Synthesis of a small repertoire of non-racemic 5a-carbahexopyranoses and 1-thio-5a-carbahexopyranoses

Article abstract of DOI:10.1002/1099-0690(200206)2002:12<1956::AID-EJOC1956>3.0.CO;2-Y

A short and practical entry to optically pure 5a-carbahexopyranose and 1-thio-5a-carbahexopyranose representatives is described. Besides a few functional group and protecting group manipulations, the synthetic scheme counts on two fundamental carbon-carbon bond-forming reactions, namely (i) a regio- and stereoselective aldol addition between heterocyclic (silyloxy)diene donors (6 or 13) and D-glyceraldehyde as the acceptor (7) and (ii) a chemo- and stereoselective silylative cycloaldolization involving bifunctional aldehydes (10, 16, and 21). The ¹H NMR based configurational and conformational assignment of target structures 1-5 and bicyclic intermediates 11, 12, 17, 18, and 22 is discussed. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200206)2002:12<1956::AID-EJOC1956>3.0.CO;2-Y

FULL PAPER
Synthesis of a Small Repertoire of Non-Racemic 5a-Carbahexopyranoses and
1-Thio-5a-carbahexopyranoses[‡]
Franca Zanardi,*[a] Lucia Battistini,[a] Lucia Marzocchi,[a] Domenico Acquotti,[b]
Gloria Rassu,[c] Luigi Pinna,[d] Luciana Auzzas,[c] Vincenzo Zambrano,[d] and
Giovanni Casiraghi*[a]
Keywords: Carbocycles / Carbohydrates / Aldol reaction / Silicon / Sulfur
A short and practical entry to optically pure 5a-carbahexopy- dehyde as the acceptor (7) and (ii) a chemo- and stereoselec-
ranose and 1-thio-5a-carbahexopyranose representatives is
described. Besides a few functional group and protecting
group manipulations, the synthetic scheme counts on two
fundamental carbon−carbon bond-forming reactions, namely
tive silylative cycloaldolization involving bifunctional alde-
hydes (10, 16, and 21). The 1H NMR based configurational
and conformational assignment of target structures 1−5 and
bicyclic intermediates 11, 12, 17, 18, and 22 is discussed.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
(i)
a regio- and stereoselective aldol addition between
heterocyclic (silyloxy)diene donors (6 or 13) and D-glyceral- 2002)
Introduction
hydrolysis and renders them chemically and biologically res-
istant; and (iv) these constructions can provide novel scaf-
folds with which carbocyclic analogues of nucleosides[5] and
designed oligomeric entities[6] can be engineered.
Functionally and stereochemically diverse collections of
small molecules can be used to explore the basic metabolic
pathways in living systems, the alteration of which often lies
at the basis of many physiological disorders and patholo-
gical conditions.[2] Natural and natural-product-like entities,
for example members of the cyclitol and carbasugar famil-
ies[3] with hydroxy moieties embodied in a ring structure,
have attracted our attention for several reasons: (i) Their
structures are analogous to those of carbohydrates, which
are amongst the most represented and property-rich build-
ing blocks used by Nature; (ii) molecules of this family have
proven to be potent inhibitors of a variety of glycosidase
enzymes that are responsible for post-translational pro-
cessing of ribosome-synthesized glycopeptides;[4] (iii) the
lack of the sugar acetal moiety Ϫ here, the ring oxygen
atom is replaced by a carbon atom Ϫ preserves them from
Our group has presented[1,7] a synthetic strategy with a
high variability potential capable of targeting carbafur-
anose and carbapyranose structures, as well as carbafura-
nosyl- and carbapyranosylamines and 1-thio derivatives in
diverse stereochemical variants. Basically, the chemistry we
employ is founded upon the use of readily available starting
materials, namely, the heterocyclic silylketene acetals of
type I[8] and glyceraldehyde II (Figure 1), and features two
key carbonϪcarbon bond-forming reactions, an inter-
molecular Mukaiyama-type aldol manoeuvre in its vinylog-
ous version (arrow a),[9] followed by an intramolecular silyl-
ative aldol junction (arrows b or c).[10] The remaining reac-
tions are simply protecting group and functional group
manipulations.
[‡]
Variable Strategy toward Carbasugars and Relatives, 3. Part 2:
Ref.[1]
[a]
`
Dipartimento Farmaceutico, Universita di Parma,
Parco Area delle Scienze 27A, 43100, Parma, Italy
Fax: (internat.) ϩ 39-0521/905006
E-mail: giovanni.casiraghi@unipr.it
[b]
[c]
`
`
Centro Interfacolta di Misure G. Casnati, Universita di Parma,
Parco Area delle Scienze 23A, 43100, Parma, Italy
Istituto per l’Applicazione delle Tecniche Chimiche Avanzate ai
Problemi Agrobiologici del CNR,
Figure 1. Basic strategy towards carbahexopyranoses and carbap-
entofuranoses and their analogues
Via Vienna 2, 07100 Sassari, Italy
[d]
`
Dipartimento di Chimica, Universita di Sassari,
When put into practice, this synthetic tactic proved to be
pleasingly efficient, reasonably short, and above all, chemic-
ally uniform, which enabled us to obtain a small library of
Via Vienna 2, 07100 Sassari, Italy
Supporting information for this article is available on the
WWW under http://www.eurjoc.com or from the author.
1956
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0612Ϫ1956 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 1956Ϫ1964

Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses
FULL PAPER
eleven pseudo-sugar compounds of both the - and -series. nylogous aldolization manoeuvre between the heterocyclic
Our intention was to demonstrate further the general utility (silyloxy)diene E and the chiral aldehyde F. Basically, E and
and applicability of our original plan and to refine the syn- F are the building blocks that account for the carbon skel-
thetic protocol for the preparation of enantiopure, richly eton and the oxygen (and sulfur) functionalities, with car-
functionalized cyclohexanoid structures. The outcome of bon atoms C-2, C-3, and C-4 (target numbering) being fur-
our efforts is presented here by the synthesis of five carbap- nished by the glyceraldehyde precursor F, and carbon atoms
yranose representatives including the β--gulo-configured C-1, C-5, C-5a, and C-6 coming from the chosen (silyloxy)-
pseudo-sugar 1, the β--allopyranose analogue 2, the cor- diene E.
responding 1-thio derivatives 3 and 4, and the -series
The two fundamental carbonϪcarbon bond-forming re-
actions (E ϩ F Ǟ D and C Ǟ B) Ϫ both aldol additions
and both of the Mukaiyama type Ϫ represent the focal
point of the whole strategy, as they orchestrate the con-
struction of the cyclohexane ring and ultimately control
four of the five stereocentres present in the targets (absolute
configuration at C-3 is that of the initial aldehyde F).
manno-configured derivative 5 (Figure 2).[11]
Synthesis of 5a-Carba-β-
β- -allopyranose (2)
D-gulopyranose (1) and 5a-Carba-
D
Targeting the title carbapyranoses 1 and 2 entailed the
use of the advanced lactone intermediate 8, whose prepara-
tion from 2-[(tert-butyldimethyl)silyloxy]furan (6) and 2,3-
O-isopropylidene--glyceraldehyde (7) has been previously
reported (four steps, 65% yield, Scheme 2).[1]
Figure 2. Carbahexopyranoses prepared in this study
Results and Discussion
Planning
In devising the carbapyranose rings of this study (struc-
ture A, Scheme 1), we imagined them to arise from the re-
ductive opening of the lactone (or thiolactone) function in
the bicyclooctane B. In turn, B was seen to originate by an
intramolecular aldol closure from the monocyclic interme-
diate C, whose aldehyde function may be easily imple-
mented onto triol D. The structure of D mandated a vi-
Scheme 2. Preparation of advanced lactone intermediate 10
Aiming at the crucial cycloaldolization, we had to un-
mask an aldehyde functionality at the C-7 terminus; to do
this, we decided to exploit a slightly modified version of
the Swern oxidation,[12] which, fortunately enough, could
be directly applied to a protected primary hydroxy group.
Thus, 8 was first subjected to complete protection of its free
OH groups as triethylsilyl ethers to give lactone 9 (TESOTf,
pyridine, DMAP, 95%), which underwent direct oxidation
to aldehyde 10 [DMSO, (COCl2)2; then Et3N, 98%].
To promote the key cycloaldolization, we then had to in-
duce the formation of an enolate of the lactone moiety and
subsequently ensure closure on the aldehyde function. Cap-
italizing on the results of preceding studies,[1] we opted to
carry out the reaction of 10 in the presence of equimolar
quantities of TBSOTf and diisopropylethylamine (DIPEA,
3.0 equiv.) at room temperature (Scheme 3). Not surpris-
ingly, the reaction proceeded smoothly, furnishing bicyclo-
Scheme 1. Retrosynthetic analysis of carbahexopyranoses A
Eur. J. Org. Chem. 2002, 1956Ϫ1964
1957

F. Zanardi, G. Casiraghi et al.
FULL PAPER
octane 11 in 69% yield, accompanied by small quantities Synthesis of 1-Thio-5a-carba-β-D-gulopyranose (3) and 1-
(6%) of its C-4 epimer 12.[13]
Thio-5a-carba-β-D-allopyranose (4)
The experience gained with the above synthetic route,
which quickly and efficiently led us to carbapyranoses, as
foreseen by the general plan, enticed us to apply this process
to the preparation of carbapyranose derivatives containing
a thio function at the pseudo-anomeric position. Such
monosaccharide analogues, until now completely unheard
of, could enrich the library of carbasugars we envisioned.
