Armed/disarmed effects and adamantyl expansion of some caged tricyclic acetals en route to tetrodotoxin

Article abstract of DOI:10.1021/jo951747o

Transformation of the previously prepared tricyclic ketone 4 into an advanced intermediate, 2a, of the Kishi-Goto synthesis of tetrodotoxin requires, among other things, cleavage of the internal acetal. In our attempts to carry this out, we were confronted by two major obstacles, one resulting from armed/disarmed effects encountered during acid-catalyzed acetolyses. Thus ester protecting groups proximal to the acetal moiety inhibited cleavage, e.g., 4 → 8a and 7 → 8b. Although the corresponding ether analogs 9a and 9b did undergo acetolysis, the products obtained, 10a and 10b, respectively, revealed the second obstacle, namely the proclivity of the caged systems to undergo adamantyl expansion. The latter result was found to depend upon the presence of properly positioned nucleophilic substituents. Thus 11b underwent adamantyl expansion to 12b but its C7 epimer 15 experienced facile cleavage to bicyclic product 16. As an alternative to solvolysis for cleavage of the internal acetal, reductive elimination was examined. For example, compound 28a, obtained from 4 by standard procedures, reacted with zinc to give, after protection and saponification, γ,δ unsaturated carboxylic acid 29a, which underwent smooth iodolactonization. Replacing the iodide of this product with an hydroxyl (32a → 32b) by a free radical process has succeeded albeit in disappointing yield. Nevertheless the resulting hydroxy lactone is a promising synthon of the advanced Kishi-Goto intermediate.

Full text of DOI:10.1021/jo951747o

J . Org. Chem. 1996, 61, 1609-1618
1609
Ar m ed /Disa r m ed Effects a n d Ad a m a n tyl Exp a n sion of Som e Ca ged
Tr icyclic Aceta ls en Rou te to Tetr od otoxin 1,2
Christopher S. Burgey,3a Roland Vollerthun,3b and Bert Fraser-Reid*
Paul M. Gross Chemical Laboratory, Duke University, Department of Chemistry,
Durham, North Carolina 27708
Received September 25, 1995X
Transformation of the previously prepared tricyclic ketone 4 into an advanced intermediate, 2a , of
the Kishi-Goto synthesis of tetrodotoxin requires, among other things, cleavage of the internal
acetal. In our attempts to carry this out, we were confronted by two major obstacles, one resulting
from armed/disarmed effects encountered during acid-catalyzed acetolyses. Thus ester protecting
groups proximal to the acetal moiety inhibited cleavage, e.g., 4 f 8a and 7 f 8b. Although the
corresponding ether analogs 9a and 9b did undergo acetolysis, the products obtained, 10a and
10b, respectively, revealed the second obstacle, namely the proclivity of the caged systems to undergo
adamantyl expansion. The latter result was found to depend upon the presence of properly
positioned nucleophilic substituents. Thus 11b underwent adamantyl expansion to 12b but its C7
epimer 15 experienced facile cleavage to bicyclic product 16. As an alternative to solvolysis for
cleavage of the internal acetal, reductive elimination was examined. For example, compound 28a ,
obtained from 4 by standard procedures, reacted with zinc to give, after protection and saponification,
γ,δ unsaturated carboxylic acid 29a , which underwent smooth iodolactonization. Replacing the
iodide of this product with an hydroxyl (32a f 32b) by a free radical process has succeeded albeit
in disappointing yield. Nevertheless the resulting hydroxy lactone is a promising synthon of the
advanced Kishi-Goto intermediate.
In tr od u ction
As part of our program for preparing densely function-
alized natural products from carbohydrate precursors,11
we are exploring a synthetic route to tetrodotoxin,12,13 and
in this paper we describe some pertinent developments.
Tetrodotoxin4 is fascinating for several reasons includ-
ing its awesome toxicity,5 value as a biological tool,6
beguiling folklore,7 and unique architecture.8 The last
item, by itself, provides enough impetus to attempt its
synthesis; however, in spite of constant effort,9 the
molecule has succumbed only once, this being the land-
mark 1972 accomplishment of the Kishi-Goto group.10
Retr osyn th etic Con sid er a tion s
We recently reported upon the preparation of caged
molecule 4 in nine steps and 35% yield from 1,6-anhydro-
4-O-(tert-butyldiphenylsilyl)-â-D-mannopyranose, 312
(Scheme 1). Compound 2a is an advanced intermediate
in the Kishi-Goto synthesis,10 and retron 2b establishes
its relationship to our synthetic intermediate 4. Two
basic operations on precursor 4 are required to obtain
synthon 2: (i) introduction of a properly functionalized
two-carbon entity at C8 and (ii) cleavage of the internal
acetal. Operations (i) and (ii) could conceivably be carried
out in either order, but because of the well-known
difficulties of cleaving internal acetals,14 we decided to
address operation (ii) first.
Cleavage of 4 could be effected at A by a solvolytic
process to give 5, or at B by an elimination process to
give 6. Ideally, option A would be preferable since C6
would retain its oxygen functionality, a valuable imple-
ment for future manipulations. Much attention was
therefore devoted to attempts at acetolysis, and the
results have been educational in emphasizing the power-
X Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) This project was supported by grants from NIH (GM 51237) and
NSF (9311356).
(2) Presented in part by C.S.B. at the Hong Kong International
Symposium on Heterocyclic Chemistry, August 1995.
(3) (a) C.S.B.: Synthetic Organic Chemistry Graduate Fellowship
Awardee of the Burroughs Wellcome Fund, 1992-1993. (b) R.V.:
Feodor Lynen Fellowship from the Alexander von Humboldt Founda-
tion, 1992-1993.
(4) Tetrodotoxin, Saxitoxin and the Molecular Biology of the Sodium
Channel. Ann. N.Y. Acad. Sci. 1986, 479, 1-448. Mosher, H. S.;
Fuhran, F. A. In Seafood Toxins; Ragelis, E. P., Ed.; ACS Symposium
Series 262; American Chemical Society: Washington, DC, 1986; pp
334-344. Kotaki, Y.; Shimizu, Y. J . Am. Chem. Soc. 1993, 115, 827.
(5) Hucho, F. Angew. Chem., Int. Ed. Engl. 1995, 34, 39. Becker,
S.; Gordon, R. D. Handbook Exp. Pharmocol. 1992, 102, 719. Lazdun-
ski, M.; Renead, J . F. Annu. Rev. Physiol. 1982, 44, 463. Sutherland,
S. K. In Australian Animal Toxins; Oxford University Press: Oxford,
U.K., 1983. Sheumack, D. D; Howden, M. E. H.; Spencer, I.; Quinn, R.
J . Science 1978, 199, 188.
(6) Booth, W. Science 1989, 240, 274. Davis, W. Science 1989, 240,
1715.
(7) Davis, W. The Serpent and the Rainbow; Simon and Schuster:
New York, 1985.
(8) Woodward, R. B. Pure Appl. Chem. 1964, 9, 49. Goto, T.; Kishi,
Y.; Takahashi, S.; Hirata, Y. Tetrahedron 1965, 21, 2059. Tsuda, K.;
Ikuma, S.; Kawamura, M.; Tachikawa, R.; Sakai, K.; Tamura, C.;
Amakasu, O. Chem. Pharm. Bull. J pn. 1963, 11, 1473.
(9) (a) For R. B. Woodward’s approach, see: Fraser-Reid, B.;
Anderson, R. C. Prog. Chem. Org. Nat. Prod. 1980, 39, 1. (b) Yamamoto,
N.; Nishikawa, T.; Isobe, M. Synlett 1995, 505 and references therein.
(c) Sato, K.; Nagai, Y.; Kajihara, Y.; Nakamura, Y.; Bokura, M.;
Yoshimura, J . Abstracts of XVIIth International Carbohydrate Sym-
posium, Ottawa, 1994, Abstract B1.70. Sato, K.; Kajihara, Y.; Naka-
mura, Y.; Yoshimura, J . Chem. Lett. 1991, 1559 and references therein.
(d) Keana, J . F. W.; Bland, J . S.; Boyle, P. J .; Erion, M.; Hartling, R.;
Husman, J . S.; Roman, R. B.; Ferguson, G.; Parvez, M. J . Org. Chem.
1983, 48, 3621, 3627.
(10) Kishi, Y.; Fukuyama, T.; Aratani, M.; Nakatsubo, F.; Goto, T.;
Inoue, S.; Tanino, H.; Sugiura, S.; Kakoi, H. J . Am. Chem. Soc. 1972,
94, 9217, 9219 and references therein.
(11) McDevitt, R. E.; Fraser-Reid, B. J . Org. Chem. 1994, 59, 3250.
Gomez, A. M.; Lopez, J . C.; Fraser-Reid, B. J . Org. Chem. 1994, 59,
4048.
(12) 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.
(13) Burgey, C. S.; Vollerthun, R.; Fraser-Reid, B. Tetrahedron Lett.
1994, 35, 2637.
(14) Hall, H. K., J r.; DeBlauwe, Fr. J . Am. Chem. Soc. 1975, 97,
655. Cerny, M.; Stanek, J . Adv. Carbohydr. Chem. Biochem. 1977, 34,
24. Cerny, M.; Pacak, J .; Stanek, J . Collect. Czech. Chem. Commun.
1965, 30, 1151. Carlson L. J . J . Org. Chem. 1965, 30, 3953.
0022-3263/96/1961-1609$12.00/0 © 1996 American Chemical Society

1610 J . Org. Chem., Vol. 61, No. 5, 1996
Burgey et al.
Sch em e 1
17b in their reactions to give the thioenols 18a and 18b,
respectively. In all of the examples in Table 1, the benzyl
ether derivatives not only reacted faster than the acety-
lated analogues but also gave better yields.
In the case of thioketal 17a there appears to be
competition between the acetal and the thioacetal for Ac+.
This idea gained support from isolation of a vinyl sulfide
1
identified as I on the bases of its (a) H NMR and mass
spectra and (b) conversion into 18a by further acetoly-
sis.16
The results in Table 1 may be summarized as depicted
in Scheme 2 which, in turn, are based upon our ration-
alizations of the armed/disarmed effect in glycoside
hydrolysis.17 Thus it may be assumed that solvolysis of
the tricyclic acetal II proceeds via acetyl oxonium ion III
and then to oxocarbenium ion IV. An electron-withdraw-
ing group at C7 and/or C2 (i.e., R′ ) EWG) deters
progress of the reaction by a combination of early and
late transition state effects, first, by draining electron
density from O6, thereby inhibiting the formation of III,
and subsequently by disfavoring the incipient oxocar-
benium ion IV which is expected to be destablized when
R′ ) Ac.
When Y is non-nucleophilic, bicyclic products are
obtained which result from elimination (e.g., 14) or
intermolecular trapping of the oxocarbenium ion IV by
acetate (16 and 18). However, the process of adamantyl
expansion (IV f VII) is favored when substituent Y is
nucleophilic, as in the C7(R) benzyl ether 11b (Table 1).
For the trigonal substrates 9a and 9b, the expansion
reaction may be envisaged as the synchronous Prins-like
process depicted in VI.
ful influence (i.e., armed/ disarmed effects)15 that protect-
ing groups can have upon this cleavage reaction and,
furthermore, in sensitizing us to the threatening specter
of adamantyl expansion in manipulating these densely-
functionalized systems (vide infra).
