Syntheses of enantiomerically pure 2-substituted pyrrolidin-3-ones via lithiated alkoxyallenes - An auxiliary-based synthesis of both enantiomers of the antibiotic anisomycin

Article abstract of DOI:10.1002/hlca.200590143

The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the 'diacetone-fructose'-substituted allene 1 and the N-Boc-protected imine precursor 2a. Addition of an excess of lithiated 1 to 2a provided a 2:1 mixture 3a

Full text of DOI:10.1002/hlca.200590143

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Helvetica Chimica Acta Vol. 88 (2005)
Syntheses of Enantiomerically Pure 2-Substituted Pyrrolidin-3-ones via
Lithiated Alkoxyallenes An Auxiliary-Based Synthesis of both Enantiomers
of the Antibiotic Anisomycin
by Silvia Kaden, Mirjam Brockmann, and Hans-Ulrich Reissig*
Freie Universit‰t Berlin, Institut f¸r Chemie und Biochemie, Takustr. 3, D-14195 Berlin
(phone: ‡ 49-30-838-55366; e-mail: hans.reissig@chemie.fu-berlin.de)
Dedicated to Professor Rolf Huisgen on the occasion of his 85th birthday
The hydrochlorides of both enantiomers of the antibiotic anisomycin were prepared starting with the
−diacetone-fructose×-substituted allene 1 and the N-Boc-protected imine precursor 2a. Addition of an excess of
lithiated 1 to 2a provided a 2 :1 mixture 3a of diastereoisomers, which were cyclized to 4a under base promotion
(Scheme 2). The two diastereoisomers of 4a were separated and converted into enantiomerically pure
pyrrolidin-3-ones (2R)-5a and (2S)-5a. A similar sequence yielded the N-Tos-protected compounds (2R)-5b and
(2S)-5b. Compounds 5a were converted into silyl enol ethers 6 and by subsequent regio-and stereoselective
hydroboration into pyrrolidine derivatives 7 (Scheme 3). Straightforward functional-group transformations led
to the hydrochlorides 9 of anisomycin (Scheme 3). The (2R) series provided the hydrochloride (2R)-9 of the
natural occurring enantiomer, whereas the (2S) series furnished the antipode (2S)-9. The overall sequence to
the natural product involved ten steps with eight purified intermediates and afforded an overall yield of 8%.
Our stereochemically divergent approach to this type of hydroxylated pyrrolidines is highly flexible and should
easily allow preparation of many analogues.
Introduction. A variety of interesting biologically active natural products contain
configurationally defined pyrrolidine substructures among which many bear 3-hydroxy
substituents or related functional groups. As a consequence, their synthesis and that of
analogues has attracted much attention1). Typical examples of these pyrrolidinol
derivatives are (‡)-preussin, (À)-detoxinine, and (À)-anisomycin (Scheme 1), which
display interesting biological activities. We have earlier prepared (À)-preussin and (À)-
detoxinine by constructing their pyrrolidine core A from alkoxyallenes B and N-
protected imines C. Lithiation of B at C(1) and addition of these strong nucleophiles to
imines C followed by ring closure of the primary adducts provided the required
dihydropyrrole derivatives A by an efficient [3 ‡ 2] cyclization mode [2]. Whereas the
stereochemical control of the synthesis of (À)-detoxinine was easily achieved with a
chiral side chain R1 of imine C [3], the preparation of (À)-preussin exploited a chiral
auxiliary R2 at the alkoxyallene building block B. In this synthesis [4], the most-difficult
problem was control of the configuration at C(5) of the pyrrolidine. In this report, we
demonstrate that a suitable auxiliary also allows the synthesis of both enantiomers of
anisomycin.
(À)-Anisomycin a compound with a 4-methoxyphenyl substituent is a secondary
metabolite of streptomyces species (Streptomyces grisoleaus and S. roseochromo-
1
)
For selected recent stereoselective syntheses of highly substituted pyrrolidin-3-ols, see [1].
¹ 2005 Verlag Helvetica Chimica Acta AG, Z¸rich

Helvetica Chimica Acta Vol. 88 (2005)
1827
Scheme 1. Structures of (‡)-Preussin, (À)-Detoxinine, and (À)-Anisomycin and Retrosynthetic Analysis of
Their Potential Precursors A
genes). It was first described in 1954 by Sobin and Tanner [5], and its constitution was
elucidated by Beereboom et al. [6]. Later relative and absolute configurations of this
compound were established by spectroscopy [7] and finally by chemical correlation [8]
with compounds of known absolute configuration. This natural product shows
antibacterial and fungicide activity [9], and more recently it has been found that
(À)-anisomycin displays high in vitro antitumor activity [10]. Quite a number of
enantioselective syntheses of this relatively simple natural product containing only
three stereogenic centers have been reported since 1970; however, despite this
apparent simplicity, all synthesis involve many steps and are usually not very flexible
due to the reliance on chiral starting materials [10b]2). A characteristic structural
feature of anisomycin, which often causes the low efficacy of its preparation, is the
existence of two OH functions in trans arrangement, one being acetylated. Therefore,
more-efficient and potentially flexible approaches to this bioactive compound also
allowing preparation of analogues are of continuing interest.
Results. Preliminary studies motivated us to select −diacetone-fructose× (ˆ1,2:4,5-
di-O-isopropylidenefructose)-substituted allene 1 as chiral C3 building block B for our
anisomycin synthesis. This compound is easily available on a multigram scale from 3-
bromoprop-1-yne and the corresponding protected fructose derivative; the resulting
prop-2-ynyl ether is then smoothly isomerized to the more-stable allene 1 [12]3). The
required imine C has to be derived from 4-methoxybenzeneacetaldehyde, but this kind
2
)
For syntheses of racemic anisomycin, see [11a d]. For syntheses (including formal total syntheses) of
enantiomerically pure anisomycin based on the chiral pool approach, see [11e s]. For syntheses (including
formal total syntheses) of enantiomerically pure anisomycin based on chiral auxiliaries or catalysts, see
[11t x].
For diastereoselective hetero-Diels Alder reactions of these carbohydrate-derived alkoxyallenes, see
[12b].
3
)

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Helvetica Chimica Acta Vol. 88 (2005)
of imine is known to rapidly isomerize giving the corresponding enamine tautomer
[13]. It has, however, successfully been demonstrated that sulfonyl derivatives such as
2a and 2b are suitable precursors for this type of imine. By treatment with base, these
compounds smoothly suffer deprotonation at the protected N-atom followed by
elimination of sulfinate to deliver the corresponding N-protected imines which then can
be trapped by the desired nucleophile [14]. Very often, the base employed is identical
with the nucleophile to be introduced. We followed this promising protocol for the
crucial CÀC connecting step of our synthesis (Scheme 2).
DAF-Allene 1 was deprotonated under standard conditions with BuLi, and 3 (series
a) or 2 (series b) equiv. of the resulting lithiated allene were combined with 1 equiv. of
2a and 2b, respectively (Scheme 2). The in situ generated N-protected imines were
immediately trapped by the excess of lithiated 1 and afforded the expected primary
addition products 3a and 3b in moderate to good yields. Since the excess of 1, generated
by reprotonation with 2 or during aqueous workup, could easily be recovered by
column chromatography and re-used, the protocol is fairly efficient with respect to the
chiral allene derivative 1.
The diastereoselectivities of the additions of lithiated 1 to the N-protected imines
were surprisingly low4), and ca. 2 :1 mixtures of diastereoisomers of allenylamines 3
were isolated, which were not separated at this stage. Additions of lithiated
alkoxyallenes with carbohydrate-derived auxiliaries to aldehydes were considerably
more stereoselective [4][15]. A few other auxiliaries examined at the alkoxyallene
moiety did not dramatically improve the asymmetric induction5). Since we planned to
prepare both enantiomers of anisomycin, we proceeded with these 2 :1 mixtures of 3
and did not continue to optimize the diastereoselectivity of the addition reaction.
It was found that N-Boc-protected allenylamine 3a cyclized to 4a most reproducibly
t
under strongly basic conditions. Employment of BuOK in DMSO [2][16] provided a
mixture of the two diastereoisomers of 4a in 65% yield. No change of the ratio of
diastereoisomers was observed during the cyclization. The isomers were easily
separated by prep. HPLC to furnish the pure diastereoisomers (2R)-4a and (2S)-4a
in 38 and 14% overall yield (based on 3a), respectively. The assignments of
configuration at C(2) of these compounds are based on the successful conversion of
the major isomer (2R)-4a into (À)-anisomycin hydrochloride (see below). In the case
of N-Tos-protected allenylamine 3b, AgNO3-promoted cyclization (in MeCN/K2CO3)
afforded good results [17]. The desired dihydropyrrole derivative 4b was obtained in
68% yield. Subsequent HPLC separation supplied us with two pure diastereoisomers
(2R)-4b and (2S)-4b in 46 and 14% overall yield (based on 3b), respectively6).
Compound 3a could also be cyclized to 4a with this AgNO3 protocol; however, the
4
)
)
)
Additions of lithiated DAF-allene 1 to other N-Tos-protected imines proceeded with diastereoselectivities
in the range of 4:1 up to 9:1; see [4].
Similar reactions of a lithiated alkoxyallene derived from d-mannose also gave diastereoselectivities of ca.
2:1; S. Kaden, unpublished results.
The assignments for the N-Tos-protected compounds is essentially based on analogy: it is unlikely that the
switch of the N-protective group from Boc to Tos will change the preferred attack of lithiated 1 to the
corresponding imines. This is supported by the fact that the optical rotations of the N-Tos-protected
compounds (2R)-5b and (2S)-5b have the same sign as those of the corresponding Boc-protected
pyrrolidinones (2R)-5a and (2S)-5a.
5
6