According to the retrosynthetic plan (Scheme 1), the thio
function of the title compounds derives from the sulfur het-
eroatom within the (silyloxy)diene E. Therefore, the syn-
thetic sequence started with the aldol addition between 2-
[(tert-butyldimethyl)silyloxy]thiophene (13) and protected
glyceraldehyde 7 (Scheme 4). As previously described,[1]
a
four-step protocol enabled us to arrive at thiolactone 14
with a 47% overall yield.
Scheme 4. Preparation of advanced thiolactone intermediate 16
Scheme 3. Preparation of 5a-carbapyranoses 1 and 2
Protection of the terminal diol function with TESOTf
brought us to the fully protected thiolactone 15 (98%),
which directly underwent oxidation to aldehyde 16 in 82%
isolated yield. With aldehyde 16 in hand, it was assumed
that the cycloaldolization event would proceed without
problems. Indeed, the TBSOTf/DIPEA reagent system (1:1,
3.0 equiv., room temperature) triggered a cascade of reac-
tions, namely, chemoselective enolsilylation of the thiolac-
tone moiety, Mukaiyama-type cycloaldolization, and silyl-
ation of the resulting OH function, which ultimately gave
rise to 3,4-trans-configured bicycle 17 (42%) along with
38% of its 3,4-cis-configured counterpart 18 (Scheme 5).[14]
The cycloadducts 17 and 18 were separately treated with
LiBH4, followed by a 1:2:2 mixture of HCl/THF/MeOH. In
this way, 1-thio-5a-carba-β--gulopyranose (3) and epi-
meric 1-thio-5a-carba-β--allopyranose (4) were obtained
in a 68% and 81% yield, respectively (two steps), corres-
ponding to overall yields of 11% and 12% over nine steps.
The stereochemistry of both products, as well as those of
the bicyclic intermediates was determined through 1D and
Some points deserve commenting here. Firstly, the
chemoselectivity of the process was complete, with the sole
lactone moiety being involved in enolization. Secondly, the
stereochemical behaviour strongly favours the 3,4-trans-
configured isomer 11 over the corresponding 3,4-cis-dis-
posed counterpart 12. Thermodynamic control is most
probably working here, where the more stable, 3,4-diequat-
orial product 11 predominates, emerging from the anti-Fel-
kin attack on the si-face of the aldehyde function (TS1).[14]
Having just crafted the cyclohexane structure of the tar-
gets, we next turned to the final stages of the synthesis,
namely the reductive opening of the γ-lactone moiety
within the bicyclooctanes 11 and 12. Treatment of the ma-
jor isomer 11 with LiBH4,[15] followed by removal of the
silyl protecting groups (HCl, THF, MeOH), finally yielded
the desired 5a-carba-β--gulopyranose (1) in a 81% yield
for the two steps. This corresponds to a nice 34% yield over
nine steps from 6 and 7.[16] According to the same proced-
ure, the minor isomer 12 was converted into the corres-
ponding carbasugar, 5a-carba-β--allopyranose (2), in a
gratifying 80% yield. The configurational and conforma-
tional assignments of carbasugars 1 and 2, as well as those
1
2D H NMR analysis (vide infra).
Synthesis of 5a-Carba-β-
In engineering the -series carbasugars, we had to control
of bicyclic intermediates 11 and 12, were unequivocally es- the configuration of the stereocentres C-1 and C-5 [(1S,5S),
L-mannopyranose (5)
1
tablished by 1D and 2D H NMR analyses (vide infra).
Scheme 1], and ultimately stereocontrol the initial aldol re-
1958
Eur. J. Org. Chem. 2002, 1956Ϫ1964

Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses
FULL PAPER
At this point, the final carbasugar target was in our re-
ach. When compound 22 was subjected to reductive treat-
ment (LiBH4), the expected protected carbasugar derivative
was obtained, although we had to greatly force the reaction
conditions (11 equiv.). The steric hindrance about the C-6
reactive site caused by the silyl protection and by the con-
cavity of the bicycle probably rendered this reduction rather
sluggish. Nonetheless, a protected carbasugar derivative
was isolated in 59% yield. Acidic deprotection finally pro-
vided 5a-carba-β--mannopyranose (5) in a quantitative
yield, corresponding to a nice 12% yield over ten steps from
6 and 7.
Structural Analysis
By observing the structure of the target carbasugars and
the chemical sequence that led to them, it can be seen that
of the five stereocentres present, C-1 and C-2 arise from the
first aldol reaction, C-3 derives from the configuration of
the glyceraldehyde chosen, and C-4 and C-5 are formed
during the cycloaldolization. With C-3 fixed as (R) [we al-
ways started from the (R)-configured glyceraldehyde], the
remaining C-1, C-2, C-4, and C-5 had to be analysed. The
diastereoselective nature of the initial Mukaiyama addition
led mainly to the butenolide (or thiobutenolide) adduct
with a 4,5-syn-5,6-anti configuration (8 or 14 in Schemes 2
and 4). This translates directly into fixing the configurations
of the stereocentres C-1 and C-2 within targets 1Ϫ4 as
(1R,2S), given the stereo-preserving nature of the synthetic
sequence followed. On the other hand, when the initial al-
dol reaction was steered to favour the 4,5-anti-5,6-anti-con-
figured butenolide (19, Scheme 6), the resultant target com-
pound would have the configuration (1S,2S).
Scheme 5. Preparation of 1-thio-5a-carbapyranoses 3 and 4
action. For this reason, dienol ether 6 was made to react
with aldehyde 7 under the influence of BF3·OEt2 (Ϫ80 °C)
and the resulting reaction mixture, rich in the 4,5-syn-5,6-
anti-configured butenolide, was allowed to equilibrate un-
der Et3N. The thermodynamically stable C-4-epimeric but-
enolide (4,5-anti-5,6-anti) endowed with the desired (4S) ab-
solute configuration was formed. The usual transforma-
tions followed,[1] consisting in nickel boride promoted re-
duction and protecting group manipulation. Butanolide 19
was isolated in 41% yield over five steps from 6 and 7
(Scheme 6).
In order to define the configuration of C-4 and C-5, we
had to trace the stereochemistry of the cycloaldolization.
1H NMR one- and two-dimensional studies extensively car-
ried out on the bicyclic adducts 11, 12, 17, 18, and 22, as
well as the final targets, proved fundamental for this deter-
mination (Tables 1 and 2).
Certification of the (1R,2S,3R,4S,5S) configuration and
1
of the C4 chair conformation of the hexanoid ring in ad-
ducts 11 and 17 (as depicted) was founded on general in-
spection of the spectra and on the following observations
3
in particular: (i) presence of the coupling constant J3,4
ϭ
8.8 Hz (for 11) and 9.1 Hz (for 17), indicating a trans-diax-
ial positioning of these protons; (ii) presence of long-range
4
4
coupling constants J1,5 ϭ 0.7/1.7 Hz and J2,5aβ ϭ 0.6/
0.8 Hz for the 11/17 couple, pointing to an equatorial copla-
nar W disposition of these protons; and (iii) existence of
strong NOE contacts between 4-H and 5a-Hα. On the other
hand, diagnosis of the epimeric bicyclic structures 12 and
Scheme 6. Preparation of 5a-carbapyranose 5
Paralleling the previously disclosed procedure, compound 18, with a 3,4-cis configuration, was solved by piecing to-
19 was transformed into aldehyde 21 via the fully protected gether the following evidence: (i) the presence of vicinal
lactone 20 (69%, two steps). The crucial ring closure Ϫ the coupling constants ranging from 0.0 to 5.2 Hz, indicating
TBSOTf/DIPEA-promoted silylative cycloaldolization Ϫ only diequatorial and axial/equatorial relationships between
4
was performed on aldehyde 21 to give 3,4-trans-configured protons; (ii) the coupling constants J1,5 ϭ 0.7 Hz (for 12)
bicycle 22 in a high yield and with complete diastereoselec- and 1.7 Hz (for 18), confirming a diequatorial orientation
tive control.
of these protons; and (iii) a strong NOE contact between
Eur. J. Org. Chem. 2002, 1956Ϫ1964
1959

F. Zanardi, G. Casiraghi et al.
FULL PAPER
1
1
Table 1. Selected H NMR resonances (δ, ppm), coupling constants (J, Hz), and HϪ1H NOE contacts of bicyclic compounds 11, 12,
17, 18, and 22
Compd.[a] 5a-Hβ 5a-Hα 3J1,2 3J2,3 3J3,4 3J4,5 3J5,5aβ 3J5,5aα 3J1,5aβ 3J1,5aα 4J1,5 4J2,5aβ 4J1,3 4J3,5 NOEs
11
17
12
18
22
2.08
2.11
1.94
2.01
2.23
2.37
2.60
2.97
3.14
2.36
5.4
3.9
5.2
3.9
0.9
3.9
3.5
4.8
3.9
4.3
8.8
9.1
4.3
3.9
2.6
2.6
3.6
4.3
4.7
4.5
5.4
4.5
5.2
4.7
0.0
0.0
0.0
0.0
0.0
5.1
5.4
3.9
5.2
4.8
0.0
0.0
1.7
0.0
1.7
6.3
0.7
1.7
0.7
1.7
1.0
0.6
0.8
0.5
0.5
0.0
0.0
0.0
0.0
0.0
1.4
0.0
0.0
0.0
0.0
1.4
4Ϫ5aα
4Ϫ5aα
4Ϫ5
4Ϫ5
2Ϫ5aβ
[a]
Measured at 300 MHz on 0.1  solutions in CDCl3 at 300 K.
