Diastereoselective synthesis of piperidine imino sugars using Aldol additions of metalated bislactim ethers to threose and erythrose acetonides

Article abstract of DOI:10.1021/jo702601z

(Chemical Equation Presented) A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched and mismatched

Full text of DOI:10.1021/jo702601z

Diastereoselective Synthesis of Piperidine Imino Sugars Using Aldol
Additions of Metalated Bislactim Ethers to Threose and Erythrose
Acetonides
Mar´ıa Ruiz,* Tania M. Ruanova, Olga Blanco, Fa´tima Nu´n˜ez, Cristina Pato, and
Vicente Ojea*
Departamento de Qu´ımica Fundamental, Facultade de Ciencias, UniVersidade da Corun˜a,
Campus da Zapateira s/n, 15071 A Corun˜a, Spain
ruizpr@udc.es; ojea@udc.es
ReceiVed December 5, 2007
A general strategy for the synthesis of 1-deoxy-azasugars from a chiral glycine equivalent and 4-carbon
building blocks is described. Diastereoselective aldol additions of metalated bislactim ethers to matched
and mismatched erythrose or threose acetonides and intramolecular N-alkylation (by reductive amination
or nucleophilic substitution) were used as key steps. The dependence of the yield and the asymmetric
induction of the aldol addition with the nature of the metallic counterion of the azaenolate and the γ-alkoxy
protecting group for the erythrose or threose acetonides has been studied. The stereochemical outcome
of the aldol additions with tin(II) azaenolates has been rationalized with the aid of density functional
theory (DFT) calculations. In accordance with DFT calculations with model glyceraldehyde acetonides,
high trans,syn,anti-selectivitity for the matched pairs and moderate to low trans,anti,anti-selectivity for
the mismatched ones may originate from (1) the intervention of solvated aggregates of tin(II) azaenolate
and lithium chloride as the reactive species and (2) favored chair-like transition structures with a Cornforth-
like conformation for the aldehyde moiety. DFT calculations indicate that aldol additions to erythrose
acetonides proceed by an initial deprotonation, followed by coordination of the alkoxy-derivative to the
tin(II) azaenolate and final reorganization of the intermediate complex through pericyclic transition
structures in which the erythrose moiety is involved in a seven-membered chelate ring. The preparative
utility of the aldol-based approach was demonstrated by application in concise routes for the synthesis
of the glycosidase inhibitors 1-deoxy-D-allonojirimycin, 1-deoxy-L-altronojirimycin, 1-deoxy-D-gulonojiri-
mycin, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin and 1-deoxy-D-talonojirimycin.
Introduction
the nitrogen renders the imino sugars metabolically inert but
does not prevent their recognition by glycoprocessing enzymes.
When protonated, imino sugars resemble the transient oxocar-
Glycobiology is a rapidly growing research area uncovering
multiple biological processes wherein carbohydrates play a
major role. Natural and synthetic alkaloidal sugar mimics with
a nitrogen in the ring (imino sugars, commonly named as aza
sugars)1 have emerged as important tools for glycobiology
research.2 The substitution of the ring oxygen of the sugars with
(1) Although in broad usage, the term aza sugar is incorrect. It should
be restricted to structures where carbon, not oxygen, is replaced by a
nitrogen. For IUPAC recommendations on the nomenclature of carbohy-
drates, see: Pure Appl. Chem. 1996, 68, 1919-2008.
(2) Dwek, R. A. Chem. ReV. 1996, 96, 683-720.
10.1021/jo702601z CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/27/2008
2240
J. Org. Chem. 2008, 73, 2240-2255

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
CHART 1
CHART 2
diabetes type 1, Gaucher disease, and lysosomal storage disorder,
and galacto-DNJ (AT1001) is currently in phase B clinical trials
for the treatment of Fabry’s disease.8 Conversely, other dias-
tereoisomers of DNJ have received less synthetic attention, and
therefore, there are few reports on glycosidase inhibition by allo-
DNJ (4),9 altro-DNJ (5),10,11 gulo-DNJ (6),12,13 ido-DNJ (7),14,15
and talo-DNJ (8,16,17 see Chart 2).18
bonium ion involved in glycoside hydrolysis and thus can act
as transition-state analogues for the competitive inhibition of
the glycosidases and glycosyltransferases. Inhibition of these
enzymes affects the maturation, transport, secretion, and function
of glycoproteins and could alter cell-cell or cell-virus recogni-
tion processes. Therefore, glycosidase inhibitors have been
shown to interact with receptors related to a wide range of
prominent diseases including viral infections, cancer, diabetes
and other metabolic disorders and are expected to find an
increasing number of applications as beneficial drugs.3
Inhibitors of glycosidases that are essential for survival, such
as the archetypal 1-deoxynojirimycin (DNJ, 1), manno-DNJ (2),
or galacto-DNJ (3), have been extensively studied in synthetic
chemical4-6 and biochemical laboratories (see Chart 1). Thus,
N-butyl-DNJ (Zavesca) and N-hydroxyethyl-DNJ (Miglitol or
Glyset)7 have been already approved for the treatment of
Although traditionally polyhydroxylated piperidines have
been synthesized through enantiospecific transformations of
(8) (a) Fan, J.-Q.; Ishii, S.; Asano, N.; Suzuki, Y. Nat. Med. 1999, 5,
112-115. (b) See: http://www.clinicaltrials.gov/ct/gui/show/NCT00231036.
(9) Previous synthesis of allo-DNJ: (a) Altenbach, H.-J.; Himmeldirk,
K. Tetrahedron: Asymmetry 1995, 6, 1077-1080. (b) Ikota, N.; Hirano,
J.-i.; Gamage, R.; Nakagawa, H.; Hama-Inaba, H. Heterocycles 1997, 46,
637-643. (c) Wu, X.-D.; Khim, S.-K.; Zhang, X.; Cederstrom, E.; Mariano,
P. S. J. Org. Chem. 1998, 63, 841-859. (d) Hong, B.-C.; Chen, Z.-Y.;
Nagarajan, A.; Kottani, R.; Chavan, V.; Chen, W.-H.; Jiang, Y.-F.; Zhang,
S.-C.; Liao, J.-H.; Sarshar, S. Carbohydr. Res. 2005, 340, 2457-2468. (e)
Ghosh, S.; Shashidhar, J.; Dutta, S. K. Tetrahedron Lett. 2006, 47, 6041-
6044. (f) Guaragna, A.; D’Errico, S.; D’Alonzo, D.; Pedatella, S.; Palumbo,
G. Org. Lett. 2007, 9, 3473-3476.
(10) For a carbohydrate-based synthesis of altro-DNJ, see ref 5f.
(11) Diastereoselective synthesis of altro-DNJ: (a) Xu, Y.-M.; Zhou,
W.-S. J. Chem. Soc., Perkin Trans. 1 1997, 741-746. (b) Kazmaier, U.;
Grandel, R. Eur. J. Org. Chem. 1998, 1833-1840. (c) Takahata, H.; Banba,
Y.; Sasatani, M.; Nemoto, H.; Kato, A.; Adachi, I. Tetrahedron 2004, 60,
8199-8205. (d) Dhavale, D. D.; Markad, S. D.; Karanjule, N. S.;
PrakashaReddy, J. J. Org. Chem. 2004, 69, 4760-4766; see also refs 6b,f,g
and 9f.
(3) (a) Asano, N. Glycobiology 2003, 13, 93R-104R. (b) Martin, O.
R., Compain, P., Eds.; Iminosugars: Recent Insights into their Bioactivity
and Potential as Therapeutic Agents. Curr. Top. Med. Chem. 2003, 3 (5).
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J. Phytochemistry 2001, 56, 265-295. (d) Iminosugars as Glycosidase
Inhibitors: Nojirimicyn and Beyond; Stu¨tz, A. E., Ed.; Wiley-VCH:
Weinheim, 1999.
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and other imino sugars, see: (a) Afarinkia, K.; Bahar, A. Tetrahedron:
Asymmetry 2005, 16, 1239-1287. (b) Pearson, M. S. M.; Mathe´-Allainmat,
M.; Fargeas, V.; Lebreton, J. Eur. J. Org. Chem. 2005, 2159-2191. (c)
Cipolla, L.; La Ferla, B.; Nicotra, F. Curr. Top. Med. Chem. 2003, 3, 485-
511.
(5) Enantiospecific (carbohydrate-based) synthesis of galacto-DNJ: (a)
Paulsen, H.; Hayauchi, Y.; Sinnwell, V. Chem. Ber. 1980, 113, 2601-
2608. (b) Legler, G.; Pohl, S. Carbohydr. Res. 1986, 155, 119-129. (c)
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McDonnell, C.; Cronin, L.; O’Brien, J. L.; Murphy, P. V. J. Org. Chem.
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(6) Diastereoselective routes to galacto-DNJ: (a) Aoyagi, S.; Fujimaki,
S.; Yamazaki, N.; Kibayashi, C. J. Org. Chem. 1991, 56, 815-819. (b)
Liu, K. K.-C.; Kajimoto,T.; Chen, L.; Zhong, Z.; Ichikawa, Y.; Wong, C.-
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S.; Katsumura, S. Chem. Commun. 1999, 41-42. (g) Mehta, G.; Mohal,
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Ouchi, H.; Nemoto, H. Org. Lett. 2003, 5, 2527-2529. (i) Pyun, S.-j.; Lee,
K.-y.; Oh, C.-y.; Ham, W.-h. Heterocycles 2004, 62, 333-341.
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R.; Hollack, C.; Aerts, J.; van Weely, S.; Hrebicek, M.; Platt, F. M.; Butters,
T. D.; Dwek, R.; Moyses, C.; Gow, L.; Elstein, D.; Zimran, A. Lancet 2000,
355, 1481-1485. (c) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top.
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(12) Enantiospecific synthesis of gulo-DNJ: (a) Leontein, K.; Lindberg,
B.; Lo¨nngren, J. Acta Chem. Scand. B 1982, 36, 515-518. (b) Joseph, C.
C.; Regeling, H.; Zwanenburg, B.; Chittenden, G. J. F. Carbohydr. Res.
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(13) Diastereoselective synthesis of gulo-DNJ: (a) Liao, L.-X.; Wang,
Z.-M.; Zhang, H.-X.; Zhou, W.-S. Tetrahedron: Asymmetry 1999, 10,
3649-3657. (b) Haukaas, M. H.; O’Doherty, G. A. Org. Lett. 2001, 3,
401-404. (c) Amat, M.; Huguet, M.; Llor, N.; Bassas, O.; Go´mez, A. M.;
Bosch, J.; Badia, J.; Baldoma, L.; Aguilar, J. Tetrahedron Lett. 2004, 45,
5355-5356. (d) Pyun, S.-J.; Lee, K.-Y.; Oh, C.-Y.; Joo, J.-E.; Cheon, S.-
H.; Ham, W.-H. Tetrahedron 2005, 61, 1413-1416; see also ref 6h.
(14) Enantiospecific synthesis of ido-DNJ: (a) Fowler, P. A.; Haines,
A. H.; Taylor, R. J. K.; Chrystal, E. J. T.; Gravestock, M. B. Carbohydr.
Res. 1993, 246, 377-381. (b) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.;
Dosbaa, I.; Geoffroy, S.; Fogliettti, M.-J. Bioorg. Med. Chem. 1997, 5, 519-
533. (c) Hugel, H. M.; Hughes, A. B.; Khalil, K. Aust. J. Chem. 1998, 51,
1149-1155. (d) Lee, B. W.; Jeong, I.-Y.; Yang, M. S.; Choi, S. U.; Park,
K. H. Synthesis 2000, 1305-1309.
(15) Diastereoselective synthesis of ido-DNJ: (a) Dhavale, D. D.; Kumar,
K. S. A.; Chaudhain, V. D.; Sharma, T.; Sabharwal, S. G.; PrakashaReddy,
J. Org. Biomol. Chem. 2005, 3, 3720-3726. (b) Schaller, C.; Vogel, P.;
Ja¨ger, V. Carbohydr. Res. 1998, 314, 25-35. See also ref 6b,h.
(16) Carbohydrate-based synthesis of talo-DNJ: Hashimoto, H.; Hay-
akawa, M. Chem. Lett. 1989, 1881-1884. See also ref 12b.
(17) Diastereoselective synthesis of talo-DNJ: C. R. Johnson, Golebio-
wski, A.; Schoffers, E.; Sundram, H.; Braun, M. P. Synlett 1995, 313-
314. See also refs 6b,c and 13a.
(18) Kato, A.; Kato, N.; Kano, E.; Adachi, I.; Ikeda, K.; Yu, L.; Okamoto,
T.; Banba, Y.; Ouchi, H.; Takahata, H.; Asano, N. J. Med. Chem. 2005,
48, 2036-2044 and references therein.
J. Org. Chem, Vol. 73, No. 6, 2008 2241

Ruiz et al.
