Formal Synthesis of (+)- and (-)-Perhydrohistrionicotoxin: A "Double Henry"/Enzymatic Desymmetrization Route to the Kishi Lactam

Article abstract of DOI:10.1021/jo990293i

Both antipodes of the Kishi lactam (3), the versatile intermediate for the synthesis of the perhydrohistrionicotoxin (pHTX) alkaloids, have been prepared. The synthetic route involved a "double Henry" condensation between glutaraldehyde and nitroacetal 5 giving meso dioxanyldiol 4 which was acetylated and reduced to afford meso dioxane amide 8. Ultrasound-promoted deacetalization of 8 followed by Wittig olefination and reduction provided meso amide ester 10. Hydrolysis of 10 with aqueous acid followed by dehydrative cyclization with dicyclohexylcarbodiimide gave lactamdiol 11. Acetylation of 11 gave meso diacetate 2 which was an excellent substrate for esterase-mediated hydrolysis to hydroxyacetate 12. Deoxygenation of 12 using a Barton protocol, followed by Zemplen deacylation and Swern oxidation, gave the (-)-antipode of the Kishi lactam (3). Moffatt oxidation of hydroxyacetate 12 followed by ketal protection and Zemplen deacylation gave ketalalcohol 19. Barton deoxygenation of 19 followed by ketal hydrolysis gave (+)-3.

Full text of DOI:10.1021/jo990293i

J . Org. Chem. 1999, 64, 5485-5493
5485
F or m a l Syn th esis of (+)- a n d (-)-P er h yd r oh istr ion icotoxin : A
“Dou ble Hen r y”/En zym a tic Desym m etr iza tion Rou te to th e Kish i
La cta m 1
Frederick A. Luzzio* and Richard W. Fitch
Department of Chemistry, University of Louisville, Louisville, Kentucky 40292
Received February 17, 1999
Both antipodes of the Kishi lactam (3), the versatile intermediate for the synthesis of the
perhydrohistrionicotoxin (pHTX) alkaloids, have been prepared. The synthetic route involved a
“double Henry” condensation between glutaraldehyde and nitroacetal 5 giving meso dioxanyldiol
4 which was acetylated and reduced to afford meso dioxane amide 8. Ultrasound-promoted
deacetalization of 8 followed by Wittig olefination and reduction provided meso amide ester 10.
Hydrolysis of 10 with aqueous acid followed by dehydrative cyclization with dicyclohexylcarbodiimide
gave lactamdiol 11. Acetylation of 11 gave meso diacetate 2 which was an excellent substrate for
esterase-mediated hydrolysis to hydroxyacetate 12. Deoxygenation of 12 using a Barton protocol,
followed by Zemple´n deacylation and Swern oxidation, gave the (-)-antipode of the Kishi lactam
(3). Moffatt oxidation of hydroxyacetate 12 followed by ketal protection and Zemple´n deacylation
gave ketalalcohol 19. Barton deoxygenation of 19 followed by ketal hydrolysis gave (+)-3.
Over 120 species of brightly colored “poison-dart” frogs
live in the tropical rain forests of South America. The
glands found in the skin of these frogs produce toxins
which are harmful to predators. Some of the skin secre-
tions having higher toxicity are used by South American
Indians to poison blowgun darts for hunting.2 The neu-
rotoxic alkaloids isolated from the skin of the South
American frog Dendrobates histrionicus are termed the
histrionicotoxins (1) and have been used extensively as
neurological probes for the acetylcholine receptor chan-
nel.3 The spirocyclic core of the histrionicotoxins together
with the high unsaturation of the side chains have made
these compounds and their perhydro analogues (1a ) an
attractive area where new strategies or methodology may
be tested.4a-c Our enantioselective route to the perhydro
azaspirocyclic core intermediate 2, a subject of earlier
reports from our laboratory,5 en route to the Kishi lactam
3.6 Thus desymmetrization of meso 2 will allow access
to either antipode of 3; from (+) or (-)-3, the desired
antipode of 1a may be obtained by established routes
involving installation of the requisite side chains.6 We
chose meso nitrodiol 4, available from the tandem Henry
condensation7 (eq 1) of glutaraldehyde and nitrodioxane
5, to serve as the progenitor of meso lactamdiacetate 2
through reduction, two-carbon homologation and spiro-
cyclization.
The Kornblum reaction8 of commercially available 2-(2-
bromoethyl)-1,3-dioxane9 with sodium nitrite in either
(4) (a) For an early review in the histrionicotoxin area, see: Kotera,
M. Bull. Soc. Chim. Fr. 1989, 370-397. (b) HTX syntheses: Carey, S.
C.; Aratani, M.; Kishi, Y. Tetrahedron Lett. 1985, 26, 5887-5890. Stork,
G.; Zhao, K. J . Am. Chem. Soc. 1990, 112, 5875-5876. (c) pHTX
syntheses and approaches: Tanner, D.; Hagberg, L.; Poulsen, A.
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(1) Presented at the 6th Meeting of the European Society of
Sonochemistry, Rostock-Warnemu¨nde Germany, May 13, 1998; 216th
National Meeting American Chemical Society, Boston, MA, August 23
and 24, 1998; ORGN 143.
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H.; Suguira, S.; Inoue, S. J . Org. Chem. 1975, 40, 2009-2001.
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10.1021/jo990293i CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/25/1999

5486 J . Org. Chem., Vol. 64, No. 15, 1999
Luzzio and Fitch
Sch em e 1
DMSO or DMF provided nitroacetal 5 in 55% yield as
described previously.5 Considering ready availability,
expense, and amenability to scale-up, we examined a
direct preparation of 5 from acrolein and nitrous acid
followed by acetalization10 and found this protocol more
suitable for our requirements thereby providing 5 in
consistent yields of 70-75% on a 30-g scale. Henry
condensation of 5 with 50% aqueous glutaraldehyde
(1 equiv) in THF with a catalytic amount of 1,1,3,3-
tetramethylguanidine (TMG)11 afforded variable yields
of crystalline nitrodiol 4 (55-80%) after silica gel column
chromatography. While optimizing the yields of 4 we
found that its high degree of crystallinity and near
insolubility in a range of solvents facilitated its isolation
by direct crystallization from the reaction mixture. The
optimal conditions entailed the condensation of 5 with
freshly distilled glutaraldehyde in dry THF while em-
ploying TMG as the base. This expedient allowed the
direct iterative crystallization of 4 from the reaction
mixture and resulted in consistent yields of 80-87% on
a 5-8-g scale. In contrast to our previous results with
similar double Henry condensations using extended
nitroacetals,5 only minimal amounts (5-10%) of the
epimeric nitrodiol and tetrahydropyranyl alcohol12a could
be observed in the crude reaction mixtures contain-
of R, as in the cases of extended nitroacetals, the
equatorial position is demanded thus requiring a pseudo-
axial orientation in the aldehyde carbonyl. Steric repul-
sion with the side chain is thus minimized and the
cis,trans (d, l) diastereomers of 4 are the result. Using
the same chairlike transition state, the dioxanyl-substi-
tuted side chain R of 4 would also be expected to assume
a pseudoequatorial orientation. However, hydrogen bond-
ing is possible between the initially formed alcohol and
an oxygen of the dioxanyl side chain thereby restricting
its orientation to the axial position. The â-oxygen effect
may be further exemplified by the decreased formation
of the meso isomers when employing nitropentanal
acetals. Presumably the steric effects of the larger side
chain and the diminished stability of the hydrogen-
bonded species due to greater ring size combine to
increase the thermodynamic favorability of the cis,trans
(d, l) product. The lesser stability of meso 4 was demon-
strated by its epimerization on standing in methanol-d4
(see Supporting Information) or DMSO-d6 during the
course of several hours to several days while monitoring
by 1H NMR. The epimerization of 4 in methanol, a highly
polar solvent with hydrogen-bonding capability, is in
contrast to its indefinite stability in anhydrous THF,
showing little or no epimerization on standing for several
days or on heating to reflux during crystallization. While
4 is nearly insoluble in THF, except at reflux, the addition
of a small amount of water renders it almost infinitely
soluble. Although DMSO does not have the hydrogen
donor/acceptor properties of methanol, small amounts of
water present in the deuterated solvent are presumably
responsible for the behavior. These results leads us to
conclude that the disruption or integrity of intramolecu-
lar hydrogen bonding is a determining factor in the
formation and stability of highly crystalline meso 4.
1
ing 4. Although H and 13C NMR analysis suggested the
meso configuration of 4, the formation of the cis,cis
diastereomer was not ruled out. Conclusive proof of the
trans,trans stereochemistry of 4 was made later in our
synthesis (vide infra) by duplication of results reported
by the Kishi group with regard to the sodium borohydride
reduction of the Kishi lactam (-)-3 to the trans lactam
alcohol (+)-16. Given the possible stereochemical path-
ways and the equilibrium nature of the double Henry
reaction, thermodynamic control operates to give the
most stable products based on steric or stereoelectronic
factors. The transition-state conformations which may be
envisioned to account for the diastereoselection in the
6-exo-trig closure of the nitronate on the aldehyde require
the orientation of the side chain R in either the pseudo-
axial or pseudoequatorial position (Scheme 1).12b With
small R (H or methyl) occupying the pseudoaxial position,
the aldehyde carbonyl will be oriented in the pseu-
doequatorial position, as the hydroxyl group from the first
condensation, thereby resulting in the overall meso
configuration. With the increasing size and steric bulk
(8) Kornblum, N.; Powers, J . W. J . Org. Chem. 1957, 22, 455-456.
Kornblum, N.; Larson, H. L.; Blackwood, R. K.; Mooberry, D. D.;
Olivetto, E. P.; Graham, G. E. J . Am. Chem. Soc. 1956, 78, 1492-
1501.