1
1
Table 2. Selected H NMR resonances (δ, ppm), coupling constants (J, Hz), and HϪ1H NOE contacts of target carbasugars 1؊5
Compd.[a] 5a-Hβ 5a-Hα 3J1,2 3J2,3 3J3,4 3J4,5 3J5,5aβ 3J5,5aα 3J1,5aβ 3J1,5aα 4J4,5aα NOEs
1
2
3
4
5
1.39
1.25
1.47
1.25
1.78
1.86
2.07
1.95
2.11
1.55
9.9 2.5
9.8 3.0
10.9 3.1
10.9 2.7
2.7 2.7
3.5
2.9
3.7
2.8
9.6
2.8 12.9
10.9 12.6
3.0 13.0
11.1 12.7
4.3
3.9
3.6
4.1
10.0
11.7
11.4
12.5
12.4
4.8
4.3
4.8
4.2
4.2
9.4
0.0
0.0
1.2
0.0
0.0
1Ϫ5, 2Ϫ5aβ
2Ϫ5aβ, 2Ϫ4, 4Ϫ5aβ, 1Ϫ5
1Ϫ5, 2Ϫ5aβ
2Ϫ5aβ, 2Ϫ4, 4Ϫ5aβ, 1Ϫ5
3Ϫ5, 4Ϫ5aα
9.7
4.8
[a]
Measured at 300 MHz on 0.2  solutions in D2O at 300 K.
4-H and 5-H, underlining the trans diequatorial disposition
One- and two-dimensional 1H NMR analysis of com-
for these protons.
pounds 1Ϫ5 not only served to back up data obtained from
In comparing the proton resonances of the 3,4-trans-con- analysis of the bicyclic structures, but also revealed the ex-
figured compounds (11 and 17) and the 3,4-cis counterparts act conformation of the final targets. Firstly, in cleaving the
(12 and 18), an obvious downfield shift for the 5a-Hβ reson- bicyclic adducts (reductive opening), all these compounds
ance and an equally significant upfield shift for the 5a-Hα underwent a conformational reversal of their six-membered
resonance were observed. The equatorial (11 and 17) or the ring, thus bringing the maximum number of substituents
axial (12 and 18) positioning of the OTBS group at C-4 into the equatorial position. In particular, the 4C1 con-
most likely induces a significant variation in the electronic formation of compounds 1Ϫ4 is supported by the presence
environment surrounding the spatially near 5a-Hα and 5a- of diagnostic upfield quadruplets (δ ϭ 1.25Ϫ1.47 ppm; J ϭ
Hβ (see Table 1).
11.4Ϫ12.5 Hz) belonging to 5a-Hβ and by the existence of
3
3
3
Moving on to consider the bicyclooctane 22, the general coupling constants J1,2, J1,5aβ, and J5,5aβ ranging from
structure, and in particular, the 4C1 conformation of the six- 9.8 to 13.0 Hz, which prove that these protons lie in axial
membered ring, together with the trans relationship of the positions. Furthermore, medium-to-strong NOE constants
substituents at positions 3 and 4, were deciphered by the 1-HϪ5-H and 2-HϪ5a-Hβ support the stereo disposition
absence of large couplings (absence of vicinal protons in a depicted in the structures of Table 2.
trans-diaxial disposition) and by the presence of diagnostic
The equatorial orientation of 4-H in the 3,4-trans prod-
4J values between 1-H and 3-H, 1-H and 5-H, and 3-H and ucts 1 and 3 was demonstrated, as expected, by the vicinal
5-H.
1960
coupling constants and, in the case of compound 3, also by
Eur. J. Org. Chem. 2002, 1956Ϫ1964

Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses
4
FULL PAPER
tions were measured with a PerkinϪElmer 341 polarimeter at am-
a diagnostic long-range W coupling constant J4,5aα
ϭ
bient temperature using a 100-mm cell with a 1-mL capacity and
1.2 Hz. In the 3,4-cis-configured counterparts 2 and 4, 4-H
was determined to lie in the axial position by the large 3J4,5
constants (10.9 and 11.1 Hz) and by the considerable NOE
correlations 2-HϪ4-H and 4-HϪ5a-Hβ. Once more, the 5a-
Hβ and 5a-Hα resonances are markedly influenced by the
are given in units of 10Ϫ1 deg cm2 Ϫ1. Elemental analyses were
g
performed by the Microanalytical Laboratory of University of Sas-
sari. Melting points were determined with an optical thermomicro-
scope Optiphot2-Pol Nikon.
configuration of C-4; in the (4S)-configured products 1 and Materials: 2-[(tert-Butyldimethylsilyl)oxy]furan (6) and 2-[(tert-bu-
tyldimethylsilyl)oxy]thiophene (13) were prepared from 2-fural-
dehyde and thiophene, respectively, according to reported
methods.[17] 2,3-O-Isopropylidene--glyceraldehyde (7) was pre-
pared from -mannitol according to a recently optimized proto-
col.[18]
3 the 5a-Hβ resonances fall downfield, whilst the protons
5a-Hα resonate upfield with respect to the corresponding
protons in the (4R)-disposed compounds 2 and 4 (δ ϭ 1.39
vs. 1.25 ppm; δ ϭ 1.47 vs. 1.25 ppm; δ ϭ 1.86 vs. 2.07 ppm;
δ ϭ 1.95 vs. 2.11 ppm). Finally, for the -series pseudo-
sugar 5, the presence of two large vicinal constants
Lactone 8: The title compound was prepared from (silyloxy)furan
3
(3J1,5aα ϭ 9.4 Hz and J5,5aα ϭ 10.0 Hz), together with the 6 (5.00 g, 25.2 mmol) and glyceraldehyde 7 (3.93 g, 30.2 mmol) ac-
cording to a recently reported four-step procedure.[1] Lactone 8
general analysis of the vicinal and long-range coupling con-
(4.76 g) was isolated in 65% yield as white crystals. M.p. 81Ϫ83 °C.
[α]2D0 ϭ Ϫ14.2 (c ϭ 2.0, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ
0.13 (s, 3 H), 0.14 (s, 3 H), 0.90 (s, 9 H), 2.14 (m, 1 H), 2.27 (m, 1
H), 2.55 (m, 2 H), 3.32 (br. s, 2 H), 3.66 (m, 1 H), 3.79 (m, 3 H),
4.76 (td, J ϭ 7.2, 3.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ Ϫ4.5, Ϫ4.4, 18.0, 23.5, 25.7 (3 C), 28.4, 63.1, 72.3, 74.3, 80.8,
177.6 ppm. C13H26O5Si (290.4): calcd. C 53.76, H 9.02; found C
53.69, H 8.81.
stants, as well as strong NOE correlations for 3-HϪ5-H and
4-HϪ5a-Hα, all but validate the C4 structure thus shown
in Table 2.
1
Conclusion
With the synthesis of five diverse carbapyranoses success-
fully executed, a further element has been woven into the
design of carbasugars and analogues. The defining step in
this approach is a direct silylative cycloaldolization that as-
sembles the densely oxygenated cyclohexane frame from di-
verse and readily obtainable aldehyde intermediates (e.g. 10,
16, and 21). The final carbocyclic construct is formed by
reductive fragmentation of a lactone/thiolactone unit that
delivers both the pseudo-anomeric function and the hydro-
xymethyl terminal in one step.
Lactone 9. Typical Procedure: To a solution of lactone 8 (4.50 g,
15.5 mmol) in dry pyridine (50 mL) under argon at room temper-
ature, were added triethylsilyl triflate (TESOTf, 10.5 mL,
46.5 mmol) and 4-(dimethylamino)pyridine (DMAP, 0.28 g,
2.3 mmol). After stirring at room temperature for 2 h, the reaction
was quenched by addition of distilled water and 5% aqueous citric
acid solution until neutral. The mixture was diluted with CH2Cl2
(30 mL), the layers were separated, and the aqueous layer was ex-
tracted three times with CH2Cl2 (3 ϫ 20 mL). The combined or-
ganic extracts were dried (MgSO4), filtered, and concentrated un-
The viability of this synthetic avenue was verified by the der reduced pressure, and the residue was subjected to flash-chro-
matographic purification (hexanes/EtOAc, 80:20), to give 7.60 g
(95% yield) of 9 as a colourless oil. [α]2D0 ϭ Ϫ23.2 (c ϭ 1.7, CHCl3).
