Efficient conversion of carbohydrates into 1-C-alditols: Application to the synthesis of chiral γ-substituted butenolides and bicyclic alkaloid analogues

Article abstract of DOI:10.1021/jo800478a

(Chemical Equation Presented) Readily available sugar derivatives were transformed in a few steps into valuable, more complex products. The tandem radical scission of carbohydrates-oxidation reaction gave acetoxy acetals, which were converted into a variety of chiral C-alditols in good global yields and excellent 1,2-trans stereoselectivity. The reaction was the key step in the synthesis of hydroxylated γ-substituted butenolides and bicyclic alkaloid analogues.

Full text of DOI:10.1021/jo800478a

Efficient Conversion of Carbohydrates into 1-C-Alditols: Application
to the Synthesis of Chiral γ-Substituted Butenolides and Bicyclic
Alkaloid Analogues
Alicia Boto,* Da´cil Hernández, and Rosendo Hernández*
Instituto de Productos Naturales y Agrobiolog´ıa del CSIC, AVda. Astrof´ısico Francisco Sa´nchez 3,
38206-La Laguna, Tenerife, Spain
alicia@ipna.csic.es; rhernandez@ipna.csic.es
ReceiVed February 29, 2008
Readily available sugar derivatives were transformed in a few steps into valuable, more complex products.
The tandem radical scission of carbohydrates-oxidation reaction gave acetoxy acetals, which were
converted into a variety of chiral C-alditols in good global yields and excellent 1,2-trans stereoselectivity.
The reaction was the key step in the synthesis of hydroxylated γ-substituted butenolides and bicyclic
alkaloid analogues.
SCHEME 1. Conversion of Carbohydrate Derivatives into
Sugars of Less Common Series and 1-C-Alditols
Introduction
Carbohydrates have proven very valuable to generate other
chiral compounds with polyhydroxylated chains.1 However,
when the required stereochemistry corresponds to sugars of
unusual series, expensive starting materials or considerable
manipulation of common chains is required. In an effort to
transform readily available, inexpensive sugars into those of
less usual series, the ꢀ-fragmentation reaction of anomeric
alkoxyl radicals 1 (Scheme 1) was studied. To generate the
O-radicals, the carbohydrates were treated with (diacetoxy-
)iodobenzene (DIB) and iodine.2,3 A ꢀ-fragmentation reaction
took place, producing a carbon radical 2, which was oxidized
in the reaction mixture to an oxycarbenium ion 3.2,3 This, in
turn, was trapped by an acetate moiety from DIB (Scheme 1)
(1) (a) Nakata, P. In Glycoscience; Fraser-Reid, B. O., Tatsuta, K., Thiem,
J., Eds.; Springer: Berlin, Germany, 2001; Vol. 2, pp 1175-1214. (b) Hanessian,
S. Total Synthesis of Natural Products. The “Chiron” Approach; Pergamon Press:
Oxford, 1983.
(2) For the preliminary communications on this work, see: (a) Boto, A.;
Herna´ndez, D.; Herna´ndez, R. Org. Lett. 2007, 9, 1721–1724. (b) Boto, A.;
Herna´ndez, R.; Sua´rez, E. Tetrahedron Lett. 2001, 42, 9176–9170.
to give the acetoxy derivatives 4. In this way, a D-galactose
chain could be transformed into a D-lyxose unit, a ribose
derivative was transformed into a threose moiety, and so on,
under very mild conditions.
10.1021/jo800478a CCC: $40.75
Published on Web 06/13/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5287–5297 5287

Boto et al.
SCHEME 2. Butenolides with Hydroxylated γ-Substituents:
Possible Targets for the Fragmentation/Alkylation
Methodology
FIGURE 1. Decahydroquinoline alkaloids and their analogues.
8 could be formed by addition of a furan-derived nucleophile
such as (trimethylsilyloxy)furan (TMSOF)10 to the acetoxy
acetals 4.
An even more challenging target would be the decahydro-
quinoline family of alkaloids11 (Figure 1), such as Lepadin B
(9),12 which has displayed potent antitumoral activity. To study
the structure-activity relationships, it would be useful to prepare
bicyclic analogues 10 with different ring sizes and substituents.
By introducing changes in the substituents, it would be possible
to modulate the hydrophilicity of the analogues and their
biological activity. The application of the scission/alkylation
procedure to the preceding examples would allow determination
of the scope and versatility of this methodology.
We reasoned that products 4 could be treated with different
carbon nucleophiles (such as allylsilanes or enolsilyl ethers),
in the presence of a Lewis acid, to give 1-C-alditols 5 (Scheme
1), which are useful precursors of many bioactive products. A
possible modification of this methodology would couple the
scission and the nucleophilic addition steps, avoiding the
purification of the acetate intermediates 4. In this article we
study the feasibility of these approaches and the application of
the scission-oxidation reaction to prepare valuable products such
as chiral butenolides with hydroxylated γ-substituents and
polyhydroxylated alkaloid analogues.
Results and Discussion
The starting materials for the fragmentation reaction were
ribose and mannose derivatives 11-13 (Scheme 3), which were
SCHEME 3. Conversion of Carbohydrate Derivatives into
Acetoxy Acetals and 1-Allyl Polyols15
The butenolide moiety with hydroxylated chains at the
γ-position (Scheme 2) is present in many natural products and
bioactive compounds,4 such as iso-cladospolide B (6)5 and
vitamin C analogues.6 Besides, it is an important synthetic
intermediate, as exemplified in the preparation of the cytotoxic
goniofufurone (7),7 hydroxylated carbocycles,8 and higher-
carbon sugars.9 A variety of γ-substituted butenolide derivatives
(3) For related work on this subject, see: (a) Boto, A.; Herna´ndez, D.;
´
Herna´ndez, R.; Alvarez, E. J. Org. Chem. 2007, 72, 9523–9532. (b) Francisco,
C. G.; Gonza´lez, C.; Sua´rez, E. J. Org. Chem. 1998, 63, 8092–8093. (c) de
Armas, P.; Francisco, C. G.; Sua´rez, E. Angew. Chem., Int. Ed. Engl. 1992, 31,
772–774. (d) For a review on the modification of carbohydrates through radical
chemistry, see: Hansen, S. G.; Skrydstrup, T. Top. Curr. Chem. 2006, 264, 135–
162.
(4) (a) Koch, S. S. C.; Chamberlin, A. R. In Enantiomerically Pure
γ-Butirolactones in Natural Products Synthesis; Atta-ur-Rahman, Ed.; Elsevier
Science: Amsterdam, 1995; pp 687-725. (b) Ma, S. Acc. Chem. Res. 2003, 36,
701–712. (c) Rassu, G.; Zanardi, F.; Battistini, L.; Casiraghi, G. Chem. Soc.
ReV. 2000, 109–118. (d) For recent articles on the subject, see: Schuyler, A.;
Caufield, C. E.; Hu, W.; Keeney, D.; Labthavikul, P.; Morris, K.; Naughton,
S. M.; Petersen, P.; Rasmussen, B. A.; Singh, G.; Yang, Y. Bioorg. Med. Chem.
Lett. 2006, 16, 176–180. (e) Li, R. T.; Han, Q. B.; Zheng, Y. T.; Wang, R. R.;
Yang, L. M.; Lu, Y.; Sang, S. Q.; Zheng, Q.-T.; Zhao, Q. S.; Sun, H. D. Chem.
Commun. 2005, 23, 2936–2938. (f) Teijeira, M.; Sua´rez, P. L.; Go´mez, G.; Tera´n,
C.; Fall, Y. Tetrahedron Lett. 2005, 46, 5889–5892, and references therein.
(5) (a) Trost, B. M.; Aponick, A. J. Am. Chem. Soc. 2006, 128, 3931–3933.
(b) Sharma, G. V. M.; Reddy, K. L.; Reddy, J. J. Tetrahedron Lett. 2006, 47,
6537–6540. (c) Pandey, S. K. Tetrahedron Lett. 2005, 46, 6625–6627. (d) Franck,
X.; Araujo, M. E.; Jullian, J.-C.; Hocquemiller, R.; Figadere, B. Tetrahedron
Lett. 2001, 42, 2801–2803.
(6) (a) Ge, P.; Kira, K. L. J. Org. Chem. 1996, 61, 8671–8673.
(7) (a) Prasad, K. R.; Gholap, S. L. J. Org. Chem. 2008, 73, 2–11. (b) Yadav,
V. K.; Agrawal, D. Chem. Commun. 2007, 5232–5234, and references therein.
(8) (a) Rassu, G.; Auzzas, L.; Zambrano, V.; Burreddu, P.; Battistini, L.;
Curti, C. Tetrahedron: Asymmetry 2003, 14, 1665–1670. (b) Rassu, G.; Auzzas,
L.; Pinna, L.; Zambrano, V.; Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti,
D.; Casiraghi, G. J. Org. Chem. 2001, 66, 8070–8075. (c) Rassu, G.; Auzzas,
L.; Pinna, L.; Battistini, L.; Zanardi, F.; Marzocchi, L.; Acquotti, D.; Casiraghi,
G. J. Org. Chem. 2000, 65, 6307–6318. (d) Horneman, A. M.; Lundt, I.
Tetrahedron 1997, 53, 6879–6892.
(9) Martin, S. F.; Zinke, P. W. J. Am. Chem. Soc. 1989, 111, 2311–2313.
5288 J. Org. Chem. Vol. 73, No. 14, 2008

ConVersion of Carbohydrates into C-Alditols
SCHEME 4. Conversion of Carbohydrates into Acetoxy Acetals and Polyhydroxylated Ketones
prepared according to reported procedures.2a,3a When they were
treated with DIB and iodine under irradiation with visible light
(80-W tungsten-filament lamp), the scission took place affording
the acetoxy acetals 14-162a,3a in good yields. The acetals 14-16
were then treated with BF3 ·OEt2 and allyltrimethylsilane, using
different solvents (CH2Cl2 or MeCN) and temperatures; the best
results were obtained with CH2Cl2 at -40 °C.
were treated under the previous scission conditions for 1 h, and
then the reaction mixture was cooled to -40 °C, followed by
dropwise addition of allylTMS and BF3 ·OEt2. The solution was
allowed to reach 0 °C and was stirred for 3 h. The one-pot
procedure generated the allyl derivatives 17 and 18, the yields
being similar to those obtained in the two-step sequence (21%
for 17, 62% for 18). In the case of product 19 (25%), the two-
step method gave better results than the one-pot procedure.
The acetoxy acetals 14 and 16 were also reacted with silyl
enol ethers. When 1-phenyl-(trimethylsilyloxy)ethene was used
as the nucleophile, the phenyl ketones 20 and 21 (Scheme 4)
were obtained quantitatively. In contrast, the one-pot scission-
alkylation from sugar substrates 11 and 13 proceeded in low
yields.