SCHEME 1
stereocontrolled aldol additions. Threose and erythrose deriva-
tives 10 were sought as appropriate precursors, delivering
various configurations at positions 2 and 3 and being suitably
functionalized at positions 1 and 4. Moreover, additions to 2,3-
O-isopropylidene-threose and -erythrose derivatives (such as 10)
proceed with variable stereoselectivity, which can be modulated
by selecting the organometallic reagent.26 On the other hand,
we found Scho¨llkopf’s bislactim ethers to be very attractive, a
result of the high π-facial discrimination shown by these
reagents in aldol-type reactions.27 In particular, the reactions
of titanium(IV), tin(II) or zinc(II) salts of bislactim ethers (such
as 11) with either matched or mismatched polyhydroxylated
aldehydes have been reported to proceed under almost complete
azaenolate control.28,29 Surprisingly, until now there was only
one other approach that relied on glycine as starting material
for the synthesis of DNJ derivatives.30 Kazmaier has reported
an elegant synthesis of 1-deoxy-altronojirimycin11b using deriva-
tives of L-tartaric acid as homologating reagents for N-
tosylglycinate esters.
readily available carbohydrate precursors,5,12,14,16 recent interest
has increasingly focused on the stereoselective synthesis of this
class of compounds.19 Prominent among these strategies are
cycloaddition-based routes,20 chemoenzymatic functionalization
of carbocyclic intermediates,21,17 aldolase-catalyzed condensation
reactions,6b,c and stereoselective elongation of homochiral short
precursors exploiting different chemical procedures.22 Moreover,
in recent years, many efforts have been devoted to develop
generally applicable and flexible methodologies, amenable to
implementation of stereochemical variations for the asymmetric
synthesis of any diastereoisomer of DNJ. Particularly useful
among the general approaches are those relying on piperidene23
or dihydropyridinone key intermediates, which can be prepared
by stereoselective transformation of D-serine derivatives24 or
aza-Achmatowicz rearrangement of â-alkoxyfurfurylamines.11a,13a,b
As part of a project directed toward an efficient synthesis of
bioactive amino polyol derivatives, we have recently developed
a convergent approach to 2-amino-2-deoxyhexoses, where the
stereoselective construction of the sugar backbone relied on an
aldol reaction using derivatives of natural amino acids as chiral
auxiliaries and building blocks.25 Looking for a general and
flexible methodology for the preparation of 1-deoxyazasugars
of various configurations, we decided to extend the applicability
of our aldol-based approach to amino sugars. In formulating
the synthetic plan, we recognized that polyhydroxy amino acids
9 might be valuable key intermediates, since the targeted aza
sugars would originate by cyclization, via reductive amination
or nucleophilic substitution of an activated hydroxyl group,
followed by reduction of the carboxylic acid group (see Scheme
1). We envisaged preparing key intermediates 9 from four-
carbon building blocks and a chiral glycine equivalent by
Thus, in this paper we wish to report in full details our results
on the aldol reactions between metalated bislactim ethers derived
from cyclo-[Gly-Val] and 2,3-O-isopropylidene-erythrose and
-threose derivatives of complementary or non-complementary
configurations.31 To gain more insight into the origins of the
stereoselection, we have also carried out a computational study
of the possible reaction pathways, and transition-state models
consistent with the stereochemical outcome of the aldol additions
are also put forward. Finally, we demonstrate the general
applicability of our aldol-based approach to piperidine imino
sugars with an efficient transformation of the addition products
into the six less-studied diastereoisomers of DNJ: D-galacto-
(26) (a) Guillarme, S.; Ple´, K.; Banchet, A.; Liard, A.; Haudrechy, A.
Chem. ReV. 2006, 106, 2355-2403. (b) Evans, D. A.; Glorius, F;, Burch,
J. D. Org. Lett. 2005, 7, 3331-3333. (c) Majewski, M.; Shao, J.; Nelson,
K.; Nowak, P.; Irvine, N. M. Tetrahedron Lett. 1998, 39, 6787-6790. (d)
Lehmann, T. E.; Berkessel, A. J. Org. Chem. 1997, 62, 302-309. (e)
Pearson, W. H.; Hembre, E. J. J. Org. Chem. 1996, 61, 7217-7221. (f)
Martin, S. F.; Chen, H.-J.; Lynch, V. M. J. Org. Chem. 1995, 60, 276-
278. (g) Gallagher, T.; Giles, M.; Subramanian, R. S.; Hadley, M. S. J.
Chem. Soc., Chem. Commun. 1992, 166-168. (h) Mekki, B.; Singh, G.;
Wightman, R. H. Tetrahedron Lett. 1991, 32, 5143-5146. (i) Mukaiyama,
T.; Suzuki, K.; Yamada, T.; Tabusa, F. Tetrahedron 1990, 46, 265-276.
(j) Bukownik, R. R.; Wilcox, C. S. J. Org. Chem. 1988, 53, 463-471. (k)
Buchanan J. G.; Jigajinni, V. B.; Singh, G.; Wightman, R. H. J. Chem.
Soc., Perkin Trans. 1 1987, 2377-2383 and references therein. (l) Corey,
E. J.; Pan, B.-C.; Duy, H. H.; Deardoff, D. R. J. Am. Chem. Soc. 1982,
104, 6816-6818.
(27) Williams, R. M. Synthesis of Optically ActiVe R-Amino Acids;
Baldwin, J. E., Magnus, P. D., Eds.; Organic Chemistry Series, Vol. 7;
Pergamon: Oxford, 1989.
(28) (a) Grauert, M.; Scho¨llkopf, U. Liebigs Ann. Chem. 1985, 1817-
1824. (b) Depezay, J. C.; Dureault, A.; Prange, T. Tetrahedron Lett. 1984,
25, 1459-1462.
(29) (a) Kobayashi, S.; Furuta, T.; Hayashi, T.; Nishijima, M.; Hanada,
K. J. Am. Chem. Soc. 1998, 120, 908-919. (b) Kobayashi, S.; Furuta, T.
Tetrahedron 1998, 54, 10275-10294. (c) Kobayashi, S.; Matsumura, M.;
Furuta, T.; Hayashi, T.; Iwamoto, S. Synlett 1997, 301-303. See also:
Cremonesi, G.; Dalla Croce, P.; Fontana, F.; Forni, A.; La Rosa, C.
Tetrahedron: Asymmetry 2007, 18, 1667-1675.
(30) For conceptually related approaches to amino- or imino sugars,
see: (a) Fujii, M.; Miura, T.; Kajimoto, T.; Ida, Y. Synlett 2000, 1046-
1048. (b) Polt, R.; Sames, D.; Chruma, J. J. Org. Chem. 1999, 64, 6147-
6158. (c) Banfi, L.; Cardani, S.; Potenza, D.; Scolastico, C. Tetrahedron
1987, 43, 2317-2322. (d) Mukaiyama, T.; Miwa, T.; Nakatsuta, T. Chem.
Lett. 1982, 145-148.
(19) Hudlicky, T.; Entwistle, D. A.; Pitzer, K. K.; Thorpe, A. J. Chem.
ReV. 1996, 96, 1195-1220.
(20) See, for example: (a) Auberson, Y.; Vogel, P. Angew. Chem., Int.
Ed. Engl. 1989, 28, 1498-1499. (b) Streith, J.; Defoin, A. Synlett 1996,
189-200.
(21) See, for example: Hudlicky, T.; Rouden, J.; Luna, H.; Allen, S. J.
Am. Chem. Soc. 1994, 116, 5099-5107.
(22) Casiraghi, G.; Zanardi, F.; Rassu, G.; Spanu, P. Chem. ReV. 1995,
95, 1677-1716.
(23) (a) Mart´ın, R.; Moyano, A.; Perica`s, M. A.; Riera, A. Org. Lett.
2000, 2, 93-95. (b) Mart´ın, R.; Murruzzu, C.; Perica`s, M. A.; Riera, A. J.
Org. Chem. 2005, 70, 2325-2328. See also ref 9f.
(24) Subramanian, T.; Lin, C.-C.; Lin, C.-C. Tetrahedron Lett. 2001,
41, 4079-4082. See also refs 6f,h, 9a,c,f, and 18.
(25) (a) Ruiz, M.; Ojea, V.; Quintela, J. M. Tetrahedron Lett. 1996, 37,
5743-5746. (b) Ojea, V.; Ruiz, M.; Quintela, J. M. Synlett 1997, 83-84.
(c) Ruiz, M.; Ojea, V.; Quintela, J. M. Tetrahedron: Asymmetry 2002, 13,
1535-1549. (d) Ruiz, M.; Ojea, V.; Quintela, J. M. Tetrahedron: Asym-
metry 2002, 13, 1863-1873.
(31) Part of this work was already presented as preliminary communica-
tions: (a) Ruiz, M.; Ojea, V.; Ruanova, T. M.; Quintela, J. M. Tetrahe-
dron: Asymmetry 2002, 13, 795-799. (b) Ruiz, M.; Ojea, V.; Quintela, J.
M. Synlett 1999, 204-206. (c) Ruiz, M.; Ruanova, T.; Ojea, V.; Quintela,
J. M. Tetrahedron Lett. 1999, 40, 2021-2024.
2242 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
SCHEME 2 a
a Legend: a, R ) Bn; b, R ) SiPh2 Bu; c, R ) H.
t
SCHEME 3 a
a Legend: a, R ) Bn; b, R ) SiPh2 Bu; c, R ) H.
t
TABLE 1. Aldol Additions of M+12- to L-Threose Acetonides
DNJ (3), D-allo-DNJ (4), L-altro-DNJ (ent-5), D-gulo-DNJ (6),
L-ido-DNJ (ent-7), and D-talo-DNJ (8).
13a-c
(R)-12
equiv
additive
(equiv)
L-threose
acetonide
(R)
(Bn)
yielda
ratiob,c
Results and Discussion
1.2
1.2
1.2
1.2
3.0
13a
13a
13b
13b
13c
64
81
57
79
76
77:15:8d
>98:2d
60:20:20d
95:5d
1. Aldol Additions of Metalated Bislactim Ethers. 1.1.
Aldol Additions to Threose Acetonides. We first examined
the aldol additions of Scho¨llkopf’s bislactim ethers derived from
cyclo-[Gly-D-Val] and cyclo-[Gly-L-Val] ((R)-12 and (S)-15),
respectively) to L-threose acetonides 13a-c (see Schemes 2 and
3). Benzyl and tert-butyldiphenylsilyl groups were selected to
protect the γ-oxygen atom of the L-threose acetonides because
of their synthetic utility and their significant steric and electronic
differences. Thus, 4-O-benzyl- and 4-O-tert-butyldiphenylsilyl-
2,3-O-isopropylidene-L-threose, 13a and 13b, respectively, were
readily obtained from L-tartaric acid, following the reported
procedures.32a-c Catalytic hydrogenation of 13a gave 2,3-O-
isopropylidene-L-threose32d (13c) in quantitative yield.
2,3-O-Isopropylidene derivatives of L-threose 13a-c under-
went stereoselective aldol additions of metalated azaenolates
M+12- and M+15-, in a fashion similar to that previously
reported for other homochiral R,â-bisalkoxyaldehydes derived
from glyceraldehyde28 or threonine25 or that were selected as
convenient precursors for sphingofungins.29 In this manner, slow
addition of n-BuLi to a solution of bislactim ether (R)-12 in
THF at -78 °C was followed 1 h later by the dropwise addition
of freshly distilled aldehydes 13a or 13b. Reactions took place
at -78 °C within 2 h, and after quenching with NH4Cl, aqueous
workup, and removal of the excess of (R)-12 by chromatogra-
phy,33 crude mixtures containing 3,6-trans-3,1′-syn-1′,2′-anti
adducts 14a or 14b along with two other minor diastereoisomers
SnCl2 (1.2)
(Bn)
(TBDPS)
(TBDPS)
(H)
SnCl2 (1.2)
SnCl2 (3.0)
87:10:3e
a Isolated yield of mixtures of diastereomeric adducts, after column
chromatography. b Determined by integration of the 1H NMR spectra of
the crude mixtures. c Relative configurations of the minor diastereoisomers
have not been assigned. d Reaction conducted at -78 °C in THF. e Reaction
conducted from -78 to 0 °C in THF.
were isolated in 64% or 57% combined yield (see Scheme 2
and Table 1). Integration of the pairs of doublets corresponding
to the isopropyl groups in the 1H NMR spectra of the mixtures
of addition products revealed a moderate asymmetric induction
in the formation of the new chiral centers. Thus, the diastere-
omeric ratios determined for the mixture of adducts obtained
in the reactions of Li+12- with the benzylated aldehyde 13a
and the silylated aldehyde 13b were 77:15:8 and 60:20:20,
respectively.
The separation of the major components of these mixtures
could be achieved by flash chromatography, to provide adducts
14a and 14b of high purity, with a diastereomeric excess (de)
higher than 98%. However, the selective formation of the major
adducts could be increased by using a tin(II) azaenolate, as was
previously reported by Kobayashi for related aldol additions.29
Thus, lithium azaenolate Li+12- was allowed to react with SnCl2
for 1 h, in THF at -78 °C, to produce the transmetalated
azaenolate SnCl+12-, prior to the addition of the aldehydes.
Reactions of the tin(II) azaenolate with the benzylated and
silylated acetonides 13a and 13b were complete under the
(32) (a) Martin, S. F.; Chen, H.-J.; Yang, C.-P. J. Org. Chem. 1993, 58,
2867-2873. (b) Uchida, K.; Kato, K.; Akita, H. Synthesis 1999, 1678-
1686. (c) Mash, E. A.; Nelson, K. A.; Van Deusen, S.; Hemperly, S. B.