1H NMR (CDCl3, 300 MHz): δ ϭ 0.07 (s, 3 H), 0.10 (s, 3 H), 0.54
(m, 12 H), 0.89 (s, 9 H), 0.94 (br. t, J ϭ 7.9 Hz, 18 H), 1.87 (dq,
J ϭ 12.4, 9.4 Hz, 1 H), 2.23 (dq, J ϭ 12.2, 5.7 Hz, 1 H), 2.46 (m,
2 H), 3.39 (dd, J ϭ 9.1, 4.8 Hz, 1 H), 3.72 (m, 2 H), 3.79 (m, 1 H),
4.62 (dt, J ϭ 8.9, 6.0 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ Ϫ4.7, Ϫ4.5, 4.2 (3 C), 4.8 (3 C), 6.7 (6 C), 18.3, 25.0, 25.9 (3
C), 29.2, 62.9, 73.5, 78.3, 82.3, 177.2 ppm. C25H54O5Si3 (519.0):
calcd. C 57.86, H 10.49; found C 57.78, H 10.58.
efficient preparation of 5a-carba-β--gulopyranose (1), 5a-
carba-β--allopyranose (2), and 5a-carba-β--mannopyr-
anose (5). The syntheses of 1-thio-5a-carba-β--gulopyr-
anose (3) and 1-thio-5a-carba-β--allopyranose (4) were
realized with a similar overall efficiency from 13 and 7.
Experimental Section
General Remarks: Moisture- and air-sensitive reactions were car-
ried out under nitrogen or argon. Reaction flasks were flame-dried
and reactants were introduced by means of syringes. All solvents
were dried by distillation from the appropriate drying agents imme-
Aldehyde 10. Typical Procedure: To a solution of oxalyl chloride
(6.3 mL, 72.3 mmol) in CH2Cl2 (50 mL) at Ϫ80 °C under argon
was added dropwise a solution of dimethyl sulfoxide (DMSO,
diately prior to use. All reagents obtained from commercial sources 10.3 mL, 144.5 mmol) in CH2Cl2 (50 mL). After 10 min, a solution
were used without further purification. Analytical thin layer chro- of protected lactone 9 (7.50 g, 14.5 mmol) in CH2Cl2 (20 mL) was
matography (TLC) was performed on silica gel 60 F254 plates added dropwise. After 20 min at Ϫ80 °C, the mixture was allowed
(0.20 mm layer thickness, Merck). Flash chromatography was per- to rise to Ϫ40 °C and was stirred at this temperature for an addi-
formed on 40Ϫ63 µm silica gel (Merck) using the indicated solvent
mixtures. The compounds were visualized by dipping the plates in
an aqueous H2SO4 solution of cerium sulfate/ammonium molybd-
ate or in an ethanolic solution of ninhydrin, followed by charring
with a heat gun. Proton and carbon NMR spectra were recorded
with Bruker AC-300, Avance 300, and with Varian XL-300 spectro-
meters. Chemical shifts are reported in parts per million (ppm)
downfield from tetramethylsilane using the δ scale. Connectivity
tional 20 min, after which time it was again placed at Ϫ80 °C and
Et3N (36.2 mL, 260.1 mmol) was added dropwise. The reaction
mixture was stirred at Ϫ80 °C for 10 min and then warmed to 25
°C over a period of 2 h. Toluene (100 mL) was added to the mix-
ture, and the solution was filtered and concentrated under vacuum.
The residue was dissolved in hexanes (100 mL), filtered again, and
concentrated under reduced pressure to give aldehyde 10 (5.70 g,
98%) as a colourless oil, which was used as such without further
purification. [α]2D0 ϭ Ϫ7.8 (c ϭ 1.4, CHCl3). 1H NMR (CDCl3,
300 MHz): δ ϭ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.60 (q, J ϭ 7.5 Hz, 6
1
was determined by HϪ1H COSY experiments. 13C NMR assign-
ments were obtained from HETCOR experiments. Optical rota-
Eur. J. Org. Chem. 2002, 1956Ϫ1964
1961

F. Zanardi, G. Casiraghi et al.
FULL PAPER
H), 0.85 (s, 9 H), 0.93 (t, J ϭ 7.9 Hz, 9 H), 1.96 (dq, J ϭ 12.6,
9.6 Hz, 1 H), 2.23 (dq, J ϭ 12.9, 7.0 Hz, 1 H), 2.50 (m, 2 H), 3.92
0.06 (s, 3 H), 0.07 (s, 3 H), 0.08 (s, 3 H), 0.10 (s, 3 H), 0.58 (q, J ϭ
7.9 Hz, 6 H), 0.89 (s, 9 H), 0.90 (s, 9 H), 0.93 (t, J ϭ 7.9 Hz, 9 H),
(dd, J ϭ 6.3, 2.7 Hz, 1 H), 3.98 (dd, J ϭ 2.8, 1.5 Hz, 1 H), 4.55 (q, 1.37 (q, J ϭ 12.3 Hz, 1 H), 1.69 (dt, J ϭ 12.3, 3.9 Hz, 1 H), 1.95
J ϭ 7.2 Hz, 1 H), 9.59 (br. s, 1 H) ppm. 13C NMR (CDCl3, (br. s, 2 H), 2.10 (m, 1 H), 3.49 (dd, J ϭ 10.3, 6.9 Hz, 1 H), 3.55
75 MHz): δ ϭ Ϫ4.8, Ϫ4.7, 4.5 (3 C), 6.5 (3 C), 18.1, 23.7, 25.6 (3 (dd, J ϭ 10.3, 7.9 Hz, 1 H), 3.71 (dd, J ϭ 9.1, 2.3 Hz, 1 H), 3.80
C), 28.4, 77.6, 78.9, 80.2, 176.2, 202.8 ppm. C19H38O5Si2 (402.7):
calcd. C 56.67, H 9.51; found C 56.75, H 9.68.
(m, 3 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ5.3, Ϫ4.6, Ϫ4.2,
Ϫ3.6, 5.1 (3 C), 6.9 (3 C), 17.9, 18.3, 25.8 (3 C), 26.0 (3 C), 29.0,
37.8, 64.0, 69.4, 72.3, 75.3, 75.5 ppm. C25H56O5Si3 (521.0): calcd.
C 57.64, H 10.83; found C 57.79, H 10.75. This carbasugar inter-
mediate (4.12 g, 7.9 mmol) was treated with a solution of 6  aque-
ous HCl/THF/MeOH (1:2:2) (50 mL) at room temperature. The
reaction mixture was stirred for 3 h and then concentrated to dry-
ness under vacuum. The oily crude residue was purified by flash
chromatography (EtOAc/MeOH, 80:20) to afford fully deprotected
carbasugar 1 (1.40 g, 100%) as a glassy solid.[7] [α]2D0 ϭ Ϫ47.0 (c ϭ
Bicycles 11 and 12. Typical Procedure: To a solution of diisopropy-
lethylamine (DIPEA, 7.4 mL, 42.5 mmol) in anhydrous CH2Cl2
(70 mL) at 0 °C under argon, was added TBSOTf (9.8 mL,
42.5 mmol), and the resulting mixture was stirred at the same tem-
perature for 10 min before adding aldehyde 10 (5.70 g, 14.2 mmol),
dissolved in anhydrous CH2Cl2 (70 mL). After 15 min, the mixture
was allowed to come to room temperature and was stirred at room
temperature for 2 h. The reaction was then quenched with distilled
water and saturated NH4Cl solution until pH ϭ 5, and extracted
with CH2Cl2 (3 ϫ 50 mL). The combined extracts were dried
(MgSO4) and concentrated under reduced pressure. The oily res-
idue was purified by flash chromatography (hexanes/EtOAc, 95:5)
to give 5.10 g (69%) of 11 accompanied by 0.44 g (6%) of 12.
1
1.15, MeOH). H NMR (D2O, 300 MHz): δ ϭ 1.39 (td, J ϭ 12.9,
11.7 Hz, 1 H, 5a-Hβ), 1.86 (dt, J ϭ 12.9, 4.3 Hz, 1 H, 5a-Hα), 2.10
(m, 1 H, 5-H),), 3.61 (dd, J ϭ 10.9, 6.5 Hz, 1 H, 6b-H), 3.71 (dd,
J ϭ 9.6, 2.5 Hz, 1 H, 2-H), 3.72 (dd, J ϭ 10.9, 7.4 Hz, 1 H, 6a-H),
3.84 (ddd, J ϭ 11.3, 9.9, 4.8 Hz, 1 H, 1-H), 4.05 (m, 2 H, 3-H, 4-
H) ppm. 13C NMR (D2O, 75 MHz): δ ϭ 29.4 (C-5a), 36.6 (C-5),
62.6 (C-6), 69.2 (C-1), 69.9 (C-4), 72.8 (C-2), 73.1 (C-3) ppm.
C7H14O5 (178.2): calcd. C 47.19, H 7.92; found C 47.13, H 8.02.