Helvetica Chimica Acta Vol. 88 (2005)
1829
Scheme 2
a) PG ˆ Boc: 1 (3 equiv.), BuLi (3 equiv.), THF, À 788, 20 min; then 2a (1 equiv.), À 50 to À 208, 4 h; 73%.
b) PG ˆ Tos : 1 (2 equiv.), BuLi (2 equiv.), THF, À 508, 20 min; then 2b (1 equiv.), À 50 to À 208, 4 h; 41%.
c) PG ˆ Boc: KOtBu, DMSO, 508, 8 h; 65%. d) PG ˆ Boc: prep. HPLC; major diastereoisomer 38%, minor
diastereoisomer 14%. e) PG ˆ Tos: AgNO3, K2CO3, MeCN, 16 h, r.t., light exclusion; 68%. f) PG ˆ Tos: prep.
HPLC; major isomer 46%, minor isomer 18%. g) PG ˆ Boc or Tos: 6n HCl, THF, 2 3 h, r.t.
base-catalyzed reaction was more reliable on a larger scale. N-Tos-protected
dihydropyrroles such as 4b can undergo elimination of sulfinate and provide pyrroles
[2], which deterred us from applying the base-promoted method to 3b. By treatment
with aqueous hydrochloric acid, all four dihydropyrroles 4a,b were smoothly converted
into the required enantiomerically pure 2-substituted N-protected pyrrolidinones (2R)-
5a, (2S)-5a, (2R)-5b, and (2S)-5b in good yields.

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Helvetica Chimica Acta Vol. 88 (2005)
After preliminary experiments with 5b [18], we decided to continue the synthesis of
anisomycin employing the N-Boc-protected pyrrolidine derivatives 5a which seem to
allow more-efficient conversions. Both enantiomers of 5a were transformed into the
(tert-butyl)dimethylsilyl-substituted enol ethers 6. Although we tried to optimize this
apparent standard reaction, we could not obtain more than 68% yield (Scheme 3).
Gratifyingly, the subsequent hydroborations of 6, which were supposed to generate the
two missing stereogenic centers of the target compound, not only proceeded with
excellent diastereofacial selectivity but also with high efficacy. Employment of borane
in THF followed by oxidative workup with H2O2 and NaOH afforded the desired
monoprotected diol derivatives (2R)-7 and (2S)-7 as single isomers in 89 and 81%
yield, respectively. The substituent at C(2) very efficiently shields one face of the enol
ether CˆC bond of 6 leading to the observed high diastereoselectivity of borane
addition. It should also be noted that the hydroboration is highly regioselective [19].
Scheme 3a)
a) LDA, THF, 45 min, À 788. b) tBuMe2SiCl, DMPU (ˆ 3,4,5,6-tetrahydro-1,3-dimethylpyrimidin-2(1H)-one),
30 min, À 788 to r.t. c) BH3 ¥ THF, THF, À 308 to r.t., 3 h; then NaOH, H2O2, À 108 to r.t., 12 h. d) Boc2O,
pyridine, 4-(N,N-dimethylamino)pyridine (DMAP), 12 h, r.t. e) Bu4NF, THF, 12 h, r.t.; then Ac2O, CH2Cl2, Et3N,
08 to r.t., 12 h. f) HCl/dioxane, 08, 3.5 h.
a) The yields of the enantiomers leading to (‡)-anisomycin hydrochloride (2S)-series are presented in
brackets.

Helvetica Chimica Acta Vol. 88 (2005)
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Conversions of compounds 7 into 8 were essentially one-pot procedures. The free OH
group of 7 was Boc-protected, and the resulting intermediate was desilylated with
Bu4NF and finally O-acetylated employing Ac2O. Again these transformations to (2R)-
8 or (2S)-8 occurred with good overall efficacies. The end game of our anisomycin
synthesis was performed according to J‰ger and Schwardt [10b] and also proceeded
without problems. Concomitant O-and N-deprotection employing HCl in dioxane and
recrystallization furnished the two enantiomeric hydrochlorides of anisomycin (2R)-9
and (2S)-9, in 66 and 61%, respectively. Having these compounds in hand, we could
finally confirm the assumed configurations at C(2) of all our intermediates in Schemes 2
and 3. The positive optical rotation of (2R)-9 established that this isomer was the
hydrochloride of the naturally occurring enantiomer [10b][20]. The major diaster-
eoisomer of 3a and all subsequent derivatives finally leading to (À)-anisomycin
hydrochloride have the drawn (2R)-configuration. The enantiomeric purity of our
sample appears to be high (ee > 95%) since we obtained fairly similar values of the
optical rotation as those reported in the literature. We have earlier established that
pyrrolidin-3-ones such as 5 are configurationally fairly stable [4] and, therefore, a
(partial) racemization at this stage is rather unlikely.
The high conformational flexibility of lithiated DAF-allene 1 and the possibility of
the lithium cation to coordinate to a manifold of O-atoms of the auxiliary make
interpretations of its addition reactions highly speculative. However, a transition
structure as depicted in Scheme 4 may operate to explain the (moderately) preferred
formation of the observed major diastereoisomer of 3a. In our model, the bulky DAF
group shields the back side of lithiated 1, and the N-protected imine approaches the
nucleophilic allene C(1) center with the sterically less-demanding CÀH moiety
pointing into this direction. This attack to the Si face of the N-protected imine provides
(R)-configuration at the newly generated stereogenic center as observed. It should be
mentioned again that the modest diastereoselectivity recorded is evidence that
alternative transition structures either adding to the Re-or to the Si-face of the N-
protected imine may be involved.
Scheme 4. Possible Transition Structure for the Addition of Lithiated 1 to the N-Boc-Protected Imine
Conclusions. Based on easily available −diacetone-fructose×-derived allene 1, (À)-
anisomycin hydrochloride (2R)-9 was synthesized in ten steps (involving eight purified

