5-exo Radical Cyclization onto 3-Alkoxyketimino-1,6-anhydromannopyranoses. Efficient Preparation of Synthetic Intermediates for (-)-Tetrodotoxin

Article abstract of DOI:10.1021/jo000325y

Ketoxime ethers at C3 of 1,6-anhydro-β-D-mannopyranose derivatives were found to be useful 5-exo radical traps of alkyl and vinyl radicals generated at a chain tethered to the C2 hydroxyl group, allowing advanced synthetic intermediates for (-)-tetrodotoxin to be prepared from D-mannose in good overall yield.

Full text of DOI:10.1021/jo000325y

5960
J . Org. Chem. 2000, 65, 5960-5968
5-exo Ra d ica l Cycliza tion on to
3-Alk oxyk etim in o-1,6-a n h yd r om a n n op yr a n oses. Efficien t
P r ep a r a tion of Syn th etic In ter m ed ia tes for (-)-Tetr od otoxin
B. Noya, M. D. Paredes, L. Ozores, and R. Alonso*
Departamento de Quı´mica Orga´nica y Unidad Asociada al CSIC, Universidad de Santiago de
Compostela, 15706 Santiago de Compostela, Spain
E-mail: qoraa@usc.es
Received March 8, 2000
Ketoxime ethers at C3 of 1,6-anhydro-â-D-mannopyranose derivatives were found to be useful 5-exo
radical traps of alkyl and vinyl radicals generated at a chain tethered to the C2 hydroxyl group,
allowing advanced synthetic intermediates for (-)-tetrodotoxin to be prepared from D-mannose in
good overall yield.
Sch em e 1
Tetrodotoxin (1) is a relatively small but biologically
important and structurally fascinating molecule.1 The
unusual combination of a hemilactal and a guanidine unit
is responsible for its zwitterionic form. Other structural
features that make it a challenging synthetic target are
its aminal at C4, its high heteroatom content (eight
oxygens and three nitrogens, giving a total equal to the
number of carbons), and the presence of eight stereogenic
centers.2,3
We plan to prepare enantiomerically pure (-)-tetro-
dotoxin from D-mannose via intermediates I, II, and III
as indicated in Scheme 1. We report here achievement
of the radical addition I f II, which creates the key
quaternary center at C8a and the C4-C4a-C5 chain.
The intramolecular 5-exo nature of this radical cyclization
guarantees the approach of the radical chain to the
concave face of the existing bicyclic structure and thus
ensures that the new quaternary center has the stereo-
chemistry as C8a in (-)-tetrodotoxin.4
Resu lts a n d Discu ssion
Ra d ica l Cycliza tion of Mod el 5-Alk oxyk etim in o
Alk yl Ra d ica l 5. We envisaged that, as Scheme 1
* Fax: 34-981-547085.
(1) Kao, C. Y.; Levinson, S. R. Ann. N.Y. Acad. Sci. 1986, 479.
(2) To date, a single total synthesis of racemic tetrodotoxin has been
accomplished: Kishi, Y.; Aratani, M.; Fukuyama, T.; Nakatsubo, F.;
Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J . Am. Chem.
Soc. 1972, 94, 9217-9219. Kishi, Y.; Fukuyama, T.; Aratani, M.;
Nakatsubo, F.; Goto, T.; Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H.
J . Am. Chem. Soc. 1972, 94, 9219-9221.
suggests, a mixed acetal at position C4 of intermediates
II (i.e., A ) OR) would be ideal for constructing the C4
aminal of tetrodotoxin. Consequently, the corresponding
R-iodoacetals were chosen as radical precursors I (A )
OR, RP ) I). In particular, we decided to begin with
simple alkyl iodoacetals (A ) OR, RP ) I, B ) R′ + H),
because alkyl haloacetals are easily obtained from alco-
hols and are known to behave well in 5-exo radical
cyclizations onto CdC double bonds.5 It is important to
note, however, that the transformation I f II involves
(3) For the main attempts at total synthesis of enantiomerically pure
toxin, see the following articles and the references therein: (a) Keana,
J . F. W.; Kim, C. U. J . Org. Chem. 1971, 36, 118-127. (b) Keana, J . F.
W.; Bland, J . S.; Boyle, P. J .; Erion, M.; Hartling, R.; Husman, J . R.;
Roman, R. B.; Ferguson, G.; Parvez, M. J . Org. Chem. 1983, 48, 3627-
3631. (c) Sato, K.; Kajihara, Y.; Nakamura, Y.; Yoshimura, J . Chem.
Lett. 1991, 1559-1562. (d) Alonso, R. A.; Burgey, C. S.; Rao, B. V.;
Vite, G. D.; Vollerthun, R.; Zottola, M. A.; Fraser-Reid, B. J . Am. Chem.
Soc. 1993, 115, 6666-6672. (e) Burgey, C. S.; Vollerthun, R.; Fraser-
Reid, B. J . Org. Chem. 1996, 61, 1609-1618. M. Isobe et al. recently
succeeded in preparing a nonnatural dideoxygenated analogue of (-)-
tetrodotoxin: (f) Nishikawa, T.; Asai, M.; Ohyabu, N.; Yamamoto, N.;
Isobe, M. Angew. Chem., Int. Ed. Engl. 1999, 38, 8, 3081-3084.
(4) Our first successful radical cyclization onto a sugar-based
ketoxime ether was announced at the IASOC Advanced Research
Workshop held in Ischia Porto (Naples, Italy) in September, 1992. A
preliminary account of this work can be found in Noya, B.; Alonso, R.
Tetrahedron Lett. 1997, 38, 2745-2748. For an approach to the (-)-
tetrodotoxin C8a center based on 1,3-dipolar cycloaddition of a keto-
nitrone, see: Torrente, S.; Noya, B.; Paredes, M. D.; Alonso, R. J . Org.
Chem. 1997, 62, 6710-6711.
(5) Free radical cyclization of bromoacetals was first reported by
Ueno and Stork: (a) Ueno, Y.; Chino, K.; Watanabe, M.; Moriya, O.;
Okawara, M. J . Am. Chem. Soc. 1982, 104, 5564-5566. (b) Stork, G.;
Mook, R. J . Am. Chem. Soc. 1983, 105, 3720-3722. Better results were
subsequently obtained with iodoacetals in cyclization-trapping experi-
ments using catalytic tin: (c) Stork, G.; Sher, P. M. J . Am. Chem. Soc.
1986, 108, 303-304.
10.1021/jo000325y CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/18/2000

Synthetic Intermediates for (-)-Tetrodotoxin
J . Org. Chem., Vol. 65, No. 19, 2000 5961
Sch em e 2
Sch em e 3
the addition to a ketoxime ether, which in marked
contrast with alkenes and aldoximes6 have received
scarce attention as radical trap. In fact at the outset of
this work only one intramolecular addition of an alkyl
radical onto a ketoxime ether had been reported.7
For a preliminary test of the key step I f II, we chose
the easily accessible analogue 4, which was efficiently
obtained from commercial R-hydroxycyclohexanone dimer
(2) as indicated in Scheme 2. Subjecting 4 to standard
tributyltin radical conditions led to the desired bicyclic
hydroxylamine ether 6 in good yield,8 thus proving the
feasibility and efficiency of cyclization for the formation
of nitrogenated quaternary centers in simple 5-alkox-
yketimino alkyl radicals such as 5.
P r ep a r a tion of Alk yl Ra d ica l P r ecu r sor s a s P o-
ten tia l In ter m ed ia tes I: F or m a tion of Mor p h olin e
Der iva tives u p on Cycliza tion . Having found that the
ketoxime ether group of model compound 4 efficiently
trapped the alkyl radical in 1,5-exo fashion, we then stud-
ied the more complex case of 1,6-anhydro-â-D-mannopy-
ranose C3-ketoxime ether derivatives (I, A ) OR, RP )
I, B ) R′ + H). We began with iodoacetal 11, which was
prepared from D-mannose (7) via known intermediates
89 and 93d (Scheme 3). The last step, treatment of R-
hydroxyketoxime ether 10 with N-iodosuccinimide and
ethyl vinyl ether in THF, afforded 11 as a 1:1 mixture of
C7-epimers that was used without separation in the
cyclization attempts described below.
Initial attempts to cyclize iodoacetal 11 under condi-
tions similar to those successfully used for 4 gave the
reduced acetal 13 as the main product; the desired
cyclized compound 14 was not detected (Scheme 4). Thus
the intermediate radical 12, unlike 5, abstracts a hydro-
gen atom from the stannane (path a ) more readily than
it undergoes the desired 5-exo cyclization (path b). This
difference between the behaviors of 12 and 5 may be due
to the 1,5 methylene ether bridge of 12; in the molecular
conformation required for 5-exo cyclization, this bridge
holds the endo H atom of C6 in close proximity to one of
the hydrogen atoms at the radical center C8, thus making
5-exo cyclization too slow to compete successfully with
alternative reaction pathways such as reduction to 13.
Cyclization of iodoacetal 11 was also attempted under
Stork’s catalytic tin radical conditions,5c an approach
where a low concentration of stannane is maintained
throughout the reaction by reduction of a substoichio-
metric amount of a tin halide, which is initially added
(6) The use of aldoxime ethers as radical traps was first reported
by Corey in 1983: (a) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983,
24, 2821-2824. Subsequently, numerous reports from different groups
have confirmed their excellent performance in radical cyclizations. For
reviews see: (b) Mart´ınez-Grau, A.; Marco-Contelles, J . Chem. Soc.
Rev. 1998, 27, 155-162. (c) Fallis, A. G.; Brinza, I. M. Tetrahedron
1997, 53, 17543-17594. For selected cyclizations see, for example, (d)
Barlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc. 1988,
110, 1633-1634. (e) Hatem, J .; Henriet-Bernard, C.; Grimaldi, J .;
Maurin, R. Tetrahedron Lett. 1992, 33, 1057-1058. (f) Parker, K. A.;
Fokas, D. J . Org. Chem. 1994, 59, 3933-3938. (g) Santagostino, M.;
Kilburn, J . D.; Tetrahedron Lett. 1995, 36, 1365-1368. (h) Miyabe,
H.; Torieda, M.; Inoue, K.; Tajiri, K.; Kiguchi, T.; Naito, T. J . Org.
Chem. 1998, 63, 4397-4407. (i) Keck, G. E.; Wager, T. W. J . Org.