Org. Synth. 1990, 68, 92-103. (d) Morgenlie, S. Carbohydr. Res. 1985,
138, 329-334. (-)-Dimethyl 2,3-O-isopropylidene L-tartrate is com-
mercially available from Fluka.
(33) The excess of Scho¨llkopf’s reagent could be almost completely
recovered and showed no racemization.
J. Org. Chem, Vol. 73, No. 6, 2008 2243

Ruiz et al.
TABLE 2. Aldol Additions of M+15- to L-Threose Acetonides
13a-c
SCHEME 4 a
(S)-15
equiv
additive
(equiv)
L-threose
acetonide
ratio
(R)
(Bn)
(Bn)
(Bn)
yielda 16/17/18b
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
3.0
13a
13a
13a
13a
13b
13b
13b
13b
13b
13c
60
65
49:37:14c
SnCl2 (1.2)
Sn(OTf)2 (1.2)
ZnCl2 (1.2)
57:43:-c
(Bn)
46
65
78
70
61
75
62
40:42:18
46:38:16c
57:35:8c
61:34:5c
53:29:18c
49:41:10c
50:50:-d
(TBDPS)
(TBDPS)
(TBDPS)
(TBDPS)
(TBDPS)
(H)
SnCl2 (1.2)
SnCl2 (2.4)
Et2AlCl (1.2)
Ti(OiPr)3Cl (1.2)
SnCl2 (3.0)
a Legend: a, R ) Bn; c, R ) H.
react with tin(II) triflate in THF at -78 °C for 1 h prior to the
addition of the aldehyde 13a. After quenching, aqueous workup,
and removal of the excess of bislactim ether (S)-15,33 mixtures
of the diastereomeric addition products 16-18 could be isolated
a Isolated yield of mixtures of diastereomeric adducts, after column
chromatography. b Determined by integration of the 1H NMR spectra of
the crude mixtures. c Reaction conducted at -78 °C in THF. d Reaction
conducted from -78 to 0 °C in THF.
1
in 60-78% combined yield. According to the H NMR of the
crude mixtures, additions of the mismatched lithium azaenolate
Li+15- to either the benzylated or the silylated aldehydes (13a
and 13b) took place with low asymmetric induction in both new
chiral centers and led to mixtures of the two possible 3,6-trans
adducts (16 and 17, almost in a 1:1 ratio) along with small
amounts of a 3,6-cis isomer (18). The use of the tin(II)
azaenolate SnCl+15- resulted in higher yields and increased
trans/cis-selectivity in the aldol addition to L-threose acetonides
13a-c, although the ratio between the major adducts, 3,1′-syn-
1′,2′-syn-16a-c and 3,1′-anti-1′,2′-anti-17a-c, were lower than
2:1 in all the cases. Prompted by the low stereoselectivity
achieved in the azaenolate additions to the mismatched threose
acetonides, we tested the process in the presence of other
metallic counterions. Thus, we prepared the zinc(II), aluminum-
(III),35 and the titanium(IV) azaenolates from Li+15- and ZnCl2,
Et2AlCl, or Ti(OiPr)3Cl (at -78 °C in THF), but their additions
to the acetonides 13a or 13b also proceeded with low stereo-
selectivity and led to mixtures of the three adducts 16/17/18
with 40:42:18, 53:29:18 and 49:41:10 ratios, respectively. All
mixtures of benzylated, silylated, or “unprotected” aldol products
were separated by flash chromatography, and thus adducts
16a-c and 17a-c could be isolated as single diastereoisomers
in 31-44% and 28-31% yield, respectively. Adducts 16b and
17b could also be prepared by monosilylation of 16c and 17c,
respectively, and adducts 16c and 17c could also be prepared
by hydrogenation of 16a and 17a, respectively (see Scheme 3
and part 3 of Results and Discussion).
1.2. Aldol Additions to Erythrose Acetonides. To explore
further the scope of these aldol reactions for the preparation of
polyhydroxy amino acids, we examined the additions of
metalated azaenolates M+12- to erythrose acetonides of the D-
and L-series, with complementary or non-complementary con-
figuration at the R-position, respectively. According to the
literature, 2,3-O-isopropylidene-D-erythrose36a ((R,R)-19c, see
Scheme 4) and its 4-O-benzyl derivative (R,R)-19a36b were
prepared from D-isoascorbic acid and D-mannose, respectively,
whereas 2,3-O-isopropylidene-L-erythrose37 ((S,S)-19c, see Scheme
5) and its 4-O-benzyl derivative (S,S)-19a38 were obtained from
L-arabinose and L-rhamnose, respectively.
standard conditions (-78 °C, THF, 2 h) and led, after quenching
with NaHCO3, aqueous workup, and removal of the excess of
(R)-12,33 to the corresponding adducts with higher yields and
selectivities than with the lithium azaenolate. In this manner,
by using SnCl+12-, the aldol addition furnished the benzylated
adduct 14a as a single diastereoisomer (>98% de) in 81%
isolated yield, while the silylated adduct 14b was obtained in
79% yield with a de of 90%.
The influence of the protecting group for the primary hydroxyl
group of the L-threose acetonides on the yield and the stereo-
selection of the aldol addition was further examined. As
reactions of organometallic reagents with lactols are often more
selective than reactions with the corresponding aldehydes,34 the
addition of the tin(II) azaenolate to 2,3-O-isopropylidene-L-
threose (13c) was also studied. To this end, lactol 13c was
slowly added to a THF solution of 3 equiv of azaenolate
SnCl+12- at -78 °C. As reaction was not observed after 2 h at
-78 °C, the reaction mixture was gradually warmed to 0 °C.
The addition of the tin(II) azaenolate to the lactol took place
smoothly at temperatures higher than -30 °C, and total
conversion was achieved after 5 h at 0 °C. In this conditions,
after quenching of the reaction mixture with NaHCO3, workup,
and removal of the excess of (R)-12 by chromatography,33
a
87:10:3 mixture containing adduct 14c along with two minor
isomers could be isolated in 76% yield. Adducts 14b and 14c
could also be prepared by monosilylation of 14c and hydrogena-
tion of 14a, respectively (see Scheme 2 and part 3 of Results
and Discussion).
Having shown the feasibility of performing stereoselective
additions of azaenolates derived from bislactim ether (R)-12 to
L-threose derived acetonides, we explored the extension of this
reactivity to the enantiomeric series of azaenolates, derived from
bislactim ether (S)-15. The most salient results obtained in the
aldol additions of mismatched azaenolates to the L-threose
acetonides are given in Scheme 3 and Table 2. Upon addition
of the protected aldehydes 13a or 13b to 1.2 equiv of Li+15-
or SnCl+15- at -78 °C in THF, reactions also took place within
2 h. Conversely, reaction was not observed between SnCl+15-
and lactol 13c at low temperature, and thus the reaction mixture
had to be gradually warmed to 0 °C during 12 h to produce the
desired adducts. Surprisingly, reaction was not observed even
in these conditions when the lithium azaenolate was allowed to
(35) Andrews, P. C.; Maguire, M.; Pombo-Villar, E. Eur. J. Inorg. Chem.
2003, 18, 3305-3308.
(36) (a) Cohen, N.; Banner, B. L.; Laurenzano, A. J.; Carozza, L. Organic
Syntheses; Wiley: New York, 1990; Collect. Vol. VII, pp 297-301. (b)
Shen, X.; Wu, Y.-L.; Wu, Y. HelV. Chim. Acta 2000, 83, 943-953.
(37) Thompson, D. K.; Hubert, C. N.; Wightman, R. H. Tetrahedron
1993, 49, 3827-3840.
(34) See, for example: Berque, I.; Le Me´nez, P.; Razon, P.; Mahuteau,
J.; Fe´re´zou, J.-P.; Pancrazi, A.; Ardisson, J.; Brion, J.-D. J. Org. Chem.
1999, 64, 373-381. See also ref 26d,e,h.
(38) Munier, P.; Krusinski, A.; Picq, D.; Anker, D. Tetrahedron 1995,
51, 1229-1244.
2244 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
TABLE 4. Aldol Additions of M+12- to L-Erythrose Acetonide
(S,S)-19a
SCHEME 5 a
(R)-12
equiv
additive
(equiv)
21a/22a/23a
entry
yielda
ratiob,c
1
2
3
4
5
6
1.2
1.2
1.2
1.2
1.2
1.2
60
14
65
65
60
60
47:37:16
46:28:25
57:38:5
65:31:3
64:22:14
64:27:9
ZnCl2 (2.4)
SnCl2 (1.2)
SnCl2 (2.4)
MgBr2‚OEt2 (2.4)
Ti(NEt2)3Cl (1.2)
a Isolated yield of mixtures of diastereomeric adducts, after column
chromatography. b Determined by integration of the 1H NMR spectra of
the crude mixtures. c Reaction conducted at -78 °C in THF.
TABLE 5. Aldol Additions of M+12- to L-Erythrose Acetonide
(S,S)-19c
(R)-12
equiv
21c/22c/23c
entry
additive (equiv)
ZnCl2 (6.0)
TMSCl + SnCl4 (3.0)
SnCl2 (3.0)
yielda
ratiob,c
a Legend: a, R ) Bn; c, R ) H.
1
2
3
4
5
6
7
8
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
52
NRd
NRd
78
89
70
62:38:-
TABLE 3. Aldol Additions of M+12- to D-Erythrose Acetonides
(R,R)-19a,c
77:3:20
91:9:-
66:33:10
30:70:-
33:6:61
(R)-12
equiv
additive
(equiv)
D-erythrose
acetonide
(R)
yielda ratio of adductsb
SnCl2 (6.0)
Ti(OiPr)3Cl (3.0)
Ti(NEt2)3Cl (3.0)
MgBr2‚OEt2 (3.0)
1.2
1.2
3.0
3.0
(R,R)-19a
SnCl2 (1.2) (R,R)-19a
(R,R)-19c
(Bn)
(Bn)
(H)
69
81
55
93
89:11:-c
91:9:- c
50:33:17d
>98:2:-d
78
70
a Isolated yield of mixtures of diastereomeric adducts, after column
chromatography. b Determined by integration of the 1H NMR spectra of
the crude mixtures. c Reaction conducted from -78 to 0 °C in THF. d No
reaction was observed.
SnCl2 (3.0) (R,R)-19c
(H)
a Isolated yield of mixtures of diastereomeric adducts, after column
chromatography. b Determined by integration of the 1H NMR spectra of
the crude mixtures. c Reaction conducted at -78 °C in THF. d Reaction
conducted from -78 to 0 °C in THF.
with ZnCl2, SnCl2, MgBr2·OEt2, or Ti(NEt2)3Cl in THF at -78
°C for 1 h, to produce the corresponding transmetalated
azaenolates M+12- prior to the addition of the benzylated
L-erythrose acetonide. Reaction of (S,S)-19a with the zinc(II)
azaenolate resulted in a very low conversion to products, and
the mixture of adducts 21a/22a/23a, with a 46:28:25 ratio, was
obtained in 14% yield (see Table 4, entry 2). After switching
the counterion of the lithium azaenolate to Sn(II), Mg(II), or
Ti(IV), the aldol additions to (S,S)-19a led to mixtures of the
same adducts 21a/22a/23a in 60-65% yield. 1H NMR analysis
of these mixtures revealed slightly higher ratios of the 3,6-trans-
3,1′-anti-1′,2′-anti diastereoisomer 21a (see Table 4 and compare
entries 3-6 with 1). In this manner, after chromatographic
purification, the benzylated adducts 21a, 22a, and 23a could
be isolated as single diastereoisomers in yields up to 42%, 25%,
and 10%, respectively.
When lactol (S,S)-19c was added to THF solutions of 3 equiv
of lithium, tin(II), titanium(IV), or magnesium(II) azaenolates
M+12- at -78 °C and the reactions were gradually warmed to
0 °C, the aldol additions took place within 12 h. After quenching,
aqueous workup, and removal of the excess of (R)-12,33 mixtures
containing up to three diastereomeric adducts 21c/22c/23c were
isolated in 52-89% yield (see Scheme 5 and Table 5).
Conversely, reactions of zinc(II) azaenolate or trimethylsilylated
azaenolate (promoted by SnCl4) with lactol (S,S)-19c were not
observed in the same conditions (12 h at 0 °C) or with longer
reaction times and higher temperatures (see Table 5, entries 2
and 3). The stereochemical course of the azaenolate additions
to the lactol (S,S)-19c was found to be markedly dependent on
the nature of the metal salt, and thus, the three diastereoisomers,
21c, 22c, or 23c, could be selectively prepared by using SnCl+,
Ti(NEt2)3+, or MgBr+ as counterion. Addition of the lithium
azaenolate to lactol (S,S)-19c took place with a complete 3,6-
trans-stereoselection and led to a 62:38 mixture of the 3,1′-
Reactions of 4-O-benzyl-2,3-O-isopropylidene-D-erythrose
((R,R)-19a) with 1.2 equiv of the lithium or the tin(II) azaeno-
lates M+12- in THF at -78 °C also took place within 2 h. The
lithium azaenolate led, after quenching, aqueous workup, and
removal of the excess of (R)-12 by flash chromatography,33 to
a crude mixture containing the 3,6-trans-3,1′-syn-1,′2′-anti
adduct 20a along with a minor isomer, in a 89:11 ratio and
69% combined yield (see Scheme 4 and Table 3). By using the
tin(II) azaenolate SnCl+12-, addition to the benzylated aldehyde
(R,R)-19a proceeded with higher yield but almost the same
stereoselectivity and gave rise to 20a in 73% yield as a single
diastereoisomer after chromatography. The additions of meta-
lated azaenolates M+12- to 2,3-O-isopropylidene-D-erythrose
((R,R)-19c) were studied next. To this end, lactol (R,R)-19c was
slowly added to THF solution of 3 equiv of azaenolate Li+12-
at -78 °C, and the reaction mixture was gradually warmed to
0 °C during 12 h. After quenching, workup, and removal of
the excess of (R)-12,33 a 50:33:17 mixture of 3,6-trans-3,1′-
syn-1,′2′-anti adduct 20c and two other diastereoisomers was
isolated in 55% yield. In contrast, when Li+12- was allowed
to react with stannous chloride (THF, -78 °C, 1 h) prior to the
addition of lactol (R,R)-19c, and the reaction was performed
under the same conditions (THF, from -78 to 0 °C, 12 h), 20c
was obtained in 93% as the sole aldol product (see Table 3).