The scission/alkylation procedure was then studied with
pyranose substrates 22 and 23. Thus, the mannopyranose and
rhamnopyranose derivatives 2216 and 232a,3a (Scheme 4) were
transformed into their acetoxy acetals 24 and 25,2a,3a respec-
tively. These acetates were treated with PhC(OTMS)dCH2 and
BF3 ·OEt2, affording the phenyl ketones 26 and 272a,3a in good
yields. However, the one-pot procedure gave low yields of the
phenyl ketones. Therefore, the other examples (giving buteno-
lides and bicyclic alkaloid precursors, see below) were carried
out using the two-step sequence.
The yield for compound 17 was low (21%);13 however, its
5-benzoate analogue 18 and the allyl derivative 19 were isolated
in satisfactory yields (62% and 46%, respectively).14
The direct transformation of carbohydrate substrates 11-13
into the allyl derivatives 17-19 was studied next. The substrates
(10) (a) For instance, the coupling of commercial 2-trimethylsilyloxyfuran
(TMSOF) with aldehydes is a remarkable strategy for butenolide synthesis
Maulide, N.; Marko, I. E. Org. Lett. 2006, 8, 3705–3707. (b) De Rosa, M.;
Citro, L.; Soriente, A. Tetrahedron Lett. 2006, 47, 8507–8510.
(11) (a) Banner, E. J.; Stevens, E. D.; Trudell, M. L. Tetrahedron Lett. 2004,
45, 4411–4414. (b) Toyooka, N.; Okumura, M.; Nemoto, H. J. Org. Chem. 2002,
67, 6078–6081. (c) Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids:
Chemical and Biological PerspectiVes; Pelletier, S. W.; Ed.; Pergamon Press:
New York, 1999; Vol. 13, pp 1-161. (d) Daly, J. W. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1988; Vol. 50, pp 141-169.
(12) Wu, Q.; Ma, D. Nat. Prod. Rep. 2006, 23, 772–788.
(13) Compound 17 was volatile, and loss of weight was observed under
vacuum.
(14) For related allyl systems and their synthetic applications, see: (a) Lievens,
S. C.; Molinski, T. F. J. Am. Chem. Soc. 2006, 128, 11764–11765. (b) Shing,
T. K. M.; Wong, W. F.; Ikeno, T.; Yamada, T. Org. Lett. 2007, 9, 207–209. (c)
Enders, D.; Lenzen, A.; Backes, M.; Janeck, C.; Catlin, K.; Lannon, M. I.;
Runsink, J.; Raabe, G. J. Org. Chem. 2005, 70, 10538–10551.
The phenyl ketones were obtained with high 1,2-trans
stereoselectivity:17,18 when the acetate precursors 14-16 and
(15) The numbering shown on the C-alditol figures does not always match
the IUPAC rules. However, this numbering system allows an easier discussion
of the results: the polyhydroxylated chain is numbered as the acetoxy acetal
precursor, and the new allyl or alkyl chain is numbered starting from the position
closer to the polyol unit.
(16) Substrate 22 was previously reported: Kapoor, V. P. Indian J. Chem.
1973, 11, 13–16. However, our synthetic strategy differs from the previous
version, and therefore, it is described in Supporting Information.
J. Org. Chem. Vol. 73, No. 14, 2008 5289

Boto et al.
TABLE 1. Addition of (TMS)Furan to Acetoxy Acetals
a Yields for products purified by chromatography on silica gel.
24-25 were treated with the Lewis acid, an oxycarbenium ion
was formed. The adjacent stereogenic center controlled the
addition of the nucleophile, which took place from the less
hindered side of the cyclic oxycarbenium intermediate,3a af-
fording the 1,2-trans products.
Application of the Fragmentation/Alkylation Procedure
to the Synthesis of Chiral γ-Substituted Butenolides. An
expedient way to prepare butenolides is shown in Table 1. The
acetoxy acetals 14, 16, 24, and 25 were reacted with (trimeth-
ylsilyloxy)furan, in the presence of BF3 ·OEt2, yielding the
furanones 28-39 in good global yield. The nucleophilic addition
was stereoselective, and in all cases, the 1,2-trans products were
obtained exclusively.18,19 As for the stereochemistry of C-1′ in
the conjugated furanones 28/29, 31/32, 34/35, and 37/38, the
major diastereomer presented an 1,1′-anti (1,1′-erythro) disposi-
tion. Their stereochemistry was unequivocally determined by
comparison with related compounds,19 which presented a J1,1′
) 0-3 Hz for the 1,1′-threo diastereomers and a J1,1′ ) 8-10
Hz for the 1,1′-erythro isomers.
(18) The experimental coupling constants observed for compounds 21 (J1,2
) 8.1 Hz) and 26 (J1,2 ) 7.8 Hz) and for the other scission-alkylation products
(J1,2 ) 6.5-8.5 Hz) matched theoretical coupling constants for 1,2-trans
derivatives. The theoretical J1,2 for the 1,2-trans and the 1,2-cis products were
calculated over minimized structures by using the Karplus-Altona equation
implemented in the Macromodel 7.0 program. The calculations were performed
with a MMFF force field, using high-quality parameters. Values of J1,2 ) 6.3-
10.0 Hz and J1,2 ) 4.0-6.0 Hz were obtained for the 1,2-trans and the 1,2-cis
compounds, respectively.
(19) (a) Hornemann, A. M.; Lundt, I. Synthesis 1999, 317–325. (b)
Hornemann, A. M.; Lundt, I. Tetrahedron 1997, 53, 6879–6892. (c) de March,
P.; Figueredo, M.; Font, J.; Raya, J.; Alvarez-Larena, A.; Piniella, J. F. J. Org.
Chem. 2003, 68, 2437–2447.
(17) NOESY experiments were carried out with compounds 21 and 26. The
spatial interactions observed for compound 21 were 1-H (δH 4.63)/3-H (δH 5.43),
2-H (δH 4.28)/1′-Ha (δH 2.86), 2-H/1′-Hb (δH 3.06). Compound 26 showed the
following spatial interactions: 1-H (δH 4.69)/3-H (δH 3.65), 1-H/4-H (δH 5.18),
2-H (δH 3.91)/1′-Ha (δH 3.16), 2-H/1′-Hb (δH 3.49)
5290 J. Org. Chem. Vol. 73, No. 14, 2008

ConVersion of Carbohydrates into C-Alditols
SCHEME 5. Conversion of Conjugated Lactones into Enol
Esters and Higher Sugars
biological activity, a short process to obtain hydroxylated
derivatives was developed (Scheme 6). Thus, the bicyclic core
in 42 could be formed by reductive amination24of diketone 43.
The latter can be prepared from the cyclohexanone derivative
44, by hydrolysis of the formate group and oxidation. Finally,
44 would be prepared from readily available sugars 45, using
the fragmentation/alkylation sequence.
Thus, the scission products 14, 16, 24, and 25 were treated
with (trimethylsilyloxy)cyclohexene and BF3 ·OEt2, yielding the
cyclohexanones 46-49 (Table 2) in good global yields. The
nucleophilic addition gave exclusively 1,2-trans products,25 but
inseparable mixtures of C-1′ epimers were formed. The dia-
stereomers were separated at a later stage.
Thus, the cyclohexanones 46, 47, and 49 were transformed
into the alkaloid analogues 56-61 (Scheme 7).
On treatment with methanolic NaHCO3, the alcohols 50-52
were generated in excellent yields and then were oxidized to
the diketones 53-55. The following step required considerable
experimentation, but finally the reductive amination24 was
achieved with the system benzylamine/AcOH/NaBH3CN, in the
presence of molecular sieves.
SCHEME 6. Retrosynthesis of Polyhydroxylated Bicyclic
Alkaloids
To our satisfaction, only two of the eight possible diastere-
omers were detected in each reaction. In all cases, a cis ring
fusion was observed. The stereochemistry was based on NOESY
experiments (Figure 2) and on the value of the H-H coupling
26
1
constants in the H NMR spectra.
Thus, for compound 56 the 1H NMR spectra gave a coupling
constant J4a,8a ) 4.7 Hz, which suggested a cis relationship
between 4a-H and 8a-H (the trans relationship would imply
J4a,8a ≈ 11 Hz).26 Similarly, J4,4a ) 11.7 Hz (4-H/4a-H trans)
and J2,3 ) 9.6 Hz (2-H/3-H trans). The NOESY experiment
(21) (a) Panda, M.; Phuan, P.; Kozlowski, C. M. J. Org. Chem. 2003, 68,
564–571. (b) Harris, J. M.; Padwa, A. J. Org. Chem. 2003, 68, 4371–4381. (c)
Qadir, M.; Priestley, R. E.; Rising, T.; Gelbrich, T.; Coles, S. J.; Hursthouse,
M. B.; Sheldrake, P. W.; Whittall, N.; Hii, K. K. Tetrahedron Lett. 2003, 44,
3675–3678. (d) Armesto, D.; Caballero, O.; Ort´ız, M. J.; Agarrabeitia, A. R.;
Mart´ın-Fontecha, M.; Torres, M. R. J. Org. Chem. 2003, 68, 6661–6671.
(22) (a) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem. 2007, 72, 2046–2052.
(b) Gray, D.; Gallagher, T. Angew. Chem., Int. Ed. 2006, 45, 2419–2423. (c)
So´snicki, J. G. Tetrahedron Lett. 2006, 47, 6809–6812. (d) Turenen, B. J.; Georg,
G. I. J. Am. Chem. Soc. 2006, 128, 8702–8703. (e) Gracias, V.; Gasiecki, A. F.;
Pagano, T. G.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 8873–8876. (f)
Voskressensky, L. G.; Akbulatov, S. V.; Borisova, T. N.; Barlamov, A. V.
Tetrahedron 2006, 62, 12392–12397. (g) Ye´pez, A. F.; Palma, A.; Stashenko,
E.; Bashas, A.; Amaro-Luis, J. M. Tetrahedron Lett. 2006, 47, 5825–5828. (h)
Holub, N.; Neidho¨fer, J.; Blechert, S. Org. Lett. 2005, 7, 1227–1229.
(23) (a) Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.; Ugenti, M. P.;
Tasso, B.; Chiarini, A.; Sparatore, F. J. Med. Chem. 2007, 50, 334–343. (b)
Tsukada, J.; Tahara, A.; Tomura, Y.; Kusayama, T.; Wada, K.; Ishii, N.;
Taniguchi, N.; Suzuki, T.; Yarsu, T.; Uchida, W; Shibasaki, M. Vasc. Pharmacol.
2005, 42, 47–55. (c) Tsukada, J.; Tahara, A.; Tomura, Y.; Wada, K.; Kusayama,
T.; Ishii, N.; Aoki, M.; Yarsu, T.; Uchida, W; Taniguchi, N.; Tanaka, A. Eur.