Acetolysis Rea ction s
We first applied solvolytic conditions using triethylsilyl
trifluoromethanesulfonate and acetic anhydride that had
been demonstrated previously in our laboratory. Thus
as indicated in Table 1, acetolysis of disarmed ketone 4
and its methylene counterpart 7 failed to produce 8a or
8b, respectively, which would have resulted from cleav-
age of their 1,6-anhydro rings. By contrast, when the
ester protecting groups were replaced with benzyl ethers
as in 9a and 9b, the resulting disarmed species under-
went cleavage. However the products were the adaman-
tane-like structures 10a and 10b, respectively.
Armed/disarmed effects were also evident in the ace-
tolyses of the protected carbinols obtained by reducing
ketones 4 and 9a . Although the 7R triacetate and
tribenzyl derivatives 11a and 11b were both solvolyzed
to give adamantane-like structures 12a and 12b, respec-
tively, the triacetate reacted 240 times slower than the
tribenzyl analog. A substantial rate difference was also
observed with the 7S counterparts 13 and 15, even
though the products were the bicyclic species 14 and 16,
respectively. Dramatic rate differences were also ob-
served between the armed/disarmed thioketals 17a and
Elim in a tion Rea ction s
The results in Table 1 and Scheme 2 clearly discour-
aged pursuit of the acetolysis route (path A, Scheme 1).
The elimination alternative (path B, Scheme 1) requires
an amenable synthon at C7. The approach in Scheme 3
was adopted in which a â-elimination process to cleave
bond B was envisaged. Accordingly, it was necessary to
replace the acetyl groups of 4 with benzyl ethers. The
benzylation step in the conversion of 4 into 9a proved to
be most demanding, requiring specific reaction conditions
in order to avoid formation of side products (see Experi-
mental Section). The Levine reagent18 was used to
provide enol ether 19 as a mixture of E/Z isomers.
Treatment with dilute hydrochloric acid at elevated
temperature produced R-enal 20a in virtually quantita-
tive yield, and PMB glycosidation afforded 20b. The path
(16) Transformations similar to 17a f I have been observed for
other thioketals.
(17) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J . Org.
Chem. 1990, 55, 6068.
(18) (a) Levine, S. G. J . Am. Chem. Soc. 1958, 80, 6150. (b)
Earnshaw, C.; Wallis, C. J .; Warren, S. J . J . Chem. Soc., Chem.
Commun. 1977, 314 and references therein.
(15) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J .
Am. Chem. Soc. 1988, 110, 5583.

Caged Tricyclic Acetals en Route to Tetrodotoxin
J . Org. Chem., Vol. 61, No. 5, 1996 1611
Ta ble 1. Acetolysis of Som e Ar m ed a n d Disa r m ed
Tr icyclic Aceta lsa
Sch em e 2
of the â-elimination route 4 f 19 f 20. The alternative
of reductive elimination promised to be more expedient.
The use of zinc or samarium(II) iodide19 was appealing,
and a model experiment with the latter reagent was
performed on ketone 4 (Scheme 4). Thus with 4 equiv of
samarium(II) iodide and ketone 4, the product proved to
be dioxaadamantane 25a , similar to 10a already encoun-
tered in Table 1. This result implied the intermediacy
of samarium enolate 24, but attempts at trapping with
various electrophiles failed, as did attempts to hydrolyze,
reduce, or oxidize 25a to a bicyclic species.
These model studies indicated that a C7 carbonyl group
was undesirable, in that its presence invariably led to
stable, adamantane-like tricyclic structures. Replace-
ment with an iodide would still permit the use of
samarium(II) iodide and/or zinc, and hence compound 4
was processed with this in mind (Scheme 5).
In order to avoid products such as 23, a nonanionic
procedure for C8-alkylation was required, and the Keck
reaction20 was applied. Thus bromination of 4 with
pyridinium bromide perbromide followed by reaction with
allyltributyltin gave 26a and its C8-epimer as a 4:1
mixture in 57% overall yield. Assignment of the major
product as 26a was based on the observation of an NOE
(14%) between H4 and H8 (Scheme 5). Reduction of the
a
Yields are not optimized.
chosen for installing the C6 oxygen proceeded via allylic
alcohol 20c to epoxy alcohol 21a , which was converted
into iodo epoxide 21b. All of these transformations
proceeded in excellent yields, as did the succeeding steps
of reductive elimination to 22a , silylation to 22b , and
finally ozonolysis to 22c.
The next requirement was a 2-carbon entity at C8, and
an allyl group seemed a promising synthon. However
attempts at alkylating 22c by use of 6 equiv of LDA
resulted in allylated acetamide 23 as the only isolable
product. A nonanionic procedure was evidently required
for C8 allylation, and it seemed best to address this issue
as early as possible into the synthesis.
(19) Pratt, D. K.; Hopkins, B. P. Tetrahedron Lett. 1987, 28, 3065.
Hanessian, S.; Girard, C.; Chiara, J . L. Tetrahedron Lett. 1992, 33,
573. Enholm, E. J .; J iang, S. Hetereocycles 1992, 34, 2244.
(20) Keck, G. E.; Yates, J . B. J . Am. Chem. Soc. 1982, 104, 5829.
Keck, G. E.; Enholm, E. J .; Yates, J . B; Wiley, M. R. Tetrahedron 1985,
41, 4079.
We therefore needed to retool our strategy, and in so
doing we were mindful of another problem, viz. the length

1612 J . Org. Chem., Vol. 61, No. 5, 1996
Burgey et al.
Sch em e 3
Sch em e 4
Iodolactonization was an alternative for installing the
properly oriented C7-OH; but when the process was
applied to ester 29b, iodohydrin 31 (structure not as-
signed) was the only outcome. Fortunately the corre-
sponding carboxylic acid 29c reacted smoothly in the
presence of iodonium dicollidine perchlorate26 as pro-
moter, to give 32a in high yield.
RI f R• f ROH
The task of replacing the C6-I with an hydroxy group,
i.e., 32a f 32b, was now addressed. Attempts at
solvolysis under the relatively mild conditions of silver
trifluoroacetate in aqueous acetone at reflux afforded
good yields of ring-expanded product 34. Participation
of the ring oxygen anti-periplanar to a leaving group,
with resultant formation of an epi-oxonium, e.g., 33, ion
is frequently encountered in pyranoside systems, but the
outcome is usually ring contraction.27 The ease of the
expansion leading to 34 is undoubtedly due to the ideal
anti-periplanar relationship that exists between oxygen
and iodine, which facilitates formation of intermediate
33.
Free radical methods should not encounter such dire
consequences; but procedures for the use of TEMPO28
were unavailing. We were aware of a timely report by
Nakamura and co-workers29 in which organic halides
were converted into the corresponding alcohols by oxy-
genation in the presence of air at 0-20 °C. When these
conditions were applied to the readily available 6-deoxy-
corresponding di-O-benzyl analog, 26b, with sodium
borohydride gave 27a as the major isomer, and Garegg’s
iodination procedure21 was used to obtain iodide 27b.
C7/C8 F u r a n o Moiety
It seemed ideal to use the C8 entity to establish the
syn C7-OH, and with this in mind, 27b was subjected to
ozonolysis under the Schreiber conditions22 which led to
desired methyl ester23 28a along with a substantial
amount of corresponding aldehyde 28b. Treating the
former with zinc in ethanol at reflux caused reductive
elimination to alkene 29a from which the p-methoxy-
benzyl glycoside 29b was prepared. Epoxidation of this
material to 30 would have provided a route to the desired
C7-OH via intramolecular displacement leading to 32b.
However the double bond of 29b proved to be very
unreactive toward epoxidation; thus with either trifluoro-
peroxyacetic acid24 or dimethyldioxirane25 only a 10%
yield of 30 could be achieved.
(26) Carlsohn, H. Ber. Deutsch. Chem. Ges. 1935, 68, 2209. Carlsohn,
H. Angew. Chem. 1933, 46, 747. Lemieux, R. U.; Morgan, A. K. Can.
J . Chem. 1965, 43, 2190.
(27) Aspinall, G. O.; Chattejree, D.; Khondo, L. Can. J . Chem. 1984,
62, 2728. Kanai, K.; Zelle, R. E.; Sham, H.; Grieco, P. A.; Callant, P.
J . Org. Chem. 1984, 49, 3867. Alslani-Shotorbani; Buchanan, J . G.;
Edgar, A. R.; Shanks, G. T.; Williams, G. C. J . Chem. Soc., Perkin
Trans. 1 1981, 2267. Capon, B. Chem. Rev. 1969, 69, 407. Mootoo, D.
R.; Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1986, 1570.
(28) Kinney, R. J .; J ones, W. D.; Bergman, R. G. J . Am. Chem. Soc.
1978, 100, 7902. Howell, A. R.; Pattenden, G. J . Chem. Soc., Chem.
Commun. 1990, 2, 103. Barrett, A. G. M.; Bezuidenhoudt, C. B.;
Melcher, L. M. J . Org. Chem. 1990, 55, 5196. Barrett, A. G. M.; Rys,
D. J . J . Chem. Soc., Chem. Commun. 1994, 837.
(21) Garegg, P. J . Pure Appl. Chem. 1984, 56, 845.
(22) Schreiber, S. L.; Claus, R. E.; Reagan, J . Tetrahedron Lett. 1982,
23, 3867.
(23) For an alternative procedure, see: Marshall, J . A.; Garofalo,
A. W.; Sedrani, R. C. Synlett 1992, 643. Marshall, J . A.; Garofalo, A.
W. J . Org. Chem. 1993, 58, 3675.
(24) Heaney, H. Aldrichimica Acta 1993, 26, 35.
(25) Adam, W.; Bialas, J .; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
(29) Nakamura, E.; Inubushi, T.; Aoki, S.; Machili, D. J . Am. Chem.
Soc. 1991, 113, 8980. Nakamura, E.; Sato, K.; Imanishii, Y. Synlett
1995, 525.

Caged Tricyclic Acetals en Route to Tetrodotoxin
J . Org. Chem., Vol. 61, No. 5, 1996 1613
Sch em e 5
Sch em e 6
NOE
Application of these conditions to substrate 32a af-
forded the desired material 32b but with a disappointing
recovery (77%) of the starting material. Thus there had
been only 11% conversion of 32a into 32b.
Con clu sion
We have accomplished a synthesis of lactone 32b, even
though the efficiency of the final iodide to hydroxyl
conversion needs to be improved. Compound 32b cor-
relates well with 2b, a synthon for the Kishi-Goto
intermediate 2a (Scheme 1). In the course of this study
we have become aware of powerful armed/disarmed
effects which influence the acetolysis of 1,6-anhydro
pyranoses and of the constant threat of adamantyl
expansion, e.g., II f VII (Scheme 2), of these tricyclic
acetals. Although initially regarded as disappointments,
these transformations could conceivably be gainfully
exploited to facilitate a synthesis of TTX, 1. Our current
efforts are directed along these lines.
Exp er im en ta l Section
For general procedures, see ref 12.
