and 1.67 (J ¼ 14.1, 11.1,
4.5 Hz) as a ddd, respectively. In the COSY spectrum of (þ)-12, Ha exhibits a cross-
peak with the neighboring Hb resonating at d(H) 2.12 – 2.04 as a multiplet.
Finally, for further functionalization of the C¼C bond, we studied the cis-
hydroxylation of compounds (ꢀ)-11 and (þ)-12. Triacetate (ꢀ)-11 was reacted with
OsO4-NMO (N-methylmorpholine N-oxide) followed by acetylation to afford
pentaacetate (ꢀ)-13. The NMR data confirmed the formation of a single isomer. The
stereochemical course of the cis-hydroxylation may be syn or anti with respect to 1,4-
substituted AcO and AcOCH2 groups. To determine the exact configuration of
pentaacetate (ꢀ)-13, first we made complete assignments for the CH H-atoms Ha, Hb,
and Hc with the help of the COSY spectrum. The H-atoms Ha, Hb, and Hc resonate at
d(H) 4.97 (J ¼ 3.2 Hz) as a quartet, 5.19 (J ¼ 3.4 Hz) as a triplet, and 5.04 (J ¼ 10.9,

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3.1 Hz) as a dd, respectively. The Ha-atom shows a cross-peak with neighboring CH2 H-
atoms (d(H) 1.84 – 1.67 as a multiplet), whereas Hc exhibits a cross-peak with the
neighboring Hd-atom. In particular, Hc resonating as a dd with coupling constants of
J ¼ 10.9 and 3.1 Hz strongly supports the trans-relation of Hc and Hd, and the cis-
relation of Hc and Hb, respectively.
Triacetate (þ)-12 was submitted to a cis-hydroxylation reaction as described above,
followed by acetylation to afford pentaacetate (ꢀ)-14 with pseudo-C2-symmetry. The
spectroscopic data confirmed the formation of a single isomer. We determined the
positions of the CH H-atoms Ha, Hb, and Hc by the COSY spectrum: Hb reveals cross-
peaks with both neighboring Ha and Hc. The signal of Ha appears at d(H) 5.01 as a dd
with coupling constants of J ¼ 8.2 and 3.1 Hz, which obviously supports the trans-
relation between Ha and the neighboring CH H-atom attached to the AcOCH2 group
and the cis-relation between Ha and Hb, respectively. The Hc-atom resonates at d(H)
5.10 as a triplet with a coupling constant of J ¼ 8.2 Hz, clearly indicating that Hc is in
trans-relations with both Hb and the neighboring AcOCH2-attached CH H-atom.
3. Conclusions. – In summary, we achieved the stereoselective synthesis of the two
novel carbasugar derivatives (ꢀ)-13 and (ꢀ)-14 via a chemo-enzymatic approach.
Enzymatic resolution of rac-1,4,5,6-tetrachloro-2-endo-(hydroxymethyl)-7,7-dimethoxy-
bicyclo[2.2.1]hept-5-ene (rac-1) employing CRL-catalyzed esterification afforded
enantiomerically enriched unreacted alcohol (ꢀ)-1 and (þ)-2 with 68 and 94% ee,
respectively. The absolute configuration was determined by X-ray single-crystal
analysis of unreacted alcohol (ꢀ)-1 anchored by optically pure (R)-1-phenylethan-
amine. Due to the configurational correlation between (ꢀ)-1 and (þ)-2, the absolute
configuration of (þ)-2 was determined as (1R,2R,4S). This is crucial since we used it as
a reference for the absolute-configuration determination of newly generated stereo-
genic centers in the target carbasugar derivatives. The key compound (þ)-2 was
successfully converted to nonchlorinated derivative (ꢀ)-6 and subsequently trans-
formed into oxo-bridged derivative (ꢀ)-7, which preserves the configuration at all C-
atoms. The OH group of (ꢀ)-7 was protected with the Ac group prior to Baeyer –
Villiger oxidation, followed by LiAlH4 reduction and acetylation. For further
functionalization of the C¼C bond, (ꢀ)-11 and (þ)-12 were submitted to a cis-
hydroxylation with OsO4-NMO, followed by acetylation to give the novel carbasugar
derivatives (ꢀ)-13 and (ꢀ)-14. The spectral data confirmed the formation of a single
isomer for each case. The stereochemical course of the hydroxylation may be syn or anti
with respect to the AcO and AcOCH2 groups. The exact configuration of these
carbasugars, (ꢀ)-13 and (ꢀ)-14, was established by NMR spectroscopy. In particular,
(ꢀ)-14 possesses a very interesting stereochemical property, namely a pseudo-C2-
symmetry. This chemo-enzymatic approach may be extended to the stereoselective
synthesis of further targets.