Addition of 4-O-benzyl-2,3-O-isopropylidene derivative of
L-erythrose (S,S)-19a to 1.2 equiv of the “mismatched” aza-
enolate Li+12- at -78 °C in THF afforded, after quenching
and aqueous workup, a mixture of three adducts 21a/22a/23a
in a combined yield of 60% (see Scheme 5). According to the
1H NMR of the mixture the ratio between the diastereoisomers
21a/22a/23a was 47:37:16 (see Table 4, entry 1). To evaluate
the counterion dependence of the stereochemical outcome of
the aldol addition, the lithium azaenolate was allowed to react
J. Org. Chem, Vol. 73, No. 6, 2008 2245

Ruiz et al.
anti-1′,2′-anti, and 3,1′-syn-1′,2′-syn adducts, 21c and 22c,
respectively, in 52% combined yield (see Table 5, entry 1). The
trans,anti,anti-stereoselectivity of this aldol addition could be
markedly increased by using the tin(II) azaenolate. Thus,
addition of SnCl+12- to lactol (S,S)-19c afforded a 77:3:20
mixture of 21c/22c/23c in 78% combined yield (see Table 5,
entry 4). We were delighted to observe that in the presence of
an excess of SnCl2 the reaction of SnCl+12- with (S,S)-19c
gave rise to a mixture of adducts 21c/22c in a 91:9 ratio and
89% yield (see Table 5, entry 5).39 In this manner, by using the
tin(II) azaenolate, the 3,6-trans-3,1′-anti-1′,2′-anti adduct 21c
could be obtained as a single diastereoisomer in 81% yield after
chromatographic purification. The stereochemical result of the
aldol addition could be further modulated by tuning the ligands
of the titanium(IV) azaenolate. In the presence of Ti(OiPr)3Cl
there was not significant change in the yield nor the stereose-
lectivity of the reaction of the lithium azaenolate with the lactol
(see Table 5, entries 1 and 6), whereas when using Ti(NEt2)3Cl
as additive, the same aldol addition proceeded with the opposite
selectivity. Thus, reaction of Ti(NEt2)3+12- with lactol (S,S)-
19c was found to be trans,syn,syn-selective and gave rise to a
30:70 mixture of adducts 21c/22c in 78% combined yield (see
Table 5, entry 7). In this case, the 3,6-trans-3,1′-syn-1′,2′-syn
adduct 22c could be obtained as a single diastereoisomer in 54%
yield after chromatographic purification. Finally, switching the
metal of the azaenolate to magnesium drastically changed the
stereochemical outcome of the addition to the lactol, which took
place with a moderate cis-selectivity. Thus, reaction of MgBr+12-
with (S,S)-19c furnished a mixture of adducts 21c/22c/23c in a
33:6:61 ratio and 70% combined yield (see Table 5, entry 8).
Formation of the 3,6-cis-3,1′-syn-1′,2′-anti diastereoisomer 23c
as the major aldol addition product was surprising, as there was
not any precedent for such cis-selective addition in the
Scho¨llkopf’s bislactim chemistry.40
(-30, -20, -10, and 0 °C) from the reaction mixture of
SnCl+12- and (S,S)-19c.
Evidence supporting the relative configuration of all aldol
adducts was obtained from NMR analyses and chemical
correlation. For the 3,6-trans diastereoisomers (14a-c, 16a-
c, 17a-c, 20a,c, 21a,c, and 22a,c) the H-6 resonance appears
5
between 3.91 and 4.02 ppm, as a triplet with J(H3,H6) close
to 3.5 Hz, which is general of the trans relationship of
substituents at the pyrazine ring. Conversely, the 1H NMR
spectrum of adduct 23a shows the absorption corresponding to
H-6 at 3.88 ppm, as a doublet of doublets with a 5J(H3,H6) of
5.9 Hz, which is typical of a 3,6-cis relationship at the bislactim
ether ring.41 Furthermore, the configurations of all the adducts
were unambiguously confirmed through their conversion into
known piperidine alkaloids. Thus, the adducts 14a-c, 16a-c,
and 17a-c, derived from L-threose, were transformed into
1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin, and
1-deoxy-L-altronojirimycin, respectively, and the adducts 20a,c,
21a,c, 22a,c, and 23a,c, derived from erythrose, were used in
the preparation of 1-deoxy-D-talonojirimycin, 1-deoxy-D-al-
lonojirimycin, 1-deoxy-D-gulonojirimycin and 1-deoxy-L-tal-
onojirimycin, respectively, as will be described below (see
Schemes 12 and 14).
2. Models for Diastereoselective Aldol Additions with Tin-
(II) Salts of Bislactim Ethers. The stereoselectivities of the
aldol additions of metalated bislactim ethers to a variety of
aldehydes have been rationalized with the Zimmerman-Traxler
six-membered ring model.42 Reaction of the metalated bislactim
ether by its less-hindered side, opposite to the isopropyl group,
through a chair-like transition-state structure (TS) with an
equatorial disposition of the aldehyde (see Ce in Scheme 6)
should be favored and can account for the formation of the major
3,6-trans-3,1′-syn addition product. The 3,6-trans-3,1′-anti minor
product could arise from a switch to an axial disposition of the
aldehyde moiety in the chair-like TS (Ca) or from involvement
of boat-like TS (Be) with less serious diaxial interactions.
Matched and mismatched situations arise in the reaction of
metalated bislactim ethers and chiral aldehydes. To explain the
high stereoselection in the additions of metalated bislactim ethers
to matched R-alkoxyaldehydes, the pericyclic TS has been
combined with the Felkin-Anh model43 or the modified
Cornforth model44 for 1,2-asymmetric induction. Thus, Scho¨llko-
pf postulated the involvement of chair-Felkin-Anh TS (like F,
see Scheme 7), stabilized through hyperconjugative interaction
of the forming bond (HOMO) with the R-alkoxy bond (LUMO),
to account for the almost exclusive formation of 3,6-trans-3,1′-
syn-1′,2′-anti adduct.28a Nevertheless, TS F should be destabi-
lized by the presence of a double gauche pentane interaction44,45
between one nitrogen atom of the bislactim and the carbon chain
The observation of remarkable trans,anti,anti-selectivity in
the addition of azaenolate SnCl+12- to the erythrose acetonide
(S,S)-19c stands in contrast to the trans,syn,syn-selectivity seen
for the additions of SnCl+15- to threose acetonides 13a,b (see
Table 2) or other mismatched R-alkoxyaldehydes.29 To account
for the striking effect of the free hydroxyl group at the acceptor
in the stereochemical outcome of the aldol addition, we initially
postulated a change of the reaction mechanism to a reversible
one. To address this possibility we subjected a 62:38 mixture
of adducts 21c/22c (prepared by reaction of Li+12- with (S,S)-
19c; see entry 1 of Table 5) to reaction with 4 equiv of tin(II)
azaenolate SnCl+12-. The reversibility of the aldol addition
would enforce the enrichment of the mixture of adducts in the
trans,anti,anti-diastereoisomer. Nevertheless, after a prolonged
reaction time at 0 °C, quenching, workup, and removal of the
excess of (R)-12, the ratio between the diastereoisomers 21c/
22c was unchanged, ruling out the involvement of the postulated
equilibrium between the aldolates in the presence of tin(II) salts.
Additional information supporting the non-involvement of
equilibrium between the tin(II) aldolates was provided by
determination of the same ratio between diastereoisomers 21c/
22c (91:9) in the aliquots retrieved at different temperatures
(41) See, for instance: (a) Busch, K.; Groth, U. M.; Ku¨hnle, W.;
Scho¨llkopf, U. Tetrahedron 1992, 48, 5607-5618. (b) Ruiz, M.; Ferna´ndez,
M. C.; D´ıaz, A.; Quintela, J. M.; Ojea, V. J. Org. Chem. 2003, 68, 7634-
7645. (c) Ferna´ndez, M. C.; D´ıaz, A.; Guill´ın, J. J.; Blanco, O.; Ruiz, M.;
Ojea, V. J. Org. Chem. 2006, 71, 6958-6974.
(42) (a) Evans, D. A.; Nelson, J. V.; Taber, T. R. Top. Stereochem. 1982,
13, 1-115. (b) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957,
79, 1920-1923.
(43) (a) Anh, N. T. Top. Curr. Chem. 1980, 88, 145-162. (b) Anh, N.
T.; Eisenstein, O. NouV. J. Chim. 1977, 1, 61-70. (c) Che´rest, M.; Felkin,
H.; Prudent, N. Tetrahedron Lett. 1968, 2199-2204.
(39) Improved diastereoselectivities and yields by using 2 equiv of metal
salts were also reported in the aldol reactions of other amino ester enolates;
see: Kazmaier, U.; Grandel, R. Synlett 1995, 945-946.
(40) Protonation of potassium azaenolates derived from cyclo-[L-Val-
Ala] with acetic acid has been reported as cis-selective; see: Hu¨nig, S.;
Klaunzer, N.; Wenner, H. Chem. Ber. 1994, 127, 165-172.
(44) (a) Evans, D. A.; Cee, V. J.; Siska, S. J. J. Am. Chem. Soc. 2006,
128, 9433-9441. (b) Evans, D. A.; Siska, S. J.; Cee, V. J. Angew. Chem.,
Int. Ed. 2003, 42, 1761-1765.
(45) Roush, W. R. J. Org. Chem. 1991, 56, 4151-4157 and references
therein.
2246 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
SCHEME 6
SCHEME 7
mediated aldol reactions has been qualitatively rationalized in
terms of tightly chelated chair-like TSs. Nevertheless, compared
to other metal enolates, the tin-oxygen bond in tin(II) enolates
is not relatively short and does not necessarily lead to tighter
cyclic TSs nor higher levels of stereoselectivity. Although
numerous theoretical investigations have shed light on the TSs
for aldol additions using different metal enolates,47 the proposed
models for the tin(II)-mediated aldol reactions have not been
supported by subsequent computational studies. We analyze
herein the extension of these models to the reaction of tin(II)
azaenolates with matched and mismatched acetonides derived
from glyceraldehyde or erythrose and show that DFT calcula-
tions provide valuable insight to rationalize the experimental
diastereoselectivity. To this end, geometry optimizations were
performed using a B3LYP DFT procedure48 with the cc-pVDZ
basis set49 and a small-core relativistic pseudopotential (PP) for
Sn.50 Single-point energy calculations were performed at the
B3LYP/cc-pVTZ-PP level (see Computational Methods in
Supporting Information).
2.1. Tin(II) Azaenolate/Lithium Chloride Aggregates. We
first studied the reaction of lithium azaenolate derived from (R)-
15 with tin(II) chloride and three molecules of THF in the gas
phase (see Scheme 8). Formation of unsolvated tin(II) azaenolate
uA and trisolvated lithium chloride was calculated to be
exothermic by more than 16 kcal/mol, and dimerization of uA
was endothermic (see Supporting Information, Scheme S1).
Conversely, association of uA and the lithium chloride generated
in situ to give a disolvated mixed aggregate dA was favored
by more than 13 kcal/mol. Most stable mixed aggregate was
of the aldehyde. This unfavorable steric interaction raises the
energy of the Felkin-Anh pathway, and other transition-state
structures (TSs) that minimize all nonbonded interactions may
become lower in energy. According to our ab initio calculations,
the Cornforth-like TS (M, see Scheme 7), minimizing both the
gauche interactions and the dipole interaction between the
R-alkoxy and carbonyl group, resulted as the preferred one in
the addition of lithiated bislactim ethers to matched glyceral-
dehyde-derived acetonides.25d
Highly diastereoselective aldol reactions using chiral tin(II)
enolates have been successfully applied in asymmetric synthe-
sis.46 In the present article we have shown that the aldol
additions of bislactim ethers to erythrose or threose acetonides
take place with the highest stereoselectivity when using tin(II)
azaenolates. The stereochemical outcome for such tin(II)-
(47) Lithium enolates: (a) Pratt, L. M.; Nguyen, N. V.; Ramachandran,
R. J. Org. Chem. 2005, 70, 4279-4283. (b) Abu-Hasanayn, F.; Streitwieser,
A. J. Org. Chem. 1998, 63, 2954-2960. (c) Henderson, K. W.; Dorigo, A.
E.; Liu, Q.-Y.; Williard, P. G.; Schleyer, P. v. R.; Bernstein, P. R. J. Am.