Sta n d a r d Acetolysis P r oced u r e. The substrate (20 µmol)
was dissolved in acetic anhydride (2 mL) under argon at 0 °C,
and triethylsilyl trifluoromethanesulfonate (9 µL, 40 µmol) was
added. The solution was stirred at 0 °C for the specified time,
allowed to warm to room temperature, and kept there until
TLC showed the disappearance of the substrate. Further
additions of reagents were made, if necessary, to bring the
reaction to completion, or to ensure that the substrate was
inert. Saturated aqueous NaHCO3 solution (∼12 mL) was
added, CH2Cl2 was used for extraction, and the organic layers
were dried and concentrated. The residue was then chromato-
graphed with the stated solvent system.
P r ep a r a tion of Solvolysis Su bstr a tes for Ta ble 1.
N-[(1S,3S,6R,7S,8S,10S)-7,10-Bis(b en zyloxy)-4-oxo-2,9-
d ioxa tr icyclo[4.3.1.03,8]d ec-6-yl]a ceta m id e (9a ). Ketone 4
(2.42 g, 7.40 mmol) was disolved in dry methanol (50 mL), and
NaH (30 mg of 60% dispersion in mineral oil) was added
slowly. After 15 min the reaction mixture was neutralized
with Amberlite IRC-50S ion-exchange resin and filtered, and
the resin was rinsed with methanol. The filtrate was concen-
trated, diluted with toluene, and concentrated. The crude diol
was diluted with THF (120 mL) and DMF (6 mL), and sodium
hydride (888 mg of 60% dispersion in mineral oil, 22.2 mmol)
was added slowly. After 10 min, benzyl bromide (1.89 mL,
15.9 mmol) and tetrabutylammonium iodide (270 mg, 0.74
mmol) were added. The reaction was quenched after 8.5 h by
the addition of saturated aqueous NH4Cl (50 mL), and the
solution was extracted with ethyl acetate (2 × 100 mL). The
combined organic extracts were washed with brine (70 mL),
dried, and concentrated. The residue was chromatographed
with 30-50% ethyl acetate/petroleum ether (to give 2.55 g 9a )
followed by 100% ethyl actetate to give 260 mg of incompletely
benzylated products which were resubjected to the benzylation
reaction: THF (20 mL), NaH (62 mg, 1.56 mmol), BnBr (0.112
mL), TBAI, for 24 h affording additional 9a (2.93 g total,
6-iodogalactose 3530 (Scheme 6), there was no success.
However, modification31 involving the use of triethyl-
borane and a stream of molecular oxygen caused the
desired replacement, alcohol 36a being obtained in 53%
yield, with only minor amounts of the reduced material
36b. A small amount of starting material (approximately
10%) was also recovered.
(30) Schmidt, O. Th. Methods Carbohydr. Chem. 1962, 1, 191.
(31) For another modification which employs AIBN at 60 °C, see:
Moutel, S.; Prandi, J . Tetrahedron Lett. 1994, 35, 8163.

1614 J . Org. Chem., Vol. 61, No. 5, 1996
Burgey et al.
94%): 1H NMR (300 MHz, CDCl3) δ 1.69 (s, 3H), 2.98 (d, J )
17.6 Hz, 1H), 3.48 (d, J ) 17.6 Hz, 1H), 3.65 (bs, 1H), 4.10 (d,
J ) 6.4 Hz, 1H), 4.41 (d, J ) 3.0 Hz, 1H), 4.43 (d, J ) 12.3 Hz,
1H), 4.59 (bs, 2H), 4.61 (dd, J ) 3.0 Hz, J ) 6.4 Hz, 1H), 4.91
(d, J ) 12.3 Hz, 1H), 5.01 (s, 1H), 5.67 (d, J ) 1.4 Hz, 1H),
7.27-7.51 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 23.87, 40.86,
58.51, 72.47, 72.56, 74.07, 75.35, 78.91, 100.42, 128.01, 128.50,
128.61, 128.89, 129.13, 137.02, 137.67, 169.68, 203.38; GC/MS
deacetylation (NaOMe, MeOH) of 4 above (16 mg, 65 µmol)
was dissolved in DMF under argon. Sodium hydride (10.3 mg,
259 mmol, 60% suspension) was added, and 5 min later BnBr
was added. After 5 h the reaction was quenched by addition
of saturated aqueous NH4
Cl, and the solution was processed
and chromatographed to give 15 (9.5 mg, 28%) and 11b (11.9
mg, 35%). For 11b: 1H NMR (300 MHz, CDCl3) δ 1.65 (s, 3H),
2.48 (dd, J ) 8.6 Hz, J ) 13.2 Hz, 1H), 2.64 (ddd, J ) 8.2 Hz,
J ) 13.2 Hz, 1H), 3.55 (bs, 1H), 3.72 (dd, J ) 8.2 Hz, J ) 8.6
Hz, 1H), 4.33-4.45 (m, 4H), 4.50 (d, J ) 11.8 Hz, 1H), 4.51 (d,
J ) 12.1 Hz, 1H), 4.55 (d, J ) 11.8 Hz, 1H), 4.62 (d, J ) 12.1
Hz, 1H), 4.89 (d, J ) 12.4 Hz, 1H), 4.98 (s, 1H), 5.50 (d, J )
1.4 Hz, 1H), 7.26-7.48 (m, 15H); 13C NMR (75 MHz, CDCl3) δ
24.01, 30.44, 58.93, 70.62, 70.81, 71.78, 72.28, 72.47, 73.31,
78.31, 98.60, 127.67, 127.80, 128.35, 128.41, 128.63, 128.66,
129.00, 137.48, 138.05, 138.25, 169.68; GC/MS (NH3) m/z 516
(NH3) m/z 441 (M + NH4)+, 424 (MH)+; [R]20 ) -98.2° (c 0.5,
D
CHCl3); HRMS calcd for C24H25NO6 424.1753, found 424.1755.
N-[(1R,3R,4R,6R,7S,8R,10S)-7,10-Dia cet oxy-4-m et h yl-
en e-2,9-d ioxa tr icyclo[4.3.1.03,8]d ec-6-yl]a ceta m id e (9b).
Methyltriphenylphosphonium iodide (91 mg, 224 µmol) was
suspended in THF (5 mL), and n-BuLi (100 µL of a 2.0 M
solution in THF, 200 µmol) was added at -10 °C. The solution
was allowed to warm to rt and stirred for 1 h, and then 9a (21
mg, 50 µmol), dissolved in THF (2 mL), was added. After 10
h the reaction was quenched by the addition of acetone. The
solution was adsorbed onto silica gel and filtered through a
pad of silica with Et2O and concentrated, and the residue was
chromatographed with 30% ethyl acetate/hexanes (17 mg, 79%,
colorless syrup): 1H NMR (300 MHz, CDCl3) δ 1.66 (s, 3H),
2.90 (d, J ) 16.1 Hz, 1H), 3.20 (ddd, J ) 2.2 Hz, J ) 2.2 Hz,
J ) 16.1 Hz, 1H), 3.56 (bs, 1H), 4.33 (d, J ) 2.6 Hz, 1H), 4.40-
4.49 (m, 3H), 4.52 (d, J ) 11.6 Hz, 1H), 4.59 (d, J ) 11.6 Hz,
1H), 4.86 (d, J ) 12.3 Hz, 1H), 4.99 (s, 1H), 5.02 (bs, 1H), 5.08
(bs, 1H), 5.47 (m, 1H), 7.25-7.45 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 24.07, 32.72, 58.19, 72.02, 72.27, 74.24, 75.41, 78.77,
79.38, 98.76, 113.99, 127.68, 127.85, 128.33 128.52, 128.60,
128.97, 137.48, 138.35, 139.97, 169.56; GC/MS (NH3) m/z 587
(M + NH4)+; 422 (MH)+; [R]20D ) -119.9° (c 0.5, CHCl3); HRMS
calcd for C25H27NO5 422.1960, found 422.1969.
(MH)+; [R]20D ) -94.6° (c 0.5, CHCl3); HRMS calcd for C31H33
-
NO6 516.2377, found 516.2375. For 15: 1H NMR (300 MHz,
CDCl3) δ 1.69 (s, 3H), 2.58-2.63 (m, 2H), 3.56 (bs, 1H), 4.04
(m, 1H), 4.25 (dd, J ) 4.4 Hz, J ) 6.0 Hz, 1H), 4.32 (d, J )
11.4 Hz, 1H), 4.42 (d, J ) 12.5 Hz, 1H), 4.43 (dd, J ) 3.2 Hz,
J ) 6.0 Hz, 1H), 4.55 (d, J ) 11.7 Hz, 1H), 4.61 (d, J ) 11.7
Hz, 1H), 4.78 (d, J ) 11.4 Hz, 1H), 4.82 (d, J ) 12.5 Hz, 1H),
4.99 (s, 1H), 5.03 (d, J ) 3.2 Hz, 1H), 5.40 (d, J ) 1.4 Hz, 1H),
7.23-7.48 (m, 15 H); 13C NMR (75 MHz, CDCl3) δ 24.21, 29.33,
57.79, 70.97, 72.13, 72.36, 72.90, 73.55, 74.41, 75.15, 78.68,
98.80, 127.63, 127.70, 128.00, 128.30, 128.42, 128.54, 128.59,
128.96, 137.50, 137.98, 138.49, 169.46; GC/MS (NH3) m/z 516
(MH)+; [R]20D ) -90.3° (c 0.5, CHCl3); HRMS calcd for C31H33
NO6 516.2377, found 516.2399.
-
N -[(1R ,3R ,5S ,6S ,7R ,9R ,10S )-6,9,10-T r ia c e t o x y -2,4-
d ioxa tr icyclo[3.3.1.13,7]d ec-7-yl]a ceta m id e (12a ). Com-
pound 11a (13 mg, 35 µmol) was subjected to the standard
acetolysis procedure at 0 °C and warmed to rt. After 24 h the
addition was repeated, no change being observed after 48 h.
After workup the residue was chromatographed on silica gel
with 80% EtOAc/hexane to give 8 mg (65%) of a brown syrup:
1H NMR (300 MHz, CDCl3) δ 1.71 (s, 3H), 2.06 (s, 3H), 2.18
(s, 3H), 2.68 (d, J ) 12.8 Hz, 1H), 3.08 (d, J ) 12.8 Hz, 1H),
3.86 (d, J ) 2.0 Hz, 1H), 4.31 (dd, J ) 1.9 Hz, J ) 1.8 Hz, 1H),
4.43-4.62 (m, 3H), 4.85 (d, J ) 12.0 Hz, 1H), 4.95 (d, J ) 1.8
Hz, 1H), 5.29 (d, J ) 1.9 Hz, 1H), 5.34 (bs, 1H), 5.40 (d, J )
2.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 20.92, 21.66, 23.91,
32.48, 57.02, 68.03, 70.88, 72.11, 72.27, 72.55, 75.34, 94.36,
97.70, 137.26, 137.77, 167.47, 170.02, 170.88; GC/MS (NH3)
m/z 526 (MH)+.
N-[(1S,3S,4S,5S,7R,8S,9S)-7,8-Dia cet oxy-4,9-b is(b en -
zyloxy)-2-oxa tr icyclo[3.3.1.13,7]d ec-5-yl]a ceta m id e (10b).