We gratefully acknowledge the finacial support of the Middle East Technical University OYP
Program. We would like to thank to Prof. Dr. Ferdinand Belaj from Karl Franzens University for the X-
ray crystal-structure analysis.

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Experimental Part
1. General. Flash column chromatography (FC): silica gel (SiO2; 60 mesh, Merck). The relative
proportion of solvents in chromatography solvent mixtures refers to the v/v ratio. The reactions were
monitored by TLC using SiO2 60 F254 anal. aluminium plates (0.2 mm, Merck). HPLC: Thermo
Separation Products, Inc., P1500-SN-4000-UV2000 instrument using a Chiralcel OD-H anal. column
(250 ꢁ 4.60 mm). Optical rotations: Rudolph research analytical, Autopol III automatic polarimeter in a
1-dm cell. IR Spectra: Varian 1000 FT-IR spectrophotometer; KBr pellets; ˜n in cmꢀ1. 1H- and 13C-NMR
spectra: Bruker Spectrospin Avance DPX 400 spectrometer in CDCl3 at 400 (1H) and 100 (13C) MHz,
resp.; d in ppm rel. to Me4Si or the residual solvent peak as internal standard, J in Hz. HR-MS: Waters
SYNAPT; in m/z.
2. Starting Materials. CRL (Candida rugosa lipase) was purchased from Aldrich. Novazyme 435 was
donated by Novo Nordisk AS, Bagsverd, Denmark. CH2Cl2 was distilled over P2O5, and THF was dried
over Na under Ar.
3. Enzymatic Resolution of rac-1. To a stirred soln. of rac-1 (500 mg) in vinyl acetate (5 ml) was
added CRL (50 mg) in one portion, and the mixture was stirred at 258 (TLC monitoring). Then, the
mixture was filtered, and vinyl acetate was evaporated under reduced pressure. The products (ꢀ)-1 and
(þ)-2 were purified by FC (AcOEt/hexane 1:4).
(1S,2S,4S)-(1,4,5,6-Tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl)methanol ((ꢀ)-1). Yield
54% (0.27 g). [a]2D0 ¼ ꢀ15.1 (c ¼ 1.8, MeOH) for 68% ee.
(1S,2R,4S)-(1,4,5,6-Tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl)methyl Acetate ((þ)-2).
Yield 44% (0.25 g). HPLC-Analysis of (þ)-2: Chiralcel OD-H at r.t., hexane/i-PrOH 99 :1, flow rate
0.3 ml/min; l, 230 nm; t1, 19.8 min (minor); t2, 21.3 min (major). [a]2D0 ¼ þ11.4 (c ¼ 1.8, MeOH) for 94%
ee.