J. Pharmacol. 2002, 446, 129–138. (d) Zucotto, F.; Zbelebil, M.; Brun, R.;
Chowdhury, S. F.; Lucrezia, R. D.; Leal, I.; Maes, L.; Ruiz-Perez, M. L.;
Pacanows, D. G.; Gilbert, I. A. Eur. J. Med. Chem. 2001, 36, 395–405. (e)
Oliveira, D. F.; Severino, E. A.; Correia, C. R. D. Tetrahedron Lett. 1999, 40,
2083–2086, and references therein.
Surprisingly, the unconjugated lactones 30, 33, 36, and 39
were the major products, and in most cases their yield was
similar to the combined yield of the conjugated isomers. Their
formation can be explained as shown in Scheme 5. The
nucleophilic addition would initially yield the conjugated
lactones, which would undergo proton abstraction at C-1′,
generating the 4′-hydroxyfuran intermediates 40. These inter-
mediates would be in tautomeric equilibrium with the uncon-
jugated lactones, as suggested by the 1H and 13C NMR spectra,
where the 3′-H2 and the 3′-C are observed at very low fields
(δH ≈ 5.0 and δC ≈ 80.0, respectively). The lactones 30, 33,
36, and 39 are useful precursors of ketoses 41.19
In a similar way, the conjugated furanones 28/29, 31/32, 34/
35, and 37/38 can be modified by reduction, alkylation,
dihydroxylation, amino hydroxylation, etc.,20 giving a variety
of functionalized butenolides and higher-carbon sugars with
different substituents and stereochemistries.
(24) (a) Gravier-Pelletier, C.; Maton, W.; Le Merrer, Y. Synlett 2003, 333–
336. (b) Manescalchi, F.; Nardi, A. R.; Savoia, D. Tetrahedron Lett. 1994, 35,
2775–2778.
(25) NOESY experiments were carried out for compound 49 and for products
derived from the cyclohexanones 46-49, such as the bicyclic systems 56-61
(commented later in the text), supporting the assigned 1,2-trans stereochemistry.
For compound 49, the following spatial interactions were observed: 1-H (δH
4.49/4.36)/3-H (δH 3.56/3.43), 2-H (δH 3.95)/1′-H (δH 2.75), 2-H (δH 3.95/3.86)/
4-H (δH 5.15), 2-H/cyclohexanone protons (δH 1.5-2.5).
Application of the Fragmentation/Alkylation Procedure
to the Synthesis of Bicyclic Alkaloid Analogues. The decahy-
droquinoline alkaloids have elicited many synthetic efforts21,22
due to their interesting biological properties.23 In order to study
the influence of substituents on their hydrophilicity and their
(26) (a) The experimental coupling constants matched theoretical ones,
calculated as described in ref 18. (b) For information on the Karplus-Altona
equation, see: Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783–2792. (c) For more information on this software, see: Mohamadi,
F.; Richard, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang,
G.; Hendrikson, T.; Stille, W. C. J. Comput. Chem. 1990, 11, 440.
(20) Ahmed, M. M.; O′Doherty, G. A. J. Org. Chem. 2005, 70, 10576–10578,
and references therein.
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Boto et al.
TABLE 2. Addition of (Trimethylsilyloxy)cyclohexene to Acetoxy Acetals
b
a Yields for products purified by chromatography. The d.r. were determined by H NMR.
1
showed the spatial correlations 2-H/8-HR, 4-H/8-HR, and 3-H/
4a-H, which supported the assigned stereochemistry. The minor
diastereomer 57 presented J2,3 ) 9.7 Hz (2-H/3-H trans) and
the following NOESY spatial correlations: 2-H/8a-H, 2-H/4-
H, and 4-H/8a-H.
spatial correlation, whereas for isomer 61 the following cor-
relations were observed: 2-Me/9a-H, 2-Me/3-H, 2-Me/5-H, 3-H/
5-H and 5-H/9a-H. The formation of the functionalized bicyclic
products 56-61 shows the versatility of this methodology. In
a similar way, other polycyclic systems could be prepared by
using different sugar-derived acetoxy acetals and cyclic silyl
enol ethers.
The other quinoline derivatives, compounds 58 and 59,
were obtained in similar overall yield (51%) and diastereo-
meric ratio. Their configurations were determined using the
1
JH,H coupling constants from the H NMR spectra and the
Conclusion
spatial correlations from the NOESY experiments, as shown
in Figure 2.
A mild, efficient strategy to prepare C-alditols, which are
valuable as synthetic intermediates or as bioactive compounds,
is reported herein. The method is based on a tandem radical
scission-oxidation reaction and uses readily available carbo-
hydrates as starting materials. The fragmentation of sugar
derivatives afforded acetoxy acetals, which were transformed
by allylation or alkylation into a variety of C-alditols in good
The formation of the polyhydroxylated decahydroben-
zoazepines 60 and 61 took place in moderate global yield (39%).
However, this result is remarkable since the formation of
medium-size rings is often difficult, and in addition, four steps
are involved in the reductive amination-cyclization reaction.
The azepine 60 presented a cis relationship between 2-H and
3-H (J2,3 ) 4.5 Hz), while its diastereomer 61 possessed a 2,3-
trans relationship (J2,3 ) 8.0 Hz).27 On the other side, the
NOESY experiment for compound 60 showed a 4-H/5a-H
(27) The theoretical calculations gave J2,3 ) 3.0-4.5 Hz for the 2,3-cis
relationship and J2,3 ) 8.5-10.1 Hz for the 2,3-trans relationship.
5292 J. Org. Chem. Vol. 73, No. 14, 2008

ConVersion of Carbohydrates into C-Alditols
Experimental Section
General Procedure for ꢀ-Fragmentation of Carbohydrate
Derivatives 11-13, 22, and 23. To a solution of the carbohydrate
(1.0 mmol) in dry CH2Cl2 (10 mL) under nitrogen were added
(diacetoxyiodo)benzene (DIB) (386 mg, 1.2 mmol) and iodine (254
mg, 1.0 mmol). The reaction mixture was stirred at room temper-
ature (26 °C) under irradiation with visible light (80-W tungsten-
filament lamp) for 1 h. Then it was poured into aqueous 10%
sodium thiosulfate (Na2S2O3) and extracted with dichloromethane.
The organic layer was washed with brine, dried on Na2SO4, filtered,
and evaporated under vacuum. The residue was purified by
chromatography on silica gel (hexanes/EtOAc), yielding the purified
acetoxy acetals 14-16,2 24, and 25.2
(1S)-1-Acetoxy-4-O-formyl-1,2-O-isopropylidene-3,5-di-O-
methyl-D-arabinitol (24). The acetate was obtained as the 1,2-
trans isomer (87%). Colorless oil; [R]D -53 (c 0.30, CHCl3); IR
1
(CHCl3) 1728, 1083, 1084 cm-1; H NMR (500 MHz) δH 1.46
(3H, s), 1.48 (3H, s), 2.08 (3H, s), 3.37 (3H, s), 3.53 (3H, s), 3.64
(1H, dd, J ) 4.8, 11.1 Hz), 3.67 (1H, dd, J ) 3.7, 6.8 Hz), 3.68
(1H, dd, J ) 2.8, 11.1 Hz), 4.28 (1H, dd, J ) 3.1, 3.3 Hz), 5.12
(1H, ddd, J ) 2.7, 4.6, 7.2 Hz), 6.21 (1H, d, J ) 2.7 Hz), 8.08
(1H, s); 13C NMR (125.7 MHz) δC 21.2 (CH3), 26.4 (CH3), 26.7
(CH3), 59.0 (CH3), 60.8 (CH3), 70.2 (CH2), 72.3 (CH), 77.8 (CH),
82.3 (CH), 96.7 (CH), 113.2 (C), 160.1 (CH), 170.4 (C); MS m/z
(rel intensity) 291 (M+ - Me, 14), 101 ([2,2-dimethyldioxolane -
H]+, 100); HRMS calcd for C12H19O8, 291.1080; found, 291.1050;
calcd for C5H9O2, 101.0603; found, 101.0645. Anal. Calcd for
C13H22O8: C, 50.98; H, 7.24. Found: C, 51.00; H, 7.55.
FIGURE 2. JH,H (from 1H NMR) and NOESY spatial correlations for
products 56-61.
SCHEME 7. Synthesis of Polyhydroxylated Bicyclic
Alkaloid Analogues 56-61
Conversion of Acetoxy Acetals 14-16 into Allyl
Derivatives 17-19. A solution of the acetoxy acetals (1 equiv) in
dry CH2Cl2 (2 mL/mmol substrate) at -40 °C was treated with
allyltrimethylsilane (3 equiv), and then BF3 ·OEt2 (2 equiv) was
added dropwise. The reaction mixture was allowed to reach 26 °C
and then was stirred for 0.5-3.0 h. Then it was poured into saturated
aqueous NaHCO3 and extracted with CH2Cl2. The organic layer
was dried on Na2SO4, filtered, and evaporated under vacuum. The
residue was purified by chromatography on silica gel (hexanes/
EtOAc) affording the allyl derivatives 17-19.
(1R/1S)-Allyl-3-O-formyl-1,2-O-isopropylidene-4-O-methyl-D-
erythritol (17). The allyl derivative 17 was obtained as a volatile
colorless oil (25%). Product 17 is an inseparable mixture of the 1R
and 1S diastereomers (trans:cis 99:1), but only the major isomer is
described. IR (CHCl3) 1725, 1117, 1089 cm-1; 1H NMR (500 MHz)
δH 1.39 (3H, s), 1.42 (3H, s), 2.35 (1H, ddd, J ) 7.1, 7.1, 14.4
Hz), 2.44 (1H, ddd, J ) 4.3, 6.3, 14.6 Hz), 3.38 (3H, s), 3.62 (1H,
dd, J ) 5.8, 11.0 Hz), 3.67 (1H, dd, J ) 3.6, 11.0 Hz), 3.91 (1H,
dd, J ) 6.3, 7.0 Hz), 4.03 (1H, ddd, J ) 4.3, 7.3, 7.4 Hz), 5.12
(1H, dd, J ) 1.4, 18.5 Hz), 5.15 (1H, d, J ) 10.3 Hz), 5.19 (1H,
ddd, J ) 3.6, 5.9, 5.9 Hz), 5.88 (1H, dddd, J ) 6.8, 6.9, 10.3, 17.2
Hz), 8.31 (1H, s); 13C NMR (125.7 MHz) δC 26.9 (CH3), 27.3
(CH3), 37.8 (CH2), 59.2 (CH3), 70.9 (CH2), 72.5 (CH), 77.9 (CH),
78.2 (CH), 108.9 (C), 117.8 (CH2), 133.6 (CH), 160.2 (CH); MS
m/z (rel intensity) 229 (M+ - Me, 100); HRMS calcd for C11H17O5,
229.1076; found, 229.1042. Anal. Calcd for C12H20O5: C, 59.00;
H, 8.25. Found: C, 59.28; H, 8.01.