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Helvetica Chimica Acta Vol. 88 (2005)
intermediates) in ca. 8% overall yield. Although this seems not to be particularly
efficient, this compares well to the best-known syntheses of this natural product [11].
The drawbacks of our approach are the moderate diastereoselectivity of the crucial
addition of lithiated 1 to the corresponding in situ generated N-protected imine
delivering compounds 3a and 3b only as ca. 2 :1 mixtures of isomers. However, this fact
allowed us to synthesize both enantiomers starting with one single compound. The
separation of diastereoisomers 4a was achieved by prep. HPLC but could also be
performed by standard column chromatography. A second step with disappointingly
low efficacy concerns formation of silyl enol ethers 6. Although we tried to improve this
process, not all conceivable alternative methods have been examined.
An important advantage of our synthetic approach to pyrrolidine derivatives via
lithiated allenes and N-protected imines is certainly its high flexibility. Instead of imine
precursors 2, analogues thereof or stable N-protected imines C could be introduced to
the synthesis. They will lead to other substituents at the N-atom or at C(2) of the
pyrrolidinol target. The allene building block B, providing three C-atoms of the
pyrrolidine core, may be substituted at C(3) (Scheme 1) and as consequence furnish
C(5)-substituted pyrrolidine derivatives as demonstrated in our synthesis of (À)-
preussin. Furthermore, the enol ether functionality as present in intermediates 4 or 6
may be exploited by introducing other functional groups at C(4). All these options
should smoothly allow the preparation of analogues of anisomycin, which may be of
importance for screening the biological activity of this type of compounds. In a more
general view, pyrrolidin-3-one derivatives such as (2R)-5a, (2S)-5a, (2R)-5b, and (2S)-
5b should be valuable intermediates for the preparation of a variety of enantiomerically
pure natural products or pharmaceuticals. Here, as well as in other applications,
lithiated alkoxyallenes served as versatile and useful C3 building block for the
stereoselective construction of the required heterocyclic core7).
The authors thank the Deutsche Forschungsgemeinschaft, the Fonds der Chemischen Industrie, and Schering
AG for generous financial support of this research. We are grateful to W. M¸nch for HPLC separations and to
Dr. R. Zimmer for his assistance during preparation of this manuscript.
Experimental Part
General. Starting materials 4-methoxybenzeneacetaldehyde [22], 1,2 :4,5-di-O-isopropylidene-3-O-(prop-
2-ynyl)-b-d-fructopyranose [12a], and 1,2 :4,5-di-O-isopropylidene-3-O-(propa-1,2-diene)-b-d-fructopyranose
[12a] were prepared by known procedures. All other chemicals were commercially available and used as
received. Unless otherwise stated, all reactions were performed under Ar in flame-dried flasks by adding the
components via syringes. All solvents were dried by using standard procedures. Column chromatography (CC):
neutral aluminium oxide (act. III, Fluka or Merck) or silica gel (0.040 0.063 mm, Fluka). HPLC: Nucleosil 50-5
(Macherey & Nagel). M.p.: Reichert Thermopan; uncorrected. Optical rotations: Perkin-Elmer 241 polarimeter.
IR Spectra: Perkin-Elmer FT-IR spectrometer Nicolet 5 SXC with DTGS detector. 1H-and 13C-NMR Spectra:
Bruker instruments (WH 270, AC 250, AC 500) and Joel Eclipse 500; d(H) in ppm rel. to SiMe4 (ˆ0.00 ppm) or
to CHCl3 (ˆ 7.26 ppm), and d(C) rel. to CDCl3 (ˆ 77.0 ppm), higher-order spectra are approximately
interpreted as first-order spectra if possible.
tert-Butyl {2-(4-Methoxyphenyl)-1-[(4-methylphenyl)sulfonyl]ethyl}carbamate (2a). A well-stirred soln. of
tert-butyl carbamate (1.13 g, 9.60 mmol) in H2O (10.5 ml), formic acid (2.94 ml), and MeOH (2.22 ml) was
treated with the sodium salt of 4-methylbenzenesulfinic acid (1.71 g, 9.60 mmol). Freshly distilled 4-
methoxybenzeneacetaldehyde (1.59 g, 10.6 mmol) was added dropwise, and the soln. was stirred at 708 for
7
)
For reviews, see [21a d]. For recently published results, see [21e j].