Chem. 1996, 61, 8366-8367. (j) Marco-Contelles, J .; Gallego, P.;
Rodr´ıguez-Ferna´ndez, M.; Khiar, N.; Destabel, C.; Bernabe´, M.;
Mart´ınez-Grau, A.; Chiara, J . L. J . Org. Chem. 1997, 62, 7397. (k)
Clive, D. L. J .; Zhang, J . Chem. Commun. 1997, 549-550. (l) Boiron,
A.; Zillig, P.; Faber, D.; Giese, B. J . Org. Chem. 1998, 63, 5877-5882.
For the particular case of acylgermane oxime ethers see: (m) Iserloh,
U.; Curran, D. P. J . Org. Chem. 1998, 63, 4711-4716. Intermolecular
carbon radical addition to aldoxime ethers has received much less
attention; see, for example: (n) Hart, D. J .; Seely, F. L. J . Am. Chem.
Soc. 1988, 110, 1631-1633. (o) Hanamoto, T.; Inanaga, J . Tetrahedron
Lett. 1991, 32, 3555-3556. (p) Bhat, B.; Swayze, E. E.; Wheeler, P.;
Dimock, S.; Perbost, M.; Sanghvi, Y. S. J . Org. Chem. 1996, 61, 8186-
8199. For more recent work in this field, see: (q) Kim, S.; Cheong, J .
H. J . Chem. Soc., Chem. Commun. 1998, 1143-1144 and (r) Miyabe,
H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T. J . Org. Chem. 2000,
65, 176-185, and references therein. Plain aldoximes have also been
shown to behave as radical traps in intermolecular reactions: Citterio,
A.; Filippini, L. Synthesis 1986, 473-474.
(7) (a) Barlett, P. A.; McLaren, K. L.; Ting, P. C. J . Am. Chem. Soc.
1988, 110, 1633-1634. During our work the use of this transformation
for the formation of bicyclo[2.2.1]heptanes was also reported: (b) Della,
E. W.; Knill, A. M. Aust. J . Chem. 1994, 47, 1833-1841. More recently,
G. Fu and T. Naito have independently reported on the intramolecular
addition of R-alkoxy alkyl radicals to form carbocycles and N-hetero-
cycles, respectively: (c) Tormo, J .; Hays, D. S.; Fu, G. C. J . Org. Chem.
1998, 63, 201-202 and (d) Naito, T.; Nakagawa, K.; Nakamura, T.;
Kasei, A.; Ninomiya, I.; Kiguchi, T. J . Org. Chem. 1999, 64, 2003-
2009. For the intramolecular addition of vinyl and aryl radicals to
ketoxime ethers see ref. 16.
(8) Cis-fusion of the tetrahydrofuran ring in 6, (also in 19, 22a , 22b,
26, and 30) is assumed on the basis of numerous precedents in which
exclusive formation of cis-fused bicyclic products in this type of radical
cyclization has been reported. See for example Stork, G.; Mook, R.;
Biller, S. A.; Rychnovsky, S. D. J . Am. Chem. Soc. 1983, 105, 3741-
3742. For 30, indirect proof of this stereochemical outcome comes from
its successful transformation into 32.
(9) Zottola, M. A.; Alonso, R. A.; Vite, G. D.; Fraser-Reid, B. J . Org.
Chem. 1989, 54, 6123-6125.

5962 J . Org. Chem., Vol. 65, No. 19, 2000
Noya et al.
Sch em e 4
Sch em e 5
as tributyltin chloride and then continuously regenerated
in situ by reaction between tin radicals and the starting
haloderivative.10 However, heating 11 with n-Bu3SnCl,
NaBH3CN, and AIBN in deoxygenated t-BuOH produced
acetal 13 (presumably via radical intermediate 12),
alcohol 10 (the result of acetal hydrolysis of 11 or 13),
and the unexpected morpholine derivative 15. Structural
determination of 15 follows from NMR data, which
include COSY, HMQC, and one- and two-dimensional
NOE experiments. Some of the most diagnostically
informative nuclear Overhauser enhancements are shown
in Scheme 4.11
The fact that no 15 had been formed on reaction of 11
with slowly added n-Bu3SnH and AIBN, conditions which
except for the solvent and the absence of the hydride
reducing agent are very similar to the Stork’s conditions,
suggested that transformation of 11 into 15 had taken
place not by 1,6-endo cyclization of the radical intermedi-
ate 12 (Scheme 4, path c)12 but through a nonradical
mechanism. Conclusive evidence for this came from the
finding that reaction of 11 with NaBH3CN in t-BuOH,
in the absence of n-Bu3SnCl and AIBN also led to 15
(Scheme 5). The formation of 15 in this reaction is at-
tributed to intramolecular N-alkylation of 11 followed by
hydride reduction of the resulting iminium intermediate
16. This mechanism also accounts for the observed ster-
eochemical outcome. First, since proper alignment of the
nitrogen lone pair and the carbon-iodine bond in 11
makes intramolecular nucleophilic displacement easier
for 7S-11 than for the 7R epimer, in which attack by the
nucleophile is hindered by the ethoxy group, 7R-11 is al-
most completely recovered and only 7S-11 is transformed
into the morpholine 15, which consequently displays only
S configuration at C7. Second, the exclusive formation
of a product with R configuration at C3 is attributable
to the hydride attacking the tricyclic alkoxyiminium ion
16 exclusively from its less hindered convex side.13,14
(12) Preferential 1,6-endo addition onto the nitrogen over the
alternative 1,5-exo addition to the sp2 carbon has been recently
observed in the tosyl radical-mediated cyclization of â-allenyl ke-
toximebenzoates: Depature, M.; Siri, D.; Grimaldi, J .; Hatem, J .
Tetrahedron Lett. 1999, 40, 4547-4550.
(13) The transformation of cyclic N-alkoxyketiminoiodoacetals de-
rived from R-hydroxycyclohexanones into cis-fused morpholines on
treatment with cyanoborohydride is possibly the rule. NaBH3CN
transformed iodoacetal 4 (1:1 diastereomeric mixture) into the corre-
sponding morpholine (unpublished results). The reaction was again
highly stereoselective, one diastereomer of 4 being cleanly converted
to the morpholine and the other recovered unchanged.
(14) R-Hydroxyketoxime ether 10 was obtained from ketone 9 as a
single stereoisomer. Transformation of the iodoacetal 11 into morpho-
line 15 strongly supports the Z configuration for both 11 and its
precursor 10.
(10) This method (ref 5c) is a modification of the borohydride plus
catalytic trialkyltin halide system (n-Bu3SnCl or Me3SnCl, NaBH4, hν,
EtOH), which was first used by Corey for dehalogenation of organic
halides: Corey, E. J .; Suggs, J . W. J . Org. Chem. 1975, 40, 2554-
2555, and was later applied by Giese to the addition of radicals derived
from alkyl iodides to electrophilic olefins: Giese, B.; Gonza´lez-Go´mez
J . A.; Witzel, T. Angew. Chem., Int. Ed. Engl. 1984, 23, 69-70 and
Gerth, D. B.; Giese, B. J . Org. Chem. 1986, 51, 3726-3729.
(11) See Supporting Information.

Synthetic Intermediates for (-)-Tetrodotoxin
J . Org. Chem., Vol. 65, No. 19, 2000 5963
Sch em e 6
P r ep a r a tion of Vin yl Ra d ica l P r ecu r sor s a s In -
ter m ed ia tes I a n d Cycliza tion to II. Having attributed
the failure of 11 to cyclize to 14 to the presence of the
1,5 methylene ether bridge we decided to replace the
π-radical 12 with the vinyl σ-radical 18a (Scheme 6). We
reasoned that the planar vinyl geometry would allow
proper alignment of the orbitals for 5-exo cyclization while
minimizing interaction with the endo H6 atom of the
ether bridge. Additionally, vinyl radicals are known to
have comparatively higher 5-exo cyclization/reduction
rate ratios,15 and since precursor vinyl halides would not
attack the oxime nitrogen it would be possible to use
Stork’s radical-forming conditions.
All these expectations were fulfilled when treatment
of substrate 17 with n-Bu3SnCl, NaBH3CN, and AIBN
in refluxing t-BuOH gave the desired tetrahydrofuran
derivative 19. Similarly, generation of tin-substituted
vinyl radicals from alkyne 21 under standard n-Bu3SnH-
AIBN conditions afforded 22a .16 Partial reduction of the
intermediate vinyl radicals was observed in both cases,
19 being accompanied by allyl ether 20 and 22a by vinyl
stannanes 23a and 24a .
the guanidine and the hydroxymethyl units. They also
have the quaternary C8a and three more of the eight
tetrodotoxin stereocenters (C7, C8, and C9). Moreover,
their precursors, 17 and 21, can be prepared in only five
steps, with excellent overall yields, from 2,3-isopropyl-
idene-1,6-anhydro-â-D-mannopyranose 8, which is readily
obtained in multigram quantities from D-mannose. How-
ever, since the yield of the radical cyclization step was
only about 30%, we next sought ways to increase the
efficiency of this transformation.
Varying the tin reagent (n-Bu3SnH, Ph3SnH, (n-Bu3-
Sn)2), the radical initiator (AIBN, hν, Et3B), the solvent
and the temperature achieved only moderate improve-
ment: 22b was obtained in 41% yield when Ph3SnH and
Et3B were slowly added to alkyne 21 in refluxing benzene
(Scheme 6). Unexpectedly, removal of the silyl protecting
group from alkyne 21 prior to the radical cyclization had
a major impact: the free alcohol 25 gave the desired
derivative 26 in 68% yield and only 3% yields of the
hydrostannylated products 27 and 28 (Scheme 7). In view
of this, we decided to check whether the same maneuver
would allow 5-exo cyclization of alkyl radical precursors.
To our delight, when the R-iodoacetal 11 was desilylated
at C4 and the resulting alcohol 29 was subjected to the
same conditions as had completely failed to cyclize 11,
hydroxylamine ether 30 was obtained in a synthetically
useful 58% yield (3 g scale).
Op tim iza tion of th e Ra d ica l Cycliza tion I f II.
Intermediates 19 and 22a contain all the carbon atoms
of tetrodotoxin except two, C2 and C11, which belong to
(15) See, for example Curran, D. P. Synthesis 1988, 428-430 and
references therein.