Compound 11: Colourless crystals. M.p. 32Ϫ33 °C. [α]2D0 ϭ ϩ54.8
1
(c ϭ 1.1, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 0.04 (s, 3 H,
Me), 0.08 (s, 3 H, Me), 0.09 (s, 3 H, Me), 0.10 (s, 3 H, Me), 0.63
(q, J ϭ 8.0 Hz, 6 H, SiϪCH2CH3), 0.87 (s, 9 H, tBu), 0.93 (s, 9 H,
tBu), 0.94 (t, J ϭ 8.2 Hz, 9 H, SiϪCH2CH3), 2.08 (dtd, J ϭ 11.9,
5.4, 0.6 Hz, 1 H, 5a-Hβ), 2.37 (d, J ϭ 11.9 Hz, 1 H, 5a-Hα), 2.53
(ddd, J ϭ 5.4, 2.5, 0.7 Hz, 1 H, 5-H), 3.63 (dd, J ϭ 8.8, 3.9 Hz, 1
H, 3-H), 3.77 (dd, J ϭ 8.8, 2.6 Hz, 1 H, 4-H), 4.07 (td, J ϭ 4.8,
0.7 Hz, 1 H, 2-H), 4.47 (td, J ϭ 5.4, 0.6 Hz, 1 H, 1-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ Ϫ4.9 (SiϪCH3), Ϫ4.6 (SiϪCH3),
Ϫ4.5 (SiϪCH3), Ϫ3.9 (SiϪCH3), 5.3 (3 C, SiϪCH2CH3), 7.0 (3 C,
SiϪCH2CH3), 18.0 [SiϪC(CH3)3], 18.1 [SiϪC(CH3)3], 25.7 [3 C,
SiϪC(CH3)3], 26.0 [3 C, SiϪC(CH3)3], 29.9 (C-5a), 44.7 (C-5), 70.8
(C-3), 72.3 (C-4), 74.1 (C-2), 78.9 (C-1), 175.1 (C-6) ppm.
C25H52O5Si3 (517.0): calcd. C 58.09, H 10.14; found C 57.96, H
10.20.
5a-Carba-β-D-allopyranose (2): The title compound was prepared
from bicycle 12 (0.44 g, 0.9 mmol) according to the two-step pro-
cedure described for compound 1. After the reductive treatment
and flash-chromatographic purification (hexanes/EtOAc, 70:30), a
partially protected carbasugar intermediate was isolated as a col-
ourless solid. [α]2D0 ϭ ϩ4.9 (c ϭ 0.4, CHCl3). 1H NMR (CDCl3,
300 MHz): δ ϭ 0.09 (s, 3 H), 0.10 (s, 3 H), 0.12 (s, 3 H), 0.13 (s, 3
H), 0.65 (q, J ϭ 7.5 Hz, 6 H), 0.93 (s, 9 H), 0.94 (s, 9 H), 0.96 (t,
J ϭ 7.9 Hz, 9 H), 1.04 (q, J ϭ 12.9 Hz, 1 H), 1.55 (br. s, 1 H), 1.87
(br. s, 1 H), 1.91 (ddd, J ϭ 13.0, 5.1, 4.2 Hz, 1 H), 2.26 (m, 1 H),
3.21 (dd, J ϭ 9.1, 1.9 Hz, 1 H), 3.44 (dd, J ϭ 10.4, 1.7 Hz, 1 H),
3.56 (dd, J ϭ 10.5, 4.4 Hz, 1 H), 3.66 (dd, J ϭ 10.5, 5.8 Hz, 1 H),
3.90 (t, J ϭ 1.8 Hz, 1 H), 3.93 (ddd, J ϭ 11.3, 9.1, 5.3 Hz, 1 H)
ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ4.9, Ϫ4.6, Ϫ4.0, Ϫ3.9,
5.5 (3 C), 7.0 (3 C), 18.0, 18.3, 26.1 (6 C), 31.4, 38.1, 65.2, 69.3,
75.8, 77.1, 78.0 ppm. C25H56O5Si3 (521.0): calcd. C 57.64, H 10.83;
found C 57.58, H 10.77. After the deprotection and flash-chroma-
tographic purification (EtOAc/MeOH, 80:20), pure carbasugar 2
was isolated (122 mg) in 80% yield (two steps) as a colourless glassy
solid.[19] [α]2D0 ϭ ϩ3.1 (c ϭ 0.32, MeOH). 1H NMR (D2O,
300 MHz): δ ϭ 1.25 (q, J ϭ 12.6 Hz, 1 H, 5a-Hβ), 1.98 (m, 1 H,
5-H), 2.07 (ddd, J ϭ 12.6, 4.9, 3.9 Hz, 1 H, 5a-Hα), 3.49 (dd, J ϭ
9.8, 3.0 Hz, 1 H, 2-H), 3.63 (dd, J ϭ 10.9, 2.9 Hz, 1 H, 4-H), 3.71
(dd, J ϭ 11.1, 5.9 Hz, 1 H, 6b-H), 3.84 (dd, J ϭ 11.3, 3.6 Hz, 1 H,
6a-H), 3.88 (ddd, J ϭ 11.4, 9.7, 4.8 Hz, 1 H, 1-H), 4.14 (t, J ϭ
2.9 Hz, 1 H, 3-H) ppm. 13C NMR (D2O, 75 MHz): δ ϭ 27.0 (C-
5a), 35.1 (C-5), 63.4 (C-6), 70.0 (C-1), 71.2 (C-4), 74.1 (C-3), 75.0
(C-2) ppm. C7H14O5 (178.2): calcd. C 47.19, H 7.92; found C 47.26,
H 7.84.
Compound 12: Colourless oil. [α]2D0 ϭ Ϫ4.2 (c ϭ 0.9, CHCl3). 1H
NMR (CDCl3, 300 MHz): δ ϭ 0.04 (s, 3 H, Me), 0.05 (s, 3 H, Me),
0.08 (s, 3 H, Me), 0.09 (s, 3 H, Me), 0.62 (q, J ϭ 7.9 Hz, 6 H,
SiϪCH2CH3), 0.87 (s, 18 H, tBu), 0.95 (t, J ϭ 7.9 Hz, 9 H,
SiϪCH2CH3), 1.94 (broad dt, J ϭ 11.8, 5.2 Hz, 1 H, 5a-Hβ), 2.65
(td, J ϭ 5.1, 0.8 Hz, 1 H, 5-H), 2.97 (d, J ϭ 11.8 Hz, 1 H, 5a-Hα),
3.61 (t, J ϭ 4.2 Hz, 1 H, 3-H), 4.03 (br. t, J ϭ 4.8 Hz, 1 H, 2-H),
4.08 (br. t, J ϭ 4.3 Hz, 1 H, 4-H), 4.55 (td, J ϭ 5.2, 0.7 Hz, 1 H,
1-H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ4.2 (2 C, SiϪCH3),
Ϫ4.4 (2 C, SiϪCH3), 5.0 (3 C, SiϪCH2CH3), 7.0 (3 C,
SiϪCH2CH3), 18.1 [2 C, Si-C(CH3)3], 24.8 (C-5a), 25.7 [6 C,
SiϪC(CH3)3], 45.2 (C-5), 68.5 (C-3), 69.9 (C-4), 70.3 (C-2), 80.1
(C-1), 177.0 (C-6) ppm. C25H52O5Si3 (517.0): calcd. C 58.09, H
10.14; found C 58.00, H 10.06.
5a-Carba-β-D-gulopyranose (1). Typical Procedure: To a solution of
bicyclic adduct 11 (5.10 g, 9.8 mmol) in anhydrous THF (100 mL)
Thiolactone 14: The title compound was prepared from (silyloxy)-
thiophene 13 (3.75 g, 17.5 mmol) and glyceraldehyde 7 (2.96 g,
under argon at room temperature was added dropwise LiBH4
(4.9 mL of a 2.0  solution in THF, 9.8 mmol). After 4 h, the reac- 22.8 mmol) according to a recently reported four-step procedure.[1]
tion was quenched with saturated NH4Cl solution and with 5%
aqueous citric acid solution. The separated aqueous layer was ex-
Thiolactone 14 (2.52 g) was isolated in 47% yield as white crystals.
M.p. 77Ϫ79 °C. [α]2D0 ϭ Ϫ86.6 (c ϭ 1.9, CHCl3). 1H NMR
tracted with CH2Cl2 (3 ϫ 10 mL). The combined organic solutions (300 MHz, CDCl3): δ ϭ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.85 (s, 9 H),
were dried, filtered, and concentrated to leave a residue that was
purified by flash chromatography (hexanes/EtOAc, 70:30 ) to give
a partially protected carbasugar (4.12 g, 81%) as a colourless oil.
[α]2D0 ϭ Ϫ38.5 (c ϭ 1.3, CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ
1.99 (tdd, J ϭ 12.4, 10.8, 8.3 Hz, 1 H), 2.20 (dtd, J ϭ 12.4, 6.3,
3.4 Hz, 1 H), 2.54 (m, 2 H), 2.82 (br. s, 1 H), 3.03 (br. s, 1 H), 3.67
(m, 3 H), 3.90 (dd, J ϭ 5.1, 3.7 Hz, 1 H), 4.13 (dt, J ϭ 10.2, 5.5 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ Ϫ4.5, Ϫ3.9, 18.2, 25.8
1962
Eur. J. Org. Chem. 2002, 1956Ϫ1964

Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses
FULL PAPER
(3 C), 28.7, 42.1, 53.7, 62.8, 73.5, 76.0, 208.8 ppm. C13H26O4SSi
(306.5): calcd. C 50.94, H 8.55; found C 50.89, H 8.50.