(1R/1S)-Allyl-4-O-benzoyl-3-O-formyl-1,2-O-isopropylidene-
D-erythritol (18). The allyl derivative 18 was obtained as a mixture
of the 1R and 1S diastereomers (67%, trans:cis 98:2). The minor
isomer could not be purified from the major diastereomer. Colorless
1
syrup; IR (CHCl3) 3075, 1728, 1643, 1274, 1173 cm-1; H NMR
(500 MHz) major isomer δH 1.43 (3H, s), 1.44 (3H, s), 2.39 (1H,
ddd, J ) 7.1, 7.1, 14.7 Hz), 2.47 (1H, ddd, J ) 4.9, 7.1, 14.6 Hz),
3.97 (1H, dd, J ) 7.1, 7.2 Hz), 4.09 (1H, ddd, J ) 4.5, 7.2, 7.2
Hz), 4.46 (1H, dd, J ) 7.0, 12.2 Hz), 4.72 (1H, dd, J ) 2.9, 12.2
Hz), 5.15 (1H, dd, J ) 1.4, 9.8 Hz), 5.16 (1H, dd, J ) 1.2, 18.8
Hz), 5.44 (1H, ddd, J ) 2.8, 6.6, 6.6 Hz), 5.87 (1H, dddd, J ) 6.9,
6.9, 10.3, 17.1 Hz), 7.45 (2H, dd, J ) 7.7, 7.9 Hz), 7.58 (1H, dd,
J ) 7.4, 7.5 Hz), 8.02 (2H, d, J ) 7.4 Hz), 8.13 (1H, s); 13C NMR
global yields and excellent 1,2-trans stereoselectivity. To
highlight its versatility, the scission/alkylation process was
applied to prepare chiral polyhydroxylated butenolides and
highly functionalized bicyclic alkaloid analogues.
J. Org. Chem. Vol. 73, No. 14, 2008 5293

Boto et al.
(125.7 MHz) δC 26.9 (CH3), 27.3 (CH3), 37.8 (CH2), 63.3 (CH2),
71.5 (CH), 78.1 (CH), 78.2 (CH), 109.9 (C), 118.1 (CH2), 128.5
(2 × CH), 129.6 (C), 129.7 (2 × CH), 133.2 (2 × CH), 159.9
(CH), 166.1 (C); MS m/z (rel intensity) 319 (M+ - Me, 43), 105
([PhCO]+, 100); HRMS calcd for C17H19O6, 319.1182; found,
319.1171; calcd for C7H5O, 105.0340; found, 105.0345. Anal. Calcd
for C18H22O6: C, 64.66; H, 6.63. Found: C, 64.65; H, 6.79.
(1S)-Allyl-3-O-formyl-1,2-O-isopropylidene-4,5-di-O-methyl-
D-arabinitol (19). The allyl derivative 19 was obtained as the 1,2-
trans isomer (45%). Colorless oil; [R]D -12 (c 0.35, CHCl3); IR
m/z (rel intensity) 315 (M+ - Me, 51), 183 (M+ - MeOCH2CH-
(OCHO)CHOMe, 62), 147 ([MeOCH2CH(OCHO)CHOMe]+, 62),
101 ([2,2-dimethyl-1,3-dioxolane - H]+, 100), 59 ([Me2CdOH]+,
26); HRMS calcd for C14H19O8, 315.1080; found, 315.1055; calcd
for C5H9O2, 101.0603; found, 101.0577. Anal. Calcd for C15H22O8:
C, 54.54; H, 6.71. Found: C, 54.53; H, 6.75. Compound 35:
colorless oil; [R]D +29 (c 0.1, CHCl3); IR (film) 1785, 1761, 1727,
1163, 1086 cm-1; 1H NMR (500 MHz) δΗ 1.33 (3H, s), 1.39 (3H,
s), 3.38 (3H, s), 3.53 (3H, s), 3.57 (1H, dd, J ) 1.8, 5.1 Hz), 3.67
(1H, dd, J ) 5.1, 10.9 Hz), 3.72 (1H, dd, J ) 3.1, 10.9 Hz), 4.30
(2H, br s), 5.15 (1H, br s), 5.21 (1H, ddd, J ) 3.1, 5.6, 5.6 Hz),
6.22 (1H, dd, J ) 2.2, 5.8 Hz), 7.50 (1H, dd, J ) 1.4, 5.8 Hz),
8.11 (1H, s); 13C NMR (100.6 MHz) δC 26.2 (CH3), 26.9 (CH3),
59.0 (CH3), 60.8 (CH3), 70.3 (CH2), 72.3 (CH), 75.0 (CH), 76.4
(CH), 77.9 (CH), 81.0 (CH), 110.5 (C), 122.9 (CH), 152.8 (CH),
160.2 (CH), 172.4 (C); MS m/z (rel intensity) 315 (M+ - Me, 69),
183 (M+ - MeOCH2CH(OCHO)CHOMe, 68), 147 ([MeOCH2CH-
(OCHO)CHOMe]+, 52), 101 ([2,2-dimethyl-1,3-dioxolane - H]+,
100), 59 ([Me2CdOH]+, 28); HRMS calcd for C14H19O8, 315.1080;
found, 315.1139; calcd for C5H9O2, 101.0603; found, 101.0625.
Anal. Calcd for C15H22O8: C, 54.54; H, 6.71. Found: C, 54.58; H,
6.66. Compound 36: colorless oil; [R]D -5 (c 0.17, CHCl3); IR
(film) 1758, 1727, 1113, 1079 cm-1; 1H NMR (500 MHz) δΗ 1.43
(3H, s), 1.47 (3H, s), 3.37 (3H, s), 3.63 (3H, s), 3.66 (1H, dd, J )
5.5, 11.1 Hz), 3.75 (1H, dd, J ) 2.4, 11.1 Hz), 3.81 (1H, dd, J )
1.9, 6.8 Hz), 3.99 (1H, dd, J ) 2.0, 8.2 Hz), 4.85 (1H, dd, J ) 1.5,
8.3 Hz), 4.88 (2H, s), 5.15 (1H, ddd, J ) 2.2, 5.5, 6.7 Hz), 7.53
(1H, d, J ) 1.4 Hz), 8.09 (1H, s); 13C NMR (125.7 MHz) δC 26.4
(CH3), 26.6 (CH3), 58.9 (CH3), 60.8 (CH3), 70.4 (CH2), 70.7 (CH2),
71.2 (CH), 73.2 (CH), 76.3 (CH), 80.7 (CH), 109.8 (C), 133.0 (C),
147.2 (CH), 160.3 (CH), 172.0 (C); MS m/z (rel intensity) 315 (M+
- Me, 42), 183 (M+ - MeOCH2CH(OCHO)CHOMe, 32), 165
(M+ - [2 × MeO + Me2CdO + OCHO, 100), 147 ([MeOCH2CH-
(OCHO)CHOMe]+, 42), 101 ([2,2-dimethyl-1,3-dioxolane - H]+,
75); HRMS calcd for C14H19O8, 315.1080; found, 315.1040; calcd
for C9H9O3, 165.0552; found, 165.0611. Anal. Calcd for C15H22O8:
C, 54.54; H, 6.71. Found: C, 54.32; H, 6.95.
1
(CHCl3) 1728, 1173, 1098 cm-1; H NMR (500 MHz, C6D6) δH
1.38 (3H, s), 1.41 (3H, s), 2.35 (1H, ddd, J ) 6.9, 7.1, 14.3 Hz),
2.43 (1H, m), 3.34 (3H, s), 3.37 (1H, dd, J ) 4.6, 10.6 Hz), 3.47
(3H, s), 3.57 (1H, ddd, J ) 2.7, 4.5, 7.6 Hz), 3.63 (1H, dd, J )
2.7, 10.6 Hz), 3.77 (1H, ddd, J ) 4.7, 7.1, 8.1 Hz), 4.02 (1H, dd,
J ) 2.3, 8.3 Hz), 5.10-5.16 (3H, m), 5.84 (1H, dddd, J ) 6.8,
7.0, 10.2, 17.0 Hz), 8.14 (1H, s); 13C NMR (125.7 MHz) δC 26.6
(CH3), 27.3 (CH3), 36.5 (CH2), 58.4 (CH3), 59.4 (CH3), 68.7 (CH),
70.6 (CH2), 75.7 (CH), 78.2 (CH), 78.7 (CH), 108.7 (C), 117.8
(CH2), 133.4 (CH), 160.0 (CH); MS m/z (rel intensity) 273 (M+ -
Me, 69), 247 (M+ - allyl, 14), 89 ([MeOCH2CHOMe]+, 100), 59
([Me2CdOH]+, 69); HRMS calcd for C13H21O6, 273.1338; found,
273.1352; calcd for C4H9O2, 89.0602; found, 89.0626. Anal. Calcd
for C14H24O6: C, 58.32; H, 8.39. Found: C, 58.38; H, 8.12.
Conversion of Acetoxy Acetals 14, 16, 24, and 25 into
Phenyl Ketone Derivatives 20, 21, 26, and 27. Similar to the
allylation reaction, but using 1-phenyl-1-(trimethylsilyloxy)ethane
as the nucleophile and carrying out the addition at 0 °C.
(1S)-1-(2-Oxo-2-phenylethyl)-4-O-formyl-1,2-O-isopropylidene-
3,5-di-O-methyl-D-arabinitol (26). Obtained from acetoxy acetal
24 (91%) as a yellow oil; [R]D -4 (c 0.2, CHCl3); IR (film) 1726,
1685, 1111, 1082 cm-1; 1H NMR (500 MHz) δH 1.38 (3H, s), 1.42
(3H, s), 3.16 (1H, dd, J ) 5.7, 16.9 Hz), 3.38 (3H, s), 3.49 (1H,
dd, J ) 6.3, 16.9 Hz), 3.57 (3H, s), 3.65 (1H, dd, J ) 2.4, 6.9 Hz),
3.68 (1H, dd, J ) 5.3, 11.0 Hz), 3.76 (1H, dd, J ) 2.6, 11.0 Hz),
3.91 (1H, dd, J ) 2.4, 7.8 Hz), 4.69 (1H, ddd, J ) 6.0, 6.2, 7.8
Hz), 5.18 (1H, ddd, J ) 2.5, 4.6, 7.1 Hz), 7.47 (2H, dd, J ) 7.6,
7.8 Hz), 7.58 (1H, dd, J ) 7.4, 7.4 Hz), 7.97 (2H, d, J ) 7.4 Hz),
8.10 (1H, s); 13C NMR (125.7 MHz) δC 26.6 (CH3), 27.3 (CH3),
42.7 (CH2), 58.9 (CH3), 60.9 (CH3), 70.5 (CH2), 72.5 (CH), 73.3
(CH), 77.3 (CH), 80.9 (CH), 109.2 (C), 128.2 (2 × CH), 128.7 (2
× CH), 133.4 (CH), 136.7 (C), 160.4 (CH), 197.4 (C); MS m/z
(rel intensity) 351 (M+ - Me, 4), 219 (M+ - MeOCH2CH-
(OCHO)CHOMe, 42), 147 ([MeOCH2CH(OCHO)CHOMe]+, 12),
105 ([PhCO]+, 100), 77 ([Ph]+, 26); HRMS calcd for C18H23O7,
351.1444; found, 351.1430; calcd for C7H5O, 105.0340; found,
105.0301. Anal. Calcd for C19H26O7: C, 62.28; H, 7.15. Found: C,
62.36; H, 7.06.