It is at first sight surprising that the cyclization yield
is so highly dependent on the presence or absence of a
bulky silyl group on the reverse side of the face ap-
proached by the attacking radical and that the yields
afforded by alkyl and vinyl radicals differ markedly when
they are silylated at C4 (0% for 12 versus 29-41% for
18a -c) but not if the C4 hydroxyl is unprotected (58%
for 35, 68% for 36) (Chart 1). However, examination of
(16) Addition of vinyl radicals generated from alkynes to methyl
ketoximes was first reported by Enholm: Enholm, E. J .; Burrof, J . A.;
J aramillo, L. M. Tetrahedron Lett. 1990, 31, 3727-3730. Use of aryl
radicals was described by J enkins: Booth, S. E.; J enkins, P. R.; Swain,
C. J .; Sweeney, J . B. J . Chem. Soc., Perkin Trans. 1 1994, 3499-3508.
For the special case of addition of vinyl radicals to ketoximes derived
from cyclobutanone, see: Pattenden, G.; Schulz, D. Tetrahedron Lett.
1993, 34, 6787-6790 and Hollingworth, G. J .; Pattenden, G.; Schulz,
D. J . Aust. J . Chem. 1995, 48, 8, 381. For a review of heteroatom radical
addition-cyclization, see Naito, T. Heterocycles 1999, 50, 505-541.

5964 J . Org. Chem., Vol. 65, No. 19, 2000
Noya et al.
Sch em e 7
Ch a r t 1
Sch em e 8
models suggests a combined effect of the silyl ether at
C4 and the C6-O-C1 bridge. It seems possible that the
bulky tert-butyldiphenylsilyl group borne by C4 in inter-
mediates 12 and 18 may force the C3 ketoxime ether
group toward the C6-O-C1 ether bridge, as a conse-
quence of which the C2-tethered radical-bearing chain,
in attacking the CdNOMe group, has to approach this
bridge more closely than in the C4-desilylated analogues
35 and 36. This would explain the lower cyclization yields
of 12 and 18. Because of their geometry (see above), this
effect must be greater for the alkyl radical 12 than for
vinyl radicals 18, to the extent that cyclization of 12 is
completely prevented. By contrast, the cyclization yields
of the C4-desilylated radicals 35 and 36 (generated from
precursors 29 and 25, respectively), should be more
similar, because in the absence of the bulky silyl group
interaction between the attacking radical and the ether
bridge must be slight regardless of which radical is used.
Com p letion of In ter m ed ia tes II. Vinyl derivatives
19, 22, and 26 possess a carbon corresponding to C5 in
tetrodotoxin but are unsubstituted at C4, while alkylac-
etal derivative 30 has the C4 oxygen of tetrodotoxin but
lacks C5. We first attempted to remedy the deficiency of
vinyl derivative 22a , but treatment with CrO3-pyridine
gave a complex mixture from which it was possible to
isolate only unsaturated aldehyde 31, the result of
oxidation followed by elimination. Gratifyingly, however,
addition of an extra carbon to acetal 30 was completely
successful, compound 30 being efficiently transformed
into the desired methylenelactone 34 in three high
yielding steps, via 32 and 33 (Scheme 8).
Su m m a r y. 1,6-Anhydro-â-D-mannopyranose deriva-
tives with both a ketoxime ether at position C3 and an
alkyl or vinyl radical precursor tethered to C2 were
efficiently prepared from D-mannose. When the C4
oxygen was protected by a tert-butyldiphenylsilyl group
and the radical precursor was an alkyl iodide, hydride-
based catalytic tin radical generation led to the stereo-
selective formation of a cis-fused morpholine by a two-
step nonradical cyclization process; when a TBDPS-
protected vinyl radical precursor was used, the same
conditions achieved the desired cyclization in modest
yield. Removal of the TBDPS group from O4 allowed
5-exo cyclization of alkyl radicals in fair yield and

Synthetic Intermediates for (-)-Tetrodotoxin
J . Org. Chem., Vol. 65, No. 19, 2000 5965
vigorously stirred for 12 h. After filtering through a pad of
Celite, the organic phase was washed with brine and water,
dried with Na2SO4 and evaporated. Flash column chromatog-
raphy (AcOEt-hexane, 17:83) afforded 6 (91 mg, 77%, 44:56
diastereomeric mixture). F a st m ovin g d ia ster eom er : 1H
NMR (CDCl3, 300 MHz) δ 5.81 (s, broad, 1H; NH), 5.08 (dd, J
) 5,8 and 2.9, 1H), 3.9 (dd, J ) 4,9, 1H), 3.82-3.74 (m, 1H),
3.52 (s, 3H), 3.46-3.41 (m, 1H), 2.07 (dd, J ′ ) 13.6 and 5.8,
1H), 1.94 (dd, J ) 13.6 and 2.9, 1H), 1.71-1.32 (m, 8H), 1.2
(t, J ) 7.1, 3H); 13C NMR (CDCl3, 75 MHz) δ 103.6, 76.8, 65.8,
63.8, 63.3, 42.3, 29.8, 28.3, 21.6, 20.8, 15.19; LRMS m/z (%)
170 [10.58, (M - OEt)+], 169 [100, (M - NHOCH3)+]; HRMS
calcd for C11H21NO3 (M+ + H) 216.159969, found 216.159414.
improved the efficiency of the vinyl radical cyclization.
The resulting products are expected to be susceptible of
transformation into tetrodotoxin.
From a more general perspective, this work shows that
ketoxime ethers derived from sugars, which have not
previously been used in radical transformations, are in
fact useful radical traps allowing the preparation of
compounds with nitrogen-bearing quaternary centers by
intramolecular cyclization. Tethering the chain contain-
ing the radical center to a sugar hydroxyl group adjacent
to the ketoxime group allows stereocontrolled formation
of a fused heterocycle on the sugar skeleton.
1
Slow m ovin g d ia ster eom er : H NMR (CDCl3, 300 MHz) δ
5.41 (s, broad, 1H; NH), 5.17 (dd, J ) 6.3 and 4.3, 1H), 3.86
(dd, J ) 9.2 and 6.0, 1H), 3.81-3.73 (m, 1H), 3.52 (s, 3H),
3.49-3.39 (m, 1H), 2.13 (dd, J ′ ) 14.0 and 6.3, 1H), 1.91 (dd,
J ′ ) 14.0 and 4.3, 1H), 2,0-1.2 (m, 8H), 1.19 (t, J ) 7.11, 3H);
13C NMR (CDCl3, 75 MHz) δ 103.7, 78.6, 67.1, 63.6, 63.1, 39.4,
30.01, 29,8, 22,5, 21.9, 15.32; LRMS m/z (%) 186 [18, (M -
Et)+], 169 [18, (M - NHOCH3)+], 81 [100, (C6H9)+]; HRMS
calcd for C11H21NO3 (M+ + H) 216.159969, found 216.159583.
(3Z)-1,6-An h ydr o-4-O-(ter t-bu tyldiph en ylsilyl)-3-deoxy-
3-m eth oxyim in e-â-D-a r a bin o-h exop yr a n ose (10). A solu-
tion of hydroxyketone 92d (2000 mg, 5.02 mmol) O-methylhy-
droxylamine hydrochloride (629 mg, 7.53 mmol, 150 mol %)
and pyridine (0.6 mL, 7.53 mmol, 150 mol %) in CH2Cl2 (7 mL)
was refluxed for 3 h. The solvent was rotary-evaporated and
the residue was redisolved in EtOAc, washed with brine, dried
and evaporated. Chromatography (EtOAc-hexane, 20:80)
afforded ketoxime ether 10 (1912 mg, 89%): 1H NMR (CDCl3,
300 MHz) δ 7.74 (m, 2H), 7.63 (m, 2H), 7.41 (m, 6H), 5.51 (d,
J 1,2 ) 1.9, 1H), 4.84 (d, J 4,5 ) 2.1, 1H), 4.61 (dd, J 2,OH ) 6.8,
J 2,1 ) 1.9,), 4.32 (m, 1H), 3.66 (s, 3H), 3.62 (dd, J ) 8.0 and
5.8, 1H), 3.32 (dd, J ) 8.0 and 0.9, 1H), 3.03 (d, J ) 6.8, 1H),
1.07 (s, 9H); 13C NMR (CDCl3, 75 MHz) δ 152.9, 135.8, 135.7,
133.2, 132.5, 129.97, 129.90, 127.7, 127.5, 102.4, 77.3, 69.8,
65.3, 65.1, 61.9, 26.7, 19.3; LRMS m/z (%) 370 [(M - tBu)+,
0.6], 350 [(M - Ph)+, 0.1], 339 [(M - tBu - NOCH3)+, 1], 91
(100), 77 (Ph+, 35), 57 (tBu+, 34). Anal. Calcd for C23H29NO5-
Si: C, 64.61; H, 6.84; N 3.28. Found: C, 64.67; H, 7.14; N,
3.37.
Exp er im en ta l Section
Gen er a l. All reactions were carried out under argon with
the exclusion of moisture. The reagents were purchased from
Sigma-Aldrich Chemical Co. and Fluka Chemical Co. and were
used without further purification. THF, Et2O, benzene and
toluene were distilled from sodium/benzophenone ketyl; CH2-
Cl2, pyridine and Et3N from calcium hydride. Anhydrous Na2-
SO4 was used to dry the organic solutions during workups.
Flash column chromatography was performed using 230-400
mesh silica gel (Merck). Analytical thin-layer chromatography
was done on precoated silica gel aluminum plates containing
a fluorescent indicator (GF-254 Merck). 1H NMR spectra were
recorded at 250, 300, or 500 MHz; 13C NMR spectra at 63, 75,
or 125 MHz; CDCl3 and CD3CN were used as solvents.
2-Hyd r oxy-1-m eth oxyim in e-cycloh exa n e 3. A suspen-
sion of dimer 2 (2 g, 8.76 mmol), O-methylhydroxylamine
hydrochloride (1.8 g, 21.02 mmol, 240 mol %) and Et3N (2.9
mL, 21.02 mmol, 240 mol %), in 80 mL of CH2Cl2 was stirred
at room temperature overnight. The reaction mixture was
washed with brine, and the organic layer was dried, filtered
and concentrated in vacuo. Purification through silica gel
(EtOAc-hexane, 30:70) afforded oxime 3 (essentially one
isomer, 2.3 g, 92%) as a pale yellow oil: 1H NMR (CDCl3, 300
MHz) δ 4.11 (m, 1H), 3.84 (s, 3H), 3.34 (d, J ) 3.2 Hz, 1H),
3.03 (m, 1H), 2.15 (m, 1H), 1.90-1.70 (m, 3H), 1.51-1.39 (m,
3H); 13C NMR (CDCl3, 63 MHz) δ 159.6, 70.1, 61.6, 36.0, 25.4,
23.6, 22.6; LRMS m/z (%) 143 [0.3, M+].
