Alkynyliodonium salts in organic synthesis. Development of a unified strategy for the syntheses of (-)-agelastatin A and (-)-agelastatin B

Article abstract of DOI:10.1021/jo026287v

The total syntheses of natural agelastatin A and agelastatin B were accomplished via a strategy that utilized an alkynyliodonium salt → alkylidenecarbene → cyclopentene transformation to convert a relatively simple amino alcohol derivative to the functionalized core of the agelastatin system. Subsequent manipulations delivered debromoagelastatin, which served as a precursor to both agelastatin A and agelastatin B. Alkylidenecarbene insertion chemoselectivity issues were explored en route to the final targets.

Full text of DOI:10.1021/jo026287v

Alk yn yliod on iu m Sa lts in Or ga n ic Syn th esis. Develop m en t of a
Un ified Str a tegy for th e Syn th eses of (-)-Agela sta tin A a n d
(-)-Agela sta tin B
Ken S. Feldman,* J oe C. Saunders, and Michelle Laci Wrobleski
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802
ksf@chem.psu.edu
Received August 5, 2002
The total syntheses of natural agelastatin A and agelastatin B were accomplished via a strategy
that utilized an alkynyliodonium salt f alkylidenecarbene f cyclopentene transformation to convert
a relatively simple amino alcohol derivative to the functionalized core of the agelastatin system.
Subsequent manipulations delivered debromoagelastatin, which served as a precursor to both
agelastatin A and agelastatin B. Alkylidenecarbene insertion chemoselectivity issues were explored
en route to the final targets.
The agelastatins comprise a small group of tetracyclic,
brominated metabolites isolated from the alcoholic ex-
tracts of several axinellid sponges.1 Their structural
elucidation rests on extensive NMR, molecular modeling,
and exciton coupling studies. The structural and relative
stereochemical assignments of agelastatin A (1) were
confirmed by total synthesis of the racemate.2 The
similarity in skeletal connectivity between the agelast-
atins and the axillenid congener oroidin (5) sparked a
biosynthesis hypothesis linking the two structures, al-
though no data which address this point have been
forthcoming.1a,e Agelastatin A displays significant cyto-
toxicity against both the L1210 and KB tumor cell lines
as well as notable activity against a doxorubicin-resistant
L1210 leukemia strain.1d In vivo activity in mice inocu-
lated with L1210 leukemia cells was recorded, but only
upon repeated intraperitoneal injection.1d A limited
number of structural analogues available through semi-
synthesis from 1 were examined in similar in vitro
assays. The upshot of these structure-activity investiga-
tions was that cytotoxicity dropped precipitously upon
any structural modification. Thus, there appears to be
very precise structural requirements for inducing cyto-
toxicity in these assays. No molecular-level biological
mechanism-of-action has been proposed to rationalize
how this particular constellation of H-bonding functional-
ity exerts its effects, but it is interesting to note that the
C(1) bromide in 1 is readily replaced with hydride upon
treatment with LiAlH4 with no concurrent reduction of
the aminal moiety.1c This result is suggestive of an
unexpectedly high level of electrophilicity at C(1), which
in conjunction with latent electrophilicity at C(9a) as
revealed by the synthesis studies (vide infra) might
support the contention that agelastatin A functions as a
novel type of bis alkylating agent in vivo.
Agelastatin A cannot be completely purified from its
congener agelastatin B (2) when isolated from the sponge,
and derivatization through trimethylation at N(5), N(6)
and the tertiary alcohol was required to effect separation
and full characterization. This problem of acquiring clean
samples of (-)-1 and (-)-2 can be rectified by total
chemical synthesis, and a full accounting of our efforts
in this area follows.3 The total synthesis of agelastatin
A and agelastatin B in enantiomerically pure form
described herein confirms the absolute stereochemical
assignment and, for the first time, provides pure samples
of both compounds for further biological evaluation.
Our interest in the polycyclic agelastatin core grew
from continuing studies designed to exploit the rich
chemistry of alkynyliodonium salts4 in complex molecule
synthesis. Alkynyliodonium salts serve as convenient
precursors to highly reactive alkylidenecarbenes, which
themselves offer many opportunities for bond formation
with normally refractory substrates.5 One characteristic
reaction of these carbenes involves insertion into an
otherwise unactivated C-H bond five atoms removed
from the carbenic center to furnish functionalized cyclo-
pentenes. The similarity between the cyclopentene prod-
uct 8 and the cyclopentane core of the agelastatins
provided the motivation for pursuing this strategy, as
* Address correspondence to this author.