Helvetica Chimica Acta Vol. 88 (2005)
1833
10 min. After cooling to r.t., the suspension was filtered, and the residue was washed with H2O, 1n HCl, and
pentane. Evaporation of the solvents gave product 2a (3.00 g, 77%). Colorless solid. M.p. 152 1538. IR (KBr):
1
3380 (NÀH), 3010 (ˆCÀH), 2980 2835 (CÀH), 1710 (CˆO), 1305, 1150 (SO2). H-NMR (CDCl3; several
doubled signals due to the occurrence of rotamers, the minor one being marked with *): 0.97* (s, 1.8 H, tBu); 1.13
t
(s, 7.2 H, Bu); 2.41, 2.43* (2s, 3 H, MeC6H4); 2.78 2.88* (m, 0.2 H, HÀC(2)); 2.97 (dd, J ˆ 15.1, 9.9, 0.8 H,
HÀC(2)); 3.51 3.63 (m, HÀC(2)); 3.77 (s, MeO); 4.77 4.85* (m, 0.4 H, 1 H, NH); 4.97 5.12 (m, 1.6 H, 1 H,
NH); 6.83, 7.13 (2d, J ˆ 8.8, 2 arom. H each); 7.32, 7.80 (2d, J ˆ 8.1, 2 arom. H each). 13C-NMR (CDCl3): 21.4 (q,
MeC6H4); 27.3*, 27.7 (2q, tBu); 31.6, 31.9* (2t, C(2)); 55.1 (q, MeO); 71.4, 73.5* (2d, C(1)); 80.3, 80.8* (2s, tBu);
113.9, 129.2*, 129.4, 129.5, 130.1 (5d, arom. C); 126.7, 133.7, 144.8, 153.6, 158.5 (5s, arom. C, CˆO). EI-MS
‡
‡
‡
‡
(80 eV): 406 (1, [M ‡ H] ), 250 (21, [M À Tos] ), 194 (60, [M À Tos À C4H8] ), 150 (100, [M À Tos À Boc] ),
‡
‡
121 (8, Tos ), 57 (84, tBu ). Anal. calc. for C21H27NO5S (405.5): C 62.20, H 6.71, N 3.45; found: C 62.20, H 6.50,
N 3.28.
N-{2-(4-Methoxyphenyl)-1-[(4-methylphenyl)sulfonyl]ethyl}-4-methylbenzenesulfonamide (2b). A well-
stirred soln. of 4-methylbenzenesulfonamide (2.02 g, 11.8 mmol) in H2O (18 ml) and formic acid (18 ml) was
treated with sodium 4-methylbenzenesulfinite (2.10 g, 11.8 mmol). Freshly distilled 4-methoxybenzeneacetal-
dehyde (1.78 g, 11.8 mmol) was added dropwise, and the soln. was stirred overnight at r.t. The suspension was
filtered, and the residue was washed with H2O and pentane and then dissolved in AcOEt (150 ml). The org.
phase was extracted with 1n HCl, dried (Na2SO4), and evaporated at 208. Drying at 1 mbar gave 2b (3.03 g,
56%). Colorless solid. M.p. 118 1198. IR (KBr): 3255 (NÀH), 3030 (ˆCÀH), 2955 2835 (CÀH), 1335, 1160
1
(SO2). H-NMR (CDCl3): 2.31, 2.45 (2s, 3 H each, MeC6H4); 2.95 (dd, J ˆ 14.0, 10.5, HÀC(2)); 3.52 (dd, J ˆ
14.0, 3.7, HÀC(2)); 3.70 (s, MeO); 4.80 (td, J ˆ 10.5, 3.7, HÀC(1)); 6.01 (d, J ˆ 10.5, NH); 6.49, 7.15 (2d, J ˆ 8.8,
2 H each, Ar); 6.91 (m, 4 H, Tos, Ar), 7.38, 7.89 (2d, J ˆ 8.1, 2 H each, Tos). 13C-NMR (CDCl3): 21.2, 21.7 (2q,
MeC6H4); 32.5 (t, C(2)), 54.9 (q, MeO); 75.6 (d, C(1)); 113.9 (d, Ar); 126.1, 129.2, 129.7, 130.0, 130.5 (5d, Tos,
‡
Ar); 125.9, 132.5, 137.6, 142.7, 145.4 (5s, Tos, Ar); 158.6 (s, Ar). FAB-MS (pos.): 304 (100, [M À Tos] ), 155 (37,
‡
‡
‡
‡
Tos ), 149 (33), 148 (44, [M À 2 Tos À H] ), 139 (21), 121 (31, MeOBn ), 91 (61, PhCH2 ), 77 (16). Anal. calc.
for C23H25NO5S2 (459.6): C 60.11, H 5.48, N 3.05; found: C 60.47, H 5.15, N 2.75.
3-O-{2-{[(tert-Butoxy)carbonyl]amino}-1-ethenylidene-3-(4-methoxyphenyl)propyl}-1,2 :4,5-di-O-isoprop-
ylidene-b-d-fructopyranose (3a). To a soln. of 1 (3.37 g, 11.3 mmol) in dry THF (70 ml), 2.4m BuLi in hexanes
(4.70 ml, 10.9 mmol) was slowly added at À 788 under Ar. After stirring for 15 min, a soln. of 2a (1.52 g,
3.76 mmol) in dry THF (10 ml) was added over 5 min. The mixture was stirred for 4 h and allowed to warm from
À 78 to À 208. After addition of sat. NaHCO3 soln. (70 ml), the aq. layer was extracted with AcOEt, the
combined extract dried (MgSO4) and evaporated, and the crude product purified by CC (aluminium oxide,
hexane/AcOEt 4 :1): starting material 1 (2.61 g; yellow oil) and 3a (1.50 g, 73%; colorless solid) as a mixture of
two diastereoisomers (d.r. 2 :1, by 13C-NMR). The separation of the diastereoisomers was achieved after
cyclization to 4a. 3a: IR (KBr): 3365 (NÀH); 2985, 2935 (CÀH); 1955 (CˆCˆC); 1690 (CˆO). 1H-NMR
(CDCl3): 1.38 1.53 (m, 21 H, 4 Me, tBu); 2.94 2.98 (m, 2 HÀC(3)); 3.79 (s, MeO); 3.88 4.17 (m, 2 HÀC(6'),
HÀC(3'), 2 HÀC(1'), HÀC(2)); 4.24 (dd, J ˆ 5.2, 2.2, HÀC(5')); 4.36 4.44 (m, 1.4 H, NH, HÀC(4')); 4.81 (d,
J ˆ 8.8, 0.6 H, NH); 5.10 5.15, 5.32 5.35 (2m, CH2ˆCˆC(1)); 6.79, 7.18 (2d, J ˆ 8.8, 2 arom. H each).
13C-NMR (CDCl3; the signals of the minor diastereoisomer marked with *): 26.0, 26.3, 26.6*, 26.9, 28.0 (5q, Me);
t
28.3 (q, Bu); 37.3, 38.6* (2t, C(3)); 52.8 (d, C(2)); 55.2 (q, MeO); 60.2, 60.4* (t, C(6')); 71.4, 71.6* (t, C(1'));
t
73.9*, 74.0, 75.5*, 75.9, 76.1* (5d, C(3'), C(4'), C(5')); 79.2 (s, Bu); 92.5*, 93.5 (2t, CH2ˆCˆC(1)); 104.1 (s,
C(2')); 109.1, 112.0 (2s, Me2C); 129.9, 130.8 (2s, arom. C, C(3)); 113.4, 130.9 (2d, arom. C); 154.9, 158.2 (2s,
‡
‡
CˆO, arom. C); 197.3 (s, CH2ˆCˆC(1)). EI-MS (80 eV): 547 (1, M ), 491 (4, [M À C4H8] ), 430 (4, [M À
OtBu] ), 370 (11, [M À MeOBn À C4H8] ), 326 (9, [M À MeOBn À Boc] ), 268 (16), 243 (14), 185 (15), 121
‡
‡
‡
‡
t
‡
‡
‡
(100, MeOBn ), 57 (83, Bu ), 43 (32, C2H3O ). HR-MS: 547.2747 (M , C29H41NO9; calc. 547.2781).
3-O-{1-Ethenylidene-3-(4-methoxyphenyl)-2-{[(4-methylphenyl)sulfonyl]amino}propyl}-1,2 :4,5-di-O-iso-
propylidene-b-d-fructopyranose (3b). As described for 3a, with 1 (1.39 g, 4.66 mmol) THF (40 ml), 2.39m BuLi
in hexanes (1.87 ml, 4.40 mmol), 2b (1.01 g, 2.20 mmol), and THF (5 ml), all at À 508 instead of À 788, then
warming up to À 208. Workup with sat. NaHCO3 soln. (60 ml) and AcOEt (3 Â 30 ml) followed by CC
(aluminium oxide, hexane/AcOEt 2 :1) yielded 1 (0.855 g, 61%; yellow oil) and 3b (0.546 g, 41%; yellow oil) as a
mixture of two diastereoisomers (d.r. 72 :28, by 1H-NMR). The separation of the diastereoisomers was achieved
after cyclization to 4b. 3b: 1H-NMR (CDCl3; the minor diastereoisomer is marked with *): 1.37, 1.42, 1.47, 1.51
(4s, 3 H each, Me); 2.40 (s, MeC6H4); 3.01 (dd, J ˆ 8.8, 5.9, 2 HÀC(3)); 3.47 4.36 (m, 2 HÀC(1'), HÀC(3'),
HÀC(4'), HÀC(5'), 2 HÀC(6'), HÀC(2)); 3.79 (s, MeO); 4.59, 5.33* (2d, J ˆ 8.8, 0.28 H and 0.72 H, NH);
5.01 5.11 (m, CH2ˆCˆC(1)); 6.75 (d, J ˆ 8.6, 2 arom. H); 7.12 7.29 (m, 4 arom. H); 7.65, 7.66* (2d, J ˆ 8.6,
2 arom. H).