(3Z)-1,6-An h yd r o-4-O-(ter t-bu tyld ip h en ylsilyl)-2-O-(1′-
eth oxy-2′-iodoeth yl)-3-deoxy-3-m eth oxyim in e-â-D-ar abin o-
h exop yr a n ose (11). Iodoacetals 11 were prepared from
alcohol 10 (400 mg, 0.93 mmol), NIS (274 mg, 1.22 mmol, 130
mol %) and ethyl vinyl ether (136 µL, 1.40 mmol, 150 mol %)
in dry THF (12.5 mL) at -60 °C, following the procedure
reported for 4. Purification by chromatography (EtOAc-
hexane, 25:75) rendered 11 as a 1:1 mixture of epimers (572
mg, 98%). Enough quantities of pure samples of each epimer
for characterization purposes were obtained by careful chro-
matography. 7R-11: 1H NMR (CDCl3, 250 MHz) δ 7.72 (m,
2H), 7.63 (m, 2H), 7.43 (m, 6H), 5.52 (d, J ) 1.9 Hz, 1H), 4.87
(m, 2H), 4.65 (d, J ) 1.9 Hz, 1H), 4.32 (m, 1H), 3.77 (m, 1H),
3.62 (s, 3H), 3.66-3.57 (m, 2H), 3.45-3.39 (m, 2H), 3.30 (dd,
J ) 10.6 Hz, J ) 7.6 Hz, 1H), 1.28 (t, J ) 7.0 Hz, 3H), 1.07 (s,
9H); 13C NMR (CDCl3, 63 MHz) δ 152.1, 135.8 (4C), 133.3,
132.8, 130.0 (2C), 127.8 (2C), 127.5 (2C), 101.9, 101.8, 77.2,
71.1, 65.5, 65.3, 61.5, 62.9, 26.7 (3C), 19.3, 14.8, 4.9; IR (neat)
1587 (sharp, weak, CdN) cm-1; LRMS m/z (%) 568 [0.02, (M
Iod oa ceta ls 4. To a solution of 3 (300 mg, 2.09 mmol) in
dry THF (22 mL) kept under Ar at -78 °C in a light protected
vessel, were added NIS (613 mg, 2.72 mmol, 130 mol %) and
ethyl vinyl ether (0.3 mL, 3.14 mmol, 150 mol %). The cold
bath was removed and the reaction was allowed to warm.
Additional NIS (30 mol %) and ethyl vinyl ether (50 mol %)
were needed to consume completely the starting material. A
saturated aqueous solution of Na2S2O3 was then added and
the aqueous phase was extracted with Et2O. The organic
extracts were dried, filtered and concentrated. Purification of
the oily residue (EtOAc-hexane, 5:95) gave iodoacetals 4 (609
mg, 85%, approximately 1:1 diastereomeric mixture) as a
colorless oil which turned to brown-yellow on standing: 1H
NMR (CDCl3, 250 MHz) δ 4.59 and 4.56 (t each, J ) 5.4 Hz,
1H), 4.17 and 4.05 (m each, 1H), 3.84 and 3.82 (s each, 3H),
3.71-3.41 (m, 2H), 3.20 (d, J ) 5.4 Hz, 1H), 3.16 (d, J ) 5.4
Hz, 1H), 3.03-2.96 (m, 1H), 2.16-1.99 (m, 2H), 1.90-1.75 (m,
2H), 1.67-1.50 (m, 2H), 1.46-1.25 (m, 1H), 1.18 (m, 6H); 13C
NMR (CDCl3, 63 MHz) δ 158.8 and 157.8, 101.0 and 99.4, 74.1
and 73.0, 62.9 and 62.3, 61.4 and 61.2, 33.0 and 32.8, 25.2 (for
both diastereomers), 22.12 and 22.07, 20.15 and 20.12, 15.2
and 14.9, 6.3 and 5.9.
O-Meth ylh yd r oxyla m in es 6. A solution of iodoacetals 4
(1:1 diastereomeric mixture, 186 mg, 0.55 mmol) in dry
benzene (27 mL) was deoxygenated (Ar bubbling for 30 min)
and brought to reflux in an oil bath. A solution of n-Bu3SnH
(0.5 mL, 1.8 mmol, 340 mol %) and AIBN (54 mg, 0.32 mmol,
59 mol %) in dry deoxygenated benzene (2 mL) was added
dropwise for 3 h. After 30 min the oil bath was removed.
Because of the volatility of the cyclized products benzene was
carefully removed in the rotavapor. The oily residue was
treated with Et2O and an aqueous solution of KF (10%), and
- tBu)+], 426 [3, (M - tBuPh2SiOH)+]; HRMS calcd for C27H36
-
NO6SiI (M+) 625.131198, found 625.131482; [R]D -10.5° (c 0.86,
CH2Cl2). 7S-11: 1H NMR (CDCl3, 250 MHz) δ 7.72 (m, 2H),
7.62 (m, 2H), 7.41 (m, 6H), 5.50 (d, J ) 1.5 Hz, 1H), 4.94 (dd,
J ) 7.7 Hz, J ) 3.6 Hz, 1H), 4.89 (d, J ) 1.8 Hz, 1H), 4.64 (d,
J ) 1.5 Hz, 1H), 4.34 (m, 1H), 3.65 (dd, J ) 8.0 Hz, J ) 6.0
Hz, 1H), 3.59 (s, 3H), 3.41 (d, J ) 8.0 Hz, 1H), 3.90-3.70 (m,
2H), 3.35 (dd, J ) 10.4 Hz, J ) 3.6 Hz, 1H), 3.21 (dd, J ) 10.4
Hz, J ) 7.7 Hz, 1H), 1.25 (t, J ) 7.0 Hz, 3H), 1.07 (s, 9H); 13
C
NMR (CDCl3, 63 MHz) δ 152.1, 135.9 (2C), 135.8 (2C), 133.4,
132.7, 130.0 (2C), 127.8 (2C), 127.6 (2C), 102.3, 101.9, 77.3,
73.4, 65.5, 65.4, 61.7, 62.1, 26.7 (3C), 19.3, 15.0, 5.2.
Mor ph olin e 15.(a) Fr om 11 by tr eatm en t with NaBH3CN.
A mixture of iodoacetals 11 (1:1 mixture of epimers, 90 mg,

5966 J . Org. Chem., Vol. 65, No. 19, 2000
Noya et al.
0.14 mmol) and NaBH3CN (19 mg, 0.28 mmol, 200 mol %) in
dry and deoxygenated t-BuOH (9.3 mL) was refluxed for 13 h.
The solvent was removed, CH2Cl2 was added and the resulting
mixture was washed with saturated NH4Cl. The aqueous layer
was extracted with CH2Cl2 (3×) and the combined organic
extracts were washed with brine. After drying and filtering,
evaporation of the solvent gave a residue which was purified
by p-TLC (EtOAc-cyclohexane, 22:78) affording morpholine
15 (28 mg, 39%) and unaltered starting iodoacetal 7R-11 (40
mg, 44%). (b) F r om 11 u n d er St or k r a d ica l for m in g
con d ition s. A solution of 11 (1:1 mixture of epimers, 90 mg,
0.14 mmol), NaBH3CN (19 mg, 0.28 mmol, 200 mol %), n-Bu3-
SnCl (4 µL, 0.014 mmol, 10 mol %) and AIBN (4 mg, 0.02
mmol, 15 mol %) in degassed t-BuOH (9.3 mL) was heated for
9 h at 90 °C. Additional n-Bu3SnCl (10 mol %) and AIBN (15
mol %) were then added. After refluxing for an additional 3 h,
the mixture was concentrated, redisolved in CH2Cl2 and
washed with a saturated aqueous solution of NH4Cl. The
aqueous phase was extracted with CH2Cl2 and the combined
organic extracts were washed with brine, dried, filtered and
concentrated in vacuo. Purification by p-TLC (EtOAc-hexane,
22:78), afforded morpholine 15 (12 mg, 17%), reduced acetal
13 (13 mg, 18% of the fast moving epimer -15% EtOAc in
hexane-; ≈2 mg of the slow moving epimer), and R-hydroxy-
ketoxime-ether 10 (5 mg, 8%). Mor p h olin e 15:14 1H NMR
(CDCl3, 500 MHz) δ 7.75 (m, 2H, ArHo), 7.69 (m, 2H, ArHo),
(d, J ) 1.7, 1H), 4.35 (m, 1H), 4.23 (d, J ) 14.6, 1H), 3.64 (dd,
J ) 8.0 and 5.8, 1H), 3.63 (s, 3H), 3.42 (d, J ) 8.0, 1H), 1.08
(s, 9H): 13C NMR (75 MHz, CDCl3) δ 151.8, 135.7 (2C), 135.6
(2C), 133.2, 132.6, 129.90, 129.87, 129.0, 127.7 (2C), 127.4 (2C),
117.9, 101.4, 77.2, 75.9, 74.7, 65.34, 65.31, 61.6, 26.7 (3C), 19.3;
LRMS m/z (%) 426 [(M - C3H4Br)+; 0.5), 213 (100), 77 (Ph+;
16), 57 (tBu+; 23).