(9) Bu¨chi, G.; Wu¨est, H. J . Org. Chem. 1969, 34, 1122-1123.
(10) (a) Miyakoshi, T.; Saito, S.; Kumanotani. Chem. Lett. 1981,
1677. (b) Ohrlein, R.; Schwab, W.; Ehrler, R.; J ager, V. Synthesis 1986,
535-538. (c) Fuji, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull.
1992, 40, 2344-2352.
(11) (a) Fitch, R. W.; Luzzio, F. A. Tetrahedron Lett. 1994, 35, 6013-
6016. (b) Simoni, D.; Invidiata, F. P.; Manfredini, S.; Ferroni, R.;
Lampronti, I.; Pollini, G. P. Tetrahedron Lett. 1997, 38, 2749-2752.
(12) (a) Lichtenthaler, F. W.; Fleischer, D. J . Org. Chem. 1972, 37,
1670-1672. (b) McNulty, J .; Mo, R. J . Chem. Soc. Chem. Commun.
1998, 933-934.
The preparation of amidodiacetate 8 was accomplished
through amidodiol 6 or nitrodiacetate 7 by a reduction/
acetylation sequence (Scheme 2). Our earlier-described
protocol for the ultrasound-promoted aluminum amalgam

Formal Synthesis of Perhydrohistrionicotoxin
J . Org. Chem., Vol. 64, No. 15, 1999 5487
Sch em e 2a
Sch em e 3a
a
Key: (a) Al(Hg), THF, H2O, ultrasound then Ac2O (55%). (b)
AcCl or BzCl, DMAP, CH2Cl2 (Ac, 81%; Bz, 99%). (c) Ra-Ni, H2,
THF then Ac2O, pyridine, reflux (91%). (d) Al(Hg), THF, H2O,
triethylamine, ultrasound then Ac2O, pyridine, reflux (51%) or
Al(Hg), THF, H2O, Ra-Ni, H2 followed by triethylamine, ultra-
sound, Ac2O, pyridine (67%).
reduction/acylation of nitroalkanols11a facilitated the
conversion of nitrodiol 4 to amidodiol 6. The employment
of power ultrasound and in situ acylation with 1-10
equiv of acetic anhydride was effective in the production
of 6 (55%) on a 50-mg scale. The amidodiacetate 8 was
obtained in similar fashion (51%) but required acetic
anhydride in refluxing pyridine to complete the acetyla-
tion. Larger-scale reductions of 4 were not amenable to
ultrasound promotion. The desired intermediate amino-
diol was accompanied by appreciable amounts of a
byproduct spectroscopically consistent with the corre-
sponding hydroxylamine and necessitated the use of
Raney nickel to force the reduction to completion. Opti-
mal yields of 8 (67%) were obtained by addition of Raney
nickel directly to the reaction mixture following con-
sumption of the nitrodiol by the amalgam while main-
taining a hydrogen atmosphere at 65 °C. Difficulties
associated with the isolation of products from the tandem
treatment with Al(Hg)/Ra-Ni prompted the employment
of Raney nickel alone for the reduction of 4. However,
the basicity of the reagent was responsible for providing
product containing 25% of the undesired epimer. The
epimerization could not be suppressed despite exhaustive
washing of the catalyst with water, methanol, and THF.
Interestingly, while ultrasound enhanced the rate of
reduction of 4 with Raney nickel alone, it did not suppress
the epimerization during the reductive process. Rosenthal
reported a similar epimerization during the reduction of
nitro alcohols in the carbohydrate series13 and solved the
problem by acylating the alcohol function prior to the
reduction. Accordingly, treatment of nitrodiol 4 with
acetyl chloride or benzoyl chloride in the presence of
DMAP provided the crystalline meso nitrodiesters 7
(81%) and 7a (99%). Reduction of 7 with Raney nickel
and hydrogen at 1 atm in THF followed by direct
N-acetylation with acetic anhydride in refluxing pyridine
afforded the crystalline amidodiacetate 8 in 91% yield
(Scheme 2). The deprotection/two-carbon homologation
of meso 8 to provide unsaturated ester 9 was ac-
complished in tandem sequence (Scheme 3). Initially,
deprotection of amidodiol 6 with aqueous acetic acid
Key: (a) AcOH, H2O, ultrasound, then EtOCOCH2PPh3+Br-,
a
Et3N (70%). (b) H2, Pd-C, MeOH (96%). (c) 1.2 N HCl, reflux, then
DCC, DMAP, py (91%). (d) AcCl, DMAP, CH2Cl2 (77%). (e) pig liver
esterase, pH ) 7, 14 d (87%). (f) MeOCOCOCl, DMAP, CH2Cl2
(87%, 13) or PhOCSCl, DMAP, CH2Cl2 (73%, 14). (g) Bu3SnH,
AIBN, PhCH3, 95 °C (93%). (h) NaOMe, MeOH (98%). (i) ClCO-
COCl, DMSO, CH2Cl2 (77%). (j) NaBH4, MeOH (86%).
(80%/80 °C) led to a complex mixture of elimination
products and was unsuitable for the subsequent olefina-
tion step. Submission of amidoacetate 8 to the same
reaction conditions as 6 gave variable crude yields (12-
54%) of the sensitive intermediate aldehyde which also
was accompanied by unidentified byproducts. Sonochem-
ical-promoted cleavage14 of the dioxane function of 8 with
aqueous acetic acid at 60 °C gave the best yield of the
intermediate aldehyde. The crude aldehyde was directly
olefinated with ethoxycarbonylmethyltriphenylphos-
phonium bromide and triethylamine and provided the
meso unsaturated ester 9 (70% from 8) after silica gel
column chromatography. Catalytic reduction of ester 9
with 10% palladium on activated charcoal under 1 atm
of hydrogen provided the saturated ester 10 as crystalline
plates in 96% yield. Ester 10 was converted to spirolac-
tam diacetate 2 by a three-step sequence. Submission of
10 to acid hydrolysis with refluxing 1.2 N HCl followed
by concentration of the reaction mixture and direct
treatment of the crude dihydroxyamino acid with dicy-
clohexylcarbodiimide15 and DMAP in pyridine effected
spirolactam formation (91% from 10). The intermediate
spirolactamdiol 11 was acetylated using acetyl chloride
and DMAP in CH2Cl2 to provide spirolactam diacetate 2
(77% from 11) as a white solid after silica gel flash
column chromatography (Scheme 3).
(14) Petrier, C.; Luche, J .-L. In Synthetic Organic Sonochemistry;
Luche, J .-L., Ed.; Plenum: New York, 1998; Chapter 2.
(13) Rosenthal, A.; Cliff, B. L. Carbohydr. Res. 1980, 79, 63-77.
(15) Klausner, Y. S.; Bodansky, M. Synthesis 1972, 453-463.

5488 J . Org. Chem., Vol. 64, No. 15, 1999
Luzzio and Fitch
Ta ble 1. Lip a se Desym m etr iza tion of Meso Su bstr a tes
provided 13 (87%) and 14 (73%). Treatment of methy-
loxalate 13 with tri-n-butyltin hydride and AIBN in
toluene resulted only in recovery of (-)-12, while treat-
ment of thionocarbonate 14 under similar conditions
afforded the desired crystalline spirolactam acetate 15
(93%) after purification by silica gel flash column chro-
matography. The spirolactam acetate 15 was deprotected
with sodium methoxide in methanol at room temperature
to provide the crystalline spirolactam alcohol 16 in 98%
yield (Scheme 3). Corey-Suggs,23 Moffatt,24 and Swern25
conditions were evaluated for the oxidation of spirolactam
alcohol 16 to the Kishi ketolactam 3. Treatment of 16
with pyridinium chlorochromate/silica gel in CH2Cl2 gave
crystalline (-)-3 in 28% yield while Moffatt conditions
employing DMSO and DCC provided pure (-)-3 in 73%
substrate
lipasea
product
yieldb (ee)
2
2
7
PLE
CRL
PLE
PLE
PLE
CRL
12
12
NR
NR
NR
NR
87% (93)
36% (50)
8
11c
11c
a
PLE ) pig liver esterase; CRL ) Candida rugosa lipase.
Yields are for isolated purified products. c Transesterification
b
with vinyl acetate.