H), 4.24 (t, J ϭ 3.9 Hz, 1 H, 3-H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ Ϫ5.2 (2 C, SiϪCH3), Ϫ4.1 (2 C, SiϪCH3), 5.1 (3 C,
SiϪCH2CH3), 7.1 (3 C, SiϪCH2CH3), 18.1 [2 C, SiϪC(CH3)3],
25.9 [6 C, SiϪC(CH3)3], 27.5 (C5a), 51.2 (C-1), 56.6 (C-5), 67.2 (C-
3), 71.8 (C-4), 73.8 (C-2), 208.1 (C-6) ppm. C25H52O4SSi3 (533.0):
calcd. C 56.34, H 9.83; found C 56.22, H 9.90.
Thiolactone 15: The title compound was prepared from thiolactone
14 (2.52 g, 8.2 mmol) according to the procedure described for
compound 9. After flash-chromatographic purification (hexanes/
EtOAc, 90:10), pure thiolactone 15 was recovered (4.32 g) in 98%
1
yield as a yellow oil. [α]2D0 ϭ Ϫ50.8 (c ϭ 10.8, CHCl3). H NMR
1-Thio-5a-carba-β-D-gulopyranose (3): The title compound was pre-
(300 MHz, CDCl3): δ ϭ 0.09 (s, 6 H), 0.51 (q, J ϭ 7.9 Hz, 4 H),
0.63 (q, J ϭ 7.7 Hz, 8 H), 0.89 (s, 9 H), 0.93 (t, J ϭ 8.0 Hz, 6 H),
0.97 (t, J ϭ 7.9 Hz, 12 H), 1.90 (tdd, J ϭ 11.6, 11.1, 8.8 Hz, 1 H),
2.31 (dtd, J ϭ 9.1, 5.8, 3.4 Hz, 1 H), 2.56 (m, 2 H), 3.45 (dd, J ϭ
9.5, 4.8 Hz, 1 H), 3.73 (dd, J ϭ 9.6, 8.0 Hz, 1 H), 3.82 (ddd, J ϭ
8.0, 4.7, 1.2 Hz, 1 H), 3.95 (dd, J ϭ 7.6, 1.1 Hz, 1 H), 4.28 (ddd,
J ϭ 10.7, 7.5, 5.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
Ϫ5.1, Ϫ3.6, 4.3 (3 C), 4.9 (3 C), 6.4, 6.7 (4 C), 6.8, 18.4, 26.0 (3
C), 29.1, 42.6, 54.4, 63.3, 74.5, 79.1, 209.0 ppm. C25H54O4SSi3
(535.0): calcd. C 56.12, H 10.17; found C 56.01, H 10.24.
pared from bicycle 17 (1.37 g, 2.6 mmol) according to the two-step
procedure described for compound 1. During the reduction stage,
further portions of LiBH4 (4 ϫ 1.3 mL of a 2.0  solution in THF,
4 ϫ 2.6 mmol) were added over a period of 5 h. After flash-chro-
matographic purification (hexanes/EtOAc,90:10), a partially pro-
tected carbasugar intermediate was isolated as a colourless oil.
1
[α]D20 ϭ Ϫ25.3 (c ϭ 1.9, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ
0.08 (s, 3 H), 0.09 (s, 6 H), 0.18 (s, 3 H), 0.60 (q, J ϭ 7.9 Hz, 6 H),
0.92 (s, 9 H), 0.94 (s, 9 H), 0.96 (t, J ϭ 7.9 Hz, 9 H), 1.40 (br. s, 1
H), 1.47 (q, J ϭ 12.7 Hz, 1 H), 1.59 (d, J ϭ 5.0 Hz, 1 H), 1.75 (br.
dt, J ϭ 12.7, 3.7 Hz, 1 H), 2.13 (m, 1 H), 3.27 (ddt, J ϭ 12.7, 9.3,
4.4 Hz, 1 H), 3.48 (dd, J ϭ 10.4, 6.1 Hz, 1 H), 3.53 (dd, J ϭ 10.4,
7.7 Hz, 1 H), 3.73 (dd, J ϭ 10.1, 2.3 Hz, 1 H), 3.77 (dd, J ϭ 3.8,
2.3 Hz, 1 H), 3.88 (m, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ
Ϫ5.3, Ϫ4.2 (2 C), Ϫ3.0, 5.2 (3 C), 7.0 (3 C), 17.9, 18.4, 25.8 (3 C),
26.3 (3 C), 31.9, 38.9, 39.2, 64.0, 72.7, 75.0, 75.4 ppm.
C25H56O4SSi3 (537.0): calcd. C 55.91, H 10.51; found C 56.02, H
10.64. After the deprotection step, a crude residue was obtained,
which was purified by flash chromatography (EtOAc/MeOH, 95:5)
utilizing silica gel and a small amount of solid NaHCO3 (30 mg)
charged on the top of the column. Pure carbasugar 3 was isolated
(0.34 g) in 68% yield (two steps) as a white solid. [α]2D0 ϭ Ϫ28.4
(c ϭ 0.8, MeOH). 1H NMR (D2O, 300 MHz): δ ϭ 1.47 (q, J ϭ
12.8 Hz, 1 H, 5a-Hβ), 1.95 (dtd, J ϭ 13.1, 4.1, 1.2 Hz, 1 H, 5a-Hα),
2.07 (dtdd, J ϭ 13.0, 7.0, 3.6, 2.7 Hz, 1 H, 5-H), 3.07 (ddd, J ϭ
12.5, 10.9, 4.2 Hz, 1 H, 1-H), 3.55 (dd, J ϭ 11.0, 6.7 Hz, 1 H, 6b-
H), 3.64 (dd, J ϭ 10.9, 3.4 Hz, 1 H, 2-H), 3.65 (dd, J ϭ 11.0,
7.4 Hz, 1 H, 6a-H), 4.00 (t, J ϭ 3.3 Hz, 1 H, 3-H), 4.05 (m, 1 H,
4-H) ppm. 13C NMR (D2O, 75 MHz): δ ϭ 32.6 (C-5a), 38.2 (C-
5), 39.0 (C-1), 62.8 (C-6), 70.5 (C-4), 72.9 (C-3), 74.2 (C-2) ppm.
C7H14O4S (194.2): calcd. C 43.28, H 7.26; found C 43.21, H 7.30.
Aldehyde 16: The title compound was prepared from thiolactone
15 (4.00 g, 7.5 mmol) according to the procedure described for
compound 10. After flash-chromatographic purification (hexanes/
EtOAc, 85:15), pure aldehyde 16 was isolated (2.57 g) in 82% yield
as a yellow oil. [α]2D0 ϭ Ϫ51.0 (c ϭ 9.9, CHCl3). 1H NMR (CDCl3,
300 MHz): δ ϭ 0.11 (s, 3 H), 0.12 (s, 3 H), 0.56 (q, J ϭ 7.9 Hz, 2
H), 0.63 (q, J ϭ 7.5 Hz, 4 H), 0.85 (s, 9 H), 0.94 (t, J ϭ 8.1 Hz, 3
H), 0.95 (t, J ϭ 7.8 Hz, 6 H), 1.75 (dq, J ϭ 12.3, 9.9 Hz, 1 H), 2.27
(dtd, J ϭ 12.3, 5.5, 4.5 Hz, 1 H), 2.58 (m, 2 H), 3.99 (t, J ϭ 1.5 Hz,
1 H), 4.01 (dt, J ϭ 10.2, 1.2 Hz, 1 H), 4.15 (ddd, J ϭ 10.1, 8.2,
5.6 Hz, 1 H), 9.61 (t, J ϭ 1.4 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ Ϫ4.9, Ϫ3.9, 4.7 (2 C), 5.8, 6.5, 6.6 (2 C), 18.2, 25.8
(3 C), 28.2, 42.4, 53.6, 79.1, 80.2, 203.7, 207.5 ppm. C19H38O4SSi2
(418.7): calcd. C 54.50, H 9.15, found C 54.38, H 9.27.
Bicycles 17 and 18: The title compounds were obtained from alde-
hyde 16 (2.57 g, 6.1 mmol) according to the procedure described
for compounds 11 and 12 (reaction time, 4 h). After flash-chroma-
tographic purification (hexanes/EtOAc, 97:3), pure bicycle 17
(1.37 g) and bicycle 18 (1.24 g) were recovered in 42% and 38%
yields, respectively.
Compound 17: White crystals. M.p. 43Ϫ47 °C. [α]2D0 ϭ ϩ91.8 (c ϭ
1.0, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 0.08 (s, 6 H, Me),
1-Thio-5a-carba-β-D-allopyranose (4): The title compound was pre-
1
pared from bicycle 18 (1.24 g, 2.3 mmol) according to the two-step
procedure described for compound 1. After the reductive step (re-
action time, 2 h), a partially protected carbasugar intermediate was
obtained as white crystals. M.p. 91Ϫ95 °C. [α]2D0 ϭ ϩ2.1 (c ϭ 1.3,
CHCl3). 1H NMR (CDCl3, 300 MHz): δ ϭ 0.08 (s, 3 H), 0.09 (s, 3
H), 0.11 (s, 3 H), 0.17 (s, 3 H), 0.65 (q, J ϭ 7.9 Hz, 6 H), 0.92 (s,
9 H), 0.94 (s, 9 H), 0.95 (t, J ϭ 7.9 Hz, 9 H), 1.09 (q, J ϭ 12.6 Hz,
1 H), 1.56 (d, J ϭ 4.9 Hz, 1 H), 1.85 (br. s, 1 H), 1.96 (dt, J ϭ
13.5, 4.2 Hz, 1 H), 2.22 (m, 1 H), 3.19 (dd, J ϭ 10.1, 1.6 Hz, 1 H),
3.31 (ddt, J ϭ 12.2, 9.3, 4.5 Hz, 1 H), 3.41 (dd, J ϭ 10.4, 1.6 Hz,
1 H), 3.52 (dd, J ϭ 10.5, 4.7 Hz, 1 H), 3.63 (dd, J ϭ 10.5, 5.5 Hz,
1 H), 3.89 (t, J ϭ 1.5 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz):
δ ϭ Ϫ5.2, Ϫ4.3, Ϫ4.1, Ϫ3.7, 5.3 (3 C), 6.8 (3 C), 17.8, 18.1, 25.9
(3 C), 26.0 (3 C), 33.9, 38.4, 39.3, 64.5, 75.4, 76.4, 78.2 ppm.