(1) (a) D’Ambrosio, M.; Guerriero, A.; Debitus, C.; Ribes, O.; Pusset,
J .; Leroy, S.; Pietra, F. J . Chem. Soc., Chem. Commun. 1993, 1305-
1306. (b) Hong, T. M.; J ´ımenez, D. R.; Molinski, T. F. J . Nat. Prod.
1998, 61, 158-161. (c) D’Ambrosio, M.; Guerriero, A.; Chiasera, G.;
Pietra, F. Helv. Chim. Acta 1994, 77, 1895-1902. (d) D’Ambrosio, M.;
Guerriero, A.; Ripamonti, M.; Debitus, C.; Waikedre, J .; Pietra, F. Helv.
Chim. Acta 1996, 79, 727-735. (e) Mourabit, A. A.; Potier, P. Eur. J .
Org. Chem. 2001, 237-243.
(2) (a) Stein, D.; Anderson, G. T.; Chase, C. E.; Koh, Y.-h.; Weinreb,
S. M. J . Am. Chem. Soc. 1999, 121, 9574-9579. (b) Synthesis of a model
system for the central core of the agelastatins has been reported:
Baron, E.; O’Brien, P.; Towers, T. D. Tetrahedron Lett. 2002, 43, 723-
726.
(3) Feldman, K. S.; Saunders: J . C. J . Am. Chem. Soc. 2002, 124,
9060-9061.
(4) (a) Stang, P. J .; Zhdankin, V. V. Tetrahedron 1998, 54, 10927-
10966. (b) Varvoglis, A. Tetrahedron 1997, 53, 1179-1255.
(5) (a) Kirmse, W. Angew. Chem., Int. Ed. 1997, 36, 1164-1170. (b)
Stang, P. J . Chem. Rev. 1978, 78, 383-405.
10.1021/jo026287v CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002
7096
J . Org. Chem. 2002, 67, 7096-7109

Alkynyliodonium Salts in Organic Synthesis
SCHEME 1
detailed in Scheme 1. However, this approach to the
agelastatins was not without its risks. Alkylidenecarbene
7 is faced with a choice: 1,5 C-H insertion to deliver
the desired cyclopentene product 8, or formal oxygen/
lone-pair insertion to provide the dihydrofuran 9 via a
putative ylide intermediate.6 Both of these reaction
channels have been described, and the only example
where they were in direct competition (:NBOC vs C-H)
does not provide support for the desired 1,5 C-H inser-
tion pathway.7 Therefore, further data on alkylidenecar-
bene insertion chemoselectivity was required, and the
systematic study pursued in support of the agelastatin
synthesis work provides insight into the electronic factors
which influence this competition. The choice of sulfinate
as the triggering nucleophile in the key cyclization
sequence was made in light of the downstream needs to
activate both C(5a) and C(9a) for sequential nucleophilic
(e.g., amine) additions. Thus, the alkenyl sulfone moiety
in 8 satisfies the former requirement, whereas the latter
strategic need can be met when the sulfone serves as a
leaving group in chemistry evolving from intermediate
10. Finally, a desire to synthesize both the monobromide
agelastatin A and the dibromide agelastatin B prompted
a careful evaluation of both the timing and the means
for bromide incorporation into the agelastatin tetracyclic
core. The later in the synthesis sequence that the
divergence to either agelastatin A or agelastatin B occurs,
the more efficient the overall route. The logical extension
of this strategy would delay pyrrole bromination until
the final step, assuming that selective mono- and dibro-
mination of a debromoagelastatin precursor could be
achieved. There is scant precedent for this selectivity, and
earlier work on agelastatin synthesis resorted to use of
a TMS directing group to enforce regioselective bromi-
nation at C(1).2 Nevertheless, this question appeared
worthy of further study, and so development of selective
debromoagelastatin bromination sequences was built into
the design strategy.
SCHEME 2
an allenic Grignard reagent with the freshly prepared
aldehyde 12 to furnish the hydroxycarbamate 13 in
modest yield, Scheme 2. No allene-containing products
were observed. Acetonide formation proceeded smoothly
from 13, and alkyne stannylation delivered the precursor
14 to the central iodonium salt intermediate. The conver-
sion of alkynylstannane 14 into the unisolated alkynyli-
odonium salt 15 proceeded through treatment with
Stang’s reagent, PhI(CN)OTf.8 The crude alkynyliodo-
nium salt was washed with hexane at -40 °C to remove
tin residues and then rapidly cannulated as a solution
in DME into a suspension of TolO2SNa in refluxing DME.