Several avenues were explored for the preparation of
optically pure monoacetate 12 (Scheme 3). In principle,
enzyme-catalyzed transacylation of meso amidodiol 11
with an appropriate enol ester or enzymatic hydrolysis
of meso diacetate 2 will generate an excess of antipodal
12. Both pathways take advantage of desymmetrization
where an achiral meso substrate is regioselectively
acylated or deacylated to afford a single enantiomeric
product.16 Treatment of lactamdiol 11 with vinyl acetate
in the presence of porcine liver esterase (PLE) failed to
provide acylated products of any type. However, treat-
ment of lactamdiacetate 2 with PLE using a modification
of a method by Seebach and Eberle17 while maintaining
the pH at 7.5 furnished the crystalline (-)-monoacetate
12 in 87% chemical yield and 93% ee as determined by
19F NMR analysis of the Mosher ester derivative.18,19 In
comparison, similar experiments utilizing lipase from
Candida rugosa provided 12 of only 50% ee as deter-
mined by comparison of rotations with recrystallized 12
derived from PLE hydrolysis. In contrast to Seebach’s
results, the enzymatic hydrolysis of our substrate pro-
ceeded at a much slower rate thereby requiring reaction
times of 14-21 days at room temperature for reasonable
conversion. Furthermore, the earlier meso intermediates
in our synthetic scheme such as nitrodiacetate 7 and
acetamidodiacetate 8 completely resisted enzymatic hy-
drolysis (Table 1). The lengthy reaction times exhibited
by substrate 2 were in accord with those results reported
by Whitesell in connection with the enzymatic hydrolyses
of trans-2-phenylcyclohexyl acetate and trans-2-(1-meth-
yl-1-phenylethyl)cyclohexyl acetate.20 Presumably the
retarded response of our substrate to hydrolysis may be
attributed to the greater steric bulk at the spiro carbon
which is the center of a neopentyl ester system. The
methyloxalate 1321 and the phenylthionocarbonate 1422
were evaluated for their response to free radical deoxy-
genation. Treatment of (-)-12 with methyloxalyl chloride
or phenylthionochloroformate and DMAP in CH2Cl2
followed by flash column chromatography on silica gel
25
yield ([R]D -59.3). The Swern oxidation proved to be
optimal for the spirocyclic lactam alcohol where treat-
ment of 16 with DMSO and oxalyl chloride in CH2Cl2
provided (-)-3 in 77% yield after silica gel flash column
chromatography. The unavailability of published high-
resolution NMR spectra for comparison prompted us to
investigate the relative stereochemistry of our (-)-3 by
chemical methods. As Kishi and co-workers described the
preparation of (()-16 by reduction of (()-3, we reproduced
the result with enantioenriched 3. Sodium borohydride
reduction of (-)-3 in methanol afforded the resulting
alcohol (86%) which was identical in all respects (NMR,
IR, melting point, mixed melting point) with the product
of the deacetylation of 15 thereby inferring the trans
stereochemistry in both compounds.
The conversion of hydroxyacetate (-)-12 to (+)-3 was
mostly a matter of protecting group manipulation (Scheme
4). Oxidation of (-)-12 under either Swern conditions
(57%) or Moffatt conditions (73%) gave ketoacetate 17
after purification by silica gel column chromatography.
Protection of ketoacetate 17 by treatment with ethylene
glycol26 and p-toluenesulfonic acid in refluxing toluene
gave ketalacetate 18. The ketalacetate was directly
deacetylated with sodium methoxide in methanol to
afford the oily hydroxyketal 19 (84% from 17). The alcohol
function of 19 was derivatized with phenylthionochloro-
formate as previously done with alcohol 12 to provide
thionocarbonate 20 (49%, 87% corrected for recovered 12).
Not surprisingly the acylation of 19 was characterized
by extended reaction times with relatively sluggish
conversion to 20 thus necessitating recovery and recy-
cling of 19. Phenylthionocarbonate 20 was deoxygenated
as before with tri-n-butyltin hydride and AIBN at 90 °C
to give ketallactam 21 in 90% yield. Deprotection of 21
was effected by employing a mixture of aqueous acetic/
trifluoroacetic acid at room temperature and provided
(+)-3 (88%) after silica gel flash column chromatography.
(16) Ohno, M.; Otsuka, M. In Organic Reactions; Kende, A. S., Ed.;
J ohn Wiley: New York, 1989; Vol. 37, Chapter 1, pp 1-55. Adachi,
K.; Kobayashi, S.; Ohno, M. Chimia 1986, 40, 311-314.
(17) Eberle, M.; Egli, M.; Seebach, D. Helv. Chim. Acta 1988, 71,
1-21. Eberle, M.; Missbach, M.; Seebach, D. In Organic Syntheses;
Paquette, L., Ed.; J ohn Wiley: New York, 1990; Vol. 69, pp 19-30.
(18) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543-2549. Dale, J . A.; Mosher, H. S. J . Am. Chem. Soc. 1973, 95,
512-519.
25
Crystalline (+)-3 was spectrally identical to (-)-3 ([R]D
+60.3).
The absolute stereochemical assignment of the keto-
lactams R-(-)-3 and S-(+)-3 follows from previous inves-
(19) For a discussion on lipase selectivity, see: (a) J ones, J . B. Pure
Appl. Chem. 1990, 62, 1445-1448. (b) Cygler, M.; Grochulski, P.;
Kaslauskas, R.; Schrag, J . D.; Bouthillier, F.; Rubin, B.; Serraqu, A.
N.; Gupta, A. K. J . Am. Chem. Soc. 1994, 116, 3180-3186.
(20) Whitesell, J . K.; Lawrence, R. M. Chimia 1986, 40, 318-321.
(21) Dolan, S. C.; MacMillan, J . J . Chem. Soc. Chem. Commun. 1985,
1588-1589. Zhang, C.; Trudell, M. L. J . Org. Chem. 1996, 61, 7189-
7191.
(23) (a) Corey, E. J .; Suggs, J . W. Tetrahedron Lett. 1975, 2647-
02550. (b) Adams, L. L.; Luzzio, F. A. J . Org. Chem. 1989, 54, 5387-
5390.
(24) Mancusco, A. J .; Huang, S.-L.; Swern, D. J . Org. Chem. 1978,
43, 2480-2482.
(25) Moffatt, J . J . In Oxidation; Augustine, R., Trecker, D. J ., Eds.;
Marcel Dekker: New York, 1971; Vol. 2, pp 1-64.
(26) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; 2nd ed.; J ohn Wiley: New York, 1991; pp 188-195.
(22) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975, 1574-1585. Robins, M. J .; Wilson, J . S. J . Am. Chem. Soc.
1989, 54, 5387-5390.

Formal Synthesis of Perhydrohistrionicotoxin
J . Org. Chem., Vol. 64, No. 15, 1999 5489
Sch em e 4a
quent intermediates until stereodiverged by enzymatic
desymmetrization. Although there are slight differences
in biological activity between the known (+)- and (-)-
perhydrohistrionicotoxins, the synthesis provides an
avenue for preparing either antipode of the perhydroh-
istrionicotoxins, with side chains of variable length and
complexity, for future biological investigations. With
limitations only on the architecture of the side chains to
be conjoined to the chiral Kishi lactam, the present
methodology will allow for the preparation of a large
array of chiral histrionicotoxin analogues.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were conducted under an
atmosphere of dry nitrogen unless otherwise noted. Where
required, THF and ether were distilled from Na/benzophenone
ketyl, CH2Cl2 and pyridine from CaH2, DMSO from CaH2
under reduced pressure, and acetone from CaSO4. All other
solvents were reagent grade and were used as received. Pig
liver esterase (EC 3.1.1.1) was purchased from Sigma-Aldrich
as a suspension of 11 mg/mL enzyme in 3.2 M ammonium
a
Key: (a) ClCOCOCl, DMSO, CH2Cl2 (57%) or DMSO, DCC,
sulfate (pH 8) at
a specific activity of 230 U/mg (ethyl
H3PO4 (73%). (b) HOCH2CH2OH, TsOH, PhCH3. (c) NaOMe,
MeOH (84% from 17). (d) PhOCSCl, DMAP, CH2Cl2 (87%). (e)
Bu3SnH, AIBN, PhCH3, 95 °C (90%). (f) AcOH, TFA, H2O (88%).
butyrate). Buffer solutions were prepared using reagent grade
potassium hydrogen phosphate and potassium hydroxide in
analytical grade deionized, distilled water. Gravity column
chromatography was carried out using E. Merck silica gel
7734, 70-230 mesh. Flash column28 chromatography employed
E. Merck silica gel 9385, 230-400 mesh. Analytical thin-layer
chromatography was performed using glass-backed plates (E.
Merck 5715 silica gel 60 F254). Visualization of thin-layer
chromatograms utilized 2% anisaldehyde/ethanol stain. Melt-
ing points are uncorrected. 1H and 13C NMR spectra were
recorded at 500.13 and 125.77 MHz, respectively, or 299.95
and 75.42 MHz, respectively. Proton coupling constants (J ) are
reported in hertz. 19F NMR spectra were recorded at 282.21
MHz. Infrared spectra (FTIR) were taken as a neat film or
KBr pellet and are expressed in cm-1. Elemental analyses were
carried out at Schwartzkopf Microanalytical Laboratory, Wood-
side, New York.
tigations involving lipase selectivity and correlation with
the homologous ketolactam 22 and its ketal derivative
23. Most lipases have been demonstrated to hydrolyze
the pro-R center with exceptions occurring in cases of
long-chain esters and/or small ring substrates. Therefore
m eso-(1r ,2R,6S)-1-Nitr ocycloh exa n e-2,6-d iol-1-a ceta l-
d eh yd e, 1,3-P r op a n ed iol Aceta l (4). Anhydrous glutaral-
dehyde was prepared by saturation of a 50% aqueous solution
with solid NaCl, extraction with ether, drying over sodium
sulfate, concentration, and vacuum distillation with collection
of the fraction boiling at 55-56 °C/2.5 mm (lit.29 71-72 °C/10
lipase-mediated hydrolysis of the pro-R center in meso 2
followed by the deoxygenation sequence at that carbon
will give the R spiroketolactam (-)-3. The preparation
of homologous enantiopure ketolactam (S)-(+)-22 and its
enantiomer was reported by Nagasaka27 and their abso-
lute configurations were established by a circular dichro-
ism and X-ray crystallography study of the corresponding
(3R,4R)-3,4-dimethyldioxolane derivative 23 of ketolac-
1
mm). Glutaraldehyde so obtained was anhydrous by H NMR
and could be stored for several days at -40 °C. Material stored
for 6 weeks had polymerized to a glassy semisolid, but could
be depolymerized by heating gently under nitrogen and
redistilling. To a solution of nitroacetal (5.84 g, 36.2 mmol) in
dry THF (25 mL) was added anhydrous glutaraldehyde (3.50
mL, 36.0 mmol) followed by 1,1,3,3-tetramethylguanidine (0.23
mL, 1.83 mmol). The resulting yellow solution was shaken
briefly and allowed to stand over 3 days during which time a
first crop (4.52 g) was obtained. The mother liquor was
decanted, and the crystals were washed with dry THF (10 mL).