1834
Helvetica Chimica Acta Vol. 88 (2005)
3-O-{[1-(tert-Butoxy)carbonyl]-2,5-dihydro-2-(4-methoxybenzyl)-1H-pyrrol-3-yl}-1,2:4,5-di-O-isopropyli-
dene-b-d-fructopyranose (4a). To a soln. of 3a (1.00 g, 1.82 mmol) in dry DMSO (30 ml), freshly sublimated
KOtBu (57 mg, 0.48 mmol) was added. The dark brown mixture was stirred for 16 h at 508. The soln. was
quenched with sat. NaHCO3 soln. (30 ml), the aq. layer extracted with AcOEt (3 Â 15 ml), the combined org.
layer washed with sat. NaCl soln., dried (Na2SO4), and evaporated, and the crude product purified by CC
(aluminium oxide, hexane/AcOEt 5 :1): 4a (0.65 g, 65%) as light yellow oil. Separation of the two
diastereoisomers by HPLC (hexane/AcOEt 4 :1) gave major isomer (2R)-4a (0.37 g, 37%) as colorless foam
and minor isomer (2S)-4a (0.14 g, 14%) as colorless resin.
20
D
Data of (2R)-4a: ‰aŠ ˆ À163.7 (c ˆ 0.61, CHCl3). IR (KBr): 3100 2835 (ˆCÀH, CÀH), 1700 (CˆO),
1660 (CˆC). 1H-NMR (CDCl3; several doubled signals due to the occurrence of rotamers): 1.37, 1.40, 1.42, 1.43,
1.49, 1.51, 1.57 (7s, 21 H, tBu, Me2C); 2.91 (br. d, J ˆ 13.2, 1 H, ArCH2); 3.03 3.24 (m, 1.5 H, HÀC(5), ArCH2);
3.37 (dd, J ˆ 13.2, 5.2, 0.5 H, ArCH2); 3.77, 3.79 (2s, each 1.5 H, MeO); 3.84 (br. d, J ˆ 13.5, 0.5 H, HÀC(5));
3.90 4.21 (m, 5.5 H, HÀC(4), HÀC(5), HÀC(1'), HÀC(3'), HÀC(6')); 4.30 (dd, J ˆ 5.5, 2.6, 1 H, HÀC(5'));
4.39 4.48 (m, 2.5 H, HÀC(2), HÀC(4'), HÀC(6')); 4.57 4.61 (m, 0.5 H, HÀC(2)); 6.73, 6.74, 7.15, 7.19 (4d,
J ˆ 8.8, 2 arom. H each). 13C-NMR (CDCl3): 25.7, 25.9, 26.2, 26.7, 26.9, 28.2, 28.5, 28.6 (8q, Me, tBu); 34.1, 35.6
(2t, ArCH2); 50.0, 50.4 (2t, C(5)); 55.1 (q, MeO); 62.3, 62.5 (2d, C(2)); 60.2, 60.4, 71.4, 71.7 (4t, C(1'), C(6'));
73.8, 75.8, 77.5 (3d, C(3'), C(4'), C(5')); 79.1, 79.7 (2s, tBu); 91.3, 91.8 (2d, C(4)); 104.0, 109.0, 112.3 (3s, C(2'),
Me2C); 112.8, 113.0, 131.3, 131.5 (4d, arom. C); 128.7, 153.6, 154.1, 154.4, 158.0 (5s, arom. C, C(3), CˆO). EI-MS
‡
‡
‡
‡
(80 eV): 547 (32, M ), 532 (6, [M À Me] ), 426 (31, [M À MeOBn] ), 370 (1, [M À MeOBn À C4H8] ), 243
‡
‡
‡
‡
(20), 185 (12, [M À MeOBn À DAF] ), 121 (38, MeOBn ), 57 (100, C4H9 ). HR-MS: 547.2763 (M ,
‡
C29H41NO9 ; calc. 547.2781). Anal. calc. for C29H41NO9 (547.6): C 63.60, H 7.55, N 2.56; found: C 63.23, H
7.20, N 2.26.
20
Data of (2S)-4a: ‰aŠ ˆ ‡4.3 (c ˆ 0.48, CHCl3). IR (neat): 2985 2935 (ˆCÀH, CÀH), 1700 (CˆO), 1660
D
(CˆC). 1H-NMR (CDCl3; several doubled signals due to the occurrence of rotamers): 1.36, 1.43, 1.49, 1.51, 1.54
t
(5s, 21 H, Bu, Me2C); 2.77 2.85, 3.20 3.28 (2m, 1 H each, ArCH2); 3.38 (dd, J ˆ 13.0, 4.8, 0.5 H, HÀC(5));
3.43 (dd, J ˆ 13.0, 5.2, 0.5 H, HÀC(5)); 3.76 (s, MeO); 3.86 4.26 (m, 7 H, HÀC(1') HÀC(3'), HÀC(6'),
HÀC(4), HÀC(5)); 4.34 (d, J ˆ 7.4, 0.5 H, HÀC(5')); 4.36 (d, J ˆ 5.2, 0.5 H, HÀC(5')); 4.50 (m, 1 H, HÀC(4'));
4.62 4.68 (m, 1 H, HÀC(2)); 6.76 (d, J ˆ 8.5, 2 arom. H); 7.10 (d, J ˆ 8.5, 2 arom. H). 13C-NMR (CDCl3): 25.9,
t
26.2, 26.6, 27.9, 28.2, 28.4 (6q, Me, Bu); 34.0, 35.7, 50.0, 50.4 (4t, C(5), ArCH2); 55.0 (q, MeO); 62.3, 62.7 (2d,
C(2)); 60.2, 60.6, 72.5, 72.6 (4t, C(1'), C(6')); 73.6, 76.3, 77.5 (3d, C(3'), C(4'), C(5')); 78.9, 79.5 (2s, tBu); 92.3,
92.5 (2d, C(4)); 104.0, 109.2, 112.3 (3s, C(2'), Me2C); 113.0, 113.2, 130.8, 131.0 (4d, arom. C); 128.9, 153.8, 154.1,
‡
‡
154.3, 158.0, 158.1 (6s, arom. C, C(3), CˆO). EI-MS (80 eV): 547 (16, M ), 426 (21, [M À MeOBn] ), 370 (53,
‡
‡
‡
[M À MeOBn À C4H8] ), 243 (18), 185 (12, [M À MeOBn À DAF] ), 121 (41, MeOBn ), 117 (12), 84 (25), 69
‡
‡
‡
(13), 59 (11), 57 (100, C4H9 ), 43 (28). HR-MS: 547.2753 (M , C29H41NO9 ; calc. 547.2781).
3-O-{2,5-Dihydro-2-(4-methoxybenzyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrrol-3-yl}-1,2 :4,5-di-O-isoprop-
ylidene-b-d-fructopyranose (4b). To a soln. of 3b (0.542 g, 0.90 mmol) in dry MeCN, K2CO3 (249 mg, 1.80 mmol)
and AgNO3 (31 mg, 0.180 mmol) were added. The soln. was stirred for 16 h at r.t. in the dark. The soln. was
filtered over Celite, the filtrate evaporated, and the crude product purified by CC (aluminium oxide, hexane/
AcOEt 2 :1): 4b (370 mg, 68%) as yellow oil. Separation of the two diastereoisomers by HPLC (hexane/iPrOH
97:3) gave major isomer (2R)-4b (252 mg, 46%) as colorless foam and minor isomer (2S)-4b (96 mg, 18%) as
light yellow crystals.
20
Data of (2R)-4b: M.p. 158 1608. ‰aŠ ˆ À109.8 (c ˆ 1.0, CHCl3). IR (KBr): 3090 3035 (ˆCÀH), 2990
D
2835 (CÀH), 1670 (CˆC), 1345, 1165 (RSO2N). 1H-NMR (CDCl3): 1.25, 1.39, 1.47, 1.48 (4s, 12 H, Me2C); 2.41
(s, MeC6H4); 3.01, 3.14 (AB of ABX, JAB ˆ 13.8, JAX ˆ 2.4, JBX ˆ 5.0, ArCH2); 3.27 (ddd, J ˆ 13.6, 4.6, 1.4,
1 HÀC(5)); 3.21, 3.61 (2d, J ˆ 8.9, 2 HÀC(1')); 3.79 (s, MeO); 3.76 3.83 (m, 1 HÀC(5), HÀC(3')); 3.99 (br. d,
J ˆ 13.4, 1 HÀC(6')); 4.10 (dd, J ˆ 13.4, 2.6, 1 HÀC(6')); 4.22 4.26 (m, HÀC(4), HÀC(5')); 4.33 (dd, J ˆ 7.4,
5.9, 1 H, HÀC(4')); 4.39 (m, HÀC(2)); 6.76 (d, J ˆ 8.8, 2 arom. H); 7.26 7.31 (m, 4 arom. H); 7.68 (d, J ˆ 8.1,
2 arom. H). 13C-NMR (CDCl3): 21.4 (q, MeC6H4); 25.7, 26.1, 26.8, 28.2 (4q, Me2C); 38.1 (t, ArCH2); 52.4 (t,
C(5)); 55.1 (q, MeO), 60.2 (t, C(6')); 65.1 (d, C(2)); 73.7 (t, C(1')); 71.0, 75.4, 76.5 (3d, C(3'), C(4'), C(5')); 91.7
(d, C(4)); 103.7 (s, C(2')); 109.0, 112.1 (2s, Me2C); 112.9, 127.1, 129.7, 132.0 (4d, arom. C); 127.8, 134.4, 143.6,
‡
‡
154.3, 158.2 (5s, arom. C, C(3)). EI-MS (80 eV): 601 (22, M ), 480 (97, [M À MeOBn] ), 274 (34), 243 (34), 185
‡
‡
‡
(44), 155 (56, Tos ), 131 (45), 127 (17), 121 (100, MeOBn ), 91 (65, PhCH2 ), 69 (41), 59 (30), 43 (32). Anal.
calc. for C31H39NO9S (601.7): C 61.88, H 6.53, N 2.33; found: C 61.84, H 6.37, N 2.14.
20
D
Data of (2S)-4b: M.p. 2008 (dec.). ‰aŠ ˆ À47.8 (c ˆ 1.0, CHCl3). IR (KBr): 3105 3000 (ˆCÀH), 2990
2875 (CÀH), 1665 (CˆC), 1345, 1160 (RSO2N). 1H-NMR (CDCl3): 1.17, 1.27, 1.51 (3s (2 :1:1), 12 H, Me2C);
2.42 (s, MeC6H4); 2.97 (dd, J ˆ 13.9, 1.1, 1 H, ArCH2); 3.25 (dd, J ˆ 13.9, 4.4, 1 H, ArCH2), 3.48 (ddd, J ˆ 13.2,