4. Anchoring of (R)-1-Phenylethanamine to (ꢀ)-1. 4.1. [(1S,2R,4S)-1,4,5,6-Tetrachloro-7,7-dimethoxy-
bicyclo[2.2.1]hept-5-en-2-yl]methyl Methanesulfonate (3). To a soln. of (ꢀ)-1 (1 g, 3.1 mmol) and Et3N
(0.87 ml, 6.2 mmol) in CH2Cl2 at 08 was slowly added MsCl (0.36 ml, 4.6 mmol). After stirring for 10 min,
the mixture was diluted with H2O, and the layers were separated. The org. layer was washed with H2O
and brine, dried (MgSO4), filtered, and concentrated at r.t. under reduced pressure to afford the crude
methanesulfonate. Product 3 was purified by FC (AcOEt/hexane 1:3): 1.22 g (98%). 1H-NMR: 4.29 (dd,
J ¼ 10.3, 5.2, 1 H); 3.91 (dd, J ¼ 10.2, 8.0, 1 H); 3.61 (s, 3 H); 3.55 (s, 3 H); 3.09 – 3.05 (m, 1 H); 3.03 (s,
3 H); 2.56 (dd, J ¼ 11.9, 9.2, 1 H); 1.73 (dd, J ¼ 12.1, 4.1, 1 H). 13C-NMR: 131.0; 127.7; 111.9; 77.4; 74.1;
67.4; 52.7; 51.7; 46.3; 39.3; 37.6.
4.2. (R)-1-Phenyl-N-{[(1S,2R,4S)-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl]meth-
yl}ethanamine (4). Compound 3 (0.5 g, 1.25 mmol) and (þ)-(R)-1-phenylethanamine (1.5 ml) were
stirred at 908 under Ar overnight. After disappearance of 3 (TLC), the mixture was dissolved in CH2Cl2
and washed with aq. Na2CO3 soln. The org. layer was separated, dried (MgSO4), and concentrated in
vacuo. The crude product was purified by FC (AcOEt/hexane 1:10 þ 1% Et3N) to afford 4 (0.32 g, 60%).
1H-NMR: 7.26 – 7.15 (m, 5 H); 3.65 – 3.60 (m, 1 H); 3.51 (s, 3 H); 3.48 (s, 3 H); 2.63 – 2.54 (m, 2 H); 2.43 –
2.37 (m, 1 H); 2.10 (dd, J ¼ 11.9, 8.4, 1 H); 1.42 (dd, J ¼ 11.5, 9.0, 1 H); 1.24 (d, J ¼ 5.7, 3 H). 13C-NMR:
144.9; 129.4; 127.9; 127.7; 126.5; 126.0; 111.3; 77.5; 74.1; 57.9; 52.3; 51.0; 47.7; 46.6; 40.6; 23.8.
4.3. (R)-1-Phenyl-N-{[(1S,2R,4S)-1,4,5,6-tetrachloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl]meth-
yl}ethanammonium Chloride (5). Compound 4 (0.32 g, 0.75 mmol) was dissolved in Et2O (15 ml). HCl
Gas produced from the reaction of NaCl with H2SO4 was passed through the amine soln. Ammonium salt
5 precipitated as white crystals.
5. X-Ray Crystal-Structure Determination of 5. All measurements were performed using graphite-
monochromatized MoKa radiation at 100 K. C18H22Cl5NO2; Mr 461.64; triclinic; space group P1; a ¼
12.6456(6) ꢂ, b ¼ 13.7775(6) ꢂ, c ¼ 14.1907(7) ꢂ, a ¼ 62.2039(15)8, b ¼ 74.7209(17)8, g ¼ 88.2506(16)8,
V¼ 2097.39(17) ꢂ3, Z ¼ 4, Dcalc ¼ 1.462 g cmꢀ3, m ¼ 0.705 mmꢀ1. A total of 31320 reflections were
collected (Vmax ¼ 26.08), of which 14943 were unique (Rint ¼ 0.0239), with 14465 having I > 2s(I). The
structure was solved by direct methods (SHELXS-97) and refined by full-matrix least-squares techniques
against F2 (SHELXL-97) [14][17]. The absolute configuration was established by anomalous dispersion
effects in the diffraction measurements on the crystal. Due to the enantiomeric impurity of the compound

Helvetica Chimica Acta – Vol. 93 (2010)
1891
containing 15.9% of the (S,R,R)-enantiomer besides 84.1% of the (R,S,S)-enantiomer (related to the
asymmetric C-atoms at C(1), C(4), and C(5) in molecule I), the molecule IV is disordered over two
orientations and was refined with site-occupation factors of 0.636(3) for the (S,R,R)-enantiomer and of
0.364(3) for the (R,S,S)-enantiomer. This disorder of the molecule IV has influences on the neighboring
molecules, mainly on the Ph ring of molecule II, and on two Clꢀ ions (Cl(93)/Cl(95) and Cl(94)/Cl(96)).