Tetr a h yd r ofu r a n 19 a n d (Z)-2-O-Allyl-1,6-a n h yd r o-4-
O-(ter t-bu tyld ip h en ylsilyl)-3-d eoxi-3-m eth oxyim in o-â-D-
a r a bin o-h exop yr a n ose (20). A solution of bromide 17 (70
mg, 0.13 mmol), NaBH3CN (17 mg, 0.26 mmol, 200 mol %),
n-Bu3SnCl (6 µL, 0.02 mmol, 15 mol %) and AIBN (3 mg, 0.02
mmol, 15 mol %) in deoxygenated t-BuOH (5 mL) was heated
at 90 °C for 8 h under Ar. The solvent was rotary-evaporated
and the residue was redisolved in CH2Cl2 and washed with
NH4OH (3%) and brine. Chromatography (EtOAc-hexane, 25:
75) afforded tetrahydrofuran 19 and allyl ether 20 (1:1
mixture, 35 mg, 58%). A careful chromatographic separation
allowed to obtain enough quantities of both compounds in pure
form for their characterization. Tetr a h yd r ofu r a n 19: 1H
NMR (CDCl3, 500 MHz) δ 7.86 (m, 4H), 7.44 (m, 6H), 6.67 (s,
broad, 1H; NH), 5.38 (d, J 1,2) 2.5, 1H), 5.00 (s, 1H), 4.81 (d, J
) 2.5, 1H), 4.72 (s broad, 2H), 4.24 (m, J ) 5.9, 1H), 4.02 (s,
1H), 3.74 (d, J ) 2.5, 1H), 3.46 (d, J ) 7.5, 1H), 3.39 (s, 3H),
3.29 (dd, J ) 7.5 and 5.9, 1H), 1.09 (s, 9H); 13C NMR (CDCl3,
125 MHz) δ 148.2, 136.2, 136.0, 133.9, 131.9, 130.1, 129.8,
127.66, 127.61, 106.7, 100.9, 80.8, 76.6, 72.5, 70.3, 66.8, 65.3,
62.4, 26.9, 19.5; LRMS m/z (%) 436 [(M - OCH3)+; 5], 410 [(M
- tBu)+; 3]. Anal. Calcd for C26H33O5NSi: C, 66.78; H, 7.11;
N 3.00. Found: C, 66.56; H, 7.08; N, 2.96. Allyl eth er 20: 1H
NMR (CDCl3, 250 MHz) δ 7.74 (m, 2H), 7.65 (m, 2H), 7.41 (m,
6H), 5.99 (m, 1H), 5.56 (d, J ) 1.7, 1H), 5.35 (dd, J ) 17.2, J
) 1.3, 1H), 5.24 (dd, J ) 10.3, J ) 1.3, 1H), 4.92 (d, J ) 2.1,
1H), 4.45-4.31 (m, 3H), 4.15 (dd, J ) 12.9, J ) 6.5, 1H), 3.65
(s, 3H), 3.66-3.61 (m, 1H), 3.42 (dd, J ) 8.0 and 0.8, 1H), 1.08
(s, 9H); 13C NMR (CDCl3, 63 MHz) δ 152.1, 135.7 (2C), 135.6
(2C), 134.4, 133.3, 132.6, 129.85, 129.79, 127.6 (2C), 127.4 (2C),
117.7, 101.4, 77.1, 75.6, 65.3, 72.0, 65.3, 61.5, 26.7 (3C), 19.2;
LRMS m/z (%) 467 (M+; 2), 426 [(M - C3H5)+; 3], 410 [(M -
tBu)+; 5].
(Z)-1,6-An h yd r o-4-O-(ter t-bu tyld ip h en ylsilyl)-3-d eoxy-
3-m eth oxyim in e-2-O-(p r op -2′-in yl)-â-D-a r a bin o-h exop y-
r a n ose (21). A solution of alcohol 10 (750 mg, 1.75 mmol) in
dry THF (13.3 mL) was added to a cold (0 °C) suspension of
NaH (60% in parafine, 105 mg, 2.63 mmol, 150 mol %) in 3.8
mL of the same solvent. When evolution of H2 ceased, 3-bro-
mopropine (0.28 mL, 2.63 mmol, 150 mol %) was added and
the ice-water bath removed. Additional 3-bromopropine (100
mol %) was needed to completely transform 10. Et2O was then
added, the mixture was washed with saturated NH4Cl and the
aqueous layer extracted with more Et2O. The combined organic
extracts were dried, filtered and concentrated. Chromatogra-
phy through silica gel (EtOAc-hexane, 20:80) afforded alkyne
21 (820 mg, quant): 1H NMR (CDCl3, 250 MHz) δ 7.75 (m,
2H), 7.67 (m, 2H), 7.41 (m, 6H), 5.59 (d, J ) 1.4 Hz, 1H), 4.92
(d, J ) 2.0 Hz, 1H), 4.70 (d, J ) 1.4 Hz, 1H), 4.48 (m, 2H),
4.38 (m, 1H), 3.66 (dd, J ) 8.0 Hz, J ) 5.9 Hz, 1H), 3.59 (s,
3H), 3.42 (d, J ) 8.0 Hz, 1H), 2.52 (t, J ) 2.4 Hz, 1H) 1.09 (s,
9H); 13C NMR (CDCl3, 63 MHz) δ 151.8, 135.7 (2C), 135.6 (2C),
133.7, 133.1, 129.9, 129.8, 127.6 (2C), 127.4 (2C), 101.4, 79.2,
77.2, 75.4, 74.3, 65.3, 65.2, 61.5, 57.9, 26.7 (3C), 19.2; LRMS
m/z (%) 465 [3, M+]; HRMS calcd for C26H31NO5Si (M+)
465.197152, found 465.196081; [R]D 67.2° (c 1.06, CH2Cl2).
Cycliza tion of Alk yn e 21 w ith n -Bu 3Sn H-Et3B. A
solution of 21 (450 mg, 0.97 mmol), n-Bu3SnH (0.30 mL, 1.06
mmol, 110 mol %) and Et3B (0.36 mL, 0.24 mmol, 25 mol %)
in toluene (121 mL) was heated at 75 °C, first under Ar (36 h)
and then allowing entrance of air through a CaCl2 tube (24
h). Chromatographic purification of the residue obtained by
evaporation of the solvent afforded 22a (230 mg, 31%), (2′E)-
23a (224 mg, 30%), (2′Z)-23a (59 mg, 8%) and 24a (18 mg,
2%) as colorless oils. O-Meth yl-h yd r oxyla m in e 22a : 1H
NMR (CDCl3, 300 MHz) δ 7.87 (m, 4H, ArHo), 7.43 (m, 6H,
ArHm, ArHp), 6.63 (br s, 1H, NH), 5.73 (t, J 9-7 ) 2.4 Hz, 1H,
H9), 5.38 (d, J 1-2 ) 2.6 Hz, 1H, H1), 4.65 (m, 2H, H7), 4.23
7.40 (m, 6H, ArHm, ArHpara), 5.45 (s, 1H, H1), 5.12 (d, J 7-8
)
8.9 Hz, 1H, H7), 4.26 (d, J 2-3 ) 6.2 Hz, 1H, H2), 4.21 (m, 1H,
H5), 4.13 (d, J 6endo-6exo ) 6.9 Hz, 1H, H6endo), 4.00 (s, 1H,
H4), 3.91 (m, 1H, H9), 3.59 (m, 1H, H9′), 3.49 (dd, J 6exo-6endo
-
J 6exo-5 ) 6.9 Hz, 1H, H6exo), 3.35 (d, J 8′-8 ) 9.7 Hz, 1H, H8′),
3.24 (s, 3H, OCH3), 3.02 (d, J 3-2 ) 6.2 Hz, 1H, H3), 2.22 (m,
1H, H8), 1.22 (t, J 10-9 ) 7.0 Hz, 3H, H10), 1.07 (s, 9H, t-Bu);
13C NMR (CDCl3, 125 MHz) δ 135.9 (Ar, 2C, Cortho), 135.8 (Ar,
2C, Cortho), 133.8 (Ar, Cipso), 132.8 (Ar, Cipso), 129.9 (Ar, Cpara),
129.8 (Ar, Cpara), 127.7 (Ar, 4C, Cmeta), 102.3 (C1), 95.9 (C7),
76.5 (C5), 72.2 (C2), 69.4 (C4), 66.6 (C3), 64.9, 64.8 (C6, C9),
59.2 (OCH3), 58.0 (C8), 26.8 (C(CH3)3), 19.2 (C(CH3)3), 15.2
(C10); LRMS m/z (%) 500 [10, (M + 1)+], 499 [28, (M)+]. Anal.
Calcd for C27H37O6NSi: C, 64.90; H, 7.46; N, 2.80. Found: C,
64.93; H, 7.44; N, 3.17. Acet a l 13: fast moving epimer; 1H
NMR (CDCl3, 300 MHz) δ 7.74 (m, 2H), 7.64 (m, 2H), 7.41 (m,
6H), 5.51 (d, J ) 1.7 Hz, 1H), 4.95 (c, J ) 5.4 Hz, 1H), 4.89 (d,
J ) 1.9 Hz, 1H), 4.69 (d, J ) 1.7 Hz, 1H), 4.30 (m, 1H), 3.80-
3.50 (m, 3H), 3.62 (s, 3H), 3.42 (d, J ) 8.0 Hz, 1H), 1.42 (d, J
) 5.4 Hz, 3H), 1.24 (t, J ) 7.1 Hz, 3H), 1.07 (s, 9H); 13C NMR
(CDCl3, 63 MHz) δ 152.3, 135.8 (2C), 135.7 (2C), 133.4, 132.7,
129.9, 129.8, 127.7 (2C), 127.4 (2C), 102.3, 100.2, 77.2, 72.4,
65.5, 65.3, 61.5, 60.1, 26.7 (3C), 20.0, 19.3, 15.3; LRMS m/z
(%) 442 [0.3, (M - tBu)+], 427 [1, (M - tBu - Me)+]. Anal.
Calcd for C27H37O6NSi: C, 64.90; H, 7.46; N, 2.80. Found: C,
1
64.64; H, 7.42; N, 3.12. Aceta l 13: slow moving epimer; H
NMR (CDCl3, 300 MHz) δ 7.73 (m, 2H), 7.63 (m, 2H), 7.46-
7.33 (m, 6H), 5.47 (br s, 1H), 4.99 (m, 1H), 4.89 (br s, 1H),
4.71 (br s, 1H), 4.32 (m, 1H), 3.85 (dd, J ) 8.7 Hz, J ) 7.3 Hz,
1H), 3.78-3.55 (m, 2H), 3.61 (s, 3H), 3.41 (d, J ) 8.7 Hz, 1H),
1.42 (d, J ) 5.5 Hz, 3H), 1.22 (t, J ) 7.1 Hz, 3H), 1.07 (s, 9H,
t-Bu); 13C NMR (CDCl3, 63 MHz) δ 152.4, 135.8 (2C), 135.7
(2C), 133.3, 132.6, 129.9, 129.8, 127.7 (2C), 127.4 (2C), 102.1,
99.2, 77.1, 70.2, 65.5, 65.3, 61.7, 61.4, 26.7 (3C), 19.6, 19.3,
15.1; LRMS m/z (%) 454 [0.3, (M - EtO)+], 442 [1, (M - tBu)+].
(Z)-1,6-An h yd r o-4-O-(ter t-bu tyld ip h en ylsilyl)-3-d eoxy-
3-m eth oxyim in e-2-O-(2′-br om o-p r op -2′-en yl)-â-D-a r a bin o-
h exop yr a n ose 17. NaH (60% in parafine, 18 mg, 0.44 mmol,
150 mol %) was added to a solution of alcohol 10 (125 mg, 0.29
mol) in dry DMF (2 mL) kept at 0 °C. After evolution of
hydrogen ceased, n-Bu4NI (27 mg, 0.07 mmol, 25 mol %) and
2,3-dibromopropene (71 µL, 0.58 mmol, 200 mol %) were added.