Resu lts a n d Discu ssion
The initial approach to a functionalized alkynyliodo-
nium salt of the type 6 commenced with combination of
(6) (a) Feldman, K. S.; Wrobleski, M. L. Org. Lett. 2000, 2, 2603-
2605. (b) Feldman, K. S.; Wrobleski, M. L. J . Org. Chem. 2000, 65,
8659-8668.
(7) Feldman, K. S.; Mingo, P. A.; Hawkins, P. C. D. Heterocycles
1999, 51, 1283-1294.
(8) Stang, P. J .; Zhdankin, V. V. J . Am. Chem. Soc. 1991, 113, 4571-
4576.
J . Org. Chem, Vol. 67, No. 20, 2002 7097

Feldman et al.
SCHEME 3
DME containing TolO2SNa, led to isolation of a suite of
cyclized products 24 -26 along with a small amount of
an alkyne-bearing product 27. On the assumption that
the bis sulfone 26 is derived from 24 and excess sulfinate
anion, the overall yield of C-H insertion product, 48%,
is 1.5 times that of the formal oxygen/lone-pair insertion
product 25. Alkyne 27 results from a third option
available to the alkylidenecarbene, 1,2-sulfone shift.10
The preponderance of C-H insertion product rather than
formal oxygen/lone-pair insertion product presumably
reflects the diminished electron availability at oxygen in
23 compared to 16, as discussed above. Thus, by the
simple expedient of replacing an acetonide protecting
group with a more electron demanding carbonyl, the
reaction has benefited by significant improvements in
yield and chemoselectivity. Continuation of this approach
to the agelastatins required the stereoselective N-attach-
ment of a pyrrole carboxamide unit at C(5a). This
transformation proceeded readily via initial conjugate
addition of benzylamine to the activated alkene in 24
followed by acylation of the resultant secondary amine
with acid chloride 28.2a The stereochemical outcome of
amine addition plausibly stems from the considerable
steric bias that attends the rigid bicyclo[3.3.0]octane
framework. Although of no consequence in the agelasta-
tin effort, the C(9a) sulfonyl in 29 emerged as a single
diastereomer, the selectivity again a likely consequence
of preferred anion protonation on the accessible convex
face of the bicyclic ring system. The stereochemical
1
assignment of 29 is based on comparison of the H NMR
Two cyclized products were isolated in only symbolic
amounts following extensive chromatography. Although
very little cyclized material was recovered, the ∼3:1
preference for the oxygen/lone pair insertion product 19
over the C-H insertion product 17 is consistent with the
expectations generated by the C-H vs :NBOC example7
alluded to earlier. Little effort was made to improve these
results, as the particular set of reaction conditions
(solvent, temperature, concentration, reagent ratio) de-
termined to be optimal for related reactions was used
here.9 The remainder of the reaction product(s) defied
either purification or characterization. Rather, a more
productive approach might involve redesigning the sub-
strate.
Toward this end, the N-benzyl oxazolidinone alkynyl-
stannane 22 was targeted next, Scheme 3. The electron-
withdrawing character of the carbonyl in 22 raises the
possibility that the offending oxygen lone pair in 23
would no longer be so readily available for capture by
the intermediate alkylidenecarbene. The synthesis of this
alkyne employed a slight variation of the chemistry used
for alkyne attachment in 14. Acetylide anion addition to
an epoxycarbamate 21 furnished the intact oxazolidinone
system in much higher yield than the allenyl Grignard-
based sequence of Scheme 2. Again, exposure of alkynyl-
stannane 22 to Stang’s reagent, followed by rapid addi-
tion of the cold alkynyliodonium salt solution to refluxing
spectrum of the precursor amine addition product with
1
the H NMR spectrum of 43c (vide infra), a compound
whose stereochemical assignment rests on the nOe
enhancements shown in Scheme 6. Unfortunately, this
agelastatin route bogged down with intermediate 29, as
all efforts to effect oxazolidinone hydrolysis led to de-
struction of this compound. In some instances, the formal
â-elimination product 24 could be identified in the
product mixture.