Helvetica Chimica Acta Vol. 88 (2005)
1835
5.2, 1.5, 1 HÀC(5)); 3.77 (s, MeO); 3.81 (m, HÀC(3'), 1 HÀC(5)); 3.93 (m, 2 HÀC(1')); 4.09 (m, 2 HÀC(6'),
HÀC(4), HÀC(5')); 4.32 (br. s, HÀC(4')); 4.55 4.56 (m, HÀC(2)); 6.79 (d, J ˆ 8.1, 2 arom. H); 7.27 7.31 (m,
4 arom. H); 7.71 (d, J ˆ 8.1, 2 arom. H). 13C-NMR (CDCl3): 21.4 (q, MeC6H4); 26.0, 26.2, 26.6, 27.5 (4q, Me2C);
37.7, 52.2 (2t, C(5), ArCH2); 55.1 (q, MeO); 60.5 (t, C(6')); 65.1 (d, C(2)); 73.6 (t, C(1')); 72.3, 75.8, 78.7 (3d,
C(3'), C(4'), C(5')); 93.4 (d, C(4)); 103.9 (s, C(2')); 108.9, 112.2 (2s, Me2C); 112.9, 127.3, 129.6, 131.5 (4d, arom.
‡
C); 128.2, 134.7, 143.1, 154.5, 158.2 (5s, arom. C, C(3)). EI-MS (80 eV): 601 (26, M ), 480 (100, [M À
‡
‡
‡
MeOBn] ), 274 (23), 243 (27), 185 (34), 155 (40, Tos ), 131 (32), 127 (14), 121 (76, MeOBn ), 91 (48,
PhCH2), 69 (34), 59 (27), 43 (43). Anal. calc. for C31H39NO9S (601.7): C 61.88, H 6.53, N 2.33; found: C 61.72, H
6.44, N 2.20.
tert-Butyl (2R)-2-(4-Methoxybenzyl)-3-oxopyrrolidine-1-carboxylate ((2R)-5a). To a soln. of (2R)-4a
(0.350 g, 0.639 mmol) in THF (13 ml), 6n aq. HCl (4.7 ml) was added. The mixture was stirred (TLC control)
for 2 h at r.t. The soln. was diluted with Et2O and neutralized with sat. NaHCO3 soln. (15 ml). The aq. layer was
extracted with Et2O (3 Â 10 ml), the combined extract dried (Na2SO4) and evaporated and the crude product
20
D
purified by CC (silica gel, hexane/AcOEt 4 :1): (2R)-5a (0.175 g, 89%). Yellow oil. ‰aŠ ˆ À192.4 (c ˆ 0.58,
CHCl3).
tert-Butyl (2S)-2-(4-Methoxybenzyl)-3-oxopyrrolidine-1-carboxylate ((2S)-5a). As described for (2R)-5a,
with (2S)-4a (0.240 g, 0.438 mmol), THF (9 ml), and 6n aq. HCl (2.5 ml) (neutralized with sat. NaHCO3 soln.
20
D
(10 ml)): (2S)-5a (88 mg, 66%). Yellow oil. ‰aŠ ˆ ‡184.8 (c ˆ 0.56, CHCl3). IR (neat): 2975 2840 (ˆCÀH,
CÀH), 1755 (CˆO), 1700 (CˆO). 1H-NMR (CDCl3; several doubled signals due to the occurrence of
rotamers): 1.54 (s, tBu); 1.89 (ddd, J ˆ 18.8, 9.2, 4.4, 1 HÀC(4)); 2.31 2.45 (m, 1 HÀC(4)); 2.77 (m, 1 HÀC(5));
3.03 (dd, J ˆ 13.6, 2.6, 1 H, ArCH2); 3.16, 3.37, 3.64, 3.71 (4m, 0.5 H each, HÀC(5), ArCH2); 3.78 (s, MeO);
4.11 4.14 (m, HÀC(2)); 6.79 (d, J ˆ 8.5, 2 arom. H); 6.98 (d, J ˆ 8.5, 2 arom. H). 13C-NMR (CDCl3): 28.5 (q,
t
tBu); 35.9, 36.1, 36.6, 41.5 (4t, C(4), C(5), ArCH2); 55.2 (q, MeO); 63.3, 63.6 (2d, C(2)); 80.4, (s, Bu); 114.0,
‡
130.8 (2d, arom. C); 128.0, 154.3, 158.5 (3s, CˆO, arom. C); 214.2 (s, C(3)). EI-MS (80 eV): 305 (24, M ), 249
‡
‡
‡
t
‡
‡
(4, [M À C4H8] ), 232 (10, [M À OtBu] ), 121 (100, MeOBn ), 83 (23), 57 (68, Bu ). HR-MS: 305.1644 (M ,
C17H23NO4; calc. 305.1627).
(2R)-2-(4-Methoxybenzyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-3-one ((2R)-5b). As described for
(2R)-5a, with (2R)-4b (0.249 g, 0.414 mmol), THF (8.5 ml), and 6n aq. HCl (2.1 ml) (neutralized with sat.
NaHCO3 soln. (10 ml)). CC (silica gel; hexane/AcOEt 1:1) yielded (2R)-5b (0.134 g, 90%). Colorless solid.
20
D
M.p. 1478. ‰aŠ ˆ À64.5 (c ˆ 1.0, CHCl3).
(2S)-2-(4-Methoxybenzyl)-1-[(4-methylphenyl)sulfonyl]pyrrolidin-3-one ((2S)-5b). As described for (2R)-
5a, with (2S)-4b (0.184 g, 0.306 mmol), THF (6 ml) and 6n aq. HCl (1.5 ml) (neutralized with sat. NaHCO3 soln.
(10 ml)). CC (silica gel; hexane/AcOEt 1:1) yielded (2S)-5b (56 mg, 51%). Colorless solid. M.p. 142 1448.
20
‰aŠ ˆ ‡55.6 (c ˆ 1.0, CHCl3). IR (KBr): 3060 3015 (ˆCÀH), 2935 2870 (CÀH), 1755 (CˆO), 1345, 1160
D
1
(RSO2N). H-NMR (CDCl3): 1.66 1.80, 1.98 2.11 (2m, 2 HÀC(4)); 2.44 (s, MeC6H4); 3.12 (dd, J ˆ 13.9, 2.9,
1 H, ArCH2); 3.18 3.36 (m, 3 H, HÀC(5), ArCH2); 3.75 (m, HÀC(2)); 3.77 (s, MeO); 7.34 (d, J ˆ 8.1, 2 H, Ar);
6.80, 7.16, 7.72 (3d, J ˆ 8.8, 2 H each, Ar, Tos). 13C-NMR (CDCl3): 21.4 (q, MeC6H4); 36.3, 37.0, 44.1 (3t, C(4),
C(5), ArCH2); 55.0 (q, MeO); 64.6 (d, C(2)); 113.6, 127.5, 129.9, 131.4 (4d, arom. C); 127.3, 133.4, 144.2, 158.5
‡
‡
‡
(4s, arom. C); 211.7 (s, C(3)). EI-MS (80 eV): 359 (14, M ), 238 (10, [M À MeOBn] ), 155 (24, Tos ), 121 (100,
‡
‡
‡
‡
MeOBn ), 91 (27, PhCH2 ). HR-MS: 359.1183 (M , C19H21NO4S ; calc. 359.1191).
tert-Butyl (2R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-2,5-dihydro-2-(4-methoxybenzyl)-1H-pyrrol-1-carboxy-
late ((2R)-6). For the preparation of LDA, 2.46m BuLi in hexanes (0.76 ml, 1.87 mmol) was dissolved in dry
THF (25 ml) at À 788 and treated with iPr2NH (0.260 ml, 0.189 g, 1.87 mmol). The mixture was stirred at 08 for
30 min and then cooled to À 788, and (2R)-5a (0.519 g, 1.70 mmol) in dry THF (5 ml) was slowly added. The
mixture was stirred for further 20 min. tBuMe2SiCl (0.641 g, 4.25 mmol) and DMPU (0.410 ml, 0.435 g,
3.40 mmol) were added. The resulting soln. was stirred for 45 min at À 788, allowed to warm to r.t., and stirred
for additional 2.5 h. The solvent was evaporated, the residue dissolved with Et2O, the soln. washed with sat.
Na2CO3 soln. (30 ml), the aq. layer extracted with Et2O (4 Â 20 ml), the combined org. layer washed with brine,
dried (Na2SO4), and evaporated and the crude product purified by CC (aluminium oxide, hexane/AcOEt 7 :1):
20
D
(2R)-6 (0.480 g, 68%). Yellow oil. ‰aŠ ˆ À68.3 (c ˆ 0.5, CHCl3).
tert-Butyl (2S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-2,5-dihydro-2-(4-methoxybenzyl)-1H-pyrrole-1-carboxy-
late ((2S)-6). As described for (2R)-6, with 2.3m BuLi in hexanes (0.14 ml, 0.31 mmol), THF (5 ml), and iPr2NH
(45 ml, 32 mg, 0.31 mmol) (stirring at À 788 instead of 08 for 30 min), then (2S)-5a (88 mg, 0.29 mmol) in THF
(1 ml), and finally tBuMe2SiCl (108 mg, 0.72 mmol) and DMPU (70 ml, 0.58 mmol). Extraction with Et2O (4 Â
20
D
1
5 ml) and CC (silica gel, hexane/AcOEt 4 :1) yielded (2S)-6 (67 mg, 56%). Yellow oil. ‰aŠ ˆ ‡52.0 (c ˆ 1.3,
CHCl3). IR (neat): 3100 3035 (ˆCÀH), 2955 2835 (CÀH), 1700 (CˆO), 1660 (CˆC). H-NMR (CDCl3;