Compound 9b (19 mg, 45 µmol) was subjected to the standard
acetolysis conditions, and after 1 h at 0 °C, TLC indicated
completion. Workup and chromatography with 30-40% ethyl
acetate/hexanes afforded 10b (12 mg, 56%) as a colorless
syrup: 1H NMR (300 MHz, CDCl3) δ 1.71 (s, 3H), 1.96 (s, 3H),
2.14 (s, 3H), 2.30 (ddd, J ) 2.2 Hz, J ) 2.2 Hz, J ) 12.5 Hz,
1H), 2.61 (bd, J ) 12.5 Hz, 1H), 2.71 (d, J ) 12.5 Hz, 1H),
2.80 (dd, J ) 2.0 Hz, J ) 12.5 Hz, 1H), 3.97 (d, J ) 3.9 Hz,
1H), 4.14 (m, 1H), 4.30 (ddd, 1H), 4.42 (d, J ) 11.9 Hz, 1H),
4.49 (d, J ) 11.6 Hz, 1H), 4.59 (d, J ) 11.6 Hz, 1H), 4.73 (d,
J ) 11.9 Hz, 1H), 4.81 (d, J ) 1.7 Hz, 1H), 5.19 (m, 1H), 5.41
(s, 1H), 7.20-7.44 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 21.11,
22.11, 24.08, 28.37, 33.34, 58.40, 69.74, 71.11, 72.02, 72.54,
72.64, 72.71, 76.12, 76.18, 127.61, 128.31, 128.46, 128.95,
137.63, 138.19, 169.70, 169.97, 170.11; GC/MS (NH3) m/z 524
N -[(1R ,3R ,5S ,6S ,7R ,9R ,10S )-9-Ace t oxy-6,10-b is(b e n -
zyloxy)-2,4-d ioxa t r icyclo[3.3.1.13,7]d ec-7-yl]a cet a m id e
(12b). Compound 11b (19 mg, 45 µmol) was subjected to the
standard acetolysis procedure at 0 °C for 1 h. Workup and
chromatography on silica gel with 30-40% EtOAc/hexane gave
12b (11.4 mg, 48%) as a colorless syrup: 1H NMR (300 MHz,
CDCl3) δ 1.73 (s, 3H), 2.19 (s, 3H), 2.45 (d, J ) 3.0 Hz, 1H),
3.91 (d, J ) 2.2 Hz, H1), 4.17 (m, 1H), 4.20 (m, 1H), 4.44 (d, J
) 12.0 Hz, H1), 4.51 (d, J ) 11.7 Hz, H1), 4.59 (bs, 1H), 4.61
(d, J ) 11.7 Hz, 1H), 4.82 (d, J ) 12.0 Hz, 1H), 4.84 (bs, 1H),
(MH)+; [R]20D ) -32.90° (c 0.3, CHCl3); HRMS calcd for C29H33
NO8 524.2275, found 524.2203.
-
N -[(1R ,3R ,4R ,6R ,7S ,8S ,10S )-4,7,10-T r ia c e t o x y -2,9-
d ioxa tr icyclo[4.3.1.03,8]d ec-6-yl]a ceta m id e (11a ) a n d Its
4-Ep im er (13). Compound 4 (48 mg, 148 µmol) was dissolved
in EtOAc (10 mL), PtO2 (9.6 mg) was added, and the mixture
was hydrogenated in a Paar apparatus (50 psi). After 9 h the
reaction was complete. The reaction was filtered and concen-
trated, and the residue was chromatographed on silica gel with
EtOAc to give (40 mg, 85%) a colorless syrup. The separation
of the two alcohol products was only possible in part. Samples
of 4R and 4S isomers were acetylated in the usual way to give
11a and 13. For 11a : 1H NMR (300 MHz, CDCl3) δ 1.95 (s,
3H), 2.17 (s, 6H), 2.30 (s, 3H), 2.45 (dd, J ) 8.8 Hz, J ) 13.4
Hz, 1H), 2.91 (dd, J ) 8.7 Hz, J ) 13.4 Hz, 1H), 4.52 (d, J )
6.2 Hz, 1H), 4.91 (dd, J ) 3 Hz, J ) 6.2 Hz, 1H), 5.08 (bs, 1H),
5.25 (dd, J ) 8.7 Hz, J ) 8.8 Hz, 1H), 5.38 (bs, 1H), 5.70 (d, J
) 3.0 Hz, 1H), 6.27 (s, 1H). For 13: 1H NMR (300 MHz,
CDCl3) δ 1.88 (s, 3H), 2.13 (s, 3H), 2.14 (s, 3H), 2.22 (s, 3H),
2.59 (d, J ) 15.6 Hz, 1H), 2.71 (dd, J ) 6.6 Hz, J ) 15.6 Hz,
1H), 4.37 (m, 1H), 4.93 (dd, J ) 3.2 Hz, J ) 6.0 Hz, 1H), 5.01-
5.04 (m, 1H), 5.28 (d, 1.9 Hz, 1H), 5.31-5.36 (m, 1H), 6.00 (d,
J ) 3.2 Hz, 1H), 6.15 (s, 1H).
5.20 (d, J ) 2.2 Hz, 1H), 5.31 (s, 1H), 7.22-7.48 (m, 10H); 13
C
NMR (75 MHz, CDCl3) δ 21.21 24.05, 29.38, 55.19, 68.86,
71.32, 72.09, 72.23, 72.56, 75.86, 77.24, 91.87, 127.63, 127.76,
128.38, 128.46, 128.59, 128.99, 137.49, 137.94, 170.18, 170.93;
GC/MS (NH3) m/z 468 (MH)+; [R]20 ) -99.6° (c 0.4, CHCl3);
D
HRMS calcd for C26H29NO7 468.2014, found 468.2040.
N-[(1S,5R,7S,8R,9S)-4,7,8,9-Tetr a a cetoxy-2-oxa bicyclo-
[3.3.1]n on -3-en -5-yl]a ceta m id e (14). Compound 13 (8 mg,
22 µmol) was subjected to the standard acetolysis conditions
and after 1 h at 0 °C the mixture was warmed to rt. After 6
and 24 h, additional TESOTf (13 µL, 57 µmol; 20 µL, 48 µmol)
was added. The reaction was then processed and the residue
chromatographed with 10, 15, and 50% acetone/CH2Cl2, yield-
1
ing a 9:1 mixture of 14 and starting material as judged by H
NMR (4 mg, 45%): 1H NMR (300 MHz, CDCl3) δ 1.95 (s, 3H),
2.00 (m, 3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.23 (s, 3H), 2.56 (dd,
J ) 6.3 Hz, J ) 13.2 Hz, 1H), 2.72 (dd, J ) 11.0 Hz, J ) 13.2
Hz, 1H), 4.65 (dd, J ) 2.1 Hz, J ) 3.3 Hz, 1H), 5.15 (dd, J )
3.3 Hz, J ) 10.1 Hz, 1H), 5.52 (ddd, J ) 6.3 Hz, J ) 10.1 Hz,
J ) 11.0 Hz, 1H), 5.80 (s, 1H), 5.82 (d, J ) 2.1 Hz, 1H), 6.63
N-[(1R,3R,4R,6R,7S,8S,10S)-4,7,10-Tr is(ben zyloxy)-2,9-
d ioxa tr icyclo[4.3.1.03,8]d ec-6-yl]a ceta m id e (11b) a n d Its
4-Ep im er (15). The mixture of alcohols from reduction and

Caged Tricyclic Acetals en Route to Tetrodotoxin
J . Org. Chem., Vol. 61, No. 5, 1996 1615
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 20.55, 20.79, 20.89, 24.23,
34.35, 54.51, 65.74, 73.14, 74.24, 126.77, 138.24, 169.64,
169.82, 169.97, 170.28, 170.49; GC/MS (NH3) m/z 431 (M +
NH4)+, 414 (MH)+; HRMS calcd for C18H23NO10 414.1393,
found 414.1400.
N -[(1S ,3R ,4S ,5R ,8S ,9S )-3,4,8,9-Te t r a a ce t oxy-7-[[3′-
(acetylth io)pr opyl]th io]-2-oxabicyclo[3.3.1]n on -6-en -5-yl]-
a ceta m id e (18a ). Compound 17a (22 mg, 53 µmol) was
subjected to the standard acetolysis conditions at 0 °C and then
warmed at rt for 12 h. Workup and chromatography on silica
gel with 20% EtOAc/hexane gave 18a (19 mg, 64%) as a
colorless syrup: 1H NMR (300 MHz, CDCl3) δ 1.90 (s, 3H),
1.90-2.04 (m, 2H), 2.09 (s, 3H), 2.16 (s, 3H), 2.17 (s, 3H), 2.18
(s, 3H), 2.32 (s, 3H), 2.80 (t, J ) 7.2 Hz, 2H), 2.98 (t, J ) 7.2
Hz, 2H), 4.67 (dd, J ) 1.9 Hz, J ) 5.4 Hz, 1H), 5.10 (d, J ) 7.8
Hz, 1H), 5.48 (dd, J ) 1.0 Hz, J ) 5.4 Hz, 1H), 5.69 (d, J ) 1.9
Hz, 1H), 5.72 (bs, 1H), 6.03 (d, J ) 7.8 Hz, 1H), 6.29 (bs, 1H);
13C NMR (75 MHz, CDCl3) δ 20.49, 20.85, 20.95, 23.72, 27.90,
28.11, 30.62, 30.83, 59.00, 68.78, 70.95, 71.02, 77.20, 89.58,
128.73, 133.62, 168.61, 169.76, 169.64, 170.18, 172.21, 195.62;
GC/MS (NH3) m/z 562 (MH)+; HRMS calcd for C23H31NO11S2
561.1338, found 561.1331.
N-[(1S,3S,4S,5R,7S,8R,9S)-3,4,8-Tr ia cetoxy-7,9-bis(ben -
zyloxy)-2-oxa bicyclo[3.3.1]n on -5-yl]a ceta m id e (16). Com-
pound 15 (9.7 mg, 18.8 µmol) was subjected to the standard
acetolysis procedure at 0 °C for 30 min. Workup and chro-
matography on silica gel with 40-50% EtOAc/hexane yielded
pure 16 (6.9 mg, 64%) as a colorless syrup: 1H NMR (300 MHz,
CDCl3) δ 1.69 (s, 3H), 1.85 (m, 1H), 2.08 (m, 3H), 2.10 (s, 3H),
2.11 (s, 3H), 2.25 (dd, J ) 3.2 Hz, J ) 15.7 Hz, 1H), 3.93 (ddd,
J ) 3.2 Hz, J ) 3.2 Hz, J ) 3.2 Hz, 1H), 4.48 (d, J ) 10.9 Hz,
1H), 4.55 (d, J ) 11.7 Hz, 1H), 4.61 (d, J ) 11.7 Hz, 1H), 4.84
(d, J ) 10.9 Hz, 1H), 5.0 (d, J ) 3.2 Hz, 1H), 5.30 (dd, J ) 3.2
Hz, J ) 3.2 Hz, 1H), 5.48 (d, J ) 3.2 Hz, 1H), 5.57 (m, 1H),
6.21 (d, J ) 3.2 Hz, 1H), 6.35 (s, 1H), 7.27-7.40 (m, 10H); 13
C
N-[(1S,3R,4S,5R,8S,9S)-3,8-Diacetoxy-4,9-bis(ben zyloxy)-
7-[[3′-(a cetylth io)p r op yl]th io]-2-oxa bicyclo[3.3.1]n on -6-
en -5-yl]a ceta m id e (18b). Compound 17b (21 mg, 41 µmol)
was subjected to the standard acetolysis conditions at 0 °C
for 0.5 h. Workup and chromatography 50% EtOAc/hexane
NMR (75 MHz, CDCl3) δ 20.94, 21.11, 21.37, 24.36, 27.01,
63.96, 65.86, 72.41, 73.47, 74.55, 75.55, 77.24, 83.31, 100.39,
127.76, 127.90, 127.95, 128.39, 128.64, 128.73, 136.96, 137.85,
170.07, 170.46; GC/MS (NH3) m/z 587 (M + NH4)+, 570 (MH)+,
510 (MH - HOAc)+; [R]20 ) -30.8° (c 0.39, CHCl3); HRMS
1
gave 18b (22 mg, 83%) as a colorless oil: H NMR (300 MHz,
D
calcd for C30H35NO10 570.2329, found 570.2316.