Chem. Soc. 1996, 118, 1339-1347. (d) Bernardi, F.; Bongini, A.; Cainelli,
G.; Robb, M. A.; Valli, G. S. J. Org. Chem. 1993, 58, 750-755. (e) Leung-
Tong, R.; Tidwell, T. T. J. Am. Chem. Soc. 1990, 112, 1042-1048. (f) Li,
Y.; Paddon-Row, M. N.; Houk, K. N. J. Org. Chem. 1990, 55, 481-493
and references therein. Boron enolates: (g) Goodman, J. M.; Paton, R. S.
Chem. Commun. 2007, 2124-2126 and references therein. (h) Cee, V. J.;
Cramer, C. J.; Evans, D. A. J. Am. Chem. Soc. 2006, 128, 2920-2930. (i)
Murga, J. Falomir, E.; Gonzalez, F.; Carda, M.; Marco, J. A. Tetrahedron
2002, 58, 9697-9707. Silicon enolates: (j) Wong, C. T.; Wong, M. W. J.
Org. Chem. 2007, 72, 1425-1430. (k) Denmark, S. E.; Fan, Y.; Eastgate,
M. D. J. Org. Chem. 2005, 70, 5235-5248. (l) Silva Lo´pez, C.; AÄ lvarez,
R.; Vaz, B.; Nieto Faza, O.; de Lera, A. R. J. Org. Chem. 2005, 70, 3654-
3659. Titanium enolates: (m) Itoh, Y.; Yamanaka, M.; Mikami, K. J. Am.
Chem. Soc. 2004, 126, 13174-13175. Tin(IV) enolates: (n) Yasuda, M.;
Chiba, K.; Baba, A. J. Am. Chem. Soc. 2000, 122, 7549-7555.
(46) (a) Gridley, J. J.; Coogan, M. P.; Knight, D. W.; Malik, K. M. A.;
Sharland, C. M.; Singkhonrat, J.; Williams, S. Chem. Commun. 2003, 2550-
2551. (b) Matsui, K.; Zheng, B.-Z.; Kusaka, S.-i.; Kuroda, M.; Yoshimoto,
K.; Yamada, H.; Yonemitsu, O. Eur. J. Org. Chem. 2001, 3615-3624. (c)
Franck-Neumann; Miesch-Gross, L.; Gateau, C. Eur. J. Org. Chem. 2000,
3693-3702. (d) Sano, S.; Ishii, T.; Miwa, T.; Nagao, Y. Tetrahedron Lett.
1999, 40, 3013-3016. (e) Paterson, I.; Franklin, A. S. Tetrahedron Lett.
1994, 35, 6925-6928. (f) Pridgen, L. N.; Abdel-Magid, A. F.; Lantos, I.;
Shilcrat, S.; Eggleston, D. S. J. Org. Chem. 1993, 58, 5107-5117. (g)
Nagao, Y.; Nagase, Y.; Kumagai, T.; Matsunaga, H.; Abe, T.; Shimada,
O.; Hayashi, T.; Inoue, Y. J. Org. Chem. 1992, 57, 4243-4249. (h) Paterson,
I.; Tillyer, R. D. Tetrahedron Lett. 1992, 33, 4233-4236. (i) Bodwell, G.
J.; Davies, S. G.; Mortlock, A. A. Tetrahedron 1991, 47, 10077-10086.
(j) Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G.
S. J. Am. Chem. Soc. 1990, 112, 866-868. See also ref 29b.
(48) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. (b) Lee,
C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-789.
(49) (a) Davidson, E. R. Chem. Phys. Lett. 1996, 260, 514-518. (b)
Woon, D. E.; Dunning, T. H., Jr. J. Chem. Phys. 1993, 98, 1358-1371. (c)
Dunning, T. H., Jr. J. Chem. Phys. 1989, 90, 1007-1023.
(50) Peterson, K. A. J. Chem. Phys. 2003, 119, 11099-11112.
J. Org. Chem, Vol. 73, No. 6, 2008 2247

Ruiz et al.
SCHEME 8
location and the azaenolate nitrogen occupying an equatorial
site. Association of uADg to lithium chloride and two THF
molecules to form dADg was favored by more than 9 kcal/mol
in the gas phase. Because separate disolvated azaenolate and
glyceraldehyde acetonide (dA + Dg) was the most stable state
for reactants, it was used as the reference for calculation of the
activation barriers.
The possible pathways for the reorganization of the inter-
mediate complexes uADg and dADg were analyzed next.
Pericyclic TSs connecting these intermediates to the corre-
sponding unsolvated or disolvated aldolates with either 3,6-cis-
3,1′-anti-1′,2′-anti, 3,6-cis-3,1′-syn-1′,2′-syn, 3,6-trans-3,1′-anti-
1′,2′-syn, or 3,6-trans-3,1′-syn-1′,2′-anti configuration were
grouped into four diastereomeric pathways that were designated
as caa, css, tas, and tsa, respectively. In each diastereomeric
pathway, different starting geometries were subjected to opti-
mization considering the following main structural features: (1)
boat-like and chair-like conformations for the pericyclic ring
(denoted “B” and “C”, respectively), (2) three different trigonal-
bipyramidal environments for the tin(II) cation, with equatorial
aldehyde-equatorial azaenolate, equatorial aldehyde-axial aza-
enolate, or axial aldehyde-equatorial azaenolate (denoted “ee”,
“ea”, and “ae”, respectively), and (3) Felkin-Anh, Cornforth,
and non-Anh52 conformations (denoted “F”, “M” and “N”,
respectively) for the aldehyde moiety (see Supporting Informa-
tion, Figure S1). In addition, clockwise and anticlockwise
configurations for the trigonal-bipyramidal tin(II) cation were
constructed for all the selected geometries. Representative
starting geometries for TS location are depicted in Figure S2
of the Supporting Information.
SCHEME 9
For a rapid computation of the stereoselectivity of the aldol
addition we first studied the TSs arising from the reorganization
of the unsolvated intermediate complex uADg. Most stable
unsolvated TSs lay in almost the same position along the
reaction coordinate (with C-C bond forming distance between
2.36 and 2.45 Å) and are characterized by a distorted tetrahedral
environment for tin(II) cation, due to contacts with the chloride,
the aldehyde oxygen, and the azaenolate nitrogen (see Figure 1
and Figure S3 of the Supporting Information). Thus, the
coordination between the tin(II) cation and the vicinal methoxy
group, which was present in the parent complex uADg, was
not maintained in the unsolvated TSs. In all the diastereomeric
pathways, TSs with S configuration at the metal center showed
energy values lower than those of their epimers with R
configuration. In agreement with the experimental results, the
most favorable unsolvated TS was located in the trans,syn,anti
diastereomeric pathway. This TS, designated as utsa-CM, was
characterized by chair-like and Cornforth-like conformations for
the pericyclic ring and the aldehyde moiety, respectively (see
Figure 1). In the trans,anti,syn diastereomeric pathway the most
favorable TS was utas-BN, which showed boat-like and non-
Anh conformations and was only 0.8 kcal/mol higher in energy
than utsa-CM. The competitive unsolvated TSs in the cis,an-
ti,anti and cis,syn,syn pathways were computed to be more than
13 kcal/mol higher in energy (see Figure S3 and Table S2 of
the Supporting Information). Assuming a Boltzmann distribution
of the unsolvated TSs at -78 °C, the calculated trans,syn,anti/
characterized by a tetrahedral environment for the lithium cation
due to contacts with two chlorides and two THF molecules and
a distorted trigonal-bipyramidal geometry about the tin(II) cation
with anticlockwise (A) configuration. In the mixed aggregate
the azaenolate coordinates to the tin(II) cation in a bidentate
fashion, with the anionic nitrogen occupying an equatorial
position and the vicinal methoxy group located at an axial site.
In addition, one chloride is located axially while the second
chloride and the lone pair of electrons occupy the remaining
equatorial sites of the tin(II) cation. Binding of a third THF
molecule to dA to give the trisolvated mixed aggregate tA was
found to be endothermic by more than 7 kcal/mol (see
Supporting Information, Table S1). The aggregation of a tin-
(II) enolate in the solid state has been previously reported.51
2.2. Models for the Addition of Tin(II) Azaenolate to
Glyceraldehyde Acetonides. The aldol reactions of D-glycer-
aldehyde acetonide (Dg) with azaenolates uA or dA proceed
first by the endothermic formation of the intermediate complexes
uADg and dADg, respectively (see Scheme 9). Both intermedi-
ate complexes maintain the distorted trigonal-bipyramidal
environment for the tin(II) cation with A configuration. While
the unsolvated complex uADg is characterized by the contact
between the vicinal methoxy group and the tin(II) cation, this
interaction is not present in the disolvated complex dADg. Most
stable unsolvated complex uADg showed both the azaenolate
nitrogen and the aldehyde ligands located at equatorial sites
about the tin(II) cation. Conversely, most stable disolvated
complex dADg showed the aldehyde ligand placed in an axial
(52) The term “non-Anh” was coined by Heathcock to designate the
reactive conformations having one of the ligands on the stereogenic R-carbon
with higher σ* orbital energy anti to the incoming nucleophile. See: (a)
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 3353-3361.
(b) Gawley, R. E.; Aube´, J. Principles of Asymmetric Synthesis; Perga-
mon: New York 1996; pp 127-130.
(51) Driess, M.; Dona, N.; Merz, K. Chem. Eur. J. 2004, 10, 5971-
5976.
2248 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
FIGURE 1. Chem3D representations of the most favored unsolvated
TSs located (B3LYP/cc-pVDZ-PP level) for the aldol addition of
unsolvated tin(II) azaenolate (uA) to D-glyceraldehyde acetonide (Dg).
Relative energies in the gas phase (B3LYP/cc-pVTZ-PP level) are
shown in parenthesis in kcal/mol. Distances are in angstroms. The
hydrogen atoms are omitted for clarity except at chiral and reaction
centers. Legend: carbon ) gray, nitrogen ) blue, oxygen ) red,
hydrogen ) turquoise, tin ) yellow, chlorine ) green.
FIGURE 2. Chem3D representations of the most favored disolvated
TSs located (B3LYP/cc-pVDZ-PP level) for the aldol addition of
disolvated tin(II) azaenolate (dA) to L-glyceraldehyde acetonide (Dg).
Relative energies in the gas phase (B3LYP/cc-pVTZ-PP level) and in
THF solution (B3LYP(SCRF)/cc-pVTZ-PP level using the PCM
method) are shown in parenthesis and brackets, respectively (kcal/mol).
Distances are in angstroms. The hydrogen atoms are omitted for clarity
except at chiral and reaction centers. Legend: carbon ) gray, nitrogen
) blue, oxygen ) red, hydrogen ) turquoise, tin ) yellow, chlorine
) light green, lithium ) green.
trans,anti,syn ratio (ca. 9:1) was lower than the experimental
trend (see Tables 1 and 3 and ref 29a,c). In this manner,
unsolvated models were very much simplified and reproduced
the sense but not the degree of the stereoselection in the aldol
additions of tin(II) azaenolates to matched acetonides derived
from glyceraldehyde.
TABLE 6. Relative Energies and Energy Barriers for TSs Located
in the Addition of Tin(II) Azaenolates to Glyceraldehyde Acetonides
gas phase
THF
To further optimize our computational model, we undertake
the study of the TSs arising from the disolvated mixed aggregate
dADg, which demanded a higher computational effort. All
optimized disolvated TSs were characterized by a distorted
trigonal-bipyramidal geometry about the tin(II) cation. In all
diastereomeric pathways, the most stable TSs showed almost
the same C-C bond-forming distances (between 2.37 and 2.45
Å) and were characterized by A configurations around the tin-
(II) cation, with the aldehyde and the azaenolate moieties located
at axial and equatorial sites, respectively (see Figure 2 and
Figure S4 of the Supporting Information). Axial bond lengths
at the tetracoordinate tin(II) cation of the mixed aggregates were
distinctly longer than for the three-coordinate metal of the
unsolvated TSs (average differences are 0.24 Å for Sn-O). In
the gas phase, disolvated TS dtsa-CaeM, with a chair-like
conformation for the pericyclic ring and a Cornforth-like
conformation for the aldehyde moiety was computed as the
lowest in energy. This trans,syn,anti TS was favored by 2.3
kcal/mol over the corresponding most favorable trans,anti,syn
TS, which showed boat and non-Anh conformations for the
pericyclic ring and the aldehyde moiety (see dtas-BaeN in Figure
2). As previously found in the unsolvated reaction channel, the
disolvated TSs in the cis pathways were computed to be more
than 12 kcal/mol higher in energy (see dcaa-CaeM and dcss-
CaeF in Figure S4 and Table S3 of the Supporting Information).