C25H56O4SSi3 (537.0): calcd. C 55.91, H 10.51; found C 55.88, H
10.44. After the deprotection step, a crude residue was obtained,
0.09 (s, 3 H, Me), 0.13 (s, 3 H, Me), 0.64 (q, J ϭ 7.9 Hz, 3 H,
SϪCH2CH3), 0.65 (q, J ϭ 7.6 Hz, 3 H, SiϪCH2CH3), 0.92 (s, 9 H,
tBu), 0.93 (s, 9 H, tBu), 0.96 (t, J ϭ 8.0 Hz, 9 H, SiϪCH2CH3),
2.11 (dddd, J ϭ 12.2, 5.0, 4.0, 0.8 Hz, 1 H, 5a-Hβ), 2.60 (dd, J ϭ
12.2, 1.5 Hz, 1 H, 5a-Hα), 2.66 (td, J ϭ 4.5, 1.5 Hz, 1 H, 5-H), 3.67
(tt, J ϭ 3.9, 1.7 Hz, 1 H, 1-H), 3.80 (dd, J ϭ 9.1, 3.6 Hz, 1 H, 4-
H), 4.09 (td, J ϭ 4.2, 0.8 Hz, 1 H, 2-H), 4.30 (dd, J ϭ 9.2, 3.5 Hz,
1 H, 3-H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ4.9 (SiϪCH3),
Ϫ4.4 (2 C, SiϪCH3), Ϫ3.9 (SiϪCH3), 5.4 (3 C, SiϪCH2CH3), 7.1
(3 C, SiϪCH2CH3), 18.1 [SiϪC(CH3)3], 18.2 [SiϪC(CH3)3], 25.8 [3
C, SiϪC(CH3)3], 26.0 [3 C, SiϪC(CH3)3], 32.2 (C-5a), 50.3 (C-1),
54.7 (C-5), 72.3 (C-3), 72.7 (C-4), 74.0 (C-2), 204.4 (C-6) ppm.
C25H52O4SSi3 (533.0): calcd. C 56.34, H 9.83; found C 56.46, H
9.91.
Compound 18: White crystals. M.p. 85Ϫ86 °C. [α]2D0 ϭ ϩ20.2 (c ϭ
1
1.1, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 0.07 (s, 3 H, Me), which was purified by flash chromatography (EtOAc/MeOH,
0.10 (s, 3 H, Me), 0.11 (s, 3 H, Me), 0.13 (s, 3 H, Me), 0.65 (q, J ϭ 70:30) utilizing silica gel and a small amount of solid NaHCO3
8.0 Hz, 6 H, SiϪCH2CH3), 0.90 (s, 9 H, tBu), 0.93 (s, 9 H, tBu),
0.99 (t, J ϭ 8.1 Hz, 9 H, SiϪCH2CH3), 2.01 (br. dt, J ϭ 11.4,
(30 mg) charged on the top of the column. Pure carbasugar 4 was
isolated (0.37 g) in 81% yield (two steps) as a colourless glassy
1
4.8 Hz, 1 H, 5a-Hβ), 2.76 (td, J ϭ 4.7, 1.7 Hz, 1 H, 5-H), 3.14 (dd, solid. [α]2D0 ϭ Ϫ34.2 (c ϭ 1.1, MeOH). H NMR (D2O, 300 MHz):
J ϭ 12.1, 1.7 Hz, 1 H, 5a-Hα), 3.75 (tt, J ϭ 3.9, 1.7 Hz, 1 H, 1-H),
δ ϭ 1.25 (q, J ϭ 12.7 Hz, 1 H, 5a-Hβ), 1.91 (m, 1 H, 5-H), 2.11
4.04 (br. t, J ϭ 4.7 Hz, 1 H, 4-H), 4.06 (br. t, J ϭ 3.9 Hz, 1 H, 2- (dt, J ϭ 13.5, 4.1 Hz, 1 H, 5a-Hα), 3.01 (ddd, J ϭ 12.4, 11.0, 4.2 Hz,
Eur. J. Org. Chem. 2002, 1956Ϫ1964
1963

F. Zanardi, G. Casiraghi et al.
1 H, 1-H), 3.36 (dd, J ϭ 10.9, 2.7 Hz, 1 H, 2-H), 3.54 (dd, J ϭ (q, J ϭ 7.9 Hz, 6 H, Si-CH2CH3), 0.87 (s, 9 H, tBu), 0.92 (s, 9 H,
FULL PAPER
11.1, 2.8 Hz, 1 H, 4-H), 3.61 (dd, J ϭ 11.2, 6.2 Hz, 1 H, 6b-H),
3.75 (dd, J ϭ 11.2, 3.7 Hz, 1 H, 6a-H), 4.06 (t, J ϭ 2.7 Hz, 1 H,
3-H) ppm. 13C NMR (D2O, 75 MHz): δ ϭ 35.1 (C-5a), 38.5 (C-
1), 39.5 (C-5), 62.8 (C-6), 70.8 (C-4), 73.8 (C-3), 76.0 (C-2) ppm.
C7H14O4S (194.2): C 43.28, H 7.26; found C 43.35, H 7.32.
tBu), 0.94 (t, J ϭ 7.9 Hz, 9 H, SiϪCH2CH3), 2.23 (dddd, J ϭ 11.4,
6.3, 5.1, 1.5 Hz, 1 H, 5a-Hα), 2.36 (d, J ϭ 11.5 Hz, 1 H, 5a-Hβ),
2.57 (tt, J ϭ 4.8, 1.0 Hz, 1 H, 5-H), 3.83 (dd, J ϭ 4.3, 0.9 Hz, 1 H,
2-H), 3.90 (ddt, J ϭ 4.1, 2.6, 1.4 Hz, 1 H, 3-H), 4.01 (ddd, J ϭ 4.5,
2.3, 1.5 Hz, 1 H, 4-H), 4.55 (bd, J ϭ 6.0 Hz, 1 H, 1-H) ppm. 13C
NMR (CDCl3, 75 MHz): δ ϭ Ϫ5.0 (SiϪCH3), Ϫ4.9 (SiϪCH3),
Ϫ4.8 (SiϪCH3), Ϫ4.3 (SiϪCH3), 4.9 (3 C, SiϪCH2CH3), 6.7 (3 C,
SiϪCH2CH3), 17.8 [SiϪC(CH3)3], 18.5 [SiϪC(CH3)3], 25.5 [3 C,
SiϪC(CH3)3], 26.1 [3 C, SiϪC(CH3)3], 31.0 (C-5a), 43.6 (C-5), 69.5
(C-2), 71.5 (C-4), 76.0 (C-3), 82.9 (C-1), 175.2 (C-6) ppm.
C25H52O5Si3 (516.9): calcd. C 58.09, H 10.14; found C 58.16, H
10.27.
Lactone 19: The title compound was prepared from (silyloxy)furan
6 (2.50 g, 12.6 mmol) and glyceraldehyde 7 (1.97 g, 15.1 mmol) ac-
cording to a recently reported five-step procedure.[1] Lactone 19
(1.5 g) was isolated in 41% yield as a colourless oil. [α]2D0 ϭ ϩ7.0
(c ϭ 9.6, CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ Ϫ0.01 (s, 3
H), 0.01 (s, 3 H), 0.79 (s, 9 H), 2.08 (m, 1 H), 2.25 (m, 1 H), 2.42
(m, 2 H), 3.50 (m, 4 H), 3.68 (m, 1 H), 3.91 (dd, J ϭ 6.8, 2.5 Hz,
1 H), 4.75 (td, J ϭ 7.6, 2.5 Hz, 1 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ Ϫ4.9, Ϫ4.4, 17.9, 20.8, 25.7 (3 C), 28.7, 63.1, 72.0,
72.3, 81.2, 178.0 ppm. C13H26O5Si (290.4) calcd. C 53.76, H 9.02;
found C 53.69, H 9.09.