Conversion of Acetoxy Acetals 14, 16, 24, and 25 into
Cyclohexanones 46-49. Similar to the allylation reaction, but using
1-(trimethylsiloxy)cyclohexene as the nucleophile and carrying out
the addition at 0 °C.
(1S,1′R/S)-4-O-Formyl-1,2-O-isopropylidene-3,5-di-O-methyl-
1-[2′-oxo-1′-cyclohexyl]-D-arabinitol (48). Obtained from acetoxy
acetal 24 (90%) as an inseparable diastereomer mixture (2.5:1).
Yellow oil; [R]D -11 (c 0.3, CHCl3); IR (CHCl3) 1724, 1712, 1102,
1078 cm-1; 1H NMR (500 MHz) major diastereomer δΗ 1.32 (3H,
s), 1.40 (3H, s), 1.66-1.68 (3H, m), 1.94 (1H, m), 2.08 (1H, m),
2.33-2.39 (3H, m), 2.48 (1H, ddd, J ) 5.8, 6.6, 12.4 Hz), 3.37
(3H, s), 3.56 (3H, s), 3.65 (1H, dd, J ) 5.6, 11.0 Hz), 3.749 (1H,
dd, J ) 2.5, 6.5 Hz), 3.754 (1H, dd, J ) 2.3, 11.2 Hz), 3.87 (1H,
dd, J ) 2.5, 6.5 Hz), 4.39 (1H, dd, J ) 6.9, 7.0 Hz), 5.13 (1H,
ddd, J ) 2.3, 5.8, 6.6 Hz), 8.09 (1H, s); minor diastereomer (the
signals overlapped with those of the major isomer are not
described): δΗ 1.32 (3H, s), 1.38 (3H, s), 1.64-1.68 (3H, m), 1.94
(1H, m), 2.08 (1H, m), 2.15 (1H, m), 2.33-2.39 (2H, m), 2.74
(1H, ddd, J ) 5.2, 5.6, 11.5 Hz), 3.37 (3H, s), 3.57 (3H, s), 3.62
(1H, dd, J ) 1.8, 8.4 Hz), 3.95 (1H, dd, J ) 1.8, 7.8 Hz), 4.50
(1H, dd, J ) 5.2, 7.9 Hz), 8.10 (1H, s); 13C NMR (125.7 MHz)
major isomer δC 24.8 (CH2), 26.8 (CH3), 27.6 (CH3), 27.7 (CH2),
30.3 (CH2), 42.5 (CH2), 54.9 (CH), 59.0 (CH3), 60.8 (CH3), 70.7
(CH2), 73.7 (CH), 75.2 (CH), 78.1 (CH), 80.6 (CH), 109.2 (C),
160.5 (CH), 211.7 (C); minor diastereomer δC 24.5 (CH2), 26.6
(CH3), 27.2 (CH3), 27.5 (CH2), 28.9 (CH2), 42.3 (CH2), 53.3 (CH),
58.8 (CH3), 60.7 (CH3), 70.6 (CH2), 73.8 (CH), 74.6 (CH), 77.5
(CH), 77.6 (CH), 108.8 (C), 160.5 (CH), 211.0 (C); MS m/z (rel
intensity) 329 (M+ - Me, 7), 246 (M+ - cyclohexanone, 53), 139
(M+ - [MeOCH2CH(OCHO)CHOMe + Me2CdO], 100), 59
([Me2CdOH]+, 77); HRMS calcd for C16H25O7, 329.1600; found,
Conversion of Acetoxy Acetals 14, 16, 24, and 25 into
Butenolides 28-39. Similar to the allylation reaction, but using
2-(trimethylsilyloxy)furan as the nucleophile and carrying out the
addition at 0 °C.
(1S)-4-O-Formyl-1,2-O-isopropylidene-3,5-di-O-methyl-1-(4′-
oxo-(1′S)-(1′H)-furanyl)-D-arabinitol (34), (1S)-4-O-Formyl-1,2-
O-isopropylidene-3,5-di-O-methyl-1-(4′-oxo-(1′R)-(1′H)-furanyl)-
D-arabinitol (35), and (1S)-4-O-Formyl-1,2-O-isopropylidene-
3,5-di-O-methyl-1-(4′-oxo-1′(3′H)-furanyl)-D-arabinitol (36).
Obtained from the acetoxy acetal 24 (21% for product 34, 11% for
35, and 30% for 36). Compound 34: colorless oil; [R]D -44 (c
0.3, CHCl3); IR (film) 1790, 1759, 1727, 1112, 1086 cm-1; 1H NMR
(500 MHz) δΗ 1.38 (3H, s), 1.40 (3H, s), 3.39 (3H, s), 3.45 (3H,
s), 3.66 (1H, dd, J ) 5.0, 11.1 Hz), 3.70 (1H, dd, J ) 2.3, 7.3 Hz),
3.74 (1H, dd, J ) 2.5, 11.1 Hz), 3.77 (1H, dd, J ) 7.9, 8.1 Hz),
4.19 (1H, dd, J ) 2.3, 7.6 Hz), 4.94 (1H, ddd, J ) 1.7, 1.7, 8.4
Hz), 5.19 (1H, ddd, J ) 2.4, 5.0, 7.3 Hz), 6.23 (1H, dd, J ) 1.9,
5.7 Hz), 7.68 (1H, dd, J ) 1.3, 5.7 Hz), 8.12 (1H, s); 13C NMR
(100.6 MHz) δC 26.6 (CH3), 26.9 (CH3), 59.0 (CH3), 60.8 (CH3),
70.4 (CH2), 72.8 (CH), 76.6 (CH), 77.0 (CH), 80.0 (CH), 83.3 (CH),
110.4 (C), 122.2 (CH), 155.2 (CH), 160.2 (CH), 172.1 (C); MS
5294 J. Org. Chem. Vol. 73, No. 14, 2008

ConVersion of Carbohydrates into C-Alditols
329.1609; calcd for C8H11O2, 139.0759; found, 139.0791. Anal.
Calcd for C17H28O7: C, 59.29; H, 8.19. Found: C, 59.25; H, 8.49.
Hydrolysis of the Formate Group in Cyclohexanones 46,
47, and 49. The cyclohexanone (0.2 mmol) was treated with 1%
methanolic NaHCO3 (2 mL). The solution was stirred at room
temperature for 30 min, poured into water, and extracted with
CH2Cl2. The organic layer was dried with sodium sulfate, filtered,
and evaporated under vacuum. The residue was purified by column
chromatography on silica gel (hexanes/EtOAc) to give alcohols 50,
51, or 52.
s), 1.57-1.74 (4H, m), 1.92-1.94 (2H, m), 2.28-2.33 (2H, m),
2.49 (1H, ddd, J ) 5.3, 6.5, 10.4 Hz), 2.83 (1H, br s), 3.26 (1H,
dd, J ) 2.7, 5.5 Hz), 3.51 (3H, s), 4.04-4.09 (2H, m), 4.46 (1H,
dd, J ) 6.7, 7.2 Hz); minor diastereomer δΗ 1.26 (3H, d, J ) 6.5
Hz), 1.35 (3H, s), 1.43 (3H, s), 1.57-1.73 (3H, m), 1.93 (1H, m),
1.96 (1H, m), 2.04 (1H, m), 2.32 (1H, m), 2.37 (1H, m), 2.71 (1H,
ddd, J ) 5.2, 6.2, 10.3 Hz), 2.83 (1H, br s), 3.13 (1H, dd, J ) 1.7,
7.3 Hz), 3.51 (3H, s), 4.06 (1H, m), 4.16 (1H, dd, J ) 1.6, 8.0
Hz), 4.53 (1H, dd, J ) 5.0, 7.9 Hz); 13C NMR (125.7 MHz) major
diastereomer δC 20.0 (CH3), 24.1 (CH2), 26.8 (CH3), 27.4 (CH2),
27.7 (CH3), 30.0 (CH2), 42.4 (CH2), 54.8 (CH), 59.0 (CH3), 67.1
(CH), 75.4 (CH), 80.4 (CH), 82.0 (CH), 108.9 (C), 211.8 (C); minor
diastereomer δC 20.1 (CH3), 24.5 (CH2), 26.6 (CH3), 27.2 (CH3),
27.6 (CH2), 29.3 (CH2), 42.3 (CH2), 53.0 (CH), 59.0 (CH3), 67.1
(CH), 75.2 (CH), 77.5 (CH), 81.7 (CH), 109.1 (C), 211.1 (C); MS
m/z(relintensity)271(M+ -Me,3),139(M+ -[MeCH(OH)CHOMe
(1R,1′R/S)-1,2-O-Isopropylidene-4-O-methyl-1-[2′-oxo-1′-cy-
clohexyl]-D-erythritol (50). Isolated as an inseparable diastereomer
mixture (2:1). Colorless oil; [R]D +30 (c 0.83, CHCl3); IR 3568,
1
3456, 1706, 1236, 1132, 1096 cm-1; H NMR (500 MHz) major
diastereomer δΗ 1.37 (3H, s), 1.39 (3H, s), 1.62-1.76 (3H, m),
1.95 (1H, m), 2.04 (1H, m), 2.21 (1H, m), 2.31 (1H, m), 2.44 (1H,
m), 2.63 (1H, ddd, J ) 5.7, 5.7, 11.0 Hz), 2.91 (1H, br s), 3.40
(3H, s), 3.48 (1H, dd, J ) 1.3, 9.7 Hz), 3.59 (1H, dd, J ) 2.5, 10.0
Hz), 3.74-3.82 (2H, m), 4.55 (1H, dd, J ) 5.5, 5.5 Hz); minor
diastereomer δΗ 1.35 (3H, s), 1.38 (3H, s), 1.62-1.76 (3H, m),
1.93-1.96 (2H, m), 2.09 (1H, m), 2.31 (1H, m), 2.44 (1H, m),
2.76 (1H, ddd, J ) 5.0, 5.0, 10.1 Hz), 3.07 (1H, d, J ) 3.9 Hz),
3.40 (3H, s, OMe), 3.50 (1H, dd, J ) 1.9, 9.7 Hz), 3.62 (1H, dd,
J ) 2.8, 9.7 Hz), 3.79 (1H, m), 3.90 (1H, dd, J ) 6.5, 7.9 Hz),
4.40 (1H, dd, J ) 4.9, 6.5 Hz); 13C NMR (125.7 MHz) major
diastereomer δC 24.4 (CH2), 27.3 (CH2), 27.6 (2 × CH3), 28.0
(CH2), 42.1 (CH2), 53.1 (CH), 59.2 (CH3), 72.4 (CH), 73.8 (CH2),
77.4 (CH), 78.5 (CH), 109.5 (C), 211.9 (C); minor diastereomer
δC 23.9 (CH2), 27.5 (CH2), 27.6 (2 × CH3), 29.6 (CH2), 42.2 (CH2),
53.2 (CH), 59.2 (CH3), 72.2 (CH), 73.7 (CH2), 77.9 (CH), 78.9
(CH), 108.9 (C), 212.4 (C); MS m/z (rel intensity) 257 (M+ - Me,
7), 197 (M+ - [MeOCH2CH(OH)], 25), 174 (M+ - cyclohexanone,
21), 139 (M+ - [MeOCH2CH(OH) + Me2CdO], 100), 59
([Me2CdOH]+, 47); HRMS calcd for C13H21O5, 257.1389; found,
257.1385; calcd for C8H11O2, 139.0759; found, 139.0755. Anal.