CDCl3) δ 1.53 (s, 3H), 1.86-1.92 (m, 2H), 2.13 (s, 3H), 2.18 (s,
3H), 2.30 (s, 3H), 2.73 (bt, J ) 7.1 Hz, 2H), 2.94 (t, J ) 7.1 Hz,
2H), 3.80 (d, J ) 7.7 Hz, 1H), 4.37 (d, J ) 11.7 Hz, 1H), 4.48
(d, J ) 1.8 Hz, 1H), 4.49 (d, J ) 12.2 Hz, 1H), 4.56-4.61 (m,
2H), 4.80 (d, J ) 12.2 Hz, 1H), 5.04 (bs, 1H), 5.32 (dd, J ) 1.2
Hz, J ) 5.3 Hz, 1H), 5.58 (d, J ) 1.2 Hz, 1H), 5.96 (d, J ) 7.7
Hz, 1H), 7.16-7.47 (m, 14H); 13C NMR (75 MHz, CDCl3) δ
20.66, 21.20, 23.50, 27.94, 30.60, 30.73, 59.72, 70.77, 71.94,
72.34, 74.13, 74.58, 75.07, 92.62, 127.46, 127.64, 128.27,
128.34, 128.52, 128.84, 128.99, 129.11, 129.17, 130.56, 133.05,
137.34, 137.87, 168.66, 169.60, 170.57, 195.57; GC/MS (NH3)
m/z 658 (MH)+; HRMS calcd for C33H40NO9S2 658.2144, found
658.2148.
N -[(1S ,3S ,6R ,7S ,8S ,10S )-7,10-Dia ce t oxy-4,4-(1′,5′-d i-
t h ia p en t a n e-1′,5′-d iyl)-2,9-d ioxa t r icyclo[4.3.1.03,8]d ec-6-
yl]a ceta m id e (17a ). Compound 4 (1.89 g, 5.76 mmol) was
dissolved in CH2Cl2 (200 mL), and 1,3-propanedithiol (1.78 mL,
17.3 mmol) and BF3‚OEt2 (2.3 mL, 17.3 mmol) were added.
After stirring for 12 h, benzaldehyde (1.24 mL, 12.1 mmol) was
added, and after another 10 h, the mixture was extracted with
saturated aqueous NaHCO3 (150 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 100 mL), and the combined organic
layers were dried, filtered, and concentrated. Chromatography
with 0-25% acetone/CH2Cl2 (linear gradient) yielded pure 17a
(2.28 g, 94%) as a colorless syrup: mp 258-268 °C dec; 1H
NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 1.92-2.13 (m, 2H), 2.15
(s, 3H), 2.25 (s, 3H), 2.52 (d, J ) 15.1 Hz, 1H), 2.73-2.85 (m,
2H), 2.97 (d, J ) 15.1 Hz, 1H), 2.98-3.19 (m, 2H), 4.84 (d, J
) 6.0 Hz, 1H), 5.00 (dd, J ) 3.1 Hz, J ) 6.0 Hz, 1H), 5.10 (bs,
1H), 5.31 (d, J ) 1.9 Hz), 6.15 (s, 1H), 6.42 (d, J ) 3.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 20.93, 21.23, 24.18, 27.65,
27.80, 38.73, 46.45, 57.91, 68.17, 73.18, 73.97, 77.18, 99.36,
169.39, 169.68, 172.63; GC/MS (NH3) m/z 435 (M + NH4)+,
N-[(1R,3S,4S,5R,9S)-4,9-Bis(ben zyloxy)-7-for m yl-3-[(p-
m et h oxyb en zyl)oxy]-2-oxa b icyclo[3.3.1]n on -7-en -5-yl]-
a ceta m id e (20b). (Methoxymethyl)triphenylphosphonium
chloride (1.78 g, 5.18 mmol) was suspended in anhydrous THF
(50 mL) under argon, and n-BuLi (2.33 mL, 4.66 mmol, 2 M
solution in hexane) was added, and the mixture was stirred
for 1 h. Ketone 4 (549 mg, 1.3 mmol) was dissolved in
anhydrous THF (5 mL) and was added to the red ylide solution.
After 8 h the reaction was quenched by the addition of acetone,
and the solution was concentrated and adsorbed onto silica
gel. The mixture was filtered through a pad of silica gel using
Et2O as the eluent. The filtrate was concentrated, and the
crude product was chromatographed on silica gel with 35-
50% ethyl acetate/hexanes yielding the E- and Z-isomers 19
as 2:1 mixture (362 mg, 62%). This material (362 mg, 0.802
mmol) was dissolved in a 6:1 mixture of THF/1 N HCl (162
mL) and heated at 57 °C for 18 h. The solution was
concentrated, dissolved in toluene, and evaporated to dryness.
The residue was dissolved in saturated sodium bicarbonate
solution and extracted with CH2Cl2 (3 × 15 mL). The
combined organic layers were dried, filtered, and concentrated.
The residue was purified on silica gel with 50% ethyl acetate/
hexanes to give compound 20a as a colorless syrup (335 mg,
95%). A portion of this material (204 mg, 0.466 mmol) was
dissolved in dry THF (50 mL), and p-methoxybenzyl alcohol
(1.74 mL, 14.0 mmol), molecular sieves (4 Å), and Amberlyst
15 ion-exchange resin were added. After 12 and 36 h the same
amounts of the reagents were added again. Although starting
material remained after 4 days, the reaction mixture was
worked up by being filtered through a pad of silica gel and
then concentrated. The residue was chromatographed on silica
gel with 15, 25, 35, and 65% ethyl acetate/hexanes to give 20b
(162 mg, 62%) and 20a (67 mg, 33%) as colorless syrups. For
20b: 1H NMR (300 MHz, CDCl3) δ 1.50 (s, 3H), 2.89 (bs, 2H),
3.73 (d, J ) 7.9 Hz, 1H), 3.81 (s, 3H), 4.50 (d, J ) 11.1 Hz,
1H), 4.51 (d, J ) 11.6 Hz, 1H), 4.57 (dd, J ) 2.4 Hz, J ) 6.4
Hz, 1H), 4.59 (d, J ) 7.9 Hz, 1H), 4.64 (d, J ) 11.6 Hz, 1H),
4.64 (d, J ) 12.3 Hz, 1H), 4.72 (d, J ) 2.4 Hz, 1H), 4.85 (d, J
) 12.3 Hz, 1H), 4.87 (d, J ) 11.1 Hz, 1H), 4.95 (s, 1H), 6.58
(d, J ) 6.4 Hz, 1H), 6.87 (d, J ) 9.0 Hz, 2H), 7.21-7.46 (m,
418 (MH)+; [R]20 ) -68.8° (c 1.0, CHCl3); HRMS calcd for
D
C17H23NO7S2 418.0988, found 418.0977.
N-[(1S,3S,6R,7S,8S,10S)-7,10-Bis(ben zyloxy)-4,4-(1′,5′-
d it h ia p e n t a n e -1′,5′-d iyl)-2,9-d ioxa t r icyclo[4.3.1.03,8]-
d ec-6-yl]a ceta m id e (17b). Compound 17a (749 mg, 1.79
mmol) was dissolved in MeOH (100 mL), and a catalytic
amount of NaH was added. After 30 min the reaction was
neutralized with Amberlite ion-exchange resin 1RC-50S. The
solution was filtered and concentrated, and after azeotroping
with toluene (2×), the crude diol (592 mg) was dissolved in
DMF (100 mL) under argon. Sodium hydride (287 mg, 7.17
mmol, 60% suspension) and 20 min later BnBr (0.636 mL, 5.38
mmol) were added, and the mixture was stirred for 10 h. The
reaction was quenched by the addition of saturated aqueous
NH4Cl, and the solution was concentrated, diluted with H2O
(50 mL), and extracted with CH2Cl2 (4 × 50 mL). The
combined organic layers were dried, filtered, and concentrated.
The crude product was adsorbed onto silica gel and chromato-
graphed with 10-50% EtOAc/hexane (linear gradient) to give
17b (900 mg, 98%) as a colorless syrup: 1H NMR (300 MHz,
CDCl3) δ 1.60 (s, 3H), 1.85-2.13 (m, 2H), 2.62 (d, J ) 11.8
Hz, 1H), 2.72-2.82 (m, 2H), 2.73 (d, J ) 14.8 Hz, 1H), 2.98
(m, 1H), 3.15 (m, 1H), 3.63 (bs, 1H), 4.37 (d, J ) 12.4 Hz, 1H),
4.52 (dd, J ) 3.2 Hz, J ) 5.9 Hz, 1H), 4.57 (d, J ) 11.6 Hz,
1H), 4.63 (d, J ) 11.6 Hz, 1H), 4.72 (d, J ) 5.9 Hz, 1H), 4.85
(s, 1H), 4.91 (d, J ) 12.4 Hz, 1H), 5.38 (d, J ) 3.2 Hz, 1H),
5.49 (d, J ) 1.6 Hz, 1H), 7.21-7.53 (m, 10H); 13C NMR (75
MHz, CDCl3) δ 23.90, 24.37, 27.52, 27.62, 39.00, 47.17, 58.52,
71.92, 72.68, 74.14, 77.24, 98.51, 127.61, 127.88, 128.28,
128.71, 128.79, 129.04, 137.37, 138.51, 169.35; GC/MS (NH3)
m/z 514 (MH)+; [R]20 ) -84.5° (c 1.0, CHCl3); HRMS calcd
D
for C27H31NO5S2 514.1715, found 514.1714.

1616 J . Org. Chem., Vol. 61, No. 5, 1996
Burgey et al.