According to the calculations, the free energy barriers for the
rel Ea
(kcal/mol)
∆Gq195 a
rel Ee
(kcal/mol)
∆Gq195 e
model (config)
(kcal/mol)
(kcal/mol)
utsa-CM(S)
utas-BN(S)
0.0
0.8
0.0
2.3
4.7
0.0
1.8
17.7b
18.0b
11.1c
13.4c
15.8c
13.2d
15.0d
dtsa-CaeM(A)
dtas-BaeN(A)
dtas-CaeN(A)
dtaa-CaeM(A)
dtss-CaeF(A)
0.0
3.1
2.3
0.0
1.4
15.4c
18.5c
17.7c
15.4d
16.8d
a Calculated at the B3LYP/cc-pVTZ-PP//B3LYP/cc-pVDZ-PP level.
b Free activation energy (195 K, 1 atm) relative to dA+Dg+THF-
(THF)3LiCl. c Free activation energy (195 K, 1 atm) relative to dA+Dg.
d Free activation energy (195 K, 1 atm) relative to dA+Lg. e Calculated at
B3LYP(SCRF)/cc-pVTZ-PP//B3LYP(SCRF)/cc-pVDZ-PP level using the
PCM method.
disolvated TSs dtsa-CaeM and dtas-BaeN were more than 4 kcal/
mol lower than those previously computed for the most
favorable unsolvated TSs (see Table 6). In this manner, the
mixed aggregates offered the lowest energy channel for the aldol
reaction. Moreover, the energy gap between dtsa-CaeM and the
competing TSs is consistent with the high diastereofacial bias
observed in the additions of tin(II) azaenolates to matched
acetonides derived from threose and erythrose.
Following the same strategy for the study of the reaction
between the disolvated tin(II) azaenolate dA and the mismatched
L-glyceraldehyde acetonide (Lg), similar results were obtained.
J. Org. Chem, Vol. 73, No. 6, 2008 2249

Ruiz et al.
was not present in the competing TSs and therefore could
contribute to the energy difference between the trans,anti,anti
and trans,syn,syn pathways.53
To further study the influence of the solvent in the reaction
path, the geometries of the most significant disolvated TSs as
calculated in the gas phase were reoptimized in THF solution
using the PCM method.54 The effect of the dielectric medium
simulating THF on the structures of the TSs was almost
negligible. Nevertheless, nonspecific solvation of the disolvated
TSs (with less charge-localized geometries) was less exothermic
than that for the reactive precursors, and thus, the free energy
barriers in solution were increased by 1.8-4.3 kcal/mol with
respect to those calculated in the gas phase. Differential
nonspecific solvation effects on the competitive TSs were rather
small in both the matched and the mismatched situations. In
THF solution the calculated stereoselectivity was maintained
for the matched pair, while the energy gap between the
mismatched TSs was reduced to 1.4 kcal/mol (see Table 6 and
Table S5 in the Supporting Information).
According to DFT computations for the reaction of tin(II)
azaenolate with glyceraldehyde acetonides, the trans,syn,anti
TS is favored for the matched pair and the trans,anti,anti TS is
favored for the mismatched one, and the calculated energy gap
between the competing TSs is greater for the matched situation
than for the mismatched one. Nevertheless, the asymmetric
induction computed for the reaction of the tin(II) azaenolate
with the mismatched glyceraldehyde model deviates from that
experimentally observed in the additions to mismatched threose
and erythrose acetonides. Thus, the trans,anti,anti/trans,syn,syn
ratio calculated for the mismatched glyceraldehyde model (ca.
9:1, assuming a Boltzmann distribution of the TSs at -78 °C)
is considerable higher than the experimental values observed
for the mismatched erythrose acetonide 19a (ca. 2:1) and even
opposite in direction to that obtained with the mismatched
threose acetonides 13a,b (ca. 1:2). Thus, the results of calcula-
tions with the glyceraldehyde model can be easily extrapolated
to the analysis of the additions to matched threose and erythrose
acetonides. On the other hand, the differences between the
stereoselectivity computed for glyceraldehyde model and ex-
perimentally observed for threose and erythrose acetonides may
uncover the influence of the â-stereocenter as a third stereo-
chemical determinant of the aldol addition. In this manner, we
speculate that nonbonding interactions between the tin(II)
azaenolate and the â-alkoxymethyl moiety of the threose and
erythrose acetonides may result in a closer energy for the
mismatched TSs and account for the reduced trans,anti,anti/
trans,syn,syn ratio.
FIGURE 3. Chem3D representations of the most favored disolvated
TSs located (B3LYP/cc-pVDZ-PP level) for the aldol addition of
disolvated tin(II) azaenolate (dA) to L-glyceraldehyde acetonide (Lg).
Relative energies in the gas phase (B3LYP/cc-pVTZ-PP level) and in
THF solution (B3LYP(SCRF)/cc-pVTZ-PP level using the PCM
method) are shown in parenthesis and brackets, respectively (kcal/mol).
Distances are in angstroms. The hydrogen atoms are omitted for clarity
except at chiral and reaction centers. Legend: carbon ) gray, nitrogen
) blue, oxygen ) red, hydrogen ) turquoise, tin ) yellow, chlorine
) light green, lithium ) green.
Full optimization of the selected geometries for the intermediate
complex dALg enabled the location of the corresponding TSs
in the 3,6-cis-3,1′-anti-2′,3′-syn, 3,6-cis-3,1′-syn-2′,3′-anti, 3,6-
trans-3,1′-anti-2′,3′-anti, and 3,6-trans-3,1′-syn-2′,3′-syn dia-
stereomeric pathways, which were designated as cas, csa, taa,
and tss. As previously found for the matched situation, the most
favorable mismatched TSs were characterized by almost the
same C-C bond-forming distances (between 2.36 and 2.40 Å)
and A configurations around the trigonal-bipyramidal tin(II)
cation, with the aldehyde-azaenolate pair of ligands placed at
axial-equatorial sites. The mismatched TS of lowest energy
was found in the trans,anti,anti diastereomeric pathway. Here
again, most stable TS showed a chair-like conformation for the
pericyclic ring and a Cornforth-like conformation for the
aldehyde moiety (see dtaa-CaeM in Figure 3). Most favored
TS in the trans,syn,syn pathway was computed to be 1.8 kcal/
mol higher in energy and showed a chair-like conformation for
the pericyclic ring and a Felkin-Anh conformation for the
aldehyde moiety (see dtss-CaeF in Figure 3), while the TSs in
the cis pathways were more than 9 kcal/mol higher in energy
(see dcas-BaeF and dcsa-CaeM in Figure S5 and Table S4 of
the Supporting Information). It should be noted that in dtaa-
CaeM the glyceraldehyde moiety is placed in an axial environ-
ment of the pericyclic ring and thus maintains a 1,3-diaxial
interaction with a methoxy group of the bislactim moiety. With
this 1,3-diaxial relationship, the distance between the oxygen
atom at R-position of the glyceraldehyde moiety and one of
the methoxy hydrogens of the bislactim was reduced to 2.35
Å, which indicated a hydrogen bond interaction. This interaction
In summary, modeling studies provided some valuable insight
to rationalize the stereochemical outcome for the aldol additions
of tin(II) azaenolates to threose and erythrose acetonides.
Calculation suggests that the experimentally observed stereo-
selectivity can be accounted for with a mechanism that involves
a kinetically controlled reaction featuring the solvated aggregates
of the tin(II) azaenolate and the lithium chloride generated in
situ as the reactive species. In these solvated aggregates the tin-
(II) cation adopts a trigonal-bipyramidal environment in which
the aldehyde-azaenolate pair of ligands are preferentially located
(53) A stabilizing hydrogen bond has been previously proposed to
rationalize the stereoselectivity observed in aldol additions. See: Paton, R.
S.; Goodman, J. M. Org. Lett. 2006, 8, 4299-4302 and references therein.
(54) (a) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys.
2002, 117, 43-54. (b) Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 106,
5151-5158.
2250 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
SCHEME 10
at axial-equatorial sites. For the reorganization of the solvated
aggregates, the chair-like TSs with Cornforth-like conformation
for the aldehyde moiety are clearly favored for both the matched
and the mismatched pairs.
2.3. Models for the Addition of Tin(II) Azaenolate to
Erythrose Acetonides. Reaction of tin(II) azaenolate uA as a
base with D-erythrose acetonide (R,R)-19c to give bislactim ether
(R)-15 and tin(II) alkoxy-derivative De was calculated to be
exothermic by more than 23 kcal/mol in the gas phase (see
Scheme 10). The most stable tin(II) alkoxy-derivative from
D-erythrose showed a hemiacetalic structure, with the tin(II)
cation chelated by the oxygen atoms at the anomeric and R
positions. Other five- and seven-membered chelate structures
for the tin(II) alkoxy-derivative, showing contacts of the tin(II)
cation with the oxygen atoms at â- and γ-positions (De-5) or
at the carbonyl group and the γ-position (De-7) were higher in
energy (see Scheme S2 of the Supporting Information). Addition
of azaenolate uA to the tin(II) alkoxy-derivative De proceeds
by the exothermic formation of the intermediate complex uADe,
which was used as the reference for calculation of the activation
barriers. Reorganization of this complex to the four possible
aldolates through the caa, css, tas, and tsa diastereomeric
pathways was studied next. Different geometries for uADe were
selected for construction and optimization of the TSs, as depicted
in Scheme S2 of the Supporting Information. We considered
five- and seven-membered chelate rings for the erythrose moiety
(denoted “5” and “7”, respectively), as the lower stability of
such chelates for the intermediates does not necessarily hold
for the TSs where the carbonyl moiety is geometrically distorted
and other steric interactions come into play. The coordination
of the tin(II) cation of the azaenolate with either the oxygen at
the carbonyl group or the oxygen at γ-position of the erythrose
moiety (denoted “c” and “g”, respectively) were also consid-
ered.55 In addition, starting geometries characterized by chair-
like or boat-like conformations for the pericyclic ring (denoted
as “C” and “B”, respectively) were subjected to optimization
in each of the diastereomeric pathways.
FIGURE 4. Chem3D representations of the most favored unsolvated
TSs located (B3LYP/cc-pVDZ-PP level) for the aldol addition of
unsolvated tin(II) azaenolate (uA) to D-erythrose acetonide (De).
Relative energies in the gas phase (B3LYP/cc-pVTZ-PP level) are
shown in parenthesis in kcal/mol. Distances are in angstroms. The
hydrogen atoms are omitted for clarity except at chiral and reaction
centers. Legend: carbon ) gray, nitrogen ) blue, oxygen ) red,
hydrogen ) turquoise, tin ) yellow, chlorine ) green.
utsa-B7cg the pericyclic ring adopts a boat-like conformation,
and the seven-membered chelate ring enables a Felkin-Anh
conformation for the erythrose moiety. The additional four-
membered ring originates from the simultaneous interaction of
one chlorine and the γ-oxygen atom with both tin(II) cations.
Most stable TSs located in the competing tas, caa, and css
pathways were computed to be 4.5, 16.7, and 18.4 kcal/mol
higher in energy than utsa-B7cg, respectively (see utas-C7g in
Figure 4 and ucaa-C7c and ucss-C5c in Figure S6 and Table
S6 of the Supporting Information), conveniently reproducing
the high trans,syn,anti-diastereoselectivity observed in the
addition of azaenolate SnCl+12- to erythrose acetonide (R,R)-
19c (see Table 3).
Reaction of uA with L-erythrose acetonide (S,S)-19c to give
the mismatched complex uALe was also favored in the gas
phase (see Table S7 in the Supporting Information). Full
optimization of the selected geometries for uALe enabled the
location of sets of TSs in the cas, csa, taa, and tss diastereomeric
pathways for the mismatched aldol addition. The TS of lowest
energy was found in the trans,anti,anti diastereomeric pathway,
19.3 kcal/mol above the intermediate complex. This TS,
designated as utaa-C7c (see Figure 5) was characterized by the
In the gas phase, the most stable TS for reaction uA and De
was located in the trans,syn,anti pathway, 12.8 kcal/mol above
the intermediate complex uADe. This TS, designated as utsa-
B7cg (see Figure 4) was characterized by a 4,6,7 ring system.
One of the tin(II) cations showed a trigonal-bipyramidal
environment because of the interaction with the nitrogen of the
azaenolate, a chloride and the oxygens of the carbonyl and
alkoxy groups of the erythrose moiety. Here again, the aldehyde-
azaenolate pair of ligands were located in axial-equatorial sites
around the tin(II) cation, which showed an A configuration. In
(55) TSs in which the tin(II) cation of the azaenolate binds to the chlorine
atom of the tin(II) alkoxy-derivative of erythrose were also located (see
utas-C7 in the Table S6 and utaa-B7 in the Table S7 of the Supporting
Information).
J. Org. Chem, Vol. 73, No. 6, 2008 2251

Ruiz et al.
SCHEME 11
acetonide by the tin(II) azaenolate leading to a tin(II) alkoxy-
derivative is followed by the addition to a second tin(II)
azaenolate to form an intermediate complex. Final reorganization
to the aldolates takes place through competing pericyclic TSs
in which the erythrose moiety is preferentially involved in seven-
membered chelate rings. The calculated TSs account for the
experimentally observed stereoselectivities: trans,syn,anti-TS
is favored for the matched pair and trans,anti,anti-TSs is favored
for the mismatched one, and the energy gap between the
competitive TSs is greater for the matched pair than for the
mismatched one. Finally, the enhanced selectivity observed in
the aldol addition of the mismatched tin(II) azaenolate to the
“unprotected” erythrose acetonide 19c relative to that obtained
with the γ-benzylated erythrose acetonide 19a (9:1 versus <2:1
trans,anti,anti/trans,syn,syn ratio) could be explained in terms
of the conformational restriction of the erythrose moiety in the
seven-membered chelate ring, which leads to tighter TSs and
superior π-facial selectivity. In this manner, chelation appears
to play a key role in both activating the “unprotected” erythrose
moiety toward the aldol addition and directing facial selectivity.