Calcd for C14H24O5: C, 61.74; H, 8.88. Found: C, 61.62; H, 8.89.
(1S,1′R/S)-1,2-O-Isopropylidene-4,5-di-O-methyl-1-[2′-oxo-1′-
cyclohexyl]-D-arabinitol (51). Isolated as an inseparable diaste-
reomer mixture (7:3). Yellow oil; [R]D -22 (c 0.08, CHCl3); IR
+
Me2CdO], 48), 89 ([MeCH(OH)CHOMe]+, 100), 59
(Me2CdOH, 49); HRMS calcd for C14H23O5, 271.1545; found,
271.1546; calcd for C4H9O2, 89.0603; found, 89.0602. Anal. Calcd
for C15H26O5: C, 62.91; H, 9.15. Found: C, 62.63; H, 8.99.
Oxidation of Hydroxyketones 50-52 to Diketones 53-55.
Jones’ reagent was added dropwise to a solution of the hydrox-
yketone (0.2 mmol) in dry acetone (4 mL) at 0 °C, until total
conversion of the starting material was observed by TLC analysis
(3-6 h). The reaction mixture was poured into a saturated aqueous
NaHCO3 solution and extracted with CH2Cl2. The combined organic
layers were dried as before, and the solvent was removed under
vacuum. The residue was purified by chromatography on silica gel
(hexanes/EtOAc), affording the diketones 53, 54, or 55.
(1R,1′R/S)-3-Deoxy-1,2-O-isopropylidene-4-O-methyl-1-[2′-
oxo-1′-cyclohexyl]-D-erythritol-3-one (53). Isolated as an insepa-
rable diastereomer mixture (3:2). Colorless oil; [R]D +10 (c 0.29,
1
CHCl3); IR 1734, 1710, 1451, 1384, 1161, 1101 cm-1; H NMR
(500 MHz) major diastereomer δ Η 1.40 (3H, s), 1.43 (3H, s), 1.52
(1H, m), 1.60-1.66 (3H, m), 1.95 (1H, m), 2.06 (1H, m), 2.28
(1H, m), 2.41 (1H, m), 2.59 (1H, ddd, J ) 5.8, 6.1, 11.2 Hz), 3.45
(3H, s), 4.15 (1H, d, J ) 7.7 Hz), 4.35 (1H, d, J ) 18.2 Hz), 4.42
(1H, d, J ) 18.2 Hz), 4.50 (1H, dd, J ) 6.4, 7.6 Hz); minor
diastereomer δH 1.42 (6H, s), 1.52 (1H, m), 1.60-1.66 (3H, m),
1.95 (1H, m), 2.06 (1H, m), 2.28 (1H, m), 2.43 (1H, m), 2.77 (1H,
ddd, J ) 5.4, 6.2, 10.7 Hz), 3.44 (3H, s), 4.33 (1H, d, J ) 18.2
Hz), 4.34 (1H, d, J ) 7.7 Hz), 4.42 (1H, d, J ) 18.2 Hz), 4.48
(1H, dd, J ) 5.1, 7.3 Hz); 13C NMR (125.7 MHz) major
diastereomer δC 24.3 (CH2), 26.1 (CH3), 27.0 (CH3), 27.5 (CH2),
28.9 (CH2), 41.9 (CH2), 52.6 (CH), 59.3 (CH3), 75.4 (CH2), 76.6
(CH), 80.4 (CH), 110.6 (C), 205.1 (C), 210.4 (C); minor diaste-
reomer δC 24.3 (CH2), 26.7 (2 × CH3), 27.0 (CH2), 29.3 (CH2),
42.1 (CH2), 52.9 (CH), 59.3 (CH3), 75.6 (CH2), 76.0 (CH), 79.9
(CH), 110.5 (C), 205.5 (C), 210.4 (C); MS m/z (rel intensity) 270
(M+, 2), 238 (M+ - MeOH, 1), 212 (M+ - Me2CdO, 4), 197
(M+ - MeOCH2CO, 39), 139 (M+ - [MeOCH2CO + Me2CdO],
100); HRMS calcd for C14H22O5, 270.1467; found, 270.1471; calcd
for C8H11O2, 139.0759; found, 139.0757. Anal. Calcd for C14H22O5:
C, 62.20; H, 8.20. Found: C, 62.03; H, 8.40.
1
3559, 1709, 1236, 1382, 1232, 1098 cm-1; H NMR (500 MHz)
major diastereomer δΗ 1.37 (3H, s), 1.43 (3H, s), 1.65-1.71 (3H,
m), 1.93 (1H, m), 2.04 (1H, m), 2.27 (1H, m), 2.40 (1H, m), 2.47
(1H, ddd, J ) 5.4, 5.4, 11.4 Hz), 2.58 (1H, d, J ) 8.4 Hz), 3.29
(1H, ddd, J ) 1.4, 4.3, 8.5 Hz), 3.38 (3H, s), 3.43 (3H, s), 3.59
(1H, dd, J ) 1.4, 10.4 Hz), 3.68 (1H, dd, J ) 1.6, 8.3 Hz), 3.70
(1H, dd, J ) 4.0, 10.2 Hz), 3.96 (1H, dd, J ) 1.7, 7.9 Hz), 4.46
(1H, dd, J ) 6.0, 7.8 Hz); minor diastereomer δΗ 1.38 (3H, s),
1.42 (3H, s), 1.65-1.71 (3H, m), 1.93-2.02 (2H, m), 2.07 (1H,
m), 2.33 (1H, m), 2.65 (1H, d, J ) 8.8 Hz), 2.69 (1H, ddd, J )
5.7, 5.7, 11.0 Hz), 3.29 (1H, m), 3.43 (3H, s), 3.44 (3H, s), 3.56
(1H, dd, J ) 1.6, 8.7 Hz), 3.60 (1H, dd, J ) 1.4, 10.4 Hz), 3.70
(1H, dd, J ) 4.0, 10.2 Hz), 4.10 (1H, dd, J ) 1.2, 8.6 Hz), 4.41
(1H, dd, J ) 6.1, 8.4 Hz); 13C NMR (125.7 MHz) major
diastereomer δC 24.5 (CH2), 27.0 (CH3), 27.3 (CH3), 27.4 (CH2),
29.0 (CH2), 42.3 (CH2), 52.8 (CH), 58.0 (CH3), 59.3 (CH3), 68.2
(CH), 71.6 (CH2), 74.6 (CH), 78.5 (CH), 80.5 (CH), 108.7 (C),
211.0 (C); minor diastereomer δC 24.3 (CH2), 27.0 (CH3), 27.1
(CH3), 27.6 (CH2), 29.5 (CH2), 42.1 (CH2), 53.3 (CH), 58.1 (CH3),
59.3 (CH3), 68.0 (CH), 71.2 (CH2), 74.9 (CH), 78.5 (CH), 80.6
(CH), 108.6 (C), 211.0 (C); MS m/z (rel intensity) 301 (M+ - Me,
4), 139 (M+ - [MeOCH2CH(OMe)CHOH + Me2CdO], 100), 59
([Me2CdOH]+, 32); HRMS calcd for C15H25O6, 301.1651; found,
301.1645; calcd for C8H11O2, 139.0759; found, 139.0765. Anal.
Calcd for C16H28O6: C, 60.74; H, 8.92. Found: C, 60.71; H, 8.95.
(1R,1′R/S)-5-Deoxy-1,2-O-Isopropylidene-3-O-methyl-1-[2′-
oxo-1′-cyclohexyl]-L-arabinitol (52). Isolated as an inseparable
diastereomer mixture (3:2). Colorless oil; [R]D +24 (c 0.36, CHCl3);
IR 3469, 1708, 1215, 1099, 1045 cm-1; 1H NMR (500 MHz) major
diastereomer δΗ 1.24 (3H, d, J ) 6.4 Hz), 1.35 (3H, s), 1.43 (3H,
(1S,1′R/S)-3-Deoxy-1,2-O-isopropylidene-4,5-di-O-methyl-1-
[2′-oxo-1′-cyclohexyl]-D-arabinitol-3-one (54). Isolated as an
inseparable diastereomer mixture (3:1). Colorless oil; [R]D +11 (c
1
0.10, CHCl3); IR 1709, 1382, 1232, 1098, 1048 cm-1; H NMR
(500 MHz, CDCl3) major diastereomer δΗ 1.41 (3H, s), 1.43 (3H,
s), 1.61-1.77 (4H, m), 2.06 (1H, m), 2.17 (1H, m), 2.33 (1H, m),
2.41 (1H, m), 2.64 (1H, ddd, J ) 6.3, 6.3, 12.3 Hz), 3.37 (3H, s),
3.52 (3H, s), 3.67 (1H, dd, J ) 6.0, 10.7 Hz), 3.78 (1H, dd, J )
3.1, 10.7 Hz), 4.22 (1H, dd, J ) 3.1, 6.0 Hz), 4.36 (1H, d, J ) 7.2
Hz), 4.51 (1H, dd, J ) 6.9, 7.1 Hz); minor diastereomer δΗ 1.42
(3H, s), 1.43 (3H, s), 1.61-1.77 (4H, m), 2.17 (1H, m), 2.31-2.37
(2H, m), 2.48 (1H, m), 2.82 (1H, m), 3.37 (3H, s), 3.51 (3H, s),
3.69 (1H, dd, J ) 5.5, 10.1 Hz), 3.77 (1H, dd, J ) 3.9, 10.1 Hz),
4.20 (1H, dd, J ) 3.2, 5.6 Hz), 4.53 (1H, s), 4.54 (1H, s); 13C
NMR (125.7 MHz, CDCl3) major diastereomer δC 24.3 (CH2), 26.2
J. Org. Chem. Vol. 73, No. 14, 2008 5295

Boto et al.