12H), 9.53 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 23.92, 27.41,
55.27, 57.68, 67.80, 71.25, 72.26, 73.99, 74.29, 77.24, 98.31,
113.81, 127.47, 127.53, 128.21, 128.57, 129.07, 129.19, 129.36,
129.69, 137.85, 138.47, 138.98, 144.22, 159.37, 169.82, 192.05;
1H), 4.52 (d, J ) 11.4 Hz, 1H), 4.61 (d, J ) 12.2 Hz, 1H), 4.68
(d, J ) 11.9 Hz, 1H), 4.80 (d, J ) 12.2 Hz, 1H), 4.83 (d, J )
11.4 Hz, 1H), 4.93, (s, 1H), 5.00 (bs, 1H), 5.04 (d, J ) 2.0 Hz,
1H), 5.14 (bs, 1H), 5.29 (d, J ) 7.8 Hz, 1H), 6.88 (d, J ) 9.4
Hz, 2H), 7.20-7.44 (m, 12H); 13C NMR (75 MHz, CDCl3), δ
24.11, 33.08, 55.28, 59.57, 70.43, 72.09, 72.74, 73.57, 74.24,
74.87, 97.58, 113.74, 117.37, 127.20, 127.32, 128.10, 128.50,
129.03, 129.19, 129.61, 129.93, 138.02, 138.93, 145.95, 159.30,
170.5; GC/MS (NH3) m/z 560 (MH)+, 422 (MH - PMBOH);
GC/MS (NH3) m/z 558 (MH)+; [R]20 ) -93.2° (c 0.5, CHCl3);
D
HRMS calcd for C33H35NO7 558.2482, found 558.2477.
N -[(1R ,3S ,4S ,5R ,9S )-4,9-Bis(b e n zyloxy)-7-(h yd r oxy-
m eth yl)-3-[(p-m eth oxyben zyl)oxy]-2-oxabicyclo[3.3.1]n on -
7-en -5-yl]a ceta m id e (20c). Compound 20b (200 mg, 0.358
mmol) was dissolved in 2:1 EtOH/H2O (32 mL), and CeCl3‚
7H2O (133 mg, 0.35 mmol) and NaBH4 (20 mg, 0.53 mmol)
were added at -10 °C. After 10 min the unreacted NaBH4
was destroyed by the addition of acetone and the solution was
concentrated. The residue was suspended in H2O, and 1 N
HCl was added until the solid dissolved. The solution was
extracted with CH2Cl2 (3 × 15 mL), and the organic layer was
dried, filtered, and concentrated. The residue was chromato-
graphed on silica gel with 75% ethyl acetate/hexanes to give
20c (175 mg, 87%) as a colorless syrup: 1H NMR (300 MHz,
CDCl3) δ 1.49 (s, 3H), 2.57 (d, J ) 18.6 Hz, 1H), 2.80 (d, J )
18.6 Hz, 1H), 3.70 (d, J ) 8.0 Hz, 1H), 3.81 (s, 3H), 4.03 (b,
2H), 4.40 (dd, J ) 2.4 Hz, J ) 6.4 Hz, 1H), 4.46 (d, J ) 11.9
Hz, 1H), 4.51 (d, J ) 11.3 Hz, 1H), 4.61 (d, J ) 2.4 Hz, 1H),
4.66 (d, J ) 11.9 Hz, 1H), 4.67 (d, J ) 12.3 Hz, 1H), 4.78 (d,
J ) 8.0 Hz, 1H), 4.85 (d, J ) 12.3 Hz, 1H), 4.87 (d, J ) 11.3
Hz, 1H), 4.95 (s, 1H), 5.68 (bd, J ) 6.4 Hz, 1H), 6.88 (d, J )
9.4 Hz, 2H), 7.21-7.46 (m, 12H); 13C NMR (75 MHz, CDCl3) δ
24.03, 31.05, 55.29, 58.22, 64.53, 68.07, 70.91, 71.85, 73.96,
75.20, 77.24, 97.84, 113.70, 115.50, 127.29, 127.45, 128.13,
128.66, 129.06, 129.21, 129.73, 129.83, 138.04, 138.79, 144.51,
[R]20 ) -46.4° (c 0.5, CHCl3); HRMS calcd for C33H37NO7
D
560.2638, found 560.2624.
N -[(1S ,3S ,4S ,5R ,8R ,9S )-4,9-B is (b e n zy lo x y )-8-(t er t -
bu tyld im eth ylsiloxy)-3-[(p-m eth oxyben zyl)oxy]-7-oxo-2-
oxabicyclo[3.3.1]n on -5-yl]acetam ide (22c). Compound 22a
(65 mg, 0.117 mmol) was dissolved in dry CH2Cl2 (10 mL).
Triethylamine (0.260 mL, 1.87 mmol), and tert-butyldimethyl-
silyl trifluoromethanesulfonate (0.213 mL, 0.935 mmol) were
added, and the mixture was stirred for 8 h. The solution was
extracted with aqueous saturated NaHCO3 (7 mL), and the
aqueous layer was twice extracted with 5 mL portions of
CH2Cl2. The combined organic layers were dried, filtered, and
concentrated. The residue was chromatographed with 13-
20% ethyl acetate/hexanes (linear gradient) to give 22b (68
mg, 86%). A portion of this material (22 mg, 0.032 mmol) was
dissolved in 1:1 CH2Cl2/MeOH (6 mL). Pyridine (33 µL, 0.040
mmol) was added, and after cooling to -78 °C, ozone was
passed through the solution until the blue color persisted. After
15 min the solution was purged with argon, dimethyl sulfide
(0.107 mL, 1.46 mmol) was added, and the mixture was
warmed to rt for 30 min. The solution was concentrated, and
the residue was dissolved in toluene and concentrated (2×).
The crude was then chromatographed on silica gel with 15%
ethyl acetate/hexanes to give the title compound 22c (15 mg,
65%) as colorless crystals: 1H NMR (300 MHz, CDCl3) δ 0.06
(s, 3H), 0.09 (s, 3H), 0.88 (s, 9H), 1.56 (s, 3H), 2.75 (dd, J )
1.6 Hz, J ) 16.2 Hz, 1H), 3.73 (d, J ) 7.7 Hz, 1H), 3.76 (d, J
) 16.2 Hz, 1H), 3.84 (s, 3H), 3.99 (dd, J ) 1.5 Hz, J ) 3.4 Hz,
1H), 4.10 (dd, J ) 2.1 Hz, J ) 3.4 Hz, 1H), 4.43-4.69 (m, 5H),
4.84 (d, J ) 12.4 Hz, 1H), 4.89 (d, J ) 11.2 Hz, 1H), 4.96 (s,
1H), 5.25 (d, J ) 2.1 Hz, 1H), 6.91 (d, J ) 9.4 Hz, 2H), 7.26-
7.49 (d, 12H); 13C NMR (75 MHz, CDCl3) δ 17.90, 23.91, 25.52,
40.54, 55.27, 58.87, 71.45, 71.80, 72.51, 73.75, 75.29, 75.37,
75.94, 76.16, 77.23, 98.62, 113.85, 127.51, 127.62, 128.24,
128.58, 129.06, 129.20, 129.79, 137.78, 138.38, 159.42, 170.05,
159.25, 169.73; GC/MS (NH3) m/z 560 (MH)+; [R]20 ) -93° (c
D
0.5, CHCl3); HRMS calcd for C34H37NO7 560.2638, found
560.2665.
N -[(1R ,3S ,5R ,6S ,8S ,9S ,10S )-9,10-B is (b e n zy lo x y )-3-
(iodom eth yl)-8-[(p-m eth oxyben zyl)oxy]-4,7-dioxatr icyclo-
[4.3.1.03,5]d ec-1-yl]a ceta m id e (21b). Compound 20c (74 mg,
132 µmol) was dissolved in dry CH2Cl2 (20 mL), and NaHCO3
(80 mg, 0.9 mmol) and MCPBA (136 mg, 394 mmol) were
added. The reaction mixture was worked up after 36 h by
addition of Na2S2O3/NaHCO3 solution. The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL), and the combined organic
layers were dried, filtered, and concentrated. The residue was
chromatographed with 65% ethyl acetate/hexanes to give
epoxide 21a (56 mg, 74%). This material (39 mg, 67 µmol)
was dissolved in dry toluene (9 mL). Triphenylphosphine (21
mg, 81 µmol), imidazole (11 mg, 162 µmol), and powdered
iodine (19 mg, 74 µmol) were added, and the suspension was
heated at 47 °C. After 5 h the same amount of the reagents
was added. After a further 5 h, the solution was cooled and
concentrated. The residue was chromatographed on silica gel
with 100%-88% toluene/ethyl acetate to give compound 21b
(43 mg, 92%) as a colorless syrup: 1H NMR (300 MHz, CDCl3)
δ 1.46 (1, 3H), 2.69 (d, J ) 15.7 Hz, 1H), 2.67 (d, J ) 15.7 Hz,
1H), 3.06 (s, 2H), 3.24 (d, J ) 3.2 Hz, 1H), 3.67 (d, J ) 8.2,
Hz, 1H), 3.81 (s, 3H), 4.49 (dd, J ) 2.5 Hz, J ) 3.2 Hz, 1H),
4.41 (d, J ) 11.9 Hz, 1H), 4.55 (d, J ) 11.9 Hz, 1H), 4.67 (d,
J ) 11.5 Hz, 1H), 4.68 (d, J ) 2.5 Hz, 1H), 4.70 (d, J ) 12.3
Hz, 1H), 4.83 (s, 1H), 4.90 (d, J ) 12.3 Hz, 1H), 4.93 (d, J )
11.5 Hz, 1H), 5.12 (d, J ) 8.2 Hz, 1H), 6.89 (d, J ) 7.5 Hz,
2H), 7.16-7.45 (m, 12H); GC/MS (NH3) m/z 686 (MH)+; HRMS
calcd for C33H36INO7 686.1604, found 686.1608.
N-[(1S,3S,4S,5R,8S,9S)-4,9-Bis(ben zyloxy)-8-h yd r oxy-
3-[(p-m eth oxyben zyl)oxy]-7-m eth ylen e-2-oxabicyclo[3.3.1]-
n on -5-yl]a ceta m id e (22a ). The iodo epoxide 21b (43 mg,
0.062 mmol) was dissolved in 96% EtOH (10 mL). Activated
zinc dust (41 mg, 0.63 mmol) was added, and the mixture was
refluxed for 2 h. It was then cooled, filtered through a pad of
silica gel, and concentrated. The residue was dissolved in H2O
(8 mL) and extracted with CH2Cl2 (3 × 6 mL). The combined
organic layers were dried, filtered, and concentrated. The
residue was chromatographed on silica gel with 50% ethyl
acetate/hexanes to give the title compound 22a (33 mg, 96%)
as a colorless syrup: 1H NMR (300 MHz, CDCl3) δ 1.47 (s,
3H), 2.66 (d, J ) 15.3 Hz, 1H), 3.38 (bd, J ) 15.3 Hz, 1H),
3.70 (d, J ) 7.8 Hz, 1H), 3.81 (s, 3H), 4.23 (dd, J ) 2.0 Hz, J
) 3.4 Hz, 1H), 4.39 (d, J ) 3.4 Hz, 1H), 4.47 (d, J ) 11.9 Hz,
206.38; GC/MS (NH3) m/z 676 (MH)+; [R]20 ) -29.4° (c 0.5,
D
CHCl3); HRMS calcd for C38H49NO8Si 676.3220, found 676.3334.