The lability of N-BOC oxazolidinones to hydrolysis11
suggested that an N-BOC analogue of 22, the oxazolidi-
none 33 (Scheme 4), might overcome the difficulties
experienced with the former species. In addition, the
presumably enhanced electron demand of the oxazolidi-
none carbonyl in the N-BOC derivative compared to the
N-Bn system 23 may provide a more substantial bias
toward 1,5 C-H insertion over formal oxygen/lone-pair
insertion within the intermediate alkylidenecarbene. The
synthesis of alkynylstannane 33 proceeded uneventfully
from allyl carbamate 30 utilizing chemistry developed
with 22. Buchwald’s tin-for-silicon exchange procedure12
(32 f 33) was necessitated by the insolubility of the free
alkyne in solvents compatible with anionic stannylation
chemistry. The key iodination/cyclization sequence with
33 delivered the desired cyclopentene 35 in comparable
yield to the N-Bn case 24, although the ratio of byprod-
ucts was markedly different. No formal oxygen/lone-pair
insertion product could be detected, either in the crude
(9) (a) Schildknegt, K.; Bohnstedt, A. C.; Feldman, K. S.; Samban-
dam, A. J . Am. Chem. Soc. 1995, 117, 7544-7545. (b) Feldman, K. S.;
Bruendl, M. M.; Schildknegt, K. J . Org. Chem. 1995, 60, 7722-7723.
(c) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt, A. C.
J . Org. Chem. 1996, 61, 5440-5452. (d) Feldman, K. S.; Bruendl, M.
M. Tetrahedron Lett. 1998, 39, 2911-2914. (e) Feldman, K. S.;
Mareska, D. A. J . Am. Chem. Soc. 1998, 120, 4027-4028. (f) Feldman,
K. S.; Mareska, D. A.; Tetrahedron Lett. 1998, 39, 47814781. (g)
Feldman, K. S.; Mareska, D. A. J . Org. Chem. 1999, 64, 5650-5660.
(10) Ochiai, M.; Kunishima, M.; Tani, S.; Nagao, Y. J . Am. Chem.
Soc. 1991, 113, 3135-3142.
(11) (a) Ishizuka, T.; Kunieda, T. Tetrahedron Lett. 1987, 28, 4185-
4188. (b) Flynn, D. L.; Zelle, R. E.; Grieco, P. A. J . Org. Chem. 1983,
48, 2424-2426.
(12) Warner, B. P.; Buchwald, S. L. J . Org. Chem. 1994, 59, 5822-
5823.
7098 J . Org. Chem., Vol. 67, No. 20, 2002

Alkynyliodonium Salts in Organic Synthesis
SCHEME 4
SCHEME 5
efforts, Scheme 5. Recent advances in osmium-mediated
asymmetric amido alcohol synthesis could foster a prom-
ising approach for controlling the absolute stereochem-
istry in 40, provided that the heretofore unexplored urea
reagent 38 functions similarly to the precedented amide
or carbamate analogues.14 Exposure of enynes 37a -c to
the conditions recommended by Sharpless furnished the
hydroxy urea products 39a -c, respectively, with com-
plete control of regiochemistry in the desired sense.
Unfortunately, no useful levels of asymmetric induction
were achieved with these systems. Modest enantioselec-
tivity resulted from use of the (DHQD)2PHAL ligand, and
use of the (DHQD)2AQN and (DHQD)2PYR alternatives
was even less fruitful. The phenyl- and benzylsilyl entries
37b and 37c, respectively, were examined under the
premise that the aryl residues might provide an ad-
ditional complementary binding element for the cleft
formed by the chiral ligand.15 The poor ee values leave it
unclear as to whether this expectation was met. Conver-
sion of the urea alcohol 39a into the corresponding
stannylated alkyne 40 proceeded smoothly utilizing
methodology developed earlier. The derived alkynyliodo-
nium salt combined with sulfinate nucleophile to furnish
the expected cyclopentene 41 along with sulfonylalkyne
42, again with no trace of a formal oxygen/lone-pair
insertion product. The yields of the two products were
similar to those observed with the N-BOC substrate 33,
indicating that the electronic influence of the urea group
upon alkylidenecarbene partitioning was not demonstra-
bly different than that of the BOC moiety.
reaction mixture or upon extensive chromatography.
However, the 1,2-sulfone shift product 34 now was
formed to a significant extent. One interpretation of these
observations might cite the BOC’s role in engaging the
nitrogen’s lone pair in resonance, thereby biasing the
competition between N and O for the oxazolidinone’s
carbonyl toward oxygen. In this scenario, the oxygen’s
lone pair would be less available to the alkylidenecarbene
than in the related carbene 23, leading to a diminution,
or in this case a complete suppression, of reaction at
oxygen. A tradeoff, however, can be seen in the increased
formation of the 1,2-sulfone shift product 34. The hydro-
gen targeted for insertion by the alkylidenecarbene (cf.