The mother liquor was concentrated, and the solids were
redissolved by heating and addition of just enough THF to
produce a homogeneous yellow-orange solution. Slow evapora-
tion of the solvent afforded a second crop (2.21 g). The process
was repeated to obtain four crops totaling 8.21 g (87%) of 4 as
colorless prisms: mp 173-175 °C (dec); Rf ) 0.22 (19:1 CH2-
Cl2/acetone); IR (pellet) ν 1539, 1343; 1H NMR (500 MHz,
DMSO-d6) δ 5.10 (br s, 2H [OH]), 4.95 (t, J ) 3.8, 1H), 3.67
(m, 4H), 3.67 (t, J ) 10.6, 2H), 2.25 (d, J ) 3.8, 2H), 1.85 (m,
1H), 1.64 (m, 1H), 1.62 (m, 2H), 1.42 (m, 2H), 1.35 (m, 1H),
1.29 (d, J ) 13.2, 1H); 13C NMR (125 MHz, CDCl3) δ 99.8, 98.8,
25.6
tam (S)-(+)-22. The optical rotations of (S)-(+)-22, [R]D
+ 68.2 (c ) 1.0, CHCl3), and its enantiomer, [R]D24.4 -68.0
(c ) 1.0, CHCl3) correlated with our (S)-(+)-3 and (R)-
(-)-3 with respect to sign of rotation.
In summary, we have developed an efficient synthetic
route to both antipodes of the Kishi lactam thereby
constituting a formal synthesis of (-)- and (+)-perhydro-
histrionicotoxin. Starting from acrolein the synthesis of
(-)-3 required a linear sequence of 13 steps and resulted
in a 11% overall yield. Compound (+)-3 required 15 steps
and resulted in a 9% overall yield. The synthesis em-
ployed a one-step double Henry nitroaldol condensation
which establishes both the tertiary carbon of the azaspi-
rocyclic system and the meso configuration of all subse-
(28) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2924.
(27) Nagasaka, T.; Sato, H.; Saeki, S. Tetrahedron: Asymmetry
1997, 8, 191-194.
(29) Stoll, A.; Lindemann, A.; J ucker, E. Helv. Chim. Acta 1953, 36,
268-274.

5490 J . Org. Chem., Vol. 64, No. 15, 1999
Luzzio and Fitch
74.0, 66.3, 32.4, 30.4, 25.0, 19.5; MS (ES+) 284.1 (M + Na);
MS (ES-) 260.3 (M - H). Anal. Calcd for C11H19NO6: C, 50.57,
H, 7.33, N, 5.36. Found: C, 50.46, H, 7.29, N, 5.28.
diacetate was concentrated and then redissolved with a small
amount of ether and allowed to slowly evaporate, affording 7
(4.83 g, 81%) as colorless rhombs: Rf ) 0.62 (19:1 CH2Cl2/
acetone); IR (pellet) ν 1750, 1550; 1H NMR (500 MHz, CDCl3)
δ 5.39 (dd, J ) 4.2, 10.0, 2H), 4.80 (t, J ) 4.2, 1H), 4.07, dd, J
) 5.1, 10.9, 2H), 3.72 (td, J ) 2.3, 12.5, 2H), 2.52 (d, J ) 4.2,
2H), 2.05 (qt, J ) 5.1, 12.5, 1H), 2.00, (s, 6H), 1.93 (dq, J )
4.4, 13.2, 2H), 1.77 (dp, J ) 3.9, 13.4, 1H), 1.64 (m, J ) 4.2,
11.2 2H) 1.53 (m, J ) 3.9, 11.3, 13.4, 1H), 1.31 (m, J ) 1.2,
13.6, 1H); 13C NMR (125 MHz, CDCl3) δ 169.0, 99.3, 92.6, 74.0,
67.1, 35.1, 27.1, 25.4, 20.9, 18.3; MS (ES+) 368.0 (M + Na).
Anal. Calcd for C15H23NO8: C, 52.17, H, 6.71, N, 4.06. Found:
C, 52.06, H, 6.83, N, 3.89.
m eso-(1r ,2R,6S)-2,6-Diben zoyloxy-1-n itr ocycloh exa n e-
1-a ceta ld eh yd e, 1,3-P r op a n ed iol Aceta l (7a ). To a suspen-
sion of nitrodiol 4 (96.9 mg, 0.37 mmol) and 4-DMAP (140 mg,
1.14 mmol) in CH2Cl2 (2 mL) was added benzoyl chloride (108
µL, 0.93 mmol) dropwise by syringe. The resulting yellow
solution was stirred (2 h), concentrated, and flash chromato-
graphed on silica gel (ether/hexanes 1:1) to afford 7a (177 mg,
99%) as a foam. Crystallization from ether/hexanes yielded
colorless prisms: mp 173-174 °Cl Rf ) 0.68 (19:1 CH2Cl2/
acetone); 1H NMR (500 MHz, CDCl3) δ 8.0 (ddapp, J ) 1.2, 8.4,
4H), 7.56 (ttapp, J ) 1.2, 6.9, 7.5 2H), 7.36 (tapp, J ) 8.0 4H),
5.92 (t, J ) 4.2, 2H), 4.78 (t, J ) 4.5, 1H), 3.95 (dd, J ) 4.9,
11.1, 2H), 3.64 (dt, J ) 2.3, 12.4, 2H), 2.61 (d, J ) 4.5, 2H),
1.98 (m, J ) 13.4, 4H), 1.93 (m, J ) 5.1, 13.1 2H) 1.61 (m, J
) 5.0, 1H), 1.22 (m, J ) 1.2, 13.5, 1H); 13C NMR (125 MHz,
CDCl3) δ 165.3, 133.3, 129.8, 129.7, 128.4, 98.3, 91.0, 72.7, 66.8,
37.5, 27.0, 25.2, 16.2; MS (ES+) 492.5 (M + Na). Anal. Calcd
for C25H27NO8: C, 63.96, H, 5.80, N, 2.98. Found: C, 63.74,
H, 5.70, N, 2.82.
meso-(1r ,2R,6S)-1-Acetam ido-2,6-diacetoxycycloh exan e-
1-a ceta ld eh yd e, 1,3-P r op a n ed iol Aceta l (8). A. F r om 4 by
Alu m in u m Am a lga m . Nitrodiol 4 (62.3 mg, 0.234 mmol) was
placed in a test tube (25 × 100 mm) immersed in a thermo-
stated jacketed reaction vessel at 25 °C and dissolved in dry
THF (4.5 mL) and water (0.5 mL). Food packaging grade
aluminum foil (129 mg, 4.8 mmol) was cut into strips (1.0 ×
5.0 cm) and spirally wound about a glass stirring rod. Each
coil was individually amalgamated by sequential agitation
(using forceps) in ether (20 s), 2% aqueous HgCl2 (20 s), and
ether (5 s). As each coil was prepared it was added to the
solution at 30-min intervals, during which time ultrasound
(power level 2) was applied. After complete addition of the
amalgam, the reaction mixture was sonolyzed for an additional
60 min, and triethylamine (0.5 mL) was added. The thick gray
slurry was filtered through a fritted glass funnel packed with
Celite (1.0 cm), and the filter cake was washed with THF (25
mL). The filtrate containing amine was concentrated and
reconstituted in pyridine (1.0 mL) and acetic anhydride (1.0
mL). The solution was refluxed (1 h) and concentrated under
vacuum, followed by trituration with CH2Cl2. The residue was
flash chromatographed (EtOAc/hexanes, 9:1) to afford 47.0 mg
(51%) of 8 as colorless needles: mp 154-156 °C; Rf ) 0.31
(EtOAc); IR (pellet) ν 3372, 1744; 1H NMR (500 MHz, CDCl3)
δ 6.70 (br s, 1H), 5.91 (dd, J ) 4.6, 11.8, 2H), 5.14 (t, J ) 5.6,
1H), 4.14, dd, J ) 4.9, 11.6, 2H), 3.79 (t, J ) 12.0, 2H), 2.12
(m, 1H), 2.09 (d, J ) 5.6, 2H), 2.02, (s, 6H), 1.91 (m, 2H), 1.70
(s, 3H), 1.66 (m, 1H), 1.55 (qt, 1H), 1.40 (m, 3H); 13C NMR
(125 MHz, CDCl3) δ 169.4, 169.2, 100.6, 71.8, 67.0, 32.7, 27.0,
25.6, 24.4, 21.1, 19.4; MS (ES+) 380.0 (M + Na); MS (ES-)
356.4 (M - H). Anal. Calcd for C17H27NO7: C, 57.13, H, 7.61,
N, 3.92. Found: C, 57.32, H, 7.72, N, 3.93. Alternatively, the
yield of 8 was increased to 67% by adding a 50% aqueous slurry
of Raney nickel to the suspension on consumption of the
aluminum amalgam. Before addition of the Raney nickel to
the suspension, it was decanted from the stock aqueous slurry
and washed with water, MeOH, and then THF. Following
addition of the Raney nickel the flask was fitted with a
hydrogen balloon and stirring was continued for 3 h. Workup
and chromatography were conducted as described above.