5a-Carba-β-L-mannopyranose (5): The title compound was prepared
from bicycle 22 (1.20 g, 2.3 mmol) according to the two-step pro-
cedure described for compound 1. During the reductive step, fur-
ther portions of LiBH4 (10 ϫ 1.2 mL of a 2.0  solution in THF,
10 ϫ 2.3 mmol) were added over a period of 24 h. After flash-
chromatographic purification (hexanes/EtOAc, 60:40), a partially
protected carbasugar intermediate was isolated a colourless oil. [α]
Lactone 20: The title compound was prepared from lactone 19
(1.50 g, 5.2 mmol) according to the procedure described for com-
pound 9. After flash-chromatographic purification (hexanes/
EtOAc, 95:5), pure lactone 20 was recovered (2.60 g) in 98% yield
as a colourless oil. [α]2D0 ϭ Ϫ15.1 (c ϭ 5.0, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.06 (s, 3 H), 0.07 (s, 3 H), 0.58 (q, J ϭ
7.9 Hz, 6 H), 0.59 (q, J ϭ 7.8 Hz, 6 H), 0.87 (s, 9 H), 0.93 (t, J ϭ
7.9 Hz, 9 H), 0.94 (t, J ϭ 7.8 Hz, 9 H), 2.10 (m, 1 H), 2.40 (m, 1
H), 2.50 (m, 2 H), 3.46 (dd, J ϭ 10.1, 6.0 Hz, 1 H), 3.58 (dd, J ϭ
10.1, 6.8 Hz, 1 H), 3.74 (td, J ϭ 6.3, 3.3 Hz, 1 H), 4.09 (t, J ϭ
2.8 Hz, 1 H), 4.72 (td, J ϭ 7.0, 2.6 Hz, 1 H) ppm. 13C NMR
(CDCl3, 75 MHz): δ ϭ Ϫ5.1, Ϫ4.8, 4.0 (3 C), 4.7 (3 C), 6.4 (3 C),
6.5 (3 C), 17.8, 21.9, 25.6 (3 C), 28.3, 64.2, 73.6, 75.8, 80.2, 176.4
ppm. C25H54O5Si3 (519.0): calcd. C 57.86, H 10.49; found C 57.93,
H 10.40.
20
1
ϭ Ϫ1.27 (c ϭ 1.2, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ
D
0.06 (s, 3 H), 0.07 (s, 3 H), 0.10 (s, 3 H), 0.13 (s, 3 H), 0.67 (q, J ϭ
8.0 Hz, 6 H), 0.89 (s, 9 H), 0.93 (s, 9 H), 1.98 (t, J ϭ 8.0 Hz, 9 H),
1.70 (m, 1 H), 1.84 (m, 4 H), 3.64 (m, 1 H), 3.76 (m, 2 H), 3.83
(dd, J ϭ 10.7, 6.3 Hz, 1 H), 3.89 (dd, J ϭ 10.9, 5.5 Hz, 1 H), 3.94
(t, J ϭ 2.7 Hz, 1 H) ppm. 13C NMR (CDCl3, 75 MHz): δ ϭ Ϫ4.9,
Ϫ4.7, Ϫ4.1, Ϫ3.9, 5.1 (3 C), 7.0 (3 C), 18.0, 18.5, 25.9 (3 C), 26.1
(3 C), 29.7, 42.5, 64.5, 71.0, 72.2, 76.8 (2 C) ppm. C25H56O5Si3
(521.0): calcd. C 57.64, H 10.83; found C 57.55, H 10.91. The de-
protection step lasted 6 h at 40 °C. After flash-chromatographic
purification (EtOAc/MeOH/28% aq NH4OH, 49:49:2), pure carba-
sugar 5 was isolated (0.24 g) in 59% yield (two steps) as colourless
needles. M.p. 218Ϫ219 °C. [α]2D0 ϭ Ϫ10.7 (c ϭ 0.6, H2O) {ref.[20]
for the β--enantiomer: M.p. 223 °C, [α]D ϩ10.4 (c ϭ 0.24, H2O)}.
1H NMR (D2O, 300 MHz): δ ϭ 1.55 (m, 2 H, 5-H and 5a-Hα),
1.78 (dtd, J 12.3, 4.8, 1.4 Hz, 1 H, 5a-Hβ), 3.45 (dd, J ϭ 9.6, 2.7 Hz,
1 H, 3-H), 3.50 (t, J ϭ 9.7 Hz, 1 H, 4-H), 3.60 (dd, J ϭ 11.2,
6.0 Hz, 1 H, 6b-H), 3.77 (dd, J ϭ 11.2, 3.3 Hz, 1 H, 6a-H), 3.80
(ddd, J ϭ 9.4, 4.8, 2.7 Hz, 1 H, 1-H), 4.02 (td, J ϭ 2.6, 1.4 Hz, 1
H, 2-H) ppm. 13C NMR (D2O, 75 MHz): δ ϭ 29.2 (C-5a), 40.8 (C-
5), 63.0 (C-6), 69.2 (C-1), 70.4 (C-4), 73.6 (C-2), 74.7 (C-3) ppm.
C7H14O5 (178.2): calcd. C 47.19, H 7.92; found C 47.21, H 7.88.
Aldehyde 21: To a solution of oxalyl chloride (3.3 mL, 38.0 mmol)
in CH2Cl2 (40 mL) at Ϫ80 °C under argon, was added dropwise a
solution of DMSO (5.4 mL, 76.0 mmol) in CH2Cl2 (40 mL). After
20 min, a solution of protected lactone 20 (2.60 g, 5.1 mmol) in
CH2Cl2 (40 mL) was added dropwise. The mixture was allowed to
come to Ϫ40 °C and, after being stirred for 20 min at this temper-
ature, the reaction mixture was stirred at Ϫ15 °C for 30 min. The
mixture was cooled again at Ϫ40 °C and Et3N (19.0 mL,
136.9 mmol) was added dropwise. The reaction mixture was stirred
at Ϫ40 °C for 5 min, and then warmed to 25 °C. After 1 h, toluene
(100 mL) was added to the mixture, and the solution was filtered
and concentrated under vacuum. The residue was dissolved in hex-
anes (50 mL), filtered again, and concentrated under reduced pres-
sure to give, after flash-chromatographic purification (hexanes/
Acknowledgments
This work was supported by a research grant from the Ministero
`
dell’Universita e della Ricerca Scientifica e Tecnologica (MURST,
EtOAc, 80:20), aldehyde 21 (1.27 g, 70%) as a yellow oil. [α]2D0
ϭ
COFIN 2000). A doctoral fellowship to V. Z. from the European
Community is gratefully acknowledged. We also wish to thank the
1
Ϫ5.3 (c ϭ 2.7, CHCl3). H NMR (CDCl3, 300 MHz): δ ϭ 0.05 (s,
3 H), 0.08 (s, 3 H), 0.58 (q, J ϭ 8.0 Hz, 6 H), 0.82 (s, 9 H), 0.91
(t, J ϭ 8.0 Hz, 9 H), 2.18 (m, 2 H), 2.46 (m, 2 H), 3.97 (dd, J ϭ
3.2, 1.8 Hz, 1 H), 4.02 (dd, J ϭ 4.8, 3.3 Hz, 1 H), 4.57 (td, J ϭ 7.5,
5.2 Hz, 1 H), 9.56 (d, J ϭ 1.7 Hz, 1 H) ppm. 13C NMR (CDCl3,
75 MHz): δ ϭ Ϫ5.0, Ϫ4.5, 4.5 (3 C), 6.5 (3 C), 17.9, 23.0, 25.6 (3
C), 28.3, 75.9, 78.9, 79.2, 176.5, 202.6 ppm. C19H38O5Si2 (402.7):
calcd. C 56.67, H 9.51; found C 56.63, H 9.64.
`
`
Centro Interfacolta di Misure ‘‘G. Casnati’’, Universita di Parma,
for the access to the analytical instrumentation.
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pounds 11 and 12. After flash-chromatographic purification (hex-
anes/EtOAc, 90:10), pure bicycle 22 (1.20 g) was recovered in 74%
as a colourless oil. [α]2D0 ϭ ϩ29.2 (c ϭ 2.4, CHCl3). 1H NMR
(CDCl3, 300 MHz): δ ϭ 0.06 (s, 3 H, Me), 0.09 (s, 9 H, Me), 0.58
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Eur. J. Org. Chem. 2002, 1956Ϫ1964

Non-Racemic 5a-Carbahexopyranoses and 1-Thio-5a-carbahexopyranoses
FULL PAPER
[4] [4a]
[11]
[12]
[13]
N. Asano, R. J. Nash, R. J. Molyneaux, G. W. J. Fleet,
The synthesis of compound 1 has been already reported by our
[4b]
Tetrahedron: Asymmetry 2000, 11, 1645Ϫ1680.
T. D.
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´
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Worthy of note is the use of LDA in a similar cycloaldolization
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ponding 3,4-trans-configured aldol adduct, but with a low con-
version of the starting aldehyde.[7] In the present silylative
cycloaldolization, a complete conversion of the starting alde-
hyde was observed. The slightly lower diastereoselectivity (dr ϭ
92:8) is largely compensated for by the greater efficiency of this
improved manoeuvre.
At the moment, we cannot completely explain the mechanism
of this transformation, which most probably proceeds through
a cascade of events (enolsilylation, aldolization, silylation). One
could argue that such subtle kinetic and thermodynamic fac-
tors dictate the diastereocontrol of this and other cycloaldoliz-
ation reactions mentioned in this study.
The same transformation could be conveniently effected by
exposure of 11 to LiAlH4 (1.0  solution in THF). The loss of
the TES group, however, was observed.
Compare this result to the 14% overall yield (11steps) of the
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1965