H, 33) is now attached to an arguably more electron
deficient carbon compared to the similar H in 23 as a
consequence of the adjacent N-BOC (vs N-Bn in 23).
Therefore, the rate of insertion of the inherently electro-
philic alkylidenecarbene13 into the C-H of 33 is likely to
be decreased compared to 23, and the normally slower
1,2-sulfone shift becomes more prominent. Ochiai has
shown that varying the electron demand of the sulfonyl
group does not appreciably influence the partitioning of
an alkylidenecarbene between 1,5 C-H insertion and 1,2-
sulfone shift,10 and so this encroaching competition with
the desired reaction channel cannot be easily suppressed.
Ultimately, this route ran afoul of the very oxazolidi-
none carbonyl lability upon which it was founded. At-
tempted benzylamine conjugate addition to the alkene
of 35 was complicated by concurrent attack of the amine
nucleophile at the carbonyl. The double addition product
carbamate 36 was isolated in poor yield, and all efforts
to steer the addition to the alkene were ineffective. Thus,
a plausibly less activating N-substituent was required.
An N-urea, such as N-CON(CH3)CH2Ar, seemed like a
logical choice in that it should serve the dual function of
diminishing the electrophilicity of the oxazolidinone
carbonyl while at the same time firmly refocusing the
route toward the N-methyl urea-containing target,
agelastatin A.
The question of paramount interest at this juncture
involved the site of nucleophilic attack upon addition of
a benzylamine to the urea-containing bicyclic 41. It was
gratifying to observe that only the product of alkene
addition was detected upon exposure of 41 to o-nitroben-
zylamine (oNB-amine), Scheme 6. The resultant second-
ary amine could be acylated with 28 to deliver the
required C(5a) pyrrole carboxamide unit without any
interference from chemistry at the oxazolidinone carbo-
nyl. The choice of the oNB-amine was in response to
(14) (a) Reddy, K. L.; Sharpless, K. B. J . Am. Chem. Soc. 1998, 120,
1207-1217. (b) Bruncko, M.; Schlingloff, G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 1997, 36, 1483-1486. (c) Rudolph, J .; Sennhenn, P.
C.; Vlaar, C. P.; Sharpless, K. B. Angew. Chem., Int. Ed. Engl. 1996,
25, 2810-2813.
(15) Corey, E. J .; Guzman-Perez, A.; Noe, M. C. J . Am. Chem. Soc.
1995, 117, 10805-10816.
The synthesis of the urea bearing cyclization substrate
40 follows a different strategy compared to the previous
(13) Gilbert, J . C.; Giamalva, D. H. J . Org. Chem. 1992, 57, 4185-
4188.
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Feldman et al.
SCHEME 6
N-deprotections and the concluding pyrrole bromination
discussed earlier. The N(5) oNB protecting group was
removed under strictly neutral conditions by irradiation
at 350 nm. Despite the neutrality of the reaction medium,
a small amount of the C(5b) epimer 47 was formed. It is
possible that incipient A1,2 strain in an intermediate 48
(R ) oNB) discourages enolization and therefore main-
tains the stereochemical integrity at C(5b) in 45, but the
presence of a sterically undemanding proton in 48 (R )
H) more readily permits this enolization. In any event,
the inseparable mixture 46/47 was subjected to hydro-
genolytic debenzylation conditions to yield (()-debromo-
agelastatin (11), which was now separable from its C(5b)/
C(8a) diastereomer derived from 47. Attempted hydrogen-
olysis of a N(5)-benzyl analogue of 45 led only to cleavage
of the N(8) benzyl unit, a result that necessitated the
reroute through the N(5) oNB series. A few scouting
experiments designed to probe bromination selectivity
with 11 revealed that the ratio of agelastatin A to
agelastatin B was quite solvent dependent. In pure CCl4,
the sparingly soluble 11 was brought into solution by
monobromination, and (()-1 in now much higher con-
centration underwent further bromination to give a
preponderance of the dibrominated product (()-agelasta-
tin B (2) (ca. 3:1). Incorporation of some methanol in the
reaction medium rendered 11 much more soluble, and
under these conditions, a slight preference for formation
of the monobromide product (()-agelastatin A (1) was
observed (ca. 1.3:1). No further effort was expended on
optimizing this step in the racemic series, as material in
hand was limited, and by this time an enantioselective
route that provided substantial quantities of (-)-11 had
been developed along parallel lines, as described next.