3. Transformation of Aldol Adducts into 1-Deoxynojiri-
mycins. Conversion of the aldol adducts into the targeted imino
sugars required, in addition to the removal of the chiral auxiliary
and reduction of the carboxylic acid group, the selective
activation of the primary hydroxyl group that would enable the
cyclization by intramolecular N-alkylation. Two different meth-
odologies to carry out the cyclization of the threose and the
erythrose derivatives were sought (see Scheme 11). Mesylation
of the primary hydroxyl group and subsequent nucleophilic
displacement by the amino group was appropriate for the
cyclization of the threose derivatives, and the selective oxidation
of the primary hydroxyl group followed by intramolecular
reductive amination was successfully performed with the
erythrose derivatives (see Schemes 12 and 14).
For the synthesis of the threose-derived imino sugars,
additional amounts of the starting compounds 14b, 16b, and
17b were obtained in excellent yields by catalytic hydrogenation
(Pd/C, P atm, rt) of the benzylated adducts 14a, 16a, and 17a
followed by monosilylation (TBDPSCl, DMAP, Et3N, CH2Cl2,
rt, 24 h) of the corresponding diols 14c, 16c, and 17c (see
Schemes 2 and 3). Orthogonal protection of the secondary
hydroxyl group of the silylated adducts 14b, 16b, and 17b was
deemed, in order to avoid competitive ring-closure processes
to furan derivatives. In this way, treatment of compounds 14b,
16b, and 17b with sodium hydride and benzyl bromide in the
presence of a catalytic amount of tetrabutylammonium iodide
led to the corresponding benzyl ethers 24b, 25b, and 26b,
respectively, in good yields (see Scheme 12). After deprotection
of the silyl ether under standard conditions, the mesylation of
FIGURE 5. Chem3D representations of the most favored unsolvated
TSs located (B3LYP/cc-pVDZ-PP level) for the aldol addition of
unsolvated tin(II) azaenolate (uA) to L-erythrose acetonide (Le).
Relative energies in the gas phase (B3LYP/cc-pVTZ-PP level) are
shown in parenthesis in kcal/mol. Distances are in angstroms. The
hydrogen atoms are omitted for clarity except at chiral and reaction
centers. Legend: carbon ) gray, nitrogen ) blue, oxygen ) red,
hydrogen ) turquoise, tin ) yellow, chlorine ) green.
presence of two pseudotetrahedral, tricoordinated tin(II) cations,
a chair-like conformation for the pericyclic ring, and a Corn-
forth-like conformation for the erythrose moiety, which was also
involved in a seven-membered chelate ring. Thus, in TS utaa-
C7c the carbonyl oxygen acts as a bidentated ligand, which binds
to the tin(II) cation of the azaenolate and also to the tin(II) cation
of the erythrose moiety. The distance between a methoxy
hydrogen of the bislactim and the oxygen at R-position of the
erythrose moiety of utaa-C7c was 2.27 Å, which indicated a
hydrogen bond. Most stable TS in the trans,syn,syn pathway
was computed to be 1.9 kcal/mol higher in energy than utaa-
C7c and showed a 4,6,7 ring system, with a boat-like conforma-
tion for the pericyclic ring and a Cornforth-like conformation
for the erythrose moiety (see utss-B7cg in Figure 5). TSs in
the cis pathways were computed to be more than 10 kcal/mol
higher in energy (see ucas-B5c and ucsa-C7c in Figure S7 and
Table S7 of the Supporting Information). Although the energy
difference between utaa-C7c and the competitive TSs suggests
a somewhat higher selectivity than the one observed experi-
mentally for this specific reaction, it is qualitatively in agreement
with the direction of the diastereofacial bias.
In summary, according to DFT calculations, the addition of
tin(II) azaenolates to the erythrose acetonides proceeds by a
three-step mechanism. The initial deprotonation of the erythrose
2252 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
SCHEME 12 a
a Legend: b, R ) SiPh2 Bu; c, R ) H; d, R ) Ms.
t
the alcohols 24c, 25c, or 26c was accomplished in almost
quantitative yields. Selective hydrolysis of the pyrazino moiety
of the mesylates 24d, 25d, or 26d, in the presence of the
isopropylidene ketal, took place without cyclization and fur-
nished the amino mesylates 27, 28, and 29 in good yields.
Although the amino mesylates underwent a slow conversion to
the corresponding pipecolates 30, 31, and 32 on standing,
cyclizations were completed by heating the amino mesylates
in dimethylsulfoxide, using triethylamine as an auxiliary base.
Reduction of the pipecolates 30, 31, and 32 with lithium
triethylborohydride proceeded cleanly, as previously described
for other piperidine derivatives with acidic functionality,56 and
the hydroxypiperidines 33, 34, and 35 were isolated in good
yields. Finally, deprotection of intermediates 33, 34, and 35 by
catalytic hydrogenation in acidic media (THF/HCl 0.25N 1:1)
and purification of the crude reactions by ion-exchange chro-
matography (Dowex, H+ form) and reversed-phase flash chro-
matography led to the isolation of the corresponding imino
sugars, 1-deoxy-D-galactonojirimycin, 1-deoxy-L-idonojirimycin,
and 1-deoxy-L-altronojirimycin (3, ent-7 and ent-5, respectively;
see Scheme 12 and Charts 1 and 2) in high yields.
SCHEME 13
Conversion of the erythrose-derived adducts 20a,c, 21a,c,
22a,c, and 23a,c into 1-deoxy-D-talonojirimycin, 1-deoxy-D-
allonojirimycin, 1-deoxy-D-gulonojirimycin, and 1-deoxy-L-
talonojirimycin, respectively, is straightforward, as depicted in
Scheme 14. In order to avoid unnecessary protection-depro-
tection steps, a chemoselective oxidation of the primary alcohol
in the presence of a secondary one was required. Thus,
debenzylation of adducts 20a, 21a, 22a, and 23a by catalytic
hydrogenation gave additional amounts of the corresponding
diols 20c, 21c, 22c, and 23c in quantitative yields (see Schemes
4 and 5), which were subsequently oxidized to the γ-lactols
37, 38, 39, and 40, respectively, by using a slight modification
of Corey’s conditions.58,59 In this way, when a solution of
compound 20c, 21c, 22c, or 23c in THF was treated with a
Pipecolic acid 36, an analogue of galacturonic acid that has
shown a potent inhibition of several R-galactosidases and
galacturonases,57 was also readily available from the pipecolate
30 (see Scheme 13). Thus, under the conditions employed for
deprotection of the piperidines, 30 gave rise to the pipecolic
acid 36, which could be isolated in excellent yield after ion-
exchange and reversed-phase flash chromatography.
(57) Tong, M. K.; Blumenthal, E. M.; Ganem, B. Tetrahedron Lett. 1990,
31, 1683-1684. Other trihydroxypipecolic acids have shown important
biological activities: (a) Le Merrer, Y.; Poitout, L.; Depezay, J.-C.; Dosbaa,
I.; Geoffroy, S.; Foglietti, M.-J. Bioorg. Med. Chem. 1997, 5, 519-533.
(b) Tsuruoka, T.; Fukuyasu, H.; Ishii, M.; Usui, T.; Shibahara, S.; Inouye,
S. J. Antibiot. 1996, 49, 155-61. (c) Fleet, G. W. J.; Karpas, A.; Dwek, R.
A.; Fellows, L. E.; Tyms, A. S.; Petursson, S.; Namgoong, S. K.; Ramsden,
N. G.; Smith, P. W.; Son, J. C.; Wilson, F.; Witty, D. R.; Jacob, G. S.;
Rademacher, T. W. FEBS Lett. 1988, 237, 128-32.
(56) See for example: Shilvock, J. P.; Wheatley, J. R.; Davis, B.; Nash,
R. J.; Griffiths, R. C.; Jones, M. G.; Mu¨ller, M.; Crook, S.; Watkin, D. J.;
Smith, C.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J. Tetrahedron Lett.
1996, 37, 8569-8572.
(58) Corey, E. J.; Palani, A. Tetrahedron Lett. 1995, 36, 3485-3488.
J. Org. Chem, Vol. 73, No. 6, 2008 2253

Ruiz et al.
SCHEME 14 a
imino sugars 3-8 were consistent with the literature values (see
Supporting Information).
In conclusion, we have demonstrated the utility of aldol
additions of metalated bislactim ethers to threose or erythrose
acetonides in the synthesis of 1,5-iminohexitols related to
1-deoxynojirimycin. The easy availability of the reagents, the
stereoselectivity in the aldol processes of matched and mis-
matched pairs, and the good yield of the steps would give easy
access for the synthesis of new polyhydroxylated alkaloids that
may be useful for glycosidase inhibition and development of
beneficial drugs. Additional studies to adapt this aldol-based
strategy to the synthesis of 2,5-iminohexitols are currently under
investigation and will be reported in due course.
Experimental Section
General Procedure 1 for Aldol Addition. Method A. A
solution of n-BuLi (1.2 equiv, 2.5 M in hexane) was added to a
stirred solution of Scho¨llkopf’s bislactim ether (1.2 equiv) in THF
(10 mL/mmol) at -78 °C, and the mixture was stirred for 1 h.
Then, a 0.5 M solution of the additive (ZnCl2, SnCl2, Sn(OTf)2,
Et2AlCl, MgBr2‚OEt, Ti(OiPr)3Cl, or Ti(NEt2)3Cl) in THF (1.2-
2.4 equiv) was added dropwise. The mixture was stirred for 1 h,
and a solution of aldehyde (1.0 equiv) in THF (2.5-4.0 mL/mmol)
was added dropwise. After being stirred at -78 °C for 2 h, the
reaction was quenched with aqueous saturated NH4Cl or NaHCO3
solution. The crude reaction mixture was warmed to room tem-
perature, and the solvent was removed in vacuo. The resulting
material was diluted with water and extracted with ether. The
combined organic layers were dried (Na2SO4) and evaporated, and
the residue was purified by flash chromatography (silica gel, EtOAc/
hexanes from 1:9 to 3:1 ratio) to yield the corresponding addition
products. Method B. A solution of n-BuLi (3.0 equiv, 2.5 M in
hexane) was added to a stirred solution of Scho¨llkopf’s bislactim
ether (3.0 equiv) in THF (10 mL/mmol) at -78 °C, and the mixture
was stirred for 1 h. Then, a 0.5 M solution of the additive (ZnCl2,
SnCl2, MgBr2‚OEt, Ti(OiPr)3Cl, Ti(NEt2)3Cl, or TMSCl and SnCl4)
in THF (3.0-6.0 equiv) was added dropwise. The mixture was
stirred for 1 h, and a solution of lactol (1.0 equiv) in THF (2.5-
4.0 mL/mmol) was added dropwise. The reaction mixture was
gradually warmed to 0 °C for 5-12 h, and the reaction was
quenched with aqueous NH4Cl or saturated NaHCO3 solution and
worked up as described in method A.
a Reagents and conditions: (a) IBX, DMSO/THF (1:1), 8 °C, 24 h. (b)
0.25 M HCl/EtOH (1:2), H2, Pd/C, rt, 4 h. (c) LiBEt3H, THF, rt, 3 h. (d)
Dowex-H+.
solution of o-iodoxybenzoic acid (IBX)60 in DMSO, a 62-68%
conversion to the desired lactols 37, 38, 39, or 40 was achieved.