The reaction mixture was left to reach room temperature and
diluted with Et2O. Washing with saturated aqueous solutions
of NH4Cl and NaCl and drying, followed by chromatography
(AcOEt-hexane 15:85), afforded the bromide 17 (112 mg,
70%): 1H NMR (CDCl3, 500 MHz) δ 7.73 (m, 2H), 7.65 (m, 2H),
7.41 (m, 6H), 6.03 (d, J ) 1.4), 5.65 (d, J ) 1.4, 1H), 5.58 (d,
J ) 1.7, 1H), 4.91 (d, J ) 2.0, 1H), 4.48 (d, J ) 14.6, 1H), 4.41

Synthetic Intermediates for (-)-Tetrodotoxin
J . Org. Chem., Vol. 65, No. 19, 2000 5967
(m, 1H, H5), 4.06 (d, J 4-5 ) 1.5 Hz, 1H, H4), 3.75 (d, J 2-1
)
(2C), 127.4 (2C), 126.7, 101.4, 77.2, 76.4, 65.4, 74.3, 65.3, 61.6,
26.7 (3C), 19.3; LRMS m/z (%) 426 [6, (M - Ph3SnCHCHCH2)+].
(3Z,2′Z)-1,6-An h ydr o-4-O-(ter t-bu tyldiph en ylsilyl)-3-deoxy-
3-(Z)-m eth oxyim in e-2-O-(3′-tr iph en ylstan n yl-pr op-2′-en yl)-
â-D-a r a bin o-h exop yr a n ose (23b). 1H NMR (CDCl3, 300
MHz) δ 7.74-7.30 (m, 25H), 7.03 (m, 1H), 6.49 (d, J ) 12.7
Hz, 1H), 5.04 (d, J ) 1.7 Hz, 1H), 4.81 (d, J ) 1.9 Hz, 1H),
4.41 (m, 1H), 4.21 (m, 1H), 4.08 (dd, J ) 12.2 Hz, J ) 6.4 Hz,
1H), 3.94 (d, J ) 1.7 Hz, 1H), 3.56 (s, 3H), 3.64-3.52 (m, 1H),
3.30 (d, J ) 8.0 Hz, 1H), 1.03 (s, 9H); 13C NMR (CDCl3, 75
MHz) δ 151.9, 148.0, 138.8 (3C), 136.8 (6C), 135.8 (2C), 135.7
(2C), 133.4, 132.7, 129.9, 129.8, 129.0 (3C), 128.6 (6C), 127.7
(2C), 127.4 (2C), 127.6, 101.2, 77.2, 76.2, 65.3, 73.5, 65.2, 61.5,
26.8 (3C), 19.3; LRMS m/z (%) 227 [6, (M - Ph3Sn-tBuPh2-
Si)+]. (Z)-1,6-An h yd r o-4-O-(ter t-bu tyld ip h en ylsilyl)-3-d e-
oxy-3-m et h oxyim in e-2-O-(2′-t r ip h en ylst a n n yl-p r op -2′-
en yl)-â-D-a r a bin o-h exop yr a n ose 24b. 1H NMR (CDCl3, 300
MHz) δ 7.71-7.53 (m, 10H), 7.45-7.30 (m, 15H), 6.19 (d, J )
1.4 Hz, 1H), 5.57 (d, J ) 1.4 Hz, 1H), 4.87-4.76 (m, 3H), 4.37
(d, J ) 13.1 Hz, 1H), 4.20 (m, 2H), 3.57 (s, 3H), 3.53 (dd, J )
7.8 Hz, J ) 5.8 Hz, 1H), 3.33 (d, J ) 7.8 Hz, 1H), 1.06 (s, 9H).
(Z)-1,6-An h yd r o-3-d eoxy-3-m eth oxyim in e-2-O-(p r op -2′-
in yl)-â-D-a r a bin o-h exop yr a n ose (25). TBAF (1M in THF,
1.62 mL, 1.62 mmol, 110 mol %) was added to a solution of
the silyl ether 21 (688 mg, 1.48 mmol) in dry THF (18 mL),
kept under Ar at -78 °C. The cold bath was immediately
removed and the progress of the reaction was monitored by
TLC. Once the starting material was completely consumed,
the reaction mixture was concentrated, redisolved in EtOAc
and washed successively with saturated aqueous solutions of
NH4Cl and NaCl. The organic layer was dried, filtered and
concentrated. The oily residue was purified by column chro-
matography through silica gel (EtOAc-hexane, 60:40) to afford
alcohol 25 (300 mg, 89%) as a pale yellow oil: 1H NMR (CDCl3,
300 MHz) δ 5.52 (d, J ) 2.3 Hz, 1H), 4.85 (d, J ) 1.3 Hz, 1H),
4.56 (m, 1H), 4.43 (m, 3H), 3.88 (s, 3H), 3.81 (dd, J ) 8.0 Hz,
J ) 5.8 Hz, 1H), 3.63 (dd, J ) 8.0 Hz, J ) 1.2 Hz, 1H), 3.08
(br s 1H), 2.47 (t, J ) 2.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
δ 153.3, 100.6, 79.1, 76.6, 75.4, 73.2, 65.7, 64.6, 62.2, 58.3; IR
(neat) 3432 (medium, broad, OH), 2215 (weak, sharp, C + N)
cm-1; LRMS m/z (%)196 [0.4, (M - MeO)+], 188 [100, (M -
CHCCH2)+].
Cycliza tion of Alk yn e 25. A solution of Ph3SnH (0.2 mL,
0.77 mmol, 250 mol %) and Et3B (0.46 mL, 0.46 mmol, 150
mol %) in 5 mL of benzene was slowly added (syringe pump,
5 h) to a refluxing solution of 25 (70 mg, 0.31 mmol) in 31 mL
of the same solvent. Chromatography of the residue obtained
by solvent removal (EtOAc-hexane, 50:50), afforded 26 (122
mg, 68%) 27 (5 mg, 3%) and 28 (5 mg, 3%). Tetr a h yd r ofu r a n
26: 1H NMR (CDCl3, 250 MHz) δ 7.61-7.55 (m, 6H), 7.45-
7.38 (m, 9H), 6.39 (t, J ) 2.5 Hz, 1H), 6.04 (br s, 1H), 5.39 (d,
J ) 2.6 Hz, 1H), 4.66 (m, 1H), 4.60 (dd, J ) 13.4 Hz, J ) 2.5
Hz, 1H), 4.44 (dd, J ) 13.4 Hz, J ) 2.5 Hz, 1H), 4.25 (m, 1H),
3.91 (d, J ) 7.5 Hz, 1H), 3.77 (d, J ) 2.6 Hz, 1H), 3.67 (dd, J
) 7.5 Hz, J ) 5.6 Hz, 1H), 3.55 (s, 3H), 3.44 (d, J ) 4.4 Hz,
1H); 13C NMR (CDCl3, 63 MHz) δ 159.5, 137.3 (3C), 136.7 (6C),
129.3 (3C), 128.7 (6C), 116.4, 100.6, 80.1, 76.9, 68.3, 73.8, 67.5,
65.7, 62.7. IR (neat): 3422 (medium, broad, OH) cm-1; LRMS
m/z (%) 546 [0.3, (M - MeO)+], 197 [100, (M - MeO - Ph3-
Sn)+]; HRMS calcd for C28H29NO5Sn (M+) 578.964183, found
578.965235; [R]D -36.3° (c 1.07, CH2Cl2). Vin ylsta n n a n e 27:
1H NMR (CDCl3, 250 MHz) δ 7.57 (m, 6H), 7.39 (m, 9H), 6.62
(d, J ) 19.0 Hz, 1H), 6.36 (ddd, J ) 19.0,_4.9 and -_4.9 Hz,
1H), 5.56 (d, J ) 1.9 Hz, 1H), 4.91 (m, 1H, H4), 4.61-4.53 (m,
2H), 4.31 (dd, J ) 13.5 and 4.9 Hz, 1H), 4.25 (d, J ) 1.9 Hz,
1H), 3.92 (s, 3H), 3.87 (dd, J ) 8.0 and 5.8 Hz, 1H), 3.72 (dd,
J ) 8.0 and 0.9 Hz, 1H), 2.69 (s, broad, 1H); 13C NMR (CDCl3,
63 MHz) δ 153.6, 147.8, 137.9 (3C), 137.0 (6C), 129.0 (3C),
128.5 (6C), 127.2, 100.7, 76.7, 74.9, 65.0, 74.7, 65.9, 62.3; LRMS
m/z (%) 502 (4), 500 [3, (M - Ph)+], 349 [21, (Ph3Sn)+], 197
[47, (M - MeO - Ph3Sn)+], 195 [35, (PhSn)+], 188 [100, (M -
Ph3SnCHCHCH2)+]. Vin ylsta n n a n e 28: 1H NMR (CDCl3, 250
MHz) δ 7.63 (m, 6H), 7.40 (m, 9H), 6.21 (d, J ) 1.4 Hz, 1H),
5.59 (d, J ) 1.4 Hz, 1H), 4.93 (d, J ) 2.0 Hz, 1H), 4.87-4.81
(m, 2H), 4.50-4.44 (m, 2H), 4.04 (d, J ) 2.0 Hz, 1H), 3.85 (s,
2.6 Hz, 1H, H2), 3.45 (dd, J 6endo-6exo ) 7.3 Hz, 1H, H6endo),
3.35 (s, 3H, OCH3), 3.26 (dd, J 6exo-6endo ) 7.3 Hz, J 6exo-5 ) 5.8
Hz, 1H, H6exo), 1.45 (m, 6H, (CH3CH2CH2CH2)3Sn), 1.29 (m,
6H, (CH3CH2CH2CH2)3Sn), 1.09 (s, 9H, t-Bu), 0.88 (m, 15H,
(CH3CH2CH2CH2)3Sn); 13C NMR (CDCl3, 75 MHz) δ 156.4 (C8),
136.3 (Ar, 2C, Co), 136.0 (Ar, 2C, Co), 134.0 (Ar, Ci), 132.0 (Ar,
Ci), 130.0 (Ar, Cp), 129.8 (Ar, Cp), 127.6 (Ar, 4C, Cm), 119.8
(C9), 101.0 (C1), 81.1 (C2), 76.6 (C5), 73.8 (C7), 70.7 (C4), 67.3
(C3), 65.3 (C6), 62.3 (OCH3), 29.1 (3C, CH3CH2CH2CH2)3Sn),
27.2 (3C, CH3CH2CH2CH2)3Sn), 26.9 (C(CH3)3), 19.5 (C(CH3)3),
13.6 (3C, CH3CH2CH2CH2)3Sn), 9.6 (3C, CH3CH2CH2CH2)3Sn);
IR (neat) 3248 (medium, sharp, NH) cm-1; LRMS m/z (%) 697
[5, (M - tBu)+]; HRMS calcd for C38H59NO5SiSn (M+ + H)
757.329039, found 757.325799; [R]D -65° (c 1.15, CH2Cl2).