difficulties encountered upon attempted deprotection of
the simpler benzylamine analogue near the end of the
route, vide infra. This benzylamine analogue 43b was
formed from 41 in overall 42% yield without rupture of
the oxazolidinone ring. The stereochemical assignment
The asymmetric synthesis of both (-)-agelastatin A (1)
and (-)-agelastatin B (2) benefited from the lessons
learned during the exploration of the racemic series. One
point of departure, the use of oNB protection for both N(5)
and N(9), offers the dual advantages of (1) consolidation
of the late-stage deprotection operations and (2) skirting
an epimerizable intermediate analogous to 46. The route
starts with the known alkynyloxirane 49,16 which is
readily available in two steps from (R)-epichlorohydrin.17
Introduction of N(6) employs azide and the reductive
cyclization conditions of Vilarrasa18 to deliver the oxazo-
1
shown in 43a is based upon comparison of its H NMR
spectrum with that of 43b, whose stereochemical assign-
ment rests on interpretation of the nOe effects shown in
Scheme 6, structure 43c. Fortunately, the susceptibility
of the oxazolidinone carbonyl to nucleophilic attack was
not diminished below the point of usefulness by the urea
moiety, as simple treatment of 43a with Cs2CO3/CH3OH
effected clean hydrolysis of the heterocyclic ring without
any concomitant loss of the pyrrole carboxamide moiety.
Acquisition of the cyclopentanol 44 sets up the second
key cyclization reaction of the synthesis. Exposure of this
alcohol to Swern oxidation conditions initiates a sequence
of events that most plausibly includes oxidation of the
alcohol to an unobserved cyclopentanone, â-elimination
of sulfinate to furnish an intermediate cyclopentenone,
and finally cyclization of the pendant pyrrole’s nitrogen
into the â-position (C(9a)) of this putative enone to deliver
the intact agelastatin tricycle 45 as the sole characteriz-
able reaction product. Evidence for the intermediacy of
the cyclopentenone was gleaned by subjecting cyclopen-
tanol 44 to oxidation under nonbasic conditions (Dess-
Martin). Signals consistent with the putative cyclopen-
tenone were detected in the 1H NMR spectrum of the
crude oxidation mixture, and addition of excess Et3N to
this mixture afforded cyclized product 45 in 48% overall
yield. Cyclization of a similar enone provided the pivotal
N(9)-C(9a) connection in earlier agelastatin work as
well.2
1
lidinone 50 in good yield. An H NMR assay of enantio-
meric purity using the chiral solvating agent (R)-(-)-
2,2,2-trifluoro-1-(9-anthryl)ethanol19 revealed that 50 was
formed in 94% ee, a value linked to the ee of the starting
(R)-epichlorohydrin. N-Acylation of 50 with oNB-protect-
ed N-methylcarbamoyl chloride followed by the usual Si-
to-Sn alkyne terminus transformation afforded the oxi-
dative cyclization precursor 51. By analogy to the related
N-Bn substrate 40, treatment of 51 with Stang’s reagent
and then TolO2SNa in refluxing DME provided the C-H
insertion product 53 in ∼27% yield along with 41% of
the 1,2-sulfone shift product 52. Optimization studies of
this key transformation probed the influence of solvent
(16) Takano, S.; Kamikubo, T.; Sugihara, T.; Ogasawara, K. Tetra-
hedron: Asymm. 1992, 3, 853-856.
(17) Furrow, M. E.; Schaus, S. E.; J acobsen, E. N. J . Org. Chem.
1998, 63, 6776-6777.
(18) Ariza, X.; Pineda, O.; Urp´ı, F.; Vilarrasa, J . Tetrahedron Lett.
2001, 42, 4995-4999.
Three further operations were necessary to complete
the syntheses of (()-agelastatins A/B via this route: two
(19) Pirkle, W. H.; Boeder, C. W. J . Org. Chem. 1977, 42, 3697-
3700.
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Alkynyliodonium Salts in Organic Synthesis
SCHEME 7
(THF, DME, 1,4-dioxane), temperature (25f85 °C),
reagent ratio (51:TolO2SNa ) 1:0.9 to 1:1.1), and sub-
strate concentration (0.10f0.01 M) on overall product
yield. The optimum conditions emerging from these
studies converged on DME solvent at 65 °C with 1.0 equiv
of TolO2SNa per alkyne at 0.05 M. Under this regime,
the yield of the desired bicycle 53 rose to 34% with 41%
of the alkynyl sulfone 52 formed as well. Although this
yield was rather disappointing, the brevity of the route
ensured that enough material was available to complete
the synthesis studies. Conjugate addition of oNB-amine
to the electron-deficient alkene of 53 proceeded without
interference from the oxazolidinone carbonyl as expected,
and acylation of the resulting secondary amine with 28
furnished the bicycle 54 bearing a pendant pyrrole
carboxamide moiety. Both oxazolidinone hydrolysis and
oxidation/cyclization under Swern’s conditions did not
deviate from the course followed by the simpler N-Bn
species 43a , and the tricycle 55 was formed in good
overall yield. The value of incorporating an oNB protect-
ing group at N(7) in 55 is expressed in the next step, the
photochemical cleavage of both nitrogen protecting groups.