A rigid bond restraint was applied to this disordered Ph ring and to the molecules IVa/IVb, and the
equivalent bonds in the bicycle of the molecules IVa/IVb were restrained to have the same lengths. The
C-atoms of the disordered Ph rings were fitted to a regular hexagon with CꢀC distances of 1.39 ꢂ. There
was also a slight disorder observable in molecule I (the two largest peaks in the difference Fourier map
are near this molecule), which could not be resolved. The entire molecules show (R)-configuration at the
stereogenic C-atom bonded to the N-atom (C(17) in molecule I).
The other non-H-atoms were refined with anisotropic displacement parameters without any
constraints. The H-atoms were refined with appropriate positional constraints and with common
isotropic displacement parameters Uiso for equivalent H-atoms. The H-atoms of the Me groups were
refined with an idealized geometry with tetrahedral angles, enabling rotation around the XꢀC bond, and
CꢀH distances of 0.98 ꢂ. Some H-atoms showing Uiso smaller than the equivalent isotropic displacement
parameters Ueq of the C-atoms they are bonded to be included at calculated positions with their Uiso are
fixed to 1.2 times Ueq of the C-atom they are bonded to. The CꢀH distances were fixed to 0.99, 1.00, and
0.95 ꢂ for the secondary, tertiary, and Ph H-atoms, resp. The H-atoms of the NHþ2 groups were refined
with common isotropic displacement parameters for the H-atoms of the same group and idealized
geometry with approximately tetrahedral angles and CꢀH distances of 0.92 ꢂ. For 1222 parameters,
final R indices of R1 ¼ 0.0436 and wR2 ¼ 0.1165 (GOF ¼ 1.049) were obtained. The largest peak in the
difference Fourier map was 1.270 e ꢂꢀ3. The structural data for 5 have been deposited with the
Cambridge Crystallographic Data Centre (CCDC-739825).
6. Synthesis of Carbasugar Derivatives (ꢀ)-13 and (ꢀ)-14. 6.1. Synthesis of [(1S,2S,4S)-7,7-
Dimethoxybicyclo[2.2.1]hept-5-en-2-yl]methanol ((ꢀ)-6). Liq. NH3 (150 ml) was distilled into a 250-ml
three-necked round-bottomed flask equipped with a condenser. Small pieces of freshly cut Na were
added to the flask with stirring at ꢀ 338, and a dark blue color appeared. Compound (þ)-2 (6 g,
16.5 mmol) was dissolved in a dry Et2O/EtOH 1:1 (40 ml) and introduced into the mixture. The mixture
was stirred at ꢀ 338 for 30 min. During the reaction, the blue color should persist. If necessary, more Na
pieces can be added. Then, solid NH4Cl was added until the soln. became colorless. The excess NH3 was
allowed to evaporate, and a cold aq. sat. NH4Cl soln. and H2O were added to the resulting residue, which
was subsequently extracted with AcOEt (3 ꢁ 100 ml). Removal of the solvent, followed by purification
of the crude product by FC (AcOEt/hexane 1:3), afforded (ꢀ)-6. (2.4 g, 79%). Colorless oil. [a]D20
¼
1
ꢀ18.7 (c ¼ 1, MeOH). IR (neat): 3403, 2935, 1290, 1114, 1077, 1050, 720. H-NMR: 6.04 (dd, J ¼ 6.0,
3.2, 1 H); 6.18 (dd, J ¼ 6.0, 3.5, 1 H); 3.38 – 3.28 (m, 2 H); 3.22 (s, 3 H); 3.15 (s, 3 H); 2.96 (m, 1 H); 2.79
(m, 1 H); 2.54 – 2.46 (m, 1 H); 2.05 – 1.99 (m, 1 H); 1.44 (br. s, 1 H); 0.55 (dd, J ¼ 11.6, 4.2, 1 H).