(3Z,2′E)-23a : 1H NMR (CDCl3, 300 MHz) δ 7.73 (m, 2H), 7.64
(m, 2H), 7.41 (m, 6H), 6.29 (d, J ) 19.1 Hz, 1H), 6.13 (ddd, J
) 19.1 Hz, J ) 5.7 Hz, J ) 4.5 Hz, 1H), 5.56 (d, J ) 1.8 Hz,
1H), 4.91 (d, J ) 2.2 Hz, 1H), 4.44 (ddd, J ) 12.8 Hz, J ) 4.5
Hz, J ) 1.2 Hz, 1H), 4.41 (d, J ) 1.8 Hz, 1H), 4.30 (m, 1H),
4.14 (ddd, J ) 12.8 Hz, J ) 5.7 Hz, J ) 0.9 Hz, 1H), 3.66 (s,
3H), 3.63 (dd, J ) 8.0 Hz, J ) 5.7 Hz, 1H), 3.42 (dd, J ) 8.0
Hz, J ) 1.0 Hz, 1H), 1.50 (m, 6H), 1.31 (m, 6H), 1.07 (s, 9H),
0.90 (m, 15H); 13C NMR (CDCl3, 75 MHz) δ 152.3, 144.4, 135.9
(2C), 135.7 (2C), 133.5, 132.7, 132.2, 129.9, 129.8, 127.7 (2C),
127.5 (2C), 101.5, 77.2, 75.7, 74.9, 65.4, 65.37, 61.5, 29.1 (3C),
27.3 (3C), 26.7 (3C), 19.3, 13.7 (3C), 9.6 (3C); IR (neat): 1588
(weak, sharp, CdN) cm-1; LRMS m/z (%) 697 [4, (M - tBu)+].
(3Z,2′Z)-23a : 1H NMR (CDCl3, 300 MHz) δ 7.74 (m, 2H), 7.65
(m, 2H), 7.41 (m, 6H), 6.63 (ddd, J ) 13.0 Hz, J - J - 6.3 Hz,
1H), 6.13 (d, J ) 13.0 Hz, 1H), 5.55 (d, J ) 1.7 Hz, 1H), 4.90
(d, J ) 2.1 Hz, 1H), 4.42 (m, 1H), 4.39 (d, J ) 1.7 Hz, 1H),
4.28 (m, 1H), 4.14 (m, J ) 12.1 Hz, J ) 6.3 Hz, J ) 1.0 Hz,
1H), 3.68 (s, 3H), 3.62 (dd, J ) 7.9 Hz, J ) 5.7 Hz, 1H), 3.40
(dd, J ) 7.9 Hz, J ) 1.0 Hz, 1H), 1.51 (m, 6H), 1.30 (m, 6H),
1.08 (s, 9H), 0.90 (m, 15H). (Z)-1,6-An h yd r o-4-O-(ter t-
bu tyldiph en ylsilyl)-3-deoxy-3-m eth oxyim in e-2-O-(2′-tr ibu -
t y ls t a n n y l-p r o p -2′-e n y l)-â-D -a r a b in o -h e x o p y r a n o s e
(24a ): 1H NMR (CDCl3, 300 MHz) δ 7.74 (m, 2H), 7.65 (m,
2H), 7.42 (m, 6H), 5.97 (d, J ) 2.4 Hz, 1H), 5.53 (d, J ) 1.7
Hz, 1H), 5.33 (d, J ) 2.4 Hz, 1H), 4.92 (d, J ) 2.1 Hz, 1H),
4.59 (dd, J ) 13.1 Hz, J ) 1.5 Hz, 1H), 4.39 (d, J ) 1.7 Hz,
1H), 4.30 (m, 1H), 4.23 (d, J ) 13.1 Hz, 1H), 3.65 (s, 3H), 3.61
(dd, J ) 8.0 Hz, J ) 5.8 Hz, 1H), 3.41 (dd, J ) 8.0 Hz, J ) 0.9
Hz, 1H), 1.53 (m, 6H), 1.30 (m, 6H), 1.08 (s, 9H), 0.87 (m, 15H).
Cycliza tion of Alk yn e 21 w ith P h 3Sn H-Et3B. A solution
of Ph3SnH (226 mg, 0.64 mmol, 300 mol %) and Et3B (0.32
mL, 0.32 mmol, 150 mol %), in 2 mL of benzene was slowly
added (syringe pump, 3 h) to a refluxing solution of alkyne 21
(100 mg, 0.21 mmol) in 22 mL of the same solvent. After
refluxing for additional 5.5 h, the solvent was removed and
the residue purified by column chromatography through silica
gel, to afford 22b (72 mg, 41%), (3Z,2′Z)-23b (14 mg, 8%) and
(3Z,2′E)-23b (49 mg, 28%) and 24b (5 mg, 3%). O-Meth yl-
h yd r oxyla m in e 22b: 1H NMR (CDCl3, 300 MHz) δ 7.90 (m,
4H), 7.63-7.35 (m, 21H), 6.69 (br s, 1H), 6.03 (t, J ) 2.4 Hz,
1H), 5.40 (d, J ) 2.5 Hz, 1H), 4.58 (dd, J ) 13.3 Hz, J ) 2.4
Hz, 1H), 4.48 (dd, J ) 13.3 Hz, J ) 2.4 Hz, 1H), 4.31 (m, 1H),
4.15 (br s, 1H), 3.78 (d, J ) 2.5 Hz, 1H), 3.60 (d, J ) 7.5 Hz,
1H), 3.39 (s, 3H), 3.34 (dd, J ) 7.5 Hz, J ) 5.8 Hz, 1H), 1.13
(s, 9H); 13C NMR (CDCl3, 75 MHz) δ 160.2, 137.5 (3C), 136.8
(6C), 136.3 (2C), 136.0 (2C), 133.8, 131.9, 130.1, 129.8, 129.2
(3C), 128.7 (6C), 127.7 (2C), 127.6 (2C), 115.9, 100.9, 81.0, 76.6,
74.1, 70.6, 67.9, 65.4, 62.4, 26.9 (3C), 19.4; LRMS m/z (%) 349
[39, (Ph3Sn)+], 196 [16, (M - Ph3Sn - tBuPh2Si - MeO)+];
HRMS calcd for
C
44H47NO5SiSn (M+) 816.248642, found
816.246401; [R]D 226.6° (c 1.72, CH2Cl2). (3Z,2′E)-23b: 1H
NMR (CDCl3, 300 MHz) δ 7.76-7.34 (m, 25H), 6.62 (d, J )
19.0 Hz, 1H), 6.38 (ddd, J ) 19.0 Hz, J ) 5.0 Hz, J ) 4.2 Hz,
1H), 5.58 (s, 1H), 4.93 (d, J ) 1.6 Hz, 1H), 4.58 (dd, J ) 13.5
Hz, J ) 4.2 Hz, 1H), 4.43 (s, 1H), 4.32 (m, 1H), 4.24 (dd, J )
13.5 Hz, J ) 5.0 Hz, 1H, H7), 3.64 (s, 3H), 3.67-3.62 (m, 1H),
3.43 (d, J ) 7.9 Hz, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 75
MHz) δ 152.2, 148.1, 138.0 (3C), 137.0 (6C), 135.8 (2C), 135.7
(2C), 133.4, 132.7, 129.9, 129.8, 129.0 (3C), 128.5 (6C), 127.7

5968 J . Org. Chem., Vol. 65, No. 19, 2000
Noya et al.
3H), 3.78 (dd, J ) 7.9 and 5.9 Hz, 1H), 3.61 (d, J ) 7.9 Hz,
1H), 2.04 (d, J ) 6.2 Hz, 1H); 13C NMR (CDCl3, 63 MHz) δ
153.3, 149.0, 137.9 (3C), 137.2 (6C), 129.6, 128.9 (3C), 128.4
(6C), 100.4, 77.1, 76.5, 74.3, 64.7, 65.7, 62.2; LRMS m/z (%)
502 (18), 500 [14, (M - Ph)+], 462 [24, (M - Ph - MeO)+], 349
[75, (Ph3Sn)+], 272 [12, (Ph2Sn)+], 197 [81, (M - MeO - Ph3-
Sn)+], 195 [60, (PhSn)+].
(Z)-1,6-An h yd r o-2-O-(1′-et h oxy-2′-iod oet h yl)-3-d eoxy-
3-m eth oxyim in e-â-D-a r a bin o-h exop yr a n ose (29). It was
prepared from iodoacetals 11 (5.53 g, 8.84 mmol) and TBAF
(1 M in THF, 9.72 mL, 9.72 mmol, 110 mol %) in dry THF
(100 mL), as described for 25. Purification (EtOAc-hexane,
50:50) afforded iodoacetals 29 (3.24 g, 95%): 1H NMR (CDCl3,
300 MHz) δ 5.48 (d, J ) 2.3 Hz, 1H), 5.45 (d, J ) 2.2 Hz, 1H),
4.90 (m, 2H), 4.85 (m, 2H), 4.57 (m, 2H), 4.46 (br s, 2H), 3.90
(s, 3H), 3.89 (s, 3H) 3.85-3.18 (m, 12H), 3.07 (br s, 2H), 1.20
(t, J ) 7.0 Hz, 3H), 1.19 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 153.2, 153.0, 102.5, 101.8, 101.1, 100.9, 76.6, 72.3,
64.8, 76.6, 69.9, 64.8, 65.8 (2C), 62.9, 62.4, 62.2, 61.7, 14.9,
14.7, 5.0, 4.8.
Aceta l 30. A deoxygenated solution of Ph3SnH (3.1 mL, 12.2
mmol, 140 mol %) and AIBN (411 mg, 2.5 mmol, 30 mol %) in
25 mL of dry toluene was slowly added (syringe pump, 8 h) to
a deoxygenated and preheated (100 °C) solution of the iodoac-
etals 29 (3.23 g, 8.34 mmol) in 334 mL of the same solvent.