N -[(1 S ,3 S ,5 R ,6 S ,7 R ,1 0 S )-1 ,6 ,1 0 -T r i a c e t o x y -2 ,4 -
d ioxa tr icyclo[3.3.1.13,7]d ec-7-yl]a ceta m id e (25b). Samar-
ium metal (174 mg, 1.16 mmol) was suspended in anhydrous
degassed THF (11 mL). Diiodomethane (89 µL, 1.10 mmol)
was added at 0 °C. After 15 min the solution was warmed to
rt and stirred for 1 h. The dark blue solution was cooled to
-78 °C, and ethylene glycol was added (146 µL, 2.6 mmol)
followed by 4 (72 mg, 220 µmol) dissolved in 4 mL of anhydrous
degassed THF. The solution was stirred at -78 °C for 10 min
and then at rt for 30 min. The reaction was quenched by the
addition of saturated aqueous NaHCO3, and after usual
workup the residue was adsorbed onto silica gel and chro-
matographed with 75-100% EtOAc/hexane (linear gradient)
to yield 25a (54 mg, 75%) as colorless crystals. The material
was dissolved in pyridine (3 mL), Ac2O (100 µL) was added,
and the solution was stirred for 12 h. The mixture was
concentrated, diluted with toluene, and evaporated (3×). The
residue was purified on silica gel using 65% of EtOAc/hexane
as the eluant to afford 25b (61 mg) colorless crystals: mp 120
1
°C dec; H NMR (300 MHz, C6D6) δ 1.49 (s, 3H), 1.52 (s, 3H),
1.60 (s, 3H), 1.70 (s, 3H), 1.79 (bd, J ) 12.8 Hz, 1H), 2.53 (ddd,
J ) 3.5 Hz, J ) 4.7, Hz, J ) 12.8 Hz, 1H), 3.02 (d, J ) 3.5 Hz,
J ) 12.6 Hz, 1H), 3.60 (d, J ) 12.6 Hz, 1H), 4.26 (ddd, J ) 1.0
Hz, J ) 2.4 Hz, J ) 4.7 Hz, 1H), 5.21 (m, 1H), 5.31 (d, J ) 2.4
Hz, 1H), 6.06 (s, 1H), 6.14 (d, J ) 1.9 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 20.99, 21.23, 22.03, 24.20, 35.29, 35.81, 56.69,
67.25, 70.53, 72.04, 94.86, 98.45, 168.05, 169.78, 170.09,
172.45; GC/CIMS (NH3) m/z 389 (M + NH4)+, 372 (MH)+; [R]20
D
) -43.5° (c 1.0, CHCl3). Anal. Calcd for C16H21NO9: C, 51.75;
H, 5.70; N, 3.77. Found: C, 51.47; H, 5.74; N, 3.72.

Caged Tricyclic Acetals en Route to Tetrodotoxin
J . Org. Chem., Vol. 61, No. 5, 1996 1617
N-[(1S,3S,5R,6R,7S,8S,10S)-5-Allyl-7,10-diacetoxy-4-oxo-
2,9-d ioxa tr icyclo[4.3.1.03,8]d ec-6-yl]a ceta m id e (26a ). To
a solution of ketone 4 (19 mg, 0.058 mmol) in glacial acetic
acid (1 mL) was added pyridinium bromide perbromide (26
mg, 0.064 mmol, tech. 80%). The reaction was heated at 70
°C for 4.5 h and then diluted with water (5 mL). The solution
was extracted with CH2Cl2 (2 × 5 mL), and the organic layers
were combined, washed with saturated aqueous NaHCO3 (5
mL), dried, and concentrated. The residue was flash chro-
matographed with 60-80% ethyl acetate/petroleum ether
(linear gradient) to yield the bromide (20 mg, 85%) as an
inseparable mixture of R-bromo epimers: GC/MS (NH3) m/z
423 (M + NH4)+. A benzene (5.2 mL) solution of this mixture
(210 mg, 0.517 mmol), allyltributyltin (0.640 mL, 2.07 mmol),
and AIBN (13 mg) was degassed with argon for 10 min. The
reaction mixture was heated at 85 °C for 7.5 h, cooled, and
concentrated. The residue was diluted with acetonitrile (20
mL) and extracted with hexanes (4 × 10 mL). The CH3CN
layer was concentrated, and the crude product was adsorbed
onto silica gel. Flash chromatography with a linear gradient
of 50-65% ethyl acetate/hexanes yielded an inseparable 4:1
mixture of 26a (130 mg, 68%) and 8-epi-26a . For 26a :
colorless solid; mp 184-186 °C; 1H NMR (300 MHz, CDCl3) δ
1.93 (s, 3H, Ac), 2.14 (s, 3H), 2.25 (s, 3H), 2.68 (m, 2H), 3.75
(dd, J 1 ) J 2 ) 7.6, 1H), 4.23 (d, J ) 6.1, 1H), 5.01 (m, 1H),
5.03-5.07 (m, 2H), 5.17 (bs, 1H), 5.51 (d, J ) 1.5, 1H), 5.56
(d, J ) 3.2, 1H), 5.82 (m, 1H), 6.46 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ 20.62, 21.18, 23.92, 34.78, 53.15, 60.10, 70.44, 73.17,
75.59, 79.21, 101.27, 116.06, 136.60, 169.35, 169.81, 172.45,
202.59; GC/MS (NH3) m/z 345 (M + NH4)+, 328 (MH)+. Anal.
Calcd for C24H25NO6: C, 55.58; H, 5.76; N, 3.81. Found: C,
55.45; H, 5.80; N, 3.78.
mmol), and powdered iodine (144 mg, 0.56 mmol) were added.
The mixture was warmed to 95 °C for 50 min, cooled, and
concentrated. The residue was adsorbed onto silica gel and
filtered through a pad of silica gel with Et2O. The solvent was
concentrated, and the residue was chromatographed on silica
gel with 20% ethyl acetate/hexanes to give 27b as a colorless
syrup (179 g, 89%): 1H NMR, (300 MHz, CDCl3) δ 1.61 (s, 3H),
2.37 (ddd, J ) 9.8 Hz, J ) 12.0 Hz, J ) 14.5 Hz, 1H), 2.64 (bd,
J ) 14.5 Hz, 1H), 3.49 (dd, J ) 3.1 Hz, J ) 12.0 Hz, 1H), 3.77
(bs, 1H), 4.25 (d, J ) 12.4 Hz, 1H), 4.33 (bd, J ) 3.3 Hz, 1H),
4.48 (dd, J ) 3.1 Hz, J ) 5.7 Hz, 1H), 4.54 (dd, J ) 3.3 Hz, J
) 5.7 Hz, 1H), 4.60 (d, J ) 11.3 Hz, 1H), 4.65 (d, J ) 11.3 Hz,
1H), 4.81 (d, J ) 12.4 Hz, 1H), 4.91 (s, 1H), 5.08-5.20 (m,
2H), 5.40 (d, J ) 3.1 Hz, 1H), 5.42 (bs, 1H), 5.72 (dddd, 1H),
7.24-7.46 (m, 10H); 13C NMR (75 MHz, CDCl3) δ 21.44, 24.10,
38.91, 48.50, 62.10, 72.39, 72.58, 72.60, 74.06 80.42, 82.42,
99.26, 117.67, 127.72, 128.06, 128.34, 128.55, 128.76, 129.15,
137.09, 137.29, 138.33, 169.48; GC/MS (NH3) m/z 576 (MH)+;
[R]20 ) -165.3° (c 1.0, CHCl3); HRMS calcd for C27H30INO5
D
576.1238, found 576.1233.
Meth yl [(1S,3S,4S,5R,6R,7S,8S,10S)-6-Aceta m id o-7,10-
bis(ben zyloxy)-4-iodo-2,9-dioxatr icyclo[4.3.1.03,8]dec-5-yl]-
a ceta te (28a ). Alkene 27b (179 mg, 0.137 mmol) was
dissolved in 5:1 CH2Cl2/MeOH (9.6 mL) and cooled to -78 °C.
Ozone was bubbled through the solution until the blue color
persisted. The solution was purged with argon, warmed to
room temperature, and concentrated. The residue was dis-
solved in toluene and concentrated (4×). The resulting crude
hydroperoxide was carefully dissolved in dry CH2Cl2 (7 mL),
and Ac2O (64 µL, 0.686 mmol) and Et3N (143 µL, 1.03 mmol)
were added. The mixture was stirred for 3 h and then
extracted with saturated NaHCO3. The layers were separated,
and the aqueous layer was extracted with CH2Cl2 (2 × 8 mL).
The combined organic layers were dried, filtered, and concen-
trated. Chromatography on silica gel with 30% ethyl acetate/
hexanes yielded 28a and the aldehyde 28b as an inseparable
mixture (77 mg). In order to isolate the pure methyl ester the
mixture was dissolved in benzene (10 mL), and PPTS (17 mg,
67 µmol) and ethylene glycol (0.150 mL, 2.67 mmol) were
added. After 1 h at reflux the solution was cooled and
concentrated. The residue was dissolved in saturated aqueous
NaHCO3, and the solution was extracted with CH2Cl2 (3 × 7
mL). The combined organic layers were dried, filtered, and
concentrated. The residue was dissolved in toluene, concen-
trated again, and then chromatographed on silica gel with 25-
50% ethyl acetate/hexanes (linear gradient). The desired ester
28a was obtained as a colorless syrup (57 mg, 62%): 1H NMR
(300 MHz, CDCl3) δ 1.60 (s, 3H), 2.75-2.90 (m, 2H), 3.71 (s,
3H), 3.76 (bs, 1H), 3.38 (dd, J ) 4.7 Hz, J ) 10.2 Hz, 1H),
4.25 (d, J ) 12.8 Hz, 1H), 4.34 (dd, J ) 0.9 Hz, J ) 3.3 Hz,
1H), 4.46-4.55 (m, 2H), 4.59 (d, J ) 11.4 Hz, 1H), 4.65 (d, J
) 11.4 Hz, 1H), 4.79 (d, J ) 12.3 Hz, 1H), 4.84 (s, 1H), 5.42
(d, J ) 1.2 Hz, 1H), 5.48 (d, J ) 3.1 Hz, 1H), 7.26-7.48 (m,
10H); 13C NMR (75 MHz, CDCl3) δ 21.21, 24.05, 38.85, 45.48,
51.81, 61.52, 71.97, 72.42, 72.66, 73.99, 80.43, 82.10, 99.28,
127.76, 128.05, 128.35, 128.63, 128.87, 129.21, 137.08, 138.23,
169.56, 173.15; GC/MS (NH3) m/z 608 (MH)+; [R]20D ) -141.6°
(c 0.5, CHCl3); HRMS calcd for C27H30INO7 608.1136, found
608.1150.
N-[(1S,3S,5R,6R,7S,8S,10S)-5-Allyl-7,10-bis(ben zyloxy)-
4-oxo-2,9-dioxatr icyclo[4.3.1.03,8]dec-6-yl]acetam ide (26b).32
Ketone 26a (10.7 mg, 29 µmol) was dissolved in dry methanol
(1 mL), and NaH (0.5 mg of 60% dispersion in mineral oil)
was added. After 10 min the reaction mixture was neutralized
with Amberlite IRC-50S ion-exchange resin and filtered, and
the resin was rinsed with methanol and concentrated. The
crude diol was diluted with THF (1 mL) and DMF (0.2 mL),
and sodium hydride (3.6 mg of 60% dispersion in mineral oil,
90 µmol) was added. After 10 min, benzyl bromide (7.5 µL,
64 µmol) and tetrabutylammonium iodide (0.5 mg) were added.