An epimerization-sensitive intermediate similar to 46,
if formed at all, only has fleeting existence en route to
the cyclized aminal unit of the product debromoagelasta-
tin (-)-11. Once the cyclopentanone carbonyl is engaged
as the aminal, epimerization at C(5b) is no longer
possible. More exacting bromination studies with dias-
tereomerically homogeneous (-)-11 revealed that in a
polar reaction medium, electrophilic pyrrole bromination
can indeed deliver (-)-agelastatin A (1) in good yield with
no more than 4% of an agelastatin B contamination. Use
of an excess of NBS under otherwise identical conditions
afforded the dibromide product (-)-agelastatin B (2) as
a clean sample. The synthetic sample of (-)-1 displayed
1H NMR, mass spectral, and TLC behavior identical with
those of an authentic sample provided by Dr. D’Ambrosio
of the Universita` di Trento, and 13C NMR and optical
rotation data that matched those published. The spectral
data for synthetic agelastatin B were congruent with
those published for the natural material. In summary,
the utility of alkynyliodonium salts in complex natural
products synthesis has been demonstrated for the first
time. Total syntheses of the tetracyclic marine alkaloids
agelastatin A and agelastatin B were completed in both
racemic and enantioselective form. The key alkynyliodo-
nium salt-based cyclization formed the central, highly
functionalized cyclopentane core of the target molecules
from which further functional group manipulation af-
forded the natural products.
from CaH2 prior to use. Deactivated silica gel was prepared
by treatment of the silica with 5% triethylamine in hexanes
solution prior to use.
Melting points are uncorrected. Low- and high-resolution
mass spectra were obtained according to the specified tech-
nique and were performed by the University of Texas, Austin,
TX and the Pennsylvania State University, University Park,
PA. Combustion analyses were performed by Midwest Micro-
labs, Indianapolis, IN. Copies of 1H and 13C NMR spectra are
supplied in the Supporting Information for those compounds
without combustion analyses.
Gen er a l P r oced u r e A: Ur ea h yd r oxyla tion of P en -
ten yn es 37a -c. N-Benzyl-N-methylurea (3 equiv vs alkene
37) was suspended in n-propanol (0.25 M). Sodium hydroxide
(3 equiv vs alkene 37) was dissolved in water (0.41 M); 95% of
this hydroxide solution was added to dissolve the urea, and
the solution was cooled in an ice-water bath. Freshly prepared
tert-butylhypochlorite21 (3 equiv vs alkene 37) was added. The
mixture was stirred at 4 °C for 1.5 h, and then the (DHQD)2-
PHAL ligand (10 mol %) dissolved in n-PrOH (0.031 M) and
the silylpent-4-en-1-ynes 37a -c22 were added, followed by
potassium osmate dihydrate (5 mol %) freshly dissolved in the
remaining hydroxide solution. The mixture was warmed with
the ice bath overnight to room temperature. The reaction was
diluted with saturated aqueous Na2SO3. The aqueous layer
was washed with 2 × EtOAc and the combined organic layers
were washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified via flash
chromatography on silica gel with the indicated solvent system
to yield urea alcohols 39a -c. Enantioselectivities were deter-
Exp er im en ta l Section
Moisture- and oxygen-sensitive reactions were carried out
in flame-dried glassware under an argon atmosphere. Tet-
rahydrofuran (THF), 1,2-dimethoxyethane (DME), and diethyl
ether (Et2O) were distilled from sodium benzophenone ketyl
under an argon atmosphere immediately before use. Toluene,
benzene, and dichloromethane (CH2Cl2) were distilled from
calcium hydride (CaH2) under an argon atmosphere im-
mediately before use. Purification of products via flash chro-
matography20 was performed with 32-63 µm silica gel and the
solvent systems indicated. Hexanes, ethyl acetate (EtOAc),
CH2Cl2, and Et2O used in flash chromatography were distilled
(21) Mintz, M. J .; Walling, C. Organic Synthesis; Wiley: New York,
1983; Vol. V.