The reaction was concentrated and the residue was redissolved
in CH2Cl2 and treated with 10% aqueous KF. After vigorous
stirring for 15 min, the solid was removed by filtration, the
phases were separated and the aqueous layer extracted with
CH2Cl2. The combined organic extracts were dried, filtered and
concentrated in vacuo obtaining an oil which was purified
through silica gel (EtOAc-hexane, 75:25). Cyclic acetals 30
were obtained as colorless oils in 58% yield (1.26 g). F a st
m ovin g ep im er : 1H NMR (CDCl3, 300 MHz) δ 6.15 (br s,
1H), 5.35 (d, J ) 2.8 Hz, 1H), 5.27 (d, J ) 5.9 Hz, 1H), 4.64
(m, 1H), 4.16 (m, 1H), 3.82-3.69 (m, 5H), 3.58 (s, 3H), 3.54-
3.45 (m, 1H), 2.58 (d, J ) 13.7 Hz, 1H), 1.87 (dd, J ) 13.7 Hz,
J ) 5.9 Hz, 1H), 1.21 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3, 75
MHz) δ 103.9, 99.5, 78.4, 77.2, 69.0, 66.4, 65.2, 63.6, 61.5, 38.8,
15.2; LRMS m/z (%) 261 [0.2, (M)+], 215 [100, (M - MeONH)+];
HRMS calcd for C11H19NO6 (M+) 261.121238, found 261.121835;
[R]D 65° (c 1.93, CH2Cl2). Slow m ovin g ep im er : 1H NMR
(CDCl3, 300 MHz) δ 6.15 (br s, 1H), 5.39 (m, 2H), 4.62 (m, 1H),
3.94-3.73 (m, 4H), 3.66-3.44 (m, 1H), 3.58 (s, 3H), 3.40 (d, J
) 2.8 Hz, 1H), 3.34 (br s, 1H), 2.56 (dd, J ) 13.3 Hz, J ) 5.2
Hz, 1H), 1.72 (dd, J ) 13.3 Hz, J ) 7.0 Hz, 1H), 1.22 (t, J )
7.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ 105.1, 99.7, 78.1,
77.4, 70.0, 67.7, 65.7, 65.1, 63.2, 39.5, 15.3; LRMS m/z (%) 261
[1, (M)+].
removed and the reaction was allowed to warm to room
temperature. A saturated aqueous solution of NH4Cl was
added and the aqueous layer was extracted with CH2Cl2. The
combined organic extracts were washed with 10% aqueous
CuSO4, dried, filtered and concentrated in vacuo. Purification
of the crude mixture (EtOAc-hexane, 70:30) afforded 32 (1:1
mixture of epimers, 801 mg, 86%) as a white solid (mp ) 121
°C): 1H NMR (CDCl3, 250 MHz) δ 5.45 (d, J ) 3.1 Hz, 1H),
5.38 (d, J ) 3.0 Hz, 1H), 5.32 (m, 1H), 5.27 (dd, J ) 5.9 Hz, J
) 0.9 Hz, 1H), 4.70 (m, 2H), 4.38 (br s, 1H), 4.32 (br s, 1H),
4.24 (d, J ) 3.0 Hz, 1H), 4.02 (d, J ) 3.1 Hz, 1H), 3.85 (s, 3H),
3.83 (s, 3H), 3.92-3.70 (m, 6H), 3.59-3.36 (m, 2H), 2.51 (dd,
J ) 13.9 Hz, J ) 5.1 Hz, 1H), 2.37 (dd, J ) 14.5 Hz, J ) 0.9
Hz, 1H), 2.23 (dd, J ) 14.5 Hz, J ) 5.9 Hz, 1H), 2.05 (dd, J )
13.9 Hz, J ) 6.1 Hz, 1H), 1.17 (t, J ) 7.0 Hz, 3H), 1.15 (t, J )
7.1 Hz, 3H); 13C NMR (CDCl3, 63 MHz) δ 156.4, 155.6, 104.1,
103.4, 98.3, 98.2, 77.4, 75.5, 73.2, 77.3, 75.2, 73.1, 67.0, 66.6,
65.1, 64.9, 64.9, 64.6, 64.8, 63.1, 44.7, 41.8, 15.0, 14.9; IR (neat)
1783 (strong, sharp, NCOO) cm-1; LRMS m/z (%) 288 [2, (M
+ 1)+], 287 [13, (M)+]; HRMS m/z C12H17NO7 calcd: 287.1005,
found 287.1003.
La cton e 33. J ones reagent (4 mL, prepared from 2 g of CrO3
in 4 mL of water and 2 mL of H2SO4) was added to a mixture
of acetals 32 (232 mg, 0.81 mmol) in 2.7 mL of acetone. A few
drops of 2-propanol were added and the mixture was neutral-
ized with saturated aqueous NaHCO3. The aqueous layer was
extracted with CH2Cl2 and the organic extracts were dried,
filtered and concentrated. Purification of the crude residue
(EtOAc-hexane, 65:35) afforded 33 as a white solid (168 mg,
80%, mp ) 230-231 °C): 1H NMR (CD3CN, 300 MHz) δ 5.54
(d, J ) 2.5 Hz, 1H), 4.87 (m, 1H), 4.63 (br s, 1H), 4.55 (d, J )
2.5 Hz, 1H), 4.06 (d, J ) 9.0 Hz, 1H), 3.86 (s, 3H), 3.80 (dd, J
) 9.0 Hz, J ) 5.4 Hz, 1H), 3.02 (d, J ) 19.2 Hz, 1H), 2.93 (d,
J ) 19.2 Hz, 1H); 13C NMR (CD3CN, 75 MHz) δ 173.2, 156.0,
97.3, 77.8, 73.7, 65.7, 65.5, 64.4, 37.0; IR (neat): 1784 (strong,
sharp, 2 × COO) cm-1; LRMS m/z (%) 257 [10, (M)+]; HRMS
m/z C10H11NO7 calcd: 257.0535, found: 257.0538. Anal. calcd
for C11H11NO7: C, 46.70; H, 4.31; N, 5.44. Found: C, 46.72;
H, 4.76; N, 5.48.
r-Meth ylen ela cton e 34. NaH (60% in parafine, 78 mg,
1.96 mmol, 120 mol %) was added to a mixture of lactone 33
(420 mg, 1.63 mmol) and paraformaldehyde (490 mg, 16.33
mmol, 1000 mol %) in 25 mL of dry THF. Additional NaH (50
mol %) and heating to 45 °C were needed to completely
consume 33. Saturated aqueous NH4Cl was added and the
mixture was extracted with CH2Cl2. The combined extracts
were dried, filtered and concentrated. Chromatography through
silica gel (EtOAc-hexane, 60:40) gave R-methylenelactone 34
as a white solid (355 mg, 81%, mp ) 218EC): 1H NMR (CD3-
CN, 250 MHz) δ 6.71 (br s, 1H), 6.44 (d, J ) 1.0 Hz, 1H), 5.56
(d, J ) 2.6 Hz, 1H), 4.87 (m, 1H), 4.70 (m, 2H), 3.77-3.70 (m,
1H), 3.70 (s, 3H), 3.66 (dd, J ) 8.7 Hz, J ) 1.1 Hz, 1H); 13C
NMR (CD3CN, 75 MHz) δ 168.0, 155.5, 134.6, 130.2, 97.2, 76.0,
Ald eh yd e 31. Powdered molecular sieves 3A (75 mg,
activated) and a solution of methylentetrahydrofurane 22a (51
mg, 0.072 mmol) in dry CH2Cl2 (0.5 mL) were added to a
suspension of CrO3 (143 mg, 1.43 mmol, 2000 mol %) in dry
pyridine (0.14 mL) and dry CH2Cl2 (1.5 mL) previously stirred
at room temperature for 30 min. The resulting mixture was
refluxed and, when finished (TLC), filtered and washed with
saturated NaHCO3. The aqueous layer was extracted with
CH2Cl2, the combined organic extracts washed with 2 N HCl,
dried, filtered and concentrated. p-TLC (EtOAc-hexane, 16:
84) of the residue so obtained afforded R,â-unsaturated alde-
hyde 31 (9 mg, 29%): 1H NMR (CDCl3, 300 MHz) δ 8.83 (s,
1H), 7.71 (m, 2H), 7.65 (m, 2H), 7.43 (m, 6H), 5.56 (d, J ) 1.6
Hz, 1H), 5.09 (m, 1H), 4.82-4.65 (m, 4H), 3.72 (dd, J ) 8.0
75.4, 73.3, 65.7, 65.6, 63.5; IR (neat) 1777 (strong, sharp) cm-1
;
LRMS m/z (%) 270 [1, (M + 1)+], 269 [27, (M)+]; HRMS calcd
for C11H11NO7 (M+) 269.053552, found 269.054059; [R]D -110.1°
(c 0.85, CH2Cl2).
Ack n ow led gm en t. We thank the Xunta de Galicia
and the DGES for funding this work through projects
XUGA 20902B97, PB95-0824 and PB98-0606. Grants
from the Xunta de Galicia are gratefully acknowledged
by M.D.P. and L.O.V., and a grant from the Fundacio´n
Bene´fico-Docente Segundo Gil Da´vila by M.D.P.
Hz, J ) 5.7 Hz, 1H), 3.36 (d, J ) 8.0 Hz, 1H), 1.09 (s, 9H); 13
C
NMR (CDCl3, 75 MHz) δ 183.9, 149.9, 137.1, 135.8 (2C), 135.6
(2C), 132.5, 132.2, 130.6, 130.4, 128.1 (2C), 128.0 (2C), 102.9,
86.1, 78.2, 67.9, 74.4, 66.5, 26.7 (3C), 19.3; IR (neat) 1676
(strong, sharp, CO) cm-1; LRMS m/z (%) 437 [0.1, (M + 1)+],
436 [1, (M)+]. HRMS m/z C25H28O5Si calcd: 436.1706, found:
436.1706.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
compounds 4, 6, 11, 15, 17, 19, 21, 22a , 22b, 25, 26, and 29-
34. This material is available free of change via the Internet
at http://pubs.acs.org.
Ur eth a n e 32. A solution of triphosgene (483 mg, 1.62 mmol,
50 mol %) in dry CH2Cl2 (10 mL) was added dropwise at -78
°C to a solution of amino alcohols 30 (1:1 epimeric mixture,
850 mg, 3.25 mmol) and pyridine (1.93 mL, 19.52 mmol, 600
mol %) in the same solvent (16.3 mL). The cold bath was
J O000325Y