B. F r om 7 by Ra n ey Nick el. A 50% aqueous slurry of
Raney Nickel (2.0 mL) was decanted and washed with water
(3 × 5 mL), MeOH (3 × 2 mL), and THF (3 × 4 mL). The solid
2-(2-Nitr oeth yl)-1,3-d ioxa n e (5). To a solution of THF (66
mL) and water (33 mL), cooled to 0 °C, was added NaNO2 (20.0
g, 0.29 mol). After dissolution, the resulting biphasic mixture
was vigorously stirred and acrolein (11.2 g, 0.20 mol) was
added in one portion. Glacial acetic acid (26.2 g, 0.44 mol) was
then added from a dropping funnel over 30 min. The solution
was stirred at 0 °C (1 h) and adjusted to a pH 1 with
concentrated H3PO4. The solution was sparged under nitrogen
flow until brown nitrogen oxides were no longer observed and
saturated with solid NaCl. The organic phase was separated,
and the aqueous layer was extracted with ethyl acetate (5 ×
50 mL). The combined organic extracts were washed with brine
(2 × 100 mL), dried over sodium sulfate, and concentrated to
a yellow oil. The crude nitropropanal was dissolved in benzene
(100 mL) and then 1,3-propanediol (30 mL, 67.8 mmol) and
p-toluenesulfonic acid monohydrate (950 mg, 1.5 mmol) were
added. The mixture was refluxed with azeotropic removal of
water until no further accumulation was noted (5 h). After
cooling, the solution was diluted with ether (100 mL) and
washed with 10% sodium bicarbonate solution (2 × 40 mL)
and brine (2 × 50 mL). The washings were back-extracted with
ether (2 × 20 mL), and the combined extracts were dried over
Na2SO4. Concentration and vacuum distillation afforded 24.15
g (75%) of 5: bp 73-75 °C/0.002 mm (lit.10c 80-83 °C/0.8 mm).
m eso-(1r ,2R,6S)-1-Aceta m id ocycloh exa n e-2,6-d iol-1-a c-
eta ld eh yd e, 1,3-P r op a n ed iol Aceta l (6). Food packaging
grade aluminum foil (104 mg, 3.85 mmol) was cut into strips
(1.0 × 5.0 cm) and spirally wound about a glass stirring rod.
Each coil was individually amalgamated by sequential agita-
tion (using forceps) in ether (20 s), 2% aqueous HgCl2 (20 s),
and ether (5 s). As each coil was prepared it was added to a
solution of nitrodiol 4 (50.4 mg, 0.19 mmol) dissolved in THF
(5 mL) and water (0.2 mL) in a test tube (25 × 100 mm)
immersed in a thermostated jacketed reaction vessel at 25 °C.
A 1/4 in. microtip ultrasonic probe was immersed below the
surface of the liquid (1 cm) and ultrasound (power level 2) was
applied. The reaction mixture was sonolyzed (3 h) and acetic
anhydride (45 µL, 0.48 mmol) was added. Sonolysis was
continued for an additional 60 min. The thick gray slurry was
filtered through a fritted glass funnel packed with Celite (1.0
cm), and the filter cake was washed with THF (10 mL). The
filtrate was concentrated and flash-chromatographed (EtOAc/
MeOH 10:0, 9:1, 25 mL each) to afford 29.2 mg (55%) of 6 as
an amorphous white solid: Rf ) 0.15 (EtOAc), 0.38 (EtOAc/
MeOH 9:1); IR (pellet) ν 3367, 1653; 1H NMR (500 MHz,
CDCl3) δ 6.69 (br s, 1H), 5.51 (br s, 2H), 4.64 (t, J ) 4.4, 1H),
4.08, (dd, J ) 4.9, 11.8, 2H), 3.73 (td, J ) 1.9, 11.8, 2H), 3.42
(br d, J ) 10.4, 2H), 2.29 (d, J ) 4.4, 2H), 2.06 (m, 1H), 2.02,
(s, 3H), 1.74 (m, 2H), 1.65 (m, 1H), 1.34 (m, 4H); 13C NMR
(125 MHz, CDCl3) δ 172.0, 100.7, 75.4, 67.2, 65.3, 29.7, 25.2,
24.1, 20.6; MS (ES+) 296.5 (M + Na); MS (ES-) 272.4 (M -
H). A less polar byproduct (12.7 mg, 24%) having spectral
properties consistent with the corresponding hydroxylamine
was isolated as a cloudy yellow oil: 1H NMR (500 MHz, CDCl3)
δ 4.91 (t, 1H, J ) 5.5), 4.08 (dd, 2H, J ) 4.6, 11.5), 2.74 (dt,
2H), 3.69 (m, 2H), 2.03 (m, 1H), 2.0 (d, 2H), 1.75 (m, 3H), 1.45
(m, 2H), 1.27 (m, 2H). Attempts to obtain the compound in
sufficient purity for further analyses were unsuccessful.
m eso-(1r ,2R,6S)-2,6-Dia cet oxy-1-n it r ocycloh exa n e-1-
a ceta ld eh yd e, 1,3-P r op a n ed iol Aceta l (7). To a suspension
of nitrodiol 4 (4.53 g, 17.4 mmol) and DMAP (5.50 g, 45 mmol)
in CH2Cl2 (80 mL) was added acetyl chloride (3.0 mL, 3.31 g,
42.2 mmol) dropwise by syringe over 20 min. The resulting
yellow solution was stirred for 2 h, during which time the diol
completely dissolved and a slight precipitate of DMAP‚HCl
developed. The reaction mixture was diluted with ethyl acetate
(50 mL), allowed to stand 10 min, and filtered through a 100
mL fritted glass funnel packed with Celite (1 cm) and silica
gel (3 cm). The yellow filtrate was concentrated to half the
original volume, diluted with ether (100 mL), and refiltered.
The filter cake was washed thoroughly, and the colorless
filtrate was diluted with hexanes (100 mL). The solution of

Formal Synthesis of Perhydrohistrionicotoxin
J . Org. Chem., Vol. 64, No. 15, 1999 5491
was rinsed with THF (5 mL) into a solution of nitrodiacetate
7 (3.45 g 10.0 mmol) in THF (45 mL) in a 100-mL Schlenk
tube equipped with a magnetic stir bar and a coldfinger
condenser. The solution was purged with hydrogen, heated to
just below reflux temperature (60 °C), and vigorously stirred
overnight (14 h) under a hydrogen atmosphere (balloon, 1 atm).
The mixture was filtered, concentrated, and reconstituted in
pyridine (15 mL) and acetic anhydride (15 mL). The solution
was refluxed (1 h), and the solvent was removed under
vacuum. Crystallization of the residual solid from warm
EtOAc/hexanes afforded 3.24 g (91%) of 8 as colorless needles
identical in all respects to that obtained by aluminum amal-
gam. The use of EtOAc as the reduction solvent instead of THF
led to similar results.
3.6, 12.9, 2H), 1.31 (m, 1H); 13C NMR (125 MHz, CDCl3) δ
176.8, 75.0, 64.3 (C6), 31.2, 29.0, 19.9, 19.2, 19.1; 1H NMR (500
MHz, CD3OD) δ 3.35 (dd, J ) 4.1, 11.4, 2H), 2.20 (t, J ) 6.3,
2H), 1.85 (sxt, J ) 5.7, 2H), 1.79 (m 2H), 1.73 (dq, J ) 2.7,
13.1, 2H), 1.70 (dp, J ) 3.1, 13.2, 2H), 1.42 (qd, J ) 3.5, 12.8,
2H), 1.31 (qt, J ) 3.0, 13.1, 1H); 13C NMR (125 MHz, CD3OD)
δ 177.9, 76.3, 65.1, 32.1, 31.0, 21.1, 20.3, 20.2; MS (ES+) 222.1
(M + Na); MS (ES-) 198.3 (M - H).
m eso-(6r ,7R ,11S )-7,11-D ia c e t o x y -1-a za s p ir o [5,5]-
u n d eca n -2-on e (2). To a solution of spirolactam diol 11 (9.5
mg, 0.041 mmol) in dry CH2Cl2 (0.50 mL) was added 4-(dim-
ethylamino)pyridine (15.4 mg, 0.12 mmol) followed by acetyl
chloride (8.0 µL, 0.11 mmol) by syringe. The solution was
stirred (20 min) and directly flash chromatographed to afford
2 (10.0 mg, 77%) as a white solid: mp 128-130 °C; Rf ) 0.60
(4:1 EtOAc/MeOH); IR (pellet) ν 1744, 1671; 1H NMR (500
MHz, CDCl3) δ 5.57 (br s, 1H), 4.61 (dd, J ) 4.0, 10.6, 2H),
2.25 (t, J ) 6.4, 2H), 2.01 (s, 6H), 1.93 (m, 2H), 1.85 (m, 4H),
1.73 (m, 1H), 1.48 (m, 2H), 1.43 (m, 1H); 13C NMR (125 MHz,
CDCl3) δ 173.9, 169.9, 76.4, 60.8, 31.3, 27.0, 21.5, 21.0, 19.3,
18.9; MS (ES+) 305.9 (M + Na). Anal. Calcd for C14H21NO5:
C, 59.35, H, 7.47, N, 4.94. Found: C, 59.32, H, 7.36, N, 5.03.