The reaction was quenched after 24 h by the addition of
saturated aqueous NH4Cl (3 mL), and the solution was
extracted with ethyl acetate (2 × 5 mL). The combined organic
extracts were dried and concentrated. The residue was
chromatographed with 20-60% ethyl acetate/petroleum ether
to give crude 26b (4.4 mg). A pure sample could be obtained
by HPLC: mp 130-131 °C; 1H NMR (300 MHz, CDCl3) δ 1.62
(s, 3H), 2.66 (m, 1H), 2.89 (m, 1H), 3.40 (dd, J ) 7.6 Hz, J )
7.6 Hz, 1H), 3.82, (s, 1H), 4.1 (dd, J ) 6.1 Hz, 1H), 4.32-4.38
(m, 2H), 4.55-4.62 (m, 3H), 4.87 (d, J ) 12.3 Hz, 1H), 4.96-
5.06 (m, 3H), 5.67 (s, 1H), 5.83 (m, 1H), 7.24-7.49 (m, 10H);
13C NMR (75 MHz, CDCl3) δ 23.86, 35.56, 53.89, 60.66, 72.47,
72.82, 74.11, 76.24, 79.44, 80.57, 100.72, 115.80, 127.80,
127.87, 128.41, 128.76, 128.93, 129.20, 136.93, 137.64, 137.89,
167.71, 205.15; GC/MS (NH3) m/z 464 (MH)+; [R]20 ) -51.9°
D
(c 0.5, CHCl3); HRMS calcd for C27H29NO6 464.2065, found
464.2061.
(1R,3S,4S,5R,6S,9S)-5-Aceta m id o-4,9-bis(ben zyloxy)-3-
[(p-m eth oxyben zyl)oxy]-2-oxabicyclo[3.3.1]n on -7-en -6-yl]-
a cetic Acid (29c). To a solution of 28a (63 mg, 0.104 mmol),
in anhydrous EtOH (8 mL), was added freshly activated zinc
dust (103 mg, 1.56 mmol). This mixture was refluxed for 2 h,
filtered through a bed of silica gel, and concentrated. The
residue was dissolved in H2O (8 mL) and extracted with
CH2Cl2 (3 × 8 mL) The combined organic layers where dried,
filtered, and concentrated. The residue was chromatographed
on silica gel with 35-40% ethyl acetate/hexanes to give 29a
(48 mg, 82%) as a colorless syrup. This material was dissolved
in anhydrous DMF (9 mL), and silver(I) oxide (300 mg, 1.26
mmol), tetrabutylammonium iodide (72 mg, 1.88 mmol), and
4-methoxybenzyl chloride (1.4 mL, 1.56 mmol) were added.
After 12 h the mixture filtered through a pad of silica gel. The
filtrate was concentrated, diluted with EtOAc, and filtered
through a bed of silica gel again. The crude product was
N -[(1S ,3S ,4S ,5R ,6R ,7S ,8S ,10S )-5-Allyl-7,10-b is(b e n -
zyloxy)-4-iod o-2,9-d ioxa t r icyclo[4.3.1.03,8]d ec-6-yl]a cet -
a m id e (27b). Ketone 26b (143 mg, 0.308 mmol) was dissolved
in EtOH (15 mL), and NaBH4 (45 mg, 1.23 mmol) was added
at 0 °C. After 15 min the unreacted NaBH4 was destroyed by
the addition of acetone. The solution was concentrated,
dissolved in H2O (10 mL), and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried, filtered, and
concentrated. The residue was chromatographed on silica gel
with a linear gradient of 40-50% ethyl acetate/hexanes to give
27a (23 mg, 86%) as a colorless syrup. This alcohol (152 mg,
0.326 mmol) was dissolved in toluene (10 mL), and triphen-
ylphosphine (162 mg, 0.73 mmol), imidazole (86 mg, 1.46
(32) A better yielding preparation is being developed which will be
described subsequently.

1618 J . Org. Chem., Vol. 61, No. 5, 1996
Burgey et al.
chromatographed on silica gel with a linear gradient of 25-
50% ethyl acetate/hexanes to afford 29b (54 mg, 92%) as a
colorless oil. A portion (46 mg, 77 µmol) was dissolved in 3:1
MeOH/H2O (4.8 mL). Lithium hydroxide (64 mg, 1.53 mmol)
was added at 0 °C, and the reaction kept at this temperature
for 6 h. The solution was concentrated, dissolved in 1 N HCl
(6 mL), and extracted with CH2Cl2 (3 × 6 mL). The combined
organic layers were dried, filtered, and concentrated. The
residue was chromatographed on silica gel with 50-100%
acetone/hexanes to give 29c (44 mg, 98%): 1H NMR (300 MHz,
CDCl3) δ 1.42 (s, 3H), 2.46 (dd, J ) 10.9 Hz, J ) 16.4 Hz, 1H),
2.85 (dd, J ) 4.2 Hz, J ) 16.4 Hz, 1H), 3.80-3.88 (m, 2H),
3.81 (s, 3H), 4.40 (dd, J ) 2.0 Hz, J ) 5.9 Hz, 1H), 4.45 (d, J
) 11.8 Hz, 1H), 4.66 (d, J ) 11.8 Hz, 1H), 4.71 (bs, 1H), 4.83
(d, J ) 12.5 Hz, 1H), 4.88 (s, 1H), 4.88 (d, J ) 11.6 Hz, 1H),
4.99 (d, J ) 8.3 Hz, 1H), 5.62 (ddd, J ) 7.6 Hz, J ) 5.9 Hz, J
) 9.6 Hz, 1H), 5.93 (dd, J ) 1.8 Hz, J ) 9.6 Hz, 1H), 6.88 (d,
J ) 8.6 Hz, 2H), 7.16-7.48 (m, 12H); 13C NMR (75 MHz,
CDCl3) δ 23.90, 35.02, 39.72, 55.28, 61.00, 68.43, 71.12, 71.88,
74.51, 75.98, 78.61, 97.68, 113.76, 120.70, 127.21, 128.69,
129.21, 129.54, 129.76, 135.72, 138.78, 138.80, 159.23, 170.22,
177.70; GC/MS (NH3) m/z 588 (MH)+, 450 (MH - PMBOH)+;
(75 MHz, CDCl3) δ 23.30, 24.01, 33.15, 39.07, 55.30, 58.01,
71.23, 71.56, 72.01, 74.25, 76.96, 83.54, 99.04, 113.86, 127.55,
128.24, 128.85, 129.27, 129.45, 129.75, 137.40, 138.01, 159.36,
170.03, 175.02; GC/MS (NH3) m/z 731 (M + NH4)+, 714 (MH)+,
576 (MH - PMBOH)+; [R]20 ) -44° (c 0.5, CHCl3); HRMS
D
calcd for C34H36INO8 714.1553, found 714.1566.
N-[(1R,2R,6R,7R,8R,10S,11S,12S)-11,12-Bis(ben zyloxy)-
7 -h y d r o x y -1 0 -[(p -m e t h o x y b e n x y l )o x y ]-4 -o x o -5 ,9 -
d ioxa tr icyclo[6.3.1.02,6]d od ec-1-yl]a ceta m id e (32b). Io-
dide 32a (10.5 mg, 14.7 µmol) was dissolved in anhydrous
toluene (1.5 mL). Oxygen was bubbled into the solution for
10 min, and then Bu3SnH (10 µL, 36.8 µmol) and Et3B (29 µL
of a 0.1 M solution in toluene) were added while the bubbling
of oxygen was continued. Further amounts of Et3B (29 µL of
a 0.1 M solution in toluene) and Bu3SnH (10 µL, 36.8 µmol)
were added after 2.75, 4.25, and 36 h. After a further 10 h
the solution was concentrated. The residue was dissolved in
acetonitrile (5 mL) and extracted with hexanes (3 × 5 mL).
The acetonitrile layer was concentrated, and the residue was
chromatographed on silica gel with a linear gradient of 35-
65% ethyl acetate/hexanes to give unreacted 32a (8.1 mg) and
32b (1.0 mg, 11%) as a colorless syrup: 1H NMR (300 MHz,
CDCl3) δ 1.43 (s, 3H), 2.45 (dd, J ) 9.5 Hz, J ) 17.8 Hz, 1H),
3.12 (d, J ) 17.8 Hz, 1H), 3.73 (d, J ) 8.0 Hz, 1H), 3.81 (s,
3H), 3.82-3.91 (m, 1H), 4.08 (bs, 1H), 4.34 (bs, 1H), 4.46-
4.66 (m, 5H), 4.70 (d, J ) 2.1 Hz, 1H), 4.79 (d, J ) 12.4 Hz,
1H), 4.86 (bs, 1H), 4.87 (d, J ) 11.2 Hz, 1H), 5.02 (d, J ) 8.0
Hz, 1H, H1), 5.30 (s, 1H), 6.88 (d, J ) 8.4 Hz, 2H), 7.20-7.45
(m, 12H); GC/MS (NH3) m/z 604 (MH)+, 446 (MH - PMBOH)+;
HRMS calcd for C34H37NO9 604.2536, found 604.2556.
[R]20 ) -56.1° (c 0.5, CHCl3); HRMS calcd for C34H37NO8
D
588.2587, found 588.2601.
N-[(1R,2R,6R,7R,8S,10S,11S,12S)-11,12-Bis(ben zyloxy)-
7-iodo-10-[(p-m eth oxyben xyl)oxy]-4-oxo-5,9-dioxatr icyclo-
[6.3.1.02,6]d od ec-1-yl]a ceta m id e (32a ). To compound 29c
(12.7 mg, 21.6 µmol), in dry CH3CN (2.5 mL), was added
iodonium dicollidine perchlorate (15.2 mg, 32.4 µmol), and the
mixture was stirred in the dark for 4 h. It was then
concentrated, dissolved in aqueous Na2S2O3 (5 mL), and
extracted with CH2Cl2 (2 × 5 mL). The combined organic
layers were dried, filtered, and concentrated. The residue was
chromatographed on silica gel with 25-75% ethyl acetate/
hexanes (linear gradient) to give the title compound 32a (13.2
mg, 86%): 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 3H), 2.42 (dd,
J ) 9.3 Hz, J ) 17.7 Hz, 1H), 3.10 (dd, J ) 17.7 Hz, 1H), 3.76
(d, J ) 8.0 Hz, 1H), 3.81 (s, 3H), 4.01 (dd, J ) 6.2 Hz, J ) 9.1
Hz, 1H), 4.46-4.54 (m, 3H), 4.57-4.63 (m, 2H), 4.71 (d, J )
1.4 Hz, 1H), 4.78 (d, J ) 12.4 Hz, 1H), 4.83-4.90 (m, 2H), 5.02
(d, 6.2 Hz, 1H), 5.20 (d, J ) 8.0 Hz, 1H), 5.22 (d, J ) 2.1 Hz,
1H), 6.89 (d, J ) 8.6 Hz, 2H), 7.23-7.48 (m, 12H); 13C NMR
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for 23 and 34 along with characterization data for 19,
20a , 21a , 22b, 23, 25a , 27a , 28b, 29a , 29b, 30, 31, and 34 (7
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O951747O