1836
Helvetica Chimica Acta Vol. 88 (2005)
several doubled signals due to rotamers): 0.17, 0.19 (2s, 3 H each, Me2Si); 0.97 (s, tBuSi); 1.49, 1.55 (2s, 5 H, 4 H,
tBuO); 2.77 2.84 (m, 1 H, ArCH2); 3.16 (dd, J ˆ 13.6, 4.8, 1 H, ArCH2); 3.24 3.39 (m, 1 HÀC(5)); 3.76, 3.78
(2s, 1.3 H, 1.7 H, MeO); 3.84 3.91 (m, 1 HÀC(5)); 4.37 (br. d, J ˆ 7.0, HÀC(4)); 4.43 (m, HÀC(2)); 6.75, 7.01,
t
7.02 (3d, J ˆ 8.8, 1 H, 1 H, 2 H, arom. H). 13C-NMR (CDCl3): À 5.1, À 4.8, À 4.7 (3q, Me2Si); 18.0 (s, BuSi);
25.5, 28.5, 28.6 (3q, tBu); 33.8, 35.3, 50.0, 50.3 (4t, C(5), ArCH2); 55.1 (q, MeO); 63.0, 63.3 (2d, C(2)); 78.8, 79.5
(2s, tBu); 96.4, 96.9 (2d, C(4)); 112.9, 113.2, 130.8, 131.0 (4d, Ar); 129.0, 129.2, 149.7, 153.8, 158.0 (5s, Ar, CˆO,
‡
‡
‡
‡
C(3)). EI-MS (80 eV): 419 (11, M ), 363 (2, [M À C4H8] ), 346 (4, [M À OtBu] ), 298 (15, [M À MeOBn] ),
‡
‡
t
‡
t
‡
242 (100, [M À MeOBn À C4H8] ), 198 (46), 121 (30, MeOBn ), 73 (20, BuO ), 57 (67, Bu ). HR-MS:
‡
‡
419.2476 (M , C23H37NO4Si ; calc. 419.2492).
tert-Butyl (2R,3S,4S)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-hydroxy-2-(4-methoxybenzyl)pyrrolidine-1-carb-
oxylate ((2R)-7). To a soln. of (2R)-6 (0.334 g, 0.795 mmol) in dry THF (16 ml), 1m BH3 ¥ THF in THF
(3.2 ml, 3.2 mmol) was added at À 308. The mixture was allowed to warm up to r.t. and stirred for further 3 h.
After cooling the soln. to À 108, 1n NaOH (4.8 ml) and 30% aq. H2O2 soln. (1.6 ml) were added. After stirring
for 16 h at r.t., sat. Na2S2O3 soln. (20 ml) was added. The aq. layer was extracted with Et2O (3 Â 20 ml), the
combined extract dried (MgSO4) and evaporated, and the crude product purified by CC (silica gel, hexane/
AcOEt 2 :1): (2R)-7a (0.311 g, 89%). Colorless oil. Only one diastereoisomer was obtained (d.r. > 95 :5, by
20
D
NMR). ‰aŠ ˆ À6.4 (c ˆ 0.90, CHCl3).
tert-Butyl (2S,3R,4R)-3-{[(tert-Butyl)dimethylsilyl]oxy}-4-hydroxy-2-(4-methoxybenzyl)pyrrolidine-1-carb-
oxylate ((2S)-7). As described for (2R)-7, with (2S)-6 (60 mg, 0.14 mmol), dry THF (3 ml), 1m BH3 ¥ THF in
THF (0.6 ml, 0.6 mmol), 1n NaOH (0.86 ml), 30% aq. H2O2 soln. (0.30 ml). Workup with sat. Na2S2O3 soln.
(5 ml) and Et2O (3 Â 5 ml): (2S)-7 (50 mg, 81%). Colorless oil. Only one diastereoisomer was obtained (d.r.
20
D
> 95 :5, by NMR). ‰aŠ ˆ ‡7.5 (c ˆ 0.90, CHCl3). IR (neat): 3430 (OH), 3060 (ˆCÀH), 2955 2835 (CÀH),
1695 (CˆO). 1H-NMR (CDCl3): 0.08, 0.11 (2s, each 3 H, Me2Si); 0.96 (s, tBuSi); 1.43 (s, tBu); 1.85 (br. s, OH);
2.82 3.32 (m, HÀC(2), 2 HÀC(5), ArCH2); 3.72 (m, HÀC(4)); 3.77 (s, MeO); 4.06 (t, J ˆ 6.8, HÀC(3)); 6.78,
7.11 (2d, J ˆ 8.6, 2 arom. H each). 13C-NMR (CDCl3; one signal for aryl not detected): À 4.8, À 4.5 (2q, Me2Si);
18.2 (s, tBuSi); 26.0, 28.5 (2q, tBu); 32.9 (t, ArCH2); 50.2 (t, C(5)); 55.3 (q, MeO); 60.7 (d, C(2)); 74.3, 78.2 (2d,
‡
C(3), C(4)); 79.5 (s, tBu); 113.7, 131.1 (2d, Ar); 154.6, 158.2 (2s, CˆO, arom. C). EI-MS (80 eV): 437 (6, M ),
‡
‡
‡
364 (5, [M À OtBu] ), 316 (24, [M À MeOBn] ), 260 (53, [M À MeOBn À C4H8] ), 242 (11), 216 (61), 121 (41,
‡
t
‡
‡
‡
MeOBn ), 75 (70), 57 (100, BuO ). HR-MS: 437.2575 (M , C23H39NO5Si ; calc. 437.2598).
tert-Butyl (2R,3S,4S)-4-{[(tert-Butoxy)carbonyl]oxy}-3-{[(tert-butyl)dimethylsilyl]oxy}-2-(4-methoxybenz-
yl)pyrrolidine-1-carboxylate. To a soln. of (2R)-7 (0.387 g, 0.884 mmol) in dry pyridine (20 ml), DMAP
(0.108 g, 0.884 mmol) and di(tert-butyl) carbonate (0.289 g, 1.32 mmol) were added at r.t. The mixture was
stirred for 12 h, and the soln. was diluted with CH2Cl2 and extracted with sat. NaHCO3 soln. (25 ml). The aq.
layer was extracted with CH2Cl2 (3 Â 20 ml), the combined extract dried (MgSO4) and evaporated, and the
20
D
crude product purified by CC (silica gel, hexane/AcOEt 6 :1): Colorless oil (0.428 g, 90%). ‰aŠ ˆ ‡21.4 (c ˆ
0.93, CHCl3).
tert-Butyl (2S,3R,4R)-4-{[(tert-Butoxy)carbonyl]oxy}-3-{[(tert-butyl)dimethylsilyl]oxy}pyrrolidine-1-carb-
oxylate. As described above, with (2S)-7 (0.127 g, 0.290 mmol), dry pyridine (5 ml), DMAP (35 mg,
0.29 mmol), and di(tert-butyl) carbonate (95 mg, 0.44 mmol). Workup with sat. NaHCO3 soln. (10 ml) and
20
D
CH2Cl2 (3  10 ml) and CC (silica gel, hexane/AcOEt 5 :1) yielded a colorless oil (147 mg, 95%). ‰aŠ ˆ À17.6
(c ˆ 0.46, CHCl3). IR (neat): 3020 2860 (ˆCÀH, CÀH), 1745, 1700 (CˆO). 1H-NMR (CDCl3): 0.05, 0.10 (2s,
Me2Si); 0.94 (s, tBuSi); 1.37 1.44 (m, 2 tBu); 2.80 3.53 (m, 2 HÀC(5), ArCH2); 3.77 (s, MeO); 4.04 4.19 (m,
1 HÀC(2)); 4.26 (br. t, J ꢀ 6.3, HÀC(3)); 4.61 4.66 (m, 1 HÀC(4)); 6.80 (d, J ˆ 8.4, 2 arom. H); 7.13 7.17 (m,
t
2 arom. H). 13C-NMR (CDCl3): À 5.0, À 4.7 (2q, Me2Si); 18.1 (s, BuSi); 25.6, 25.9, 27.8, 27.9, 28.4, 28.6 (6q,
tBu); 31.6 (t, ArCH2); 48.4 (t, C(5)); 55.3 (q, MeO); 60.6, 75.2, 79.0 (3d, C(2), C(3), C(4)); 79.6, 82.3 (2s, tBu);
‡
113.8, 130.8 (2d, arom. C); 128.2, 152.8, 154.4, 158.3 (4s, CˆO, arom. C). EI-MS (80 eV): 537 (3, M ), 424 (8,
t
‡
‡
‡
[M À C4H8 À Bu] ), 416 (11, [M À MeOBn] ), 360 (12, [M À C4H8 À MeOBn] ), 304 (40), 260 (16), 242 (24),
‡
t
‡
‡
‡
198 (30), 121 (36, MeOBn ), 75 (12), 73 (16), 57 (100, Bu ). HR-MS: 537.3154 (M , C28H47NO7Si ; calc.
537.3122).
tert-Butyl (2R,3S,4S-3-(Acetyloxy)-4-{[(tert-butoxy)carbonyl]oxy}-2-(4-methoxybenzyl)pyrrolidine-1-carb-
oxylate ((2R)-8). To a soln. of intermediate silyl ether (0.428 g, 0.795 mmol) in dry THF (9 ml), 1m Bu4NF in
THF (1.0 ml, 1.0 mmol) was added, and the mixture was stirred for 16 h at r.t. The soln. was diluted with CH2Cl2
(50 ml), and Et3N (0.15 ml, 104 mg, 1.03 mmol) and DMAP (6.4 mg, 0.52 mmol) were added. After cooling to
08, Ac2O (0.097 ml, 105 mg, 1.03 mmol) was added, and the resulting soln. was stirred for 12 h. The mixture was
diluted with CH2Cl2, the aq. layer extracted with CH2Cl2 (4 Â 20 ml), the combined org. layer washed with sat.