13C-NMR: 134.2; 130.6; 119.3; 64.7; 51.8; 49.5; 46.3; 44.6; 38.8; 27.0. HR-MS: 184.1100 (Mþ, C10H16Oþ3 ;
calc. 184.1099).
6.2. Synthesis of (1S,2S,4S)-5-(Hydroxymethyl)bicyclo[2.2.1]hept-2-en-7-one ((ꢀ)-7). To a stirred
soln. of (ꢀ)-6 (2.4 g, 13 mmol) in acetone (50 ml) containing H2O (0.75 ml) was added Amberlyst-15
(0.52 g). The mixture was stirred overnight. The resin was filtered, and the filtrate was evaporated to
afford (ꢀ)-7 (1.78 g, 99%). Colorless oil. [a]2D0 ¼ ꢀ40.0 (c ¼ 1, MeOH). IR (neat): 3396, 2937, 1770, 1030,
1
732, 706. H-NMR: 6.59 (dd, J ¼ 6.6, 3.7, 1 H); 6.44 (dd, J ¼ 6.6, 3.4, 1 H); 3.43 (ddd, J ¼ 14.5, 9.7, 4.6,
1 H); 3.35 (ddd, J ¼ 14.6, 9.6, 4.6, 1 H); 3.08 – 3.06 (m, 1 H); 2.87 (t, J ¼ 3.4, 1 H); 2.56 – 2.48 (m, 1 H);
2.13 (ddd, J ¼ 12.1, 9.7, 4.1, 1 H); 1.43 (br. s, 1 H); 0.75 (dd, J ¼ 12.1, 5.4, 1 H). 13C-NMR: 204.6; 133.6;
130.0; 64.2; 48.5; 46.3; 36.1; 25.3. HR-MS: 138.0679 (Mþ, C8H10O2þ ; calc. 138.0681).
6.3. Synthesis of [(1S,2S,4S)-7-Oxobicyclo[2.2.1]hept-5-en-2-yl]methyl Acetate ((ꢀ)-8). To a stirred
soln. of (ꢀ)-7 (2.4 g, 13.0 mmol) in CH2Cl2 (50 ml) was added dry pyridine (1.47 g, 18.6 mmol) at 08, and
the mixture was stirred for 30 min under Ar. AcCl (1.12 g, 14.1 mmol) was added dropwise. The resultant
mixture was stirred for 3 h at r.t. The mixture was extracted with 0.1m HCl (3 ꢁ 50 ml), sat. NaHCO3 (3 ꢁ
50 ml), and brine (2 ꢁ 50 ml). The collected org. phase was dried (MgSO4), and the solvent was
concentrated in vacuo. The crude product was purified by FC (AcOEt/hexane 1:3) to afford (ꢀ)-8

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Helvetica Chimica Acta – Vol. 93 (2010)
(3.07 g, 98%). Colorless liquid. [a]2D0 ¼ ꢀ53.2 (c ¼ 1, MeOH). 1H-NMR: 6.60 (dd, J ¼ 6.6, 3.4, 1 H); 6.42
(dd, J ¼ 6.6, 3.5, 1 H); 3.87 (dd, J ¼ 10.9, 5.9, 1 H); 3.74 (dd, J ¼ 10.9, 5.9, 1 H); 2.99 – 2.98 (m, 1 H); 2.88 –
2.87 (m, 1 H); 2.63 – 2.59 (m, 1 H); 2.17 – 2.11 (m, 1 H); 2.04 (s, 3 H); 0.78 (dd, J ¼ 12.0, 5.3, 1 H).
13C-NMR: 203.3; 170.7; 134.0; 130.0; 65.3; 48.6; 46.2; 32.7; 25.6; 20.8.