(-)-(6S,7S,11R)-7-Acetoxy-11-h yd r oxy-1-a za sp ir o[5,5]-
u n d eca n -2-on e (12). To a suspension of spirolactam diacetate
2 (105.5 mg, 0.37 mmol) in 0.27 M phosphate buffer (5 mL,
pH ) 7) was added pig liver esterase (1.0 mL, 2530 U),
resulting in a pH of 7.5. The resulting suspension was stirred
at room temperature (14 days) with periodic (24-48 h)
readjustment of pH to 7.5 using 1 N KOH. When the reaction
was judged complete by TLC analysis (performed by direct
spotting of the aqueous suspension, followed by removal of
water from the TLC plate under vacuum and development),
the mixture was saturated with solid NaCl and adjusted to
pH 5 with 1.2 N HCl. The solution was then filtered slowly
through glass wool. Ethyl acetate (10 × 5 mL) was used to
sequentially wash the filter cake and extract the filtrate. The
combined washings/extracts were dried over sodium sulfate
and concentrated under vacuum to a white solid. The residue
was flash chromatographed on silica gel (10 × 100 mm, packed
with EtOAc, and eluted with EtOAc/MeOH [10:0/9:1/4:1, 50
m eso-(E)-(1r ,2R,6S))-1-Aceta m id o-2,6-d ia cetoxycyclo-
h exa n e-2-bu ten oic Acid , Eth yl Ester (9). Amide 8 (200 mg,
0.51 mmol) was placed in a test tube (25 × 100 mm). Glacial
acetic acid (4.0 mL) and water (1.0 mL) were added. The
solution was sonolyzed (power level 2) at ambient temperature
(1 h). The solution containing the intermediate aldehyde was
concentrated under vacuum and redissolved in CH2Cl2 (4.0
mL). Ethoxycarbonylmethyltriphenylphosphonium bromide
(443 mg, 1.03 mmol) was added, followed by triethylamine
(0.22 mL, 1.58 mmol). The solution was stirred at room
temperature (14 h), concentrated to an oil, and flash chro-
matographed on silica gel (9:1 EtOAc/hexanes) to afford 9 (144
mg, 70%) as an amorphous solid: Rf ) 0.48 (EtOAc); IR (pellet)
1
ν 1742, 1685; H NMR (500 MHz, CDCl3) δ 7.06 (dt, J ) 7.6,
15.5, 1H), 5.88 (d, J ) 15.7, 1H), 5.39 (dd, J ) 4.2, 10.4, 2H),
5.38 (br s, 1H), 4.17 (q, J ) 7.2, 2H), 2.97 (dd, J ) 1.0, 15.6,
2H), 2.03 (s, 6H), 1.85 (s, 3H), 1.82 (m, 2H), 1.76 (dp, J ) 4.1,
13.2, 1H), 1.57 (ad, J ) 4.2, 12.5, 2H), 1.48 (qt, J ) 4.2, 12.3,
1H), 1.26 (t, J ) 7.2, 3H); 13C NMR (125 MHz, CDCl3) δ 170.3,
169.9, 166.17, 144.9, 123.47, 73.49, 62.7, 60.3, 29.9, 27.1, 24.6,
21.0, 18.9, 14.2; MS (ES+) 392.4 (M + Na); MS (ES-) 368.4 (M
- H). Anal. Calcd for C18H27NO7: C, 58.52, H, 7.37, N, 3.79.
Found: C, 58.48, H, 7.36, N, 3.67.
m eso-(1r ,2R,6S)-1-Acet a m id o-2,6-d ia cet oxycycloh ex-
a n ebu ta n oic Acid , Eth yl Ester (10). To a solution of
unsaturated ester 9 (60 mg, 0.15 mmol) in methanol (5.0 mL)
was added 10% palladium on activated charcoal (6.0 mg) under
hydrogen (1 atm). The resulting black suspension was stirred
at room temperature (18 h) and filtered through a fritted glas
funnel packed with Celite (1.0 cm). The filtrate was concen-
trated to afford the saturated ester 10 (57.5 mg, 96%) as an
off-white solid. Recrystallization afforded colorless needles: mp
25
mL each]) to afford 78.1 mg (87%) of 12: mp 165-166 °C; [R]D
-15.0 (c ) 1.04, CHCl3) after crystallization; 93% ee as
determined by integration of the 19F signals of the correspond-
ing (S)-(+)-MTPA ester, major 4.92, minor 4.42 (relative to 3%
TFA in CDCl3) [equally good results could be obtained by
integration of the CHO MTPA proton resonance (major 4.83,
minor 4.91)]; Rf ) 0.07 (EtOAc), 0.37, (EtOAc/MeOH, 4:1); IR
1
116-118 °C; Rf ) 0.43 (EtOAc); IR (pellet) ν 1735, 1684; H
1
NMR (500 MHz, CDCl3) δ 5.86 (br s, 1H), 5.47 (dd, J ) 3.7,
10.0, 2H), 4.13 (q, J ) 7.2, 2H), 2.33 (t, J ) 6.9, 2H), 2.01 (s,
6H), 1.95 (m, 2H), 1.89 (s, 3H), 1.80 (m, 2H), 1.73 (m, 2H),
1.53 (m, 2H), 1.47 (m, 1H), 1.25 (t, J ) 7.2, 3H); 13C NMR (125
MHz, CDCl3) δ 174.1, 170.1, 73.3, 62.1, 60.4, 34.3, 26.9, 26.8,
24.4, 21.1, 18.9, 18.6, 14.2; MS (ES+) 394.3 (M + Na); MS (ES-)
370.4 (M - H). Anal. Calcd for C18H29NO7: C, 58.21, H. 7.87,
N. 3.77. Found: C, 58.46, H, 7.94, N, 3.72.
(film) ν 3317, 1742; H NMR (500 MHz, CDCl3) δ 6.33 (br s,
1H), 4.66 (dd, J ) 4.4, 11.6, 1H), 3.79 (br s, 1H), 3.45 (dt, J )
3.0, 10.9, 1H), 2.23 (t, J ) 6.9, 2H), 2.02 (s, 3H), 1.93 (m, 1H),
1.83 (m, 5H), 1.71 (m, 1H), 1.48 (qd, J ) 4.4, 12.9, 1H), 1.42
(pd, J ) 2.0, 13.2, 1H), 1.36 (qt, J ) 3.7, 13.2, 1H); 13C NMR
(125 MHz, CDCl3) δ 175.4, 170.3, 76.8, 75.3, 62.8, 31.3, 28.8,
27.3, 21.2, 20.2, 19.6, 19.1; MS (ES+) 264.1 (M + Na); MS (ES-)
240.3 (M - H). Anal. Calcd for C12H19NO4‚1/4H2O: C, 58.64;
H, 8.00; N, 5.70. Found: C, 58.96; H, 8.18; N, 5.75.
m eso-(6r ,7R,11S)-2-Oxo-1-a za sp ir o[5,5]u n d eca n -7,11-
d iol (11). Crude saturated ester 10 (17.9 mg, 0.045 mmol) was
suspended in 1.2 N HCl (2.0 mL), refluxed (48 h), and
concentrated under vacuum to afford the crude intermediate
aminocyclohexylbutanoic acid, which was used directly for the
next step but was identified from its NMR spectra: 1H NMR
(500 MHz, D2O) δ 3.47 (dd, J ) 4.5, 12, 2H), 2.37 (t, J ) 5,
2H), 1.7-1.5 (m, 8H), 1.40 (qd, J ) 5, 12, 2H), 1.19 (qt, J ) 4,
13, 1H); 13C NMR (125 MHz, D2O, unreferenced) δ 180.5, 77.6,
66.3, 36.6, 31.4, 26.7, 21.9, 21.3. The crude acid was reconsti-
tuted in pyridine (1.0 mL). 4-(Dimethylamino)pyridine (18.7
mg, 0.15 mmol) and dicyclohexylcarbodiimide (30 mg, 0.15
mmol) were added, and the solution was stirred at room
temperature (24 h). The solution was concentrated under
vacuum and flash chromatographed (2:1 EtOAc/MeOH) to
afford 11 (9.5 mg, 95%, 91% from 10) as a white solid: mp
124-126 °C; Rf ) 0.22 (4:1 EtOAc/MeOH); IR (pellet) ν 3337,
1644; 1H NMR (500 MHz, CDCl3) δ 7.55 (br s, 1H), 3.73 (br s,
2H), 3.39 (dd, J ) 4.0, 11.5, 2H), 2.19 (t, J ) 5.9, 2H), 1.85 (m,
2H), 1.80 (m, 2H), 1.72 (m, 2H), 1.66 (m, 2H), 1.42 (qd, J )
(-)-(6R ,7R ,11S )-11-Ac e t o x y -7-m e t h y lo x a ly lo x y -1-
a za sp ir o[5,5]u n d eca n -2-on e (13). To a solution of monoac-
etate 12 (20 mg, 0.08 mmol) in dry dichloromethane (5 mL)
was added 4-(dimethylamino)pyridine (16.1 mg, 0.13 mmol),
followed by addition of methyloxalyl chloride (12 µL, 0.13
mmol) by syringe. The resulting pale yellow solution was
stirred at room temperature followed by addition of EtOAc (5
mL) and concentration to 0.5 mL. The residual oil was flash
chromatographed on silica gel (10 × 100 mm) with EtOAc to
25
afford (24.0 mg, 87%) of 13 as an amorphous white solid: [R]D
-22.5 (c ) 0.32, CHCl3); Rf ) 0.52 (EtOAc/MeOH, 4:1); IR
1
(neat) ν 1762, 1743; H NMR (500 MHz, CDCl3) δ 5.71 (br s,
1H, NH), 4.74 (dd, J ) 4.4, 11.3, 1H), 4.68 (dd, J ) 4.2, 10.9,
1H), 3.86 (s, 3H), 2.31 (ddd, J ) 4.6, 7.2, 17.1, 1H), 2.21 (ddd,
J ) 6.5, 8.6, 17.1, 1H), 2.02 (s, 3H), 1.96 (m, 3H), 1.80 (m,
3H), 1.59 (qd, J ) 4.4, 13.0, 1H), 1.48 (pd, J ) 3.7, 12.7, 1H),
1.48 (qt, J ) 3.9, 13.0, 1H); 13C NMR (125 MHz, CDCl3) δ 173.9,
170.0, 157.5, 156.4, 79.6, 76.0, 60.8, 53.7, 31.2, 26.8, 26.7, 21.7,
21.0, 19.1, 18.6; MS (ES+) 350.4 (M + Na). Anal. Calcd for

5492 J . Org. Chem., Vol. 64, No. 15, 1999
Luzzio and Fitch
C15H21NO7‚1/4H2O: C, 54.29; H, 6.53; N, 4.22. Found: C,
54.41; H, 6.96; N, 3.94.