Helvetica Chimica Acta Vol. 88 (2005)
1837
NaHCO3 and NaCl soln., dried (MgSO4), and evaporated. The crude product was purified by CC (silica gel,
20
D
hexane/AcOEt 2 :1): (2R)-8 (0.342 g, 92%). Pale yellow oil. ‰aŠ ˆ ‡35.6 (c ˆ 1.05, CHCl3).
tert-Butyl (2S,3R,4R)-3-(Acetyloxy)-4-{[(tert-butoxy)carbonyl]oxy}-2-(4-methoxybenzyl)pyrrolidine-1-
carboxylate ((2S)-8). As described for (2R)-8, with intermediate silyl ether (50 mg, 0.092 mmol), dry THF
(1 ml), 1m Bu4NF in THF (0.12 ml, 0.12 mmol), then CH2Cl2 (4 ml), Et3N (17 ml, 13 mg, 0.130 mmol), and
DMAP (ca. 1 mg, 8 mmol), followed by Ac2O (11 ml, 13 mg, 0.13 mmol): (2S)-8 (34 mg, 79%). Pale yellow oil.
20
‰aŠ ˆ À29.6 (c ˆ 0.41, CHCl3). IR (neat): 3030 2835 (ˆCÀH, CÀH); 1745, 1700 (CˆO). 1H-NMR (CDCl3):
D
1.46 1.52 (m, 2 tBu); 2.04 (s, Ac); 2.79 3.62 (m, 2 HÀC(5), ArCH2); 3.77 (s, MeO); 4.38 4.46 (m, HÀC(2));
4.84 (m, HÀC(4)); 5.13 (dd, J ˆ 6.6, 5.9, HÀC(3)); 6.81 (br. d, J ꢀ 7.5, 2 arom. H); 7.07 (d, J ꢀ 7.5, 2 arom. H).
13C-NMR (CDCl3): 20.6 (q, MeCO); 27.6, 28.3 (2q, tBu); 33.8 (t, ArCH2); 48.4 (t, C(5)); 55.2 (q, MeO); 58.4 (d,
C(2)); 74.6, 75.8 (d, br. d, C(3), C(4)); 80.1, 83.0 (2s, tBu); 113.9, 130.3 (2d, arom. C); 129.5, 152.4, 154.1, 158.2
‡
‡
(4s, COtBu, arom. C); 169.6 (s, COMe). EI-MS (80 eV): 465 (17, M ), 344 (35, [M À MeOBn] ), 336 (10), 288
‡
‡
(25, [M À MeOBn À C4H8] ), 244 (15), 232 (100, [M À MeOBn À C4H8 À C4H8] ), 188 (34), 170 (16), 128 (20),
‡
‡
t
‡
‡
126 (25), 121 (51, MeOBn ), 84 (16), 57 (30, Bu8 ). HR-MS: 465.2400 (M , C24H35NO ; calc. 465.2363).
(2R,3S,4S)-3-(Acetyloxy)-4-hydroxy-2-(4-methoxybenzyl)pyrrolidinium Chloride (ˆ(À8)-Anisomycin Hy-
drochloride [10b]; (2R)-9). A soln. of (2R)-8 (0.230 g, 0.494 mmol) in 4m HCl in dioxane (10 ml) was stirred for
5 h at 08. H2O (11 ml, 0.59 mmol) was added, and the mixture was stirred for further 30 min at 08. After
evaporation, the residue was recrystallized from MeOH/Et2O: (2R)-9 (99 mg, 66%). Colorless crystals. M.p.
20
20
178 1868 ([10b][20]: m.p. 187 1888). ‰aŠ ˆ ‡3.95 (c ˆ 0.96, MeOH) ([10b]: ‰aŠ ˆ ‡4.2 (c ˆ 0.51, MeOH);
D
D
20
[20]: ‰aŠ ˆ ‡4.0 (c ˆ 0.28, MeOH)). 1H-NMR (CD3OD): 2.20 (s, Ac); 2.96, 3.06 (AB of ABX, JAB ˆ 14.1, JAX
ˆ
D
8.3, JBX ˆ 7.1, ArCH2); 3.14 (d, J ˆ 12.5, 1 HÀC(5)); 3.58 (dd, J ˆ 2.5, 4.8, 1 HÀC(5)); 3.81 (s, MeO); 4.07 (ddd,
J ˆ 8.3, 7.1, 3.3, HÀC(2)); 4.34 (br. d, J ꢀ 4.8, HÀC(4)); 5.04 (br. d, J ꢀ 3.3, HÀC(3)); 6.94, 7.24 (2d, J ˆ 8.7,
2 arom. H each). 13C-NMR (CD3OD): 17.0 (q, MeCO); 28.6 (t, ArCH2); 49.0 (t, C(5)); 52.1 (q, MeO); 60.1 (d,
C(2)); 69.8 (d, C(4)); 74.6 (d, C(3)); 112.0, 127.4 (2d, arom. C); 125.4, 157.0 (2s, arom. C), 167.2 (s, CˆO). FAB-
‡
‡
‡
MS (pos.): 266 (100, [M À Cl] ), 206 (5, [M À Cl À AcOH] ), 121 (28, MeOBn ), 89 (11), 84 (11), 77 (12).
Anal. calc. for C14H20ClNO4 (301.8): C 55.72, H 6.68, N 4.64; found: C 55.10, H 6.39, N 4.49.
(2S,3R,4R)-3-(Acetyloxy)-4-hydroxy-2-(4-methoxybenzyl)pyrrolidinium Chloride (ˆ(‡)-Anisomycin Hy-
drochloride; (2S)-9). As described for (2R)-9, with (2S)-8 (33 mg, 0.071 mmol), 4m HCl in dioxane (1.50 ml),
and H2O (2 ml, 0.11 mmol): (2S)-9 (13 mg, 61%). Colorless crystals. M.p. 179 1878; because of the small
amount of product the low optical rotation, a specific value could not be unambiguously determined.
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¡
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Received March 1, 2005