6.4. Baeyer– Villiger Oxidation of [(1S,2S,4S)-7-Oxobicyclo[2.2.1]hept-5-en-2-yl]methyl Acetate (8).
m-CPBA (70%, 3.20 g, 13.0 mmol) was added to a stirred suspension of (ꢀ)-8 (2.34 g, 13 mmol) and
Na2CO3 (1.38 g, 13.0 mmol) in CH2Cl2 (50 ml) at 08. The mixture was stirred for 6 h at r.t., before the
reaction was quenched with 10% aq. soln. of Na2S2O5 (25 ml). The org. layer was separated, and the aq.
phase was extracted with CH2Cl2 (2 ꢁ 50 ml). The combined org. phase was washed with sat. aq. NaHCO3
soln. (50 ml), followed by brine (50 ml), prior to drying (anh. Na2SO4). After filtration, the soln. was
concentrated in vacuo followed by FC (AcOEt/hexane 1:3) to afford the regioisomeric mixture of
lactones 9 and 10 (1.91 g, 75% total yield).
LiAlH4 Reduction of the Mixture 9/10. To a soln. of 9/10 (1.91 g, 9.7 mmol) in dry THF (45 ml),
cooled at ꢀ 158, was added LiAlH4 (114 mg, 29 mmol), and the mixture was stirred for 2 h at the same
temp. The reaction was cautiously quenched with AcOEt (50 ml), followed by sat. Na2SO4 soln. (25 ml),
to precipitate out Al salts. The filtrate was concentrated in vacuo to afford a mixture of trihydroxylated
cyclohexene derivatives, which was directly subjected to an acetylation reaction prior to separation
according to the procedure described for the synthesis of compound (ꢀ)-8. The isomers were separated
by FC (AcOEt/hexane 1:5) to afford (ꢀ)-11 (0.99 g, 36%) and (þ)-12 (1.25 g, 45%).
6.4.1. [(1S,2S,5S)-5-(Acetyloxy)cyclohex-3-ene-1,2-diyl]dimethanediyl Diacetate (ꢀ)-(11). Colorless
oil. [a]2D0 ¼ ꢀ22.0 (c ¼ 1, MeOH). IR (neat): 2952, 1732, 1368, 1229, 1032. 1H-NMR: 5.83 (ddd, J ¼ 10.1,
4.1, 2.1, 1 H); 5.78 (dd, J ¼ 10.1, 2.3, 1 H); 5.17 (q, J ¼ 3.6, 1 H); 4.14 (dd, J ¼ 11.1, 5.5, 1 H); 4.08 (dd, J ¼
11.3, 5.8, 1 H); 4.04 (dd, J ¼ 11.3, 5.8, 1 H); 3.99 (dd, J ¼ 11.1, 6.2, 1 H); 2.29 – 2.23 (m, 1 H); 2.00 (s, 7 H);
1.98 (s, 3 H); 1.82 (dt, J ¼ 14.1, 3.5, 1 H); 1.67 (ddd, J ¼ 14.1, 11.1, 4.5, 1 H). 13C-NMR: 170.5; 170.4; 170.1;
132.5; 126.5; 66.0; 65.8; 65.5; 37.2; 31.5; 30.2; 21.2; 20.7. HR-MS: 307.1150 ([M þ Na]þ, C14H20NaO6þ ; calc.
307.1158).
6.4.2. [(1R,3S,6S)-6-(Acetyloxy)cyclohex-4-ene-1,3-diyl]dimethanediyl Diacetate (þ)-(12). Colorless
1
oil. [a]2D0 ¼ þ11.6 (c ¼ 1, MeOH). IR (neat): 2952, 1731, 1367, 1223, 1018. H-NMR: 5.74 (dd, J ¼ 10.2,
1.6, 1 H); 5.69 (dd, J ¼ 10.2, 2.6, 1 H); 5.09 (dd, J ¼ 5.0, 1.6, 1 H); 4.01 – 3.91 (m, 4 H); 2.44 – 2.43 (m, 1 H),
2.12 – 2.04 (m, 1 H); 2.02 (s, 9 H), 1.66 (t, J ¼ 6.3, 2 H). 13C-NMR: 169.5; 169.4; 169.1; 129.7; 126.6; 67.6;
65.2; 63.3; 33.9; 31.7; 23.8; 20.0; 19.8; 19.7. HR-MS: 307.1150 ([M þ Na]þ, C14H20NaO6þ ; calc. 307.1158).