As the overoxidation to the corresponding lactones was com-
pletely suppressed, the yield of lactols 37-40 could be increased
to 82-89% by resubjecting recovered starting materials to these
oxidation conditions. Selective hydrolysis of the bislactim ether
in the presence of the isopropylidene ketal and subsequent
intramolecular reductive amination were achieved in a one-pot
procedure. Stirring the lactols 37, 38, 39, or 40 in a 1:2 mixture
of 0.25 M HCl and EtOH under a hydrogen atmosphere and
palladium catalyst afforded the piperidine esters (-)-41, 42, 43,
or (+)-41 in good yields. Reduction of (-)-41, 42, or 43 with
LiBEt3H also proceeded cleanly. Filtering of the reduction
crudes through Dowex (H+ form) and purification by reversed-
phase flash chromatography afforded 1-deoxy-D-talononojiri-
mycin, 1-deoxy-D-allonojirimycin, or 1-deoxy-D-gulonojirimycin
in excellent yields (8, 4, and 6, respectively; see Scheme 14
and Chart 2). Specific rotations and spectral data obtained for
(3S,6R,1′S,2′S,3′S)-3-[4-Benzyloxy-1-hydroxy-2,3-isopropy-
lidenedioxybutyl]-2,5-diethoxy-3,6-dihydro-6-isopropylpyra-
zine (14a). Following method A of the general procedure 1, reaction
of (R)-12 (314 mg, 1.48 mmol) with 13a (308 mg, 1.23 mmol)
using SnCl2 as additive (280 mg, 1.48 mmol) gave, after flash
chromatography (silica gel, EtOAc/hexanes from 1:9 to 1:4 ratio),
460 mg of adduct 14a (81%). Colorless oil; Rf ) 0.67 (EtOAc/
hexanes 1:2); [R]29D -5.2 (c 1.1, CH2Cl2); IR (film) ν 3450, 2973,
1
1695, 1480, 1369, 1233 cm-1; H NMR (CDCl3) δ 0.76 (d, J )
6.8 Hz, 3H), 1.04 (d, J ) 6.8 Hz, 3H), 1.23-1.34 (m, 6H), 1.45 (s,
6H), 2.21 (dsp, J ) 6.8, 3.4 Hz, 1H), 3.67 (d, J ) 5.4 Hz, 2H),
3.97 (t, J ) 3.4 Hz, 1H), 4.03-4.31 (m, 8H), 4.61 (s, 2H), 7.27-
7.35 (m, 5H); 13C NMR (CDCl3) δ 14.3 (CH3), 17.0 (CH3), 19.1
(CH3), 27.1 (CH3), 27.2 (CH3), 32.2 (CH), 56.5 (CH), 60.8 (CH2),
61.1 (CH), 71.2 (CH2), 72.9 (CH), 73.4 (CH2), 76.4 (CH), 78.9
(CH), 109.5 (C), 127.6 (CH), 128.3 (CH), 137.8 (C), 161.2 (C),
166.0 (C); FABMS (thioglycerol) m/z 463 (MH+, 85). Anal. Calcd
for C25H38N2O6: C, 64.91; H, 8.28; N, 6.06. Found: C, 64.75; H,
8.38; N, 6.00.
(59) Attempts to obtain the γ-lactols by treatment of the diols in the
conditions reported by Kim (NCS, iPr2S, Et3N, CH2Cl2, 0 °C) or Skarzewski
(TEMPO, NaOCl, CH2Cl2, from 0 °C to rt) were unsuccessful. (a) Kim, K.
S.; Cho, I. H.; Yoo, B. K.; Song, Y. H.; Hahn, C. S. J. Chem. Soc., Chem.
Commun. 1984, 762-763. (b) Siedlecka, R.; Skarzewski, J.; Mlochowski,
J. Tetrahedron Lett. 1990, 31, 2177-2180.
(60) IBX was prepared as described in: Frigerio, M.; Santagostino, M.;
Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60, 7272-7276. CAU-
TION: IBX has been reported to detonate upon heavy impact and heating
over 200 °C: (a) Plumb, J. B.; Harper D. J. Chem. Eng. News 1990, July
16, 3. See also: (b) Dess, B. D.; Martin, J. C. J. Am. Chem. Soc. 1991,
113, 7277-7287.
(3S,6R,1′S,2′S,3′S)-3-[4-tert-Butyldiphenylsilyloxy-1-hydroxy-
2,3-isopropylidenedioxybutyl]-2,5-diethoxy-3,6-dihydro-6-iso-
propylpyrazine (14b). Following method A of the general proce-
dure 1, reaction of (R)-12 (0.96 g, 4.52 mmol) with 13b (1.5 g,
3.77 mmol) using SnCl2 as additive (0.86 g, 4.52 mmol) gave, after
flash chromatography (silica gel, EtOAc/hexanes from 1:9 to 1:3
2254 J. Org. Chem., Vol. 73, No. 6, 2008

DiastereoselectiVe Synthesis of Piperidine Imino Sugars
ratio), 1.74 g of adduct 14b (75%). Compound 14b was also
prepared according to the general procedure 3 (see Supporting
Information); silylation of 14c (350 mg, 0.94 mmol) gave 562 mg
Hz, 1H), 3.82 (dd, J ) 9.9, 6.9 Hz, 1H), 3.97 (t, J ) 3.5 Hz, 1H),
4.12-4.28 (m, 6H), 4.44-4.48 (m, 2H), 4.56/4.63 (AB system, J
) 11.8 Hz, 2H), 7.26-7.35 (m, 5H); 13C NMR (75 MHz, CDCl3)
δ 14.3 (CH3), 14.4 (CH3), 16.9 (CH3), 19.1 (CH3), 25.6 (CH3), 28.1
(CH3), 32.0 (CH), 56.4 (CH), 60.7 (CH2), 60.8 (CH2), 60.9 (CH),
68.7 (CH2), 69.1 (CH), 73.8 (CH2), 75.8 (CH), 76.0 (CH), 108.6
(C), 127.9 (CH), 128.5 (CH), 137.3 (C), 161.2 (C), 165.3 (C);
FABMS (thioglycerol) m/z 463 (MH+, 100), 165 (51). Anal. Calcd
for C25H38N2O6: C, 64.91; H, 8.28; N, 6.06. Found: C, 65.10; H,
8.21; N, 6.23.
(3S,6R,1′S,2′S,3′R)-3-[1,4-dihydroxy-2,3-isopropylidenedioxy-
butyl]-2,5-diethoxy-3,6-dihydro-6-isopropylpyrazine (20c). Fol-
lowing method B of the general procedure 1, reaction of (R)-12
(3.58 g, 16.87 mmol) with (R,R)-19c (900 mg, 5.62 mmol) using
SnCl2 as additive (3.20 g, 16.87 mmol) gave, after flash chroma-
tography (silica gel, EtOAc/hexanes from 1:4 to 2:3 ratio), 1.94 g
of adduct 20c (93%). Compound 20c was also prepared according
to the general procedure 2 (see Supporting Information); hydro-
genation of 20a (350 mg, 0.76 mmol) gave 281 mg of 20c (100%).
Colorless oil; Rf ) 0.31 (EtOAc/hexanes 1:3); [R]23D -69.0 (c 0.5,
CH2Cl2); IR (film) ν 3395, 2978, 1693, 1459, 1381, 1237, 1144,
1036 cm-1; 1H NMR (CDCl3) δ 0.76 (d, J ) 6.8 Hz, 3H), 1.02 (d,
J ) 6.8 Hz, 3H), 1.28 (t, J ) 6.8 Hz, 3H), 1.29 (t, J ) 6.8 Hz,
3H), 1.39 (s, 3H), 1.46 (s, 3H), 2.22 (dsp, J ) 6.8, 3.9 Hz, 1H),
2.49 (brd, J ) 8.3 Hz, 1H), 3.07 (brt, J ) 5.9 Hz, 1H), 3.75-4.00
(m, 2H), 3.97 (t, J ) 3.9 Hz, 1H), 4.03-4.42 (m, 8H); 13C NMR
(CDCl3) δ 14.2 (CH3), 17.1 (CH3), 19.0 (CH3), 25.5 (CH3), 27.9
(CH3), 32.3 (CH), 55.9 (CH), 60.6 (CH2), 60.9 (CH2), 61.1 (CH),
69.1 (CH), 75.8 (CH), 77.4 (CH), 108.4 (C), 161.4 (C), 166.3 (C);
FABMS (thioglycerol) m/z 373 (MH+, 100). Anal. Calcd for
C18H32N2O6: C, 58.05; H, 8.66; N, 7.52. Found: C, 58.31; H, 8.39;
N, 7.28.
of 14b (98%). Colorless oil; Rf ) 0.35 (EtOAc/hexanes 1:9); [R]20
D
-8.5 (c 2.0, CH2Cl2); IR (film) ν 3450, 2900, 1700, 1480, 1380,
1250, 1100 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.77 (d, J ) 6.8
Hz, 3H), 1.04 (d, J ) 6.8 Hz, 3H), 1.05 (s, 9H), 1.23 (t, J ) 7.3
Hz, 3H), 1.31 (t, J ) 7.3 Hz, 3H), 1.45 (s, 6H), 2.02 (d, J ) 9.3
Hz, 1H), 2.25 (dsp, J ) 6.8, 3.9 Hz, 1H), 3.84 (d, J ) 4.4 Hz, 2H),
3.98 (t, J ) 3.9 Hz, 1H); 4.01-4.28 (m, 7H); 4.40 (dd, J ) 8.8,
6.3 Hz, 1H), 7.33-7.44 (m, 6H), 7.66-7.73 (m, 4H); 13C NMR
(CDCl3) δ 14.3 (CH3), 17.1 (CH3), 19.1 (CH3), 19.2 (CH3), 19.2
(C), 26.7 (CH3), 27.4 (CH3), 32.3 (CH), 56.5 (CH), 60.8 (CH2),
60.9 (CH2), 61.1 (CH), 64.5 (CH2), 73.1 (CH), 76.4 (CH), 80.4
(CH), 109.4 (C), 127.7 (CH), 129.7 (CH), 133.1 (C), 135.6 (CH),
161.3 (C), 166.2 (C); FABMS (thioglycerol) m/z 611 (MH+, 40).
Anal. Calcd for C34H50N2O6Si: C, 66.85; H, 8.25; N, 4.59. Found:
C, 66.62; H, 8.56; N, 4.36.
(3S,6R,1′S,2′S,3′S)-3-[1,4-Dihydroxy-2,3-isopropylidenedioxy-
butyl]-2,5-diethoxy-3,6-dihydro-6-isopropylpyrazine (14c). Fol-
lowing method B of the general procedure 1, reaction of (R)-12
(388 mg, 1.83 mmol) with 13c (98 mg, 0.61 mmol) using SnCl2 as
additive (347 mg, 1.83 mmol) gave, after flash chromatography
(silica gel, EtOAc/hexanes from 1:9 to 2:1 ratio), 150 mg of adduct
14c (66%). Compound 14c was also prepared according to the
general procedure 2 (see Supporting Information); hydrogenation
of 14a (350 mg, 0.76 mmol) gave 282 mg of 14c (100%). Colorless
solid; mp (EtOAc/hexanes) 67-69 °C; Rf ) 0.28 (EtOAc/hexanes
1:1); [R]27D -15.4 (c 1.0, CH2Cl2); IR (KBr) ν 3384, 2972, 1698,
1
1233, 1035 cm-1; H NMR (CDCl3) δ 0.76 (d, J ) 6.8 Hz, 3H),
1.04 (d, J ) 6.8 Hz, 3H), 1.29 (t, J ) 6.8 Hz, 3H), 1.30 (t, J ) 6.8
Hz, 3H), 1.45 (s, 6H), 2.1 (brd, 1H), 2.24 (dsp, J ) 6.8, 3.6 Hz,
1H), 2.77 (brs, 1H), 3.75-3.85 (m, 2H), 3.98 (t, J ) 3.6 Hz, 1H);
4.06-4.28 (m, 8H); 13C NMR (CDCl3) δ 14.2 (CH3), 14.2 (CH3),
17.0 (CH3), 19.1 (CH3), 27.0 (CH3), 27.1 (CH3), 32.3 (CH), 56.4
(CH), 61.2 (CH2), 61.2 (CH), 63.5 (CH2), 72.4 (CH), 77.8 (CH),
79.8 (CH), 109.0 (C), 160.9 (C), 166.7 (C); FABMS (thioglycerol)
m/z 373 (MH+, 100). Anal. Calcd for C18H32N2O6: C, 58.05; H,
8.66; N, 7.52. Found: C, 58.31; H, 8.60; N, 7.44.
Acknowledgment. We gratefully acknowledge Ministerio
de Ciencia y Tecnolog´ıa (BQU2003-00692) and Xunta de
Galicia (PGIDIT05BTF10301PR) for financial support, Novartis
Pharma for the generous gift of bislactim ethers derived from
cyclo-[Val-Gly], and Noa Castro and Isaac Va´zquez for technical
assistance. The authors are indebted to Centro de Supercom-
putacio´n de Galicia for providing the computer facilities. O.B.
thanks Xunta de Galicia for an “Isidro Parga Pondal” position
at Universidade da Corun˜a.
(3S,6R,1′S,2′S,3′R)-3-[4-Benzyloxy-1-hydroxy-2,3-isopropy-
lidenedioxybutyl]-2,5-diethoxy-3,6-dihydro-6-isopropylpyra-
zine (20a). Following method A of the general procedure 1, reaction
of (R)-12 (300 mg, 1.41 mmol) with (R,R)-19a (293 mg, 1.17 mmol)
using SnCl2 as additive (267 mg, 1.41 mmol) gave, after flash
chromatography (silica gel, EtOAc/hexanes from 1:9 to 1:4 ratio),
395 mg of adduct 20a (73%). Colorless oil; Rf ) 0.67 (EtOAc/
hexanes 1:2); [R]29D +11.9 (c 1.0, CH2Cl2); IR (film) ν 2980, 2933,
1697, 1235, 1074 cm-1; 1H NMR (300 MHz, CDCl3) δ 0.74 (d, J
) 6.8 Hz, 3H), 1.04 (d, J ) 6.8 Hz, 3H), 1.27 (t, J ) 6.8 Hz, 3H),
1.30 (t, J ) 6.8 Hz, 3H), 1.40 (s, 3H), 1.46 (s, 3H), 2.27 (dsp, J )
6.8, 3.5 Hz, 1H), 2.75 (d, J ) 7.1 Hz, 1H), 3.62 (dd, J ) 9.9, 5.3
Supporting Information Available: Experimental procedures
and full characterization of new compounds and computational
methods, Cartesian coordinates, and absolute energies for all models
reported. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO702601Z
J. Org. Chem, Vol. 73, No. 6, 2008 2255