(-)-(6R)-1-azaspir o[5,5]u n decan -2,7-dion e[(-)-3]. To dry
dichloromethane (0.5 mL) maintained at -78 °C was added
oxalyl chloride (11 µL, 0.12 mmol) by syringe. To this solution
was added DMSO (13 µL, 0.18 mmol) by syringe in one portion.
The solution was stirred (5 min) followed by dropwise addition
of a solution of alcohol 16 (11.3 mg, 0.06 mmol) in dry
dichloromethane (0.5 mL). The solution was stirred for an
additional 5 min followed by dropwise addition of Et3N (34
µL, 0.24 mmol) over 5 min. The pale yellow solution was stirred
at -78 °C (2 h) and at 0 °C for an additional 12 h. The reaction
mixture was diluted with EtOAc (1 mL), and the solvents were
removed by rotary evaporation. Flash chromatography of the
residual solid on silica gel (5 × 100 mm) packed with EtOAc
and eluted with EtOAc/MeOH (10:0/9:1/4:1 [10 mL each])
afforded (-)-3 (8.6 mg, 77%) as a white solid: mp 155-157 °C
(+)-(6R,7R,11S)-11-Acetoxy-7-p h en oxyth ion oca r bon yl-
oxy-1-a za sp ir o[5,5]u n d eca n -2-on e (14). To a solution of
monoacetate 12 (129 mg, 0.54 mmol) in dry dichloromethane
(8 mL) was added 4-(dimethylamino)pyridine (101 mg, 0.83
mmol), followed by dropwise addition of phenylthionochloro-
formate (90 µL, 0.65 mmol) by syringe. The resulting pale
yellow solution was stirred (24 h) at room temperature followed
by addition of EtOAc (5 mL) and concentration to 0.5 mL. The
residual oil was flash chromatographed on silica gel (15 × 100
mm) with EtOAc to afford 14 (146.8 mg, 73%) as a white
25
solid: mp 65-80 °C (dec); [R]D +57.48 (c ) 1, CHCl3); Rf )
0.35 (EtOAc), 0.62 (EtOAc/MeOH, 9:1); IR (neat) ν 1743, 1673;
1H NMR (500 MHz, CDCl3) δ 7.38 (t, J ) 7.9, 2H), 7.25 (t, J )
7.4, 1H), 7.06 (d, J ) 7.9, 2H), 5.39 (br s, 1H), 5.13 (dd, J )
4.6, 11.6, 1H), 4.68 (dd, J ) 4.2, 11.1, 1H), 2.29 (ddd, J ) 5.8,
6.7, 17.1, 1H), 2.25 (dt, J ) 6.5, 17.1, 1H), 2.19 (dq, J ) 3.7,
13.0, 1H), 2.04 (s, 3H, Ac), 2.00 (t, J ) 6.3, 2H), 1.90 (m, 1H),
1.84 (p, J ) 6.5, 2H), 1.81 (m, 1H), 1.64 (qd, J ) 4.2, 13.0,
1H), 1.55 (pd, J ) 3.9, 13.2, 1H), 1.48 (qt, J ) 3.7, 13.2, 1H);
13C NMR (125 MHz, CDCl3) δ 194.3, 173.5, 170.0, 153.2, 129.6,
126.7, 121.8, 86.5, 76.2, 61.5, 31.3, 27.0, 26.1, 21.9, 21.0, 19.1,
18.8; MS (ES+) 400.1 (M + Na); MS (ES-) 376.4 (M - H). Anal.
Calcd for C19H23NO5S‚1/4H2O: C, 59.75; H, 6.20; N, 3.67.
Found: C, 59.81; H, 6.31; N, 3.60.
(lit.6 150-152 °C, for the racemate)l [R]D -59.3 (c ) 1.0,
25
CHCl3); Rf ) 0.33 (EtOAc/MeOH, 4:1); IR (neat) ν 1712, 1655;
1H NMR (500 MHz, CDCl3) δ 6.07 (br s, 1H), 2.50 (ddd, J )
5.8, 12.2, 13.9, 2H), 2.46 (ddd, J ) 3.9, 5.8, 13.9, 2H), 2.33 (dt,
J ) 6.7, 18.0, 2H), 2.28 (ddd, J ) 6.7, 7.4, 18.0, 2H), 2.14 (dq,
J ) 3.2, 6.8, 1H), 2.04 (m, 2H), 1.88 (ddd, J ) 3.5, 9.7, 13.4,
1H), 1.82 (m, 3H), 1.63 (m, 3H); 13C NMR (125 MHz, CDCl3)
δ 209.3, 172.0, 65.2, 40.9, 38.5, 30.8, 29.2, 27.3, 21.6, 17.0; MS
(ES+) 204.2 (M + Na). Anal. Calcd for C10H15NO2: C, 66.27;
H, 8.34; N, 7.73. Found: C, 66.33; H, 8.56; N, 7.86.
(+)-(6S,11S)-11-Acetoxy-1-a za sp ir o[5,5]u n d eca n -2,7-d i-
on e (17). A. By Sw er n Oxid a tion . To solution of oxalyl
chloride (82 µL, 0.94 mmol) in dry CH2Cl2 (7 mL) under argon
at -78 °C was added DMSO (70 µL, 0.99 mmol). The solution
was stirred (5 min) followed by dropwise addition of alcohol
12 (78.1 mg, 0.32 mmol) in dry dichloromethane (2.0 mL). The
solution was stirred (45 min) followed by dropwise addition of
Et3N (180 µL, 1.29 mmol) over 5 min. The solution was stirred
at -78 °C (4 h) and at 0 °C (12 h). The reaction mixture was
diluted with EtOAc (1 mL), and the solvent was removed under
vacuum. Flash chromatography on silica gel (EtOAc/MeOH
[10:0 (25 mL)/9:1 (50 mL)/4:1(50 mL)]) afforded 44.5 mg (57%)
of 17 as a colorless oil: [R]D25 +88.2 (c ) 2.2, CHCl3); IR (neat)
ν 1712, 1655; 1H NMR (500 MHz, CDCl3) δ 6.00 (br s, 1H),
4.80 (dd, J ) 4.4, 10.9, 2H), 2.50 (m, 2H), 2.31 (dt, J ) 5.1,
17.6, 1H), 2.22 (ddd, J ) 6.5, 10.2, 17.6, 1H), 2.09 (dq, J )
3.9, 13.9, 2H), 2.04 (s, 3H), 1.99 (m, 3H, 1.90 (m, 1H), 1.83 (m,
1H), 1.60 (m, 1H), 1.49 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 206.4, 173.0, 69.9, 75.9, 69.4, 37.0, 30.8, 26.7, 24.7, 21.0, 21.0,
19.9, 17.1; MS (ES+) 262.2 (M + Na); MS (ES-) 238.4 (M -
H).
(+)-(6R,7S)-7-Acetoxy-1-azaspir o[5,5]u n decan -2-on e (15).
To a solution of thionocarbonate 14 (130 mg, 0.35 mmol) and
AIBN (17.2 mg, 0.10 mmol) in dry toluene (13 mL) under argon
was added tributylstannane (170 µL, 0.63 mmol) by syringe.
The solution was heated (95 °C) in an oil bath (1.5 h) and
concentrated under vacuum to an oily residue. The residue
was flash-chromatographed on silica gel (10 × 100 mm) packed
with EtOAc and eluted with EtOAc/MeOH [9:1/4:1, 25 mL
each] to afford 15 (72.4 mg, 93%) as a white solid containing
a trace of a tin impurity which could be removed by recrys-
tallization from ether/hexanes to afford colorless prisms: mp
123-124 °C (lit.6 143-144 °C for the racemate); [R]D +43.9
25
(c ) 1.0, CHCl3); Rf ) 0.57 (EtOAc/MeOH, 4:1); IR (neat) ν
1739, 1663; 1H NMR (500 MHz, CDCl3) δ 5.93 (br s, 1H), 4.66
(dd, J ) 3.9, 9.3, 1H), 2.26 (m, 2H), 2.01 (s, 3H), 1.80 (m, 4H),
1.65 (m, 3H), 1.53 (m, 2H), 1.39 (m, 3H); 13C NMR (125 MHz,
CDCl3) δ 172.5, 170.2, 75.9, 57.2, 36.8, 31.3, 27.0, 25.8, 22.4,
21.3, 21.1, 16.9; MS (ES+) 248.2 (M + Na). Anal. Calcd for
C
12H19NO3: C, 63.98; H, 8.50; N, 6.22. Found: C, 63.63; H,
8.70; N, 6.22.
(+)-(6R,7S)-2-Oxo-1-a za sp ir o[5,5]u n d eca n -7-ol (16). A.
F r om Aceta te 15. To a flask containing acetate 15 (54.0 mg,
0.35 mmol) was added a solution of NaOMe prepared by
dissolving sodium metal (7.0 mg, 0.30 mmol) in dry MeOH (5
mL). The resulting solution was stirred (1.5 h), and the
reaction was quenched by filtration through a pipet packed
with silica gel/MeOH and washed with additional MeOH (5
mL). The filtrate was concentrated under vacuum to afford
16 (43.1 mg, 98%) as a white solid: mp 137-139 °C (lit.6 160-
162 °C for the racemate). Repeated recrystallization from
B. By Moffa tt Oxid a tion . To a solution of alcohol 12 (26.6
mg, 0.14 mmol) in dry DMSO (1 mL) was added dicyclohexy-
lcarbodiimide (92.4 mg, 0.44 mmol) and crystalline orthophos-
phoric acid (3.0 mg, 0.03 mmol). The mixture was stirred
overnight during which time a precipitate of dicyclohexylurea
formed. The mixture was directly flash chromatographed on
silica gel with EtOAc (3×) to afford 19.1 mg (73%) of 17,
identical in all respects with the previous material provided
by the Swern method.