6.5. Dihydroxylation of (ꢀ)-(11) and (þ)-(12). To the soln. of (ꢀ)-(11) or (þ)-(12) (142 mg,
0.5 mmol) in acetone/H2O 4 :1 (5 ml) was added OsO4 (12 mg, 0.05 mol) and 50% NMO soln. (0.3 ml).
The resulting soln. was stirred overnight until the complete consumption of the starting material. The
reaction was quenched with Na2S2O5 (100 mg, 0.526 mmol), and the mixture was filtered. The filtrate was
concentrated in vacuo and dried (Na2SO4). The crude product was dissolved in pyridine (2 ml). To the
mixture was added Ac2O (0.25 ml, 2.6 mmol), followed by stirring for 30 h at r.t., until the starting
material was consumed. The mixture was concentrated in vacuo and then dissolved in H2O (2 ml). It was
extracted with AcOEt (3 ꢁ 15 ml). The combined org. layer was washed with 5% HCl (3 ml), H2O
(3 ml), and brine (10 ml), and dried (Na2SO4). The filtrate was concentrated in vacuo, and the crude
product was purified by FC (AcOEt/hexane 2 :5).
6.5.1. (1S,2R,3S,4S,5S)-4,5-Bis(acetoxymethyl)cyclohexane-1,2,3-triyl Triacetate (ꢀ)-(13). Yield 70%
1
(0.14 g). Colorless oil. [a]2D0 ¼ ꢀ2.3 (c ¼ 1, MeOH). IR (neat): 2963, 1734, 1367, 1213, 1021. H-NMR:
5.19 (t, J ¼ 3.4, 1 H); 5.04 (dd, J ¼ 10.9, 3.1, 1 H); 4.97 (q, J ¼ 3.2, 1 H); 4.16 – 4.01 (m, 4 H); 2.07 (s, 3 H);
2.05 (s, 3 H); 2.03 – 2.01 (m, 2 H); 2.00 (s, 3 H); 1.99 (s, 3 H); 1.94 (s, 3 H), 1.84 – 1.67 (m, 2 H). 13C-NMR:
171.5; 170.9; 170.7; 170.2; 170.0; 69.8; 69.3; 68.9; 66.3; 60.8; 38.3; 32.4; 29.5; 22.0; 21.8; 21.7. HR-MS:
425.1418 ([M þ Na]þ, C18H26NaO1þ0 ; calc. 425.1424).
6.5.2. (1R,3R,4R,6R)-4,6-Bis(acetoxymethyl)cyclohexane-1,2,3-triyl Triacetate (ꢀ)-(14). Yield 65%
(0.13 g). Colorless oil. [a]2D0 ¼ ꢀ2.2 (c ¼ 1, MeOH). IR (neat): 2959, 1738, 1367, 1223, 1038. H-NMR:
1
5.21 (dd, J ¼ 5.2, 3.1, 1 H); 5.10 (t, J ¼ 8.2, 1 H); 5.01 (dd, J ¼ 8.2, 3.1, 1 H); 4.11 (dd, J ¼ 11.2, 6.8, 1 H);
4.04 (dd, J ¼ 10.0, 6.6, 2 H); 3.97 (dd, J ¼ 11.2, 5.1, 1 H); 2.04 (s, 3 H); 2.03 (s, 3 H); 2.00 (s, 3 H); 1.99 (s,
3 H); 1.97 – 2.04 (m, overlapping with H-atoms of the Ac group, 2 H); 1.95 (s, 3 H); 1.79 – 1.72 (m, 1 H);

Helvetica Chimica Acta – Vol. 93 (2010)
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1.69 – 1.63 (m, 1 H). 13C-NMR: 171.9; 171.1; 171.0; 71.8; 71.3; 71.2; 65.4; 64.9; 38.0; 36.9; 26.4; 22.4; 22.2;
22.1. HR-MS: 425.1418 ([M þ Na]þ, C18H26NaO1þ0 ; calc. 425.1424).
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Received May 31, 2010