(CH3), 27.0 (CH2), 27.3 (CH3), 29.4 (CH2), 41.9 (CH2), 53.7 (CH),
58.7 (CH3), 59.3 (CH3), 72.0 (CH2), 76.3 (CH), 79.7 (CH), 85.2
(CH), 110.6 (C), 205.8 (C), 210.7 (C); minor diastereomer δC 24.1
(CH2), 26.2 (CH3), 26.9 (CH3), 27.7 (CH2), 29.3 (CH2), 42.2 (CH2),
52.7 (CH), 58.8 (CH3), 59.3 (CH3), 72.0 (CH2), 76.4 (CH), 78.9
(CH), 84.7 (CH), 110.6 (C), 206.0 (C), 210.8 (C); MS m/z (rel
intensity) 299 (M+ - Me, 1), 256 (M+ - Me2CdO, 1), 139 (M+
- [MeOCH2CH(OMe)CO + Me2CdO], 100), 59 ([Me2CdOH]+,
22); HRMS calcd for C15H23O6, 299.1495; found, 299.1483; calcd
for C8H11O2, 139.0759; found, 139.0754. Anal. Calcd for C16H26O6:
C, 61.13; H, 8.34. Found: C, 61.31; H, 8.19.
300.1963. Anal. Calcd for C21H31NO3: C, 73.01; H, 9.04; N, 4.05.
Found: C, 72.97; H, 9.09; N, 4.16. Compound 57: colorless oil;
[R]D +37 (c 0.10, CHCl3); IR 3081, 3064, 1454, 1373, 1120 cm-1
;
1H NMR (500 MHz) δΗ 1.10 (1H, m), 1.22-1.28 (2H, m), 1.48
(3H, s), 1.49 (3H, s), 1.60-1.80 (3H, m), 2.00 (1H, m), 2.10-2.13
(2H, m), 2.28 (1H, m), 2.92 (1H, dd, J ) 3.4, 9.7 Hz), 3.18 (1H,
m), 3.21 (3H, s), 3.50 (1H, dd, J ) 9.3, 9.4 Hz), 3.55 (1H, dd, J )
4.7, 10.5 Hz), 3.73 (1H, d, J ) 10.5 Hz), 3.90 (1H, d, J ) 17.2
Hz), 4.14 (1H, d, J ) 17.1 Hz), 7.24 (1H, dd, J ) 7.1, 7.2 Hz),
7.32 (2H, dd, J ) 7.4, 7.6 Hz), 7.42 (2H, d, J ) 7.5 Hz); 13C NMR
(125.7 MHz) δC 24.8 (CH2), 25.6 (CH2), 26.9 (CH3), 27.1 (CH3),
28.9 (CH2), 31.5 (CH2), 44.5 (CH), 52.8 (CH2), 58.8 (CH3), 64.8
(CH), 66.1 (CH), 71.9 (CH2), 76.8 (CH), 82.7 (CH), 110.0 (C),
126.1 (CH), 127.5 (2 × CH), 128.0 (2 × CH), 142.2 (C); MS m/z
(1R,1′R/S)-4,5-Dideoxy-1,2-O-isopropylidene-3-O-methyl-1-
[2′-oxo-1′-cyclohexyl]-L-arabinitol-4-one (55). Isolated as an
inseparable diastereomer mixture (2:1). Colorless oil; [R]D +92 (c
(rel intensity) 345 (M+, 1), 330 (M+ - Me, 4), 300 (M+
-
1
0.20, CHCl3); IR 1707, 1450, 1216, 1133, 1075, 1034 cm-1; H
MeOCH2, 99), 242 (M+ - [MeOCH2 + Me2CdO], 80), 91
([PhCH2]+, 100); HRMS calcd for C21H31NO3, 345.2304; found,
345.2297; calcd for C7H7, 91.0548; found, 91.0551. Anal. Calcd
for C21H31NO3: C, 73.01; H, 9.04; N, 4.05. Found: C, 72.94; H,
9.25; N, 3.74.
NMR (500 MHz) major diastereomer δ 1.32 (3H, s), 1.43 (3H,
Η
s), 1.53-1.60 (3H, m), 1.92 (1H, m), 2.08 (1H, m), 2.24 (3H, s),
2.34 (1H, m), 2.37-2.41 (2H, m), 2.50 (1H, m), 3.51 (3H, s), 3.88
(1H, d, J ) 2.9 Hz), 4.01 (1H, dd, J ) 2.9, 6.2 Hz), 4.39 (1H, dd,
J ) 6.2, 8.2 Hz); minor diastereomer δ 1.33 (3H, s), 1.43 (3H,
Η
s), 1.53-1.60 (3H, m), 1.97 (1H, m), 2.08 (1H, m), 2.16 (1H, m),
2.24 (3H, s), 2.37-2.41 (2H, m), 2.79 (1H, m), 3.52 (3H, s), 3.74
(1H, d, J ) 2.6 Hz), 4.06 (1H, dd, J ) 2.5, 7.7 Hz), 4.61 (1H, dd,
J ) 4.8, 7.7 Hz); 13C NMR (125.7 MHz) major diastereomer δC
24.6 (CH2), 26.7 (CH3), 27.2 (CH3), 27.4 (CH3), 27.8 (CH2), 30.8
(CH2), 42.6 (CH2), 55.3 (CH), 59.5 (CH3), 75.5 (CH), 78.9 (CH),
86.4 (CH), 109.6 (C), 211.2 (C), 211.8 (C); minor diastereomer δC
24.4 (CH2), 26.5 (CH3), 27.1 (CH3), 27.3 (CH3), 27.4 (CH2), 28.2
(CH2), 42.2 (CH2), 53.0 (CH), 59.4 (CH3), 74.5 (CH), 78.5 (CH),
86.1 (CH), 109.0 (C), 211.0 (C), 211.5 (C); MS m/z (rel intensity)
269 (M+ - Me, 2), 252 (M+ - MeOH, 6), 241 (M+ - MeCO,
13), 197 (M+ - MeCOCHOMe, 57), 139 (M+ - [MeCOCHOMe
+ Me2CdO], 100), 87 ([MeCOCHOMe]+, 50); HRMS calcd for
C14H21O5, 269.1389; found, 269.1379; calcd for C8H11O2, 139.0759;
found, 139.0762. Anal. Calcd for C15H24O5: C, 63.36; H, 8.51.
Found: C, 63.31; H, 8.39.
Reductive Amination of Diketones 53-55. Synthesis of
Chiral Decahydroquinolines 56-59 and Benzodiazepines 60
and 61. To a solution of the diketone (0.1 mmol), dry benzylamine
(11 µL, 0.1 mmol), and AcOH (6µL, 0.1 mmol) in dry MeOH (2
mL), at 60 °C, was added dropwise a solution of NaBH3CN (8
mg, 0.12 mmol) in dry MeOH (0.25 mL). The resulting mixture
was stirred at 60 °C for 24 h, cooled to room temperature, poured
into 10% aqueous NaOH, and extracted with CH2Cl2. The organic
layer was dried, evaporated, and purified as usual to yield the
decahydroquinolines 56-59 (from diketones 53 and 54) and the
benzodiazepines 60 and 61 (from diketone 55).
N-Benzyl-(2S,3S,4S,4aR,8aS)-3,4-O-Isopropylidene-2-[(1′S)-
2′-dimethoxyethyl)-4a,8a-decahydroquinoline (58) and N-Ben-
zyl-(2S,3S,4S,4aS,8aR)-3,4-O-Isopropylidene-2-[(1′S)-2′-dimethox-
yethyl)-4a,8a-decahydroquinoline (59). Generated from diketone
54 (10% of product 58 and 41% of its isomer 59). Compound 58:
colorless oil; [R]D -48 (c 0.12, CHCl3); IR 3084, 3064, 1493, 1373,
1
1232, 1120, 1074 cm-1; H NMR (500 MHz) δΗ 1.13 (1H, m),
1.25-1.42 (3H, m), 1.34 (3H, s), 1.35 (3H, s), 1.53 (1H, m),
1.65-1.75 (2H, m), 1.98 (1H, m), 2.35 (1H, m), 2.63 (1H, ddd, J
) 4.8, 5.0, 12.4 Hz), 3.26 (1H, dd, J ) 4.8, 10.7 Hz), 3.36 (3H, s),
3.47 (3H, s), 3.57 (1H, m), 3.60 (1H, dd, J ) 9.1, 10.3 Hz), 3.66
(1H, dd, J ) 4.3, 10.3 Hz), 3.74 (1H, ddd, J ) 4.6, 4.7, 6.8 Hz),
3.77 (1H, d, J ) 16.1 Hz), 3.79 (1H, dd, J ) 3.0, 9.1 Hz), 4.42
(1H, d, J ) 15.7 Hz), 7.20 (1H, dd, J ) 7.1, 7.1 Hz), 7.30 (2H, dd,
J ) 7.4, 7.8 Hz), 7.34 (2H, d, J ) 7.4 Hz); 13C NMR (125.7 MHz)
δC 20.3 (CH2), 26.0 (CH2), 26.2 (CH2), 26.9 (CH2), 27.0 (CH3),
27.1 (CH3), 34.9 (CH), 52.7 (CH2), 58.4 (CH), 58.8 (CH), 59.0
(CH3), 59.3 (CH3), 73.5 (CH2), 75.1 (CH), 77.8 (CH), 79.9 (CH),
108.5 (C), 126.3 (CH), 127.2 (2 × CH), 128.2 (2 × CH), 141.7
(C); MS m/z (rel intensity) 374 (M+ - Me, 4), 300 (M+
-
+
MeOCH2CHOMe, 98), 242 (M+
- [MeOCH2CHOMe
Me2CdO], 99), 91 ([PhCH2]+, 100); HRMS calcd for C22H32NO4,
374.2331; found, 374.2338; calcd for C16H20NO, 242.1545; found,
242.1555; calcd for C7H7, 91.0548; found, 91.0552. Anal. Calcd
for C23H35NO4: C, 70.92; H, 9.06; N, 3.60. Found: C, 70.72; H,
9.12; N, 3.99. Compound 59: colorless oil; [R]D -25 (c 0.11,
CHCl3); IR 3064, 3035, 1452, 1382, 1232, 1164, 1101, 1079 cm-1
;
1H NMR (500 MHz) δΗ 1.05 (1H, m), 1.25-1.45 (3H, m), 1.45
(6H, s), 1.60 (1H, m), 1.67 (1H, m), 1.76 (1H, m), 1.96 (1H, m),
2.13 (1H, m), 2.71 (1H, ddd, J ) 4.7, 4.7, 12.5 Hz), 3.22 (1H, d,
J ) 9.9 Hz), 3.36 (3H, s), 3.37 (3H, s), 3.50 (1H, dd, J ) 9.1, 9.8
Hz), 3.61 (1H, dd, J ) 4.8, 8.9 Hz), 3.71 (1H, ddd, J ) 1.5, 4.7,
5.2 Hz), 3.73 (1H, dd, J ) 4.6, 9.2 Hz), 3.81 (1H, dd, J ) 8.8,
11.7 Hz), 3.86 (1H, d, J ) 15.5 Hz), 4.05 (1H, d, J ) 15.5 Hz),
7.22 (1H, dd, J ) 7.1, 7.2 Hz), 7.30 (2H, dd, J ) 7.3, 7.7 Hz),
7.34 (2H, d, J ) 7.2 Hz); 13C NMR (125.7 MHz) δC 20.5 (CH2),
21.9 (CH2), 25.6 (CH2), 26.5 (CH2), 27.0 (CH3), 27.2 (CH3), 37.3
(CH), 52.1 (CH2), 58.0 (CH), 58.2 (CH3), 58.9 (CH3), 59.0 (CH),
73.1 (CH2), 76.6 (CH), 77.6 (CH), 80.9 (CH), 109.2 (C), 126.5
(CH), 127.5 (2 × CH), 128.3 (2 × CH), 141.1 (C); MS m/z (rel
MeCH2CHOMe, 88), 242 (M+ - [MeOCH2CHOMe + Me2CdO],
73), 91 ([PhCH2]+, 100); HRMS calcd for C23H35NO4, 389.2566;
found, 389.2550; calcd for C7H7, 91.0547; found, 91.0548. Anal.