(+)-(6S,12S)-12-Acetoxy-7-a za -1,4-d ioxa d isp ir o[4,0,5,4]-
p en ta d eca n -8-on e (18). To a solution of ketolactam 17 (36.7
mg, 0.15 mmol) and ethylene glycol (60 µL, 1.08 mmol) in dry
toluene (5 mL) was added TsOH (3.2 mg, 0.02 mmol). The
mixture was stirred at reflux (3 h). After the mixture cooled
to room temperature it was filtered through silica gel using
EtOAc as eluent to afford 46.2 mg (>99%) of crude 18 as an
oil containing 15% ethylene glycol. The crude material was
used directly for the next step; however, an analytical sample
was prepared by acetylation (AcCl/DMAP/CH2Cl2) of the
mixture followed by separation of 18 from the ethylene glycol
diacetate by silica gel column chromatography (EtOAc/MeOH,
9:1): 1H NMR (CDCl3, 500 MHz) δ 5.65 (br s, 1H), 4.83 (dd, J
) 4.9, 11.3, 1H), 4.07 (m, 1H), 3.93 (m, 1H), 3.86 (m, 2H), 2.24
(t, J ) 6.5), 2.02 (m, 1H), 2.00 (s, 3H), 1.83 (m, 4H), 1.58 (m,
3H), 1.50 (m, 1H); 13C NMR (CDCl3, 125 MHz) δ 174.1, 170.1,
111.5, 76.2, 65.6, 65.5, 63.0, 31.3, 30.9, 26.8, 23.3, 21.1, 19.0,
18.7; MS (ES+) 306.2 (M + Na).
25
EtOAc/ether/hexanes failed to raise the melting point: [R]D
+57.5 (c ) 1.0, CHCl3); Rf ) 0.33 (EtOAc/MeOH, 4:1); IR (neat)
ν 3310, 1649; 1H NMR (500 MHz, CDCl3) δ 6.79 (br s, 1H),
3.88 (br s, 1H), 3.42 (dt, J ) 3.9, 10.9, 1H), 2.28 (ddd, J ) 1.6,
4.2, 17.6, 1H), 2.19 (ddd, J ) 6.0, 10.6, 17.6, 2H), 1.83 (m, 4H),
1.67 (m, 3H), 1.52 (m, 1H), 1.40 (qd, J ) 3.7, 12.3, 1H), 1.31
(m, 2H), 1.25 (qd, J ) 3.7, 12.5, 1H); 13C NMR (125 MHz,
CDCl3) δ 174.1, 75.6, 59.7, 36.7, 31.5, 29.6, 23.7, 22.4, 22.0,
17.2; MS (ES+) 206.0 (M + Na); MS (ES-) 182.3 (M - H).
B. F r om Ketola cta m (-)-3. To a solution of ketolactam
(-)-3 in dry MeOH (2 mL) under nitrogen at 0 °C was added
solid NaBH4. Upon addition and dissolution of the reagent,
gas was evolved. After 15 min TLC analysis indicated con-
sumption of starting ketone. The solution was concentrated
and triturated with MeOH (3 × 2 mL) to afford 16 (7.4 mg,
86%) as a white powder. Recrystallization from EtOAc/ether/
hexanes afforded colorless rhombs: mp 137-139 °C; mixed
mp 136-138 °C, identical in all respects with the previous
material obtained by deacylation.
(+)-(6S,12S)-12-Hyd r oxy-7-a za -1,4-d ioxa d isp ir o[4,0,5,4]-
p en ta d eca n -8-on e (19). To a solution of ketal 18 (46.2 mg)

Formal Synthesis of Perhydrohistrionicotoxin
J . Org. Chem., Vol. 64, No. 15, 1999 5493
in MeOH (1 mL) was added a solution of NaOMe (3 mL). The
resulting colorless solution was stirred at room temperature
(30 min) and then neutralized by filtration through silica gel.
The resulting solution was concentrated and flash chromato-
graphed on silica gel (EtOAc/MeOH [10:0 (10 mL)/9:1 (25 mL)/
4:1 (25 mL)]) to afford 31.0 mg (84% from ketolactam 17) of
and tributylstannane (34 µL, 34.7 mg, 0.12 mmol). The solution
was heated to 95 °C (oil bath), and stirring was continued
under argon for 2.5 h. The reaction mixture was directly flash
chromatographed with EtOAc/MeOH [10:0 (10 mL)/9:1 (25
mL)/4:1 (25 mL)] to afford 13.4 mg (95%) of 21 as a white solid
contaminated with ∼5% tin products: Rf ) 0.54 (EtOAc/
MeOH, 4:1); [R]D25 -33.7 (c ) 0.67, CHCl3); 1H NMR (500 MHz,
CDCl3) δ 5.8 (br s, 1H), 4.03 (m, 1H), 3.93 (m, 1H), 3.87 (m,
2H), 2.29 (dddd, J ) 1.4, 3.7, 5.3, 17.5, 1H), 2.20 (ddd, J )
5.6, 10.4, 17.5, 2H), 1.83 (m, 3H), 1.76 (m, 1H), 1.64 (m, 2H),
1.54 (m, 4H), 1.33 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 172.8,
110.6, 65.5, 65.2, 59.7, 36.3, 31.5, 25.7, 22.6, 21.5, 17.5; MS
(ES) 225 (M + H).
25
19 as white solid: [R]D +17.2 (c ) 0.64, CHCl3); IR (neat) ν
3343, 1645; 1H NMR (500 MHz, CDCl3) δ 5.94 (br s, 1H), 4.03
(m, 1H), 3.86 (m, 3H), 3.66 (br s, 1H), 3.62 (m, 1H), 2.21 (m,
2H) 2.00 (m, 1H), 1.90 (m, 1H), 1.78 (m, 3H), 1.56 (m, 2H),
1.43 (m, 2H); 13C NMR (125 MHz, CDCl3) δ 175.5, 111.8, 74.5,
65.3, 65.2, 64.6, 31.2, 30.9, 28.6, 22.0, 19.0, 18.9; MS (ES+)
264.2 (M + Na). Anal. Calcd for C12H19NO4‚H2O: C, 55.58; H,
8.16; N, 5.40. Found: C, 55.63; H, 8.45; N, 5.38.
(+)-(6S)-1-Aza sp ir o[5,5]u n d eca n -2,7-d ion e [(+)-3)]. To
a solution of glacial acetic acid (1.6 mL), trifluoroacetic acid
(0.7 mL), and water (0.9 mL) was added ketallactam 21 (13.4
mg, 0.06 mmol). The colorless solution was stirred at room
temperature (24 h), and the solvent was removed under
vacuum to afford a residue which was flash chromatographed
(CH2Cl2/acetone 9:1) to furnish 9.5 mg (88%) of (+)-3 as a white
(-)-(6S,12S)-12-P h en oxyth ion oca r bon yloxy-7-a za -1,4-
d ioxa d isp ir o-[4,0,5,4]p en t a d eca n -8-on e (20). To a solu-
tion of lactam alcohol 19 31 mg (0.13 mmol) in dry CH2Cl2
(2.0 mL) was added DMAP (24.2 mg, 0.20 mmol) followed by
phenythionochloroformate (20.0 µL, 0.14 mmol) by syringe
while stirring under nitrogen. The resulting yellow solution
was stirred for 24 h, during which time the yellow color
discharged. The solution was directly flash-chromatographed
on silica gel to afford 23.6 mg (49%, 87% corrected for recovered
19) of thionocarbonate 20; and 13.6 mg (44%) of unchanged
25
solid: [R]D +60.3 (c ) 0.54, CHCl3). The product was
spectrally identical with (-)-3, save for direction of optical
rotation.
25
starting material: [R]D -60.4 (c ) 1.18, CHCl3); IR (neat) ν
Ack n ow led gm en t. The authors thank Glaxo-
Wellcome for an instrument grant and the University
of Louisville Graduate School, College of Arts and
Sciences, and the University International Center for
travel support (F.A.L.) to Rostock, Germany.
3389, 1665; 1H NMR (500 MHz, CDCl3) δ 7.38 (t, J ) 7.6, 2H),
7.25 (td, J ) 7.6, 8.5, 1H), 7.06 (dd, J ) 7.6, 8.5, 2H), 5.75 (br
s, 1H), 5.33 (dd, J ) 4.6, 11.1, 1H), 4.11 (m, 1H), 3.95 (m, 1H),
3.90 (m, 2H), 2.26 (m, 2H), 2.19 (m, 1H), 2.06 (m, 1H), 1.93
(m, 1H), 1.89 (m, 1H), 1.80 (m, 1H), 1.64 (m, 2H), 1.60 (m,
2H), 1.25 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 194.4, 174.0,
153.3, 129.6, 126.6, 121.9, 111.4, 86.6, 65.6, 63.6, 31.3, 30.8,
25.8, 23.6, 18.7, 18.5; MS (ES) 377 (M + H).
Su p p or tin g In for m a tion Ava ila ble: 1H and13C spectra
of compounds 6, 11, 16-18, 20, 21 and 1H spectra of the
epimerization of 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
(-)-6S)-7-Aza -1,4-d ioxa d isp ir o[4,0,5,4]p en t a d eca n -8-
on e (21). To a solution of thionocarbonate 20 (23.6 mg, 0.06
mmol) in toluene (2 mL) were added AIBN (3.5 mg, 0.02 mmol)
J O990293I