Calcd for C23H35NO4: C, 70.92; H, 9.06; N, 3.60. Found: C, 70.94;
H, 9.14; N, 3.58.
N-Benzyl-(2R,3S,4S,5R,5aS,9aR)-4,5-O-Isopropylidene-2-meth-
yl-3-methoxy-5a,9a-decahydro-1H-benzo[b]azepine(60)andN-Ben-
zyl-(2S,3S,4S,5R,5aR,9aS)-4,5-O-isopropylidene-2-methyl-3-meth-
N-Benzyl-(2R,3R,4R,4aS,8aR)-3,4-O-Isopropylidene-2-meth-
oxymethyl-4a,8a-decahydroquinoline (56) and N-Benzyl-
(2R,3R,4R,4aR,8aS)-3,4-O-Isopropylidene-2-methoxymethyl-
4a,8a-decahydroquinoline (57). Generated from diketone 53 (43%
of product 56 and 12% of its isomer 57). Compound 56: colorless
oil; [R]D +20 (c 0.14, CHCl3); IR 3084, 3063, 1452, 1372, 1231,
1106, 1092 cm-1; 1H NMR (500 MHz) δΗ 1.05 (1H, m), 1.34 (1H,
m), 1.38-1.43 (2H, m), 1.45 (3H, s), 1.46 (3H, s), 1.52 (1H, m),
1.72-1.80 (2H, m), 1.94 (1H, m), 2.09 (1H, m), 2.75 (1H, ddd, J
) 4.7, 4.7, 12.5 Hz), 3.13 (1H, ddd, J ) 1.9, 6.5, 9.6 Hz), 3.26
(3H, s), 3.36 (1H, dd, J ) 9.0, 9.7 Hz), 3.51 (1H, dd, J ) 6.6, 10.5
Hz), 3.73 (1H, dd, J ) 1.8, 10.5 Hz), 3.77 (1H, d, J ) 14.7 Hz),
3.83 (1H, dd, J ) 8.8, 11.7 Hz), 4.05 (1H, d, J ) 14.8 Hz), 7.22
(1H, dd, J ) 7.2, 7.3 Hz), 7.30 (2H, dd, J ) 7.3, 7.7 Hz), 7.36
(2H, d, J ) 7.2 Hz); 13C NMR (125.7 MHz) δC 20.5 (CH2), 20.6
(CH2), 25.4 (CH2), 26.4 (CH2), 26.8 (CH3), 27.2 (CH3), 38.1 (CH),
51.8 (CH2), 57.7 (CH), 58.5 (CH), 58.6 (CH3), 72.4 (CH2), 76.2
(CH), 78.4 (CH), 109.5 (C), 126.5 (CH), 127.9 (2 × CH), 128.1 (2
intensity) 389 (M+, <1), 344 (M+ - MeOCH2, 1), 300 (M+
-
× CH), 141.4 (C); MS m/z (rel intensity) 345 (M+, 2), 330 (M+
-
Me, 3), 300 (M+ - MeOCH2, 100), 242 (M+ - [MeOCH2 +
Me2CdO], 79), 91 ([PhCH2]+, 74); HRMS calcd for C21H31NO3,
345.2304; found, 345.2308; calcd for C19H26NO2, 300.1964; found,
5296 J. Org. Chem. Vol. 73, No. 14, 2008

ConVersion of Carbohydrates into C-Alditols
oxy-5a,9a-decahydro-1H-benzo[b]azepine (61). Generated from
diketone 55 (22% of product 60 and 17% of its isomer 61).
Compound 60: colorless oil; [R]D +55 (c 0.12, CHCl3); IR 3081,
3064, 1506, 1457, 1369 cm-1; 1H NMR (500 MHz) δΗ 1.10-1.65
(5H, m), 1.20 (3H, d, J ) 6.9 Hz), 1.41 (3H, s), 1.43 (3H, s),
1.72-1.78 (2H, m), 2.12 (1H, m), 2.30 (1H, m), 2.60 (1H, ddd, J
) 4.3, 4.5, 12.5 Hz), 3.31 (1H, dd, J ) 4.6, 5.8 Hz), 3.39 (1H,
dddd, J ) 4.5, 6.8, 6.9, 6.9 Hz), 3.47 (3H, s), 3.64 (1H, d, J )
16.1 Hz), 3.87 (1H, dd, J ) 5.9, 9.2 Hz), 3.94 (1H, dd, J ) 9.4,
10.5 Hz), 4.28 (1H, d, J ) 16.2 Hz), 7.20 (1H, m), 7.25-7.33
(4H, m); 13C NMR (125.7 MHz) δC 17.7 (CH3), 21.4 (CH2), 26.6
(CH2), 27.1 (CH3), 27.2 (CH3), 27.5 (CH2), 28.2 (CH2), 38.4 (CH),
50.4 (CH), 50.8 (CH2), 57.1 (CH), 59.5 (CH3), 74.0 (CH), 86.3
(CH), 87.6 (CH), 108.3 (C), 126.2 (CH), 127.4 (2 × CH), 128.1 (2
([PhCH2]+, 100); HRMS calcd for C22H33NO3, 359.2460; found,
359.2470; calcd for C7H7, 91.0548; found, 91.0552. Anal. Calcd
for C22H33NO3: C, 73.50; H, 9.25; N, 3.90. Found: C, 73.14; H,
9.32; N, 3.89.
Acknowledgment. This work was supported by the Inves-
tigation Programmes PPQ2000-0728, PPQ2003-01379, and
CTQ2006-14260/PPQ of the Plan Nacional de Investigacio´n
Cient´ıfica, Desarrollo e Innovacio´n Tecnolo´gica, Ministerio de
Educacio´n y Ciencia and Ministerio de Ciencia y Tecnolog´ıa,
Spain. We also acknowledge financial support from FEDER
funds. D.H. thanks the CSIC-Gobierno de Canarias, CSIC (I3P)
and Ministerio de Educacio´n y Ciencia (Plan Nacional FPU)
for fellowships.
× CH), 142.5 (C); MS m/z (rel intensity) 359 (M+, 4), 344 (M+
-
Me, 68), 328 (M+ - MeO, 67), 270 (M+ - [MeO + Me2CdO],
30), 91 ([PhCH2]+, 100); HRMS calcd for C22H33NO3, 359.2460;
found, 359.2448; calcd for C7H7, 91.0548; found, 91.0545. Anal.
Calcd for C22H33NO3: C, 73.50; H, 9.25; N, 3.90. Found: C, 73.72;
H, 9.12; N, 3.99. Compound 61: colorless oil; [R]D +14 (c 0.12,
Supporting Information Available: Preparation of substrate
22, including spectroscopic data of the synthetic intermediates
and the final product. Procedures for the allylation and
alkylation reactions, and spectroscopic data of phenyl ketones
20, 21, 27, butenolides 28-33 and 37-39, and cyclohex-
1
CHCl3); IR 3084, 3062, 1456, 1371, 1235, 1152, 1090 cm-1; H
NMR (500 MHz) δΗ 1.17 (3H, d, J ) 6.6 Hz), 1.20-1.60 (5H,
m), 1.45 (3H, s), 1.46 (3H, s), 1.80 (1H, m), 1.85-1.95 (3H, m),
2.82 (1H, m), 2.92 (1H, dddd, J ) 6.9, 6.9, 7.0, 7.1 Hz), 3.10 (1H,
dd, J ) 8.8, 9.0 Hz), 3.54 (3H, s), 3.87-3.94 (3H, m), 4.09 (1H,
dd, J ) 9.1, 9.4 Hz), 7.21 (1H, m), 7.23-7.31 (4H, m); 13C NMR
(125.7 MHz) δC 19.0 (CH3), 20.2 (CH2), 26.5 (CH2), 27.2 (CH3),
27.3 (CH3), 27.6 (CH2), 29.3 (CH2), 40.1 (CH), 59.8 (CH2), 60.1
(CH3), 61.1 (CH), 61.4 (CH), 77.8 (CH), 81.8 (CH), 86.4 (CH),
107.9 (C), 126.7 (CH), 127.9 (2 × CH), 128.2 (2 × CH), 141.7
(C); MS m/z (rel intensity) 359 (M+, 5), 328 (M+ - MeO, 66), 91
1
anones 46, 47, and 49. H and 13C NMR spectra for acetoxy
acetal 24, allyl derivatives 18 and 19, phenyl ketones 20,
21, 26, and 27, butenolides 28-39, cyclohexanones 46-48
and 50-55, alkaloid analogues 56-61, and substrates 63-65
and 22. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO800478A
J. Org. Chem. Vol. 73, No. 14, 2008 5297