(22) (a) Shapiro, E. A.; Kalinin, A. V.; Platonov, D. N.; Nefedov, O.
M. Russ. Chem. Bull. 1993, 42, 1191-1195. (b) Fleming, I.; Takaki,
K.; Thomas, A. P. J . Chem. Soc., Perkin Trans. 1 1987, 2269-2273.
(20) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.
J . Org. Chem, Vol. 67, No. 20, 2002 7101

Feldman et al.
mined with the Chiralcel OD and OD-H HPLC columns with
5% i-PrOH/hexanes as eluent.
extracted with 3 × 5 mL of CH2Cl2. The combined organic
layers were dried over Na2SO4 and filtered through a short
pad of silica gel (20% EtOAc/hexanes as eluent) to yield 75
mg of an acetonide product (59%). IR (CDCl3) 3309, 2124, 1696
cm-1; 1H NMR (360 MHz, CDCl3) δ 4.22 (m, 1H), 3.76 (m, 1H),
3.26 (m, 1H), 2.57 (ddd, J ) 16.7, 5.0, 2.6 Hz, 1H), 2.46 (ddd,
J ) 16.7, 6.9, 2.5 Hz, 1H), 2.04 (br s, 1H), 1.57 (s, 3H), 1.51 (s,
3H), 1.48 (s, 9H); 13C NMR (90 MHz, CDCl3, amide rotomers)
δ 152.0, 151.8, 94.1, 93.6, 80.1, 79.5, 79.2, 77.2, 71.7, 70.4, 50.2,
28.4, 28.3, 27.1, 26.1, 25.4, 24.5, 23.2; CIMS m/z (rel intensity)
240 (MH+, 18).
Gen er a l P r oced u r e B: P yr r ole Ca r boxa m id e F or m a -
tion . Pyrrole-2-carboxylic acid (10 equiv vs amine) was
suspended in dry benzene (0.2 M), and oxalyl chloride (20
equiv) was added. One drop of DMF was added, leading to
immediate gas evolution. The mixture was stirred until all
solids were dissolved (2 h). The solution was concentrated with
use of an aspirator equipped with a CaCl2-filled drying tube
and then under high vacuum to afford a white solid. This solid
was dissolved in dry CH2Cl2 (0.8 M) and distilled pyridine (20
equiv) was added with immediate formation of a yellow
precipitate. The secondary amine was dissolved in dry CH2-
Cl2 (0.04 M) and added to the pyrrole-2-carboxylic acid chloride
solution. 4-(Dimethylamino)pyridine (0.1 equiv) then was
added and the mixture was stirred at room temperature for 2
d. The yellow suspension was diluted with CH2Cl2 and poured
into ice cold 1 M H3PO4. The organic layer was washed with
brine and the aqueous layers were extracted with EtOAc. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo to furnish the crude amide. This crude
residue was purified via flash chromatography with the
indicated solvents.
Gen er a l P r oced u r e C: Sw er n Oxid a tion of Cyclop en -
ta n ols. Dimethyl sulfoxide (2.4 equiv) was dissolved in CH2-
Cl2 (3.5 M) and cooled to -78 °C. Oxalyl chloride (1.2 equiv)
was added dropwise, and the resulting solution was stirred
at -78 °C for 10 min and room temperature for 3 min, and
then recooled to -78 °C. The cyclopentanol was added drop-
wise as a solution in CH2Cl2 (0.12 M). The mixture was stirred
at -78 °C for 2 h, and then Et3N (10 equiv) was added
dropwise. This mixture was stirred at -78 °C for 10 min, and
then at room temperature overnight. Saturated aqueous NH4-
Cl was poured into the reaction mixture, and the organic phase
was dried over Na2SO4, filtered, and concentrated in vacuo.
The crude product was purified via flash chromatography with
the indicated solvents.
ter t-Bu t yl-N-(2-h yd r oxyp en t -4-yn yl)ca r b a m a t e (13).
Magnesium turnings (6.0 g, 250 mmol) were flame dried under
vacuum, suspended in 100 mL of Et2O, and treated with HgCl2
(246 mg, 0.9 mmol). The mixture was stirred at room temper-
ature for 30 min then cooled to 4 °C, and propargyl bromide
(1.5 mL of an 80% solution in toluene, 14 mmol) was added.
The mixture was stirred for 14 min at room temperature and
a rise in temperature was observed. The solution was main-
tained at 4 °C and the remainder of the propargyl bromide
(20.5 mL, 198 mmol total) was added dropwise. The mixture
was stirred at 0 °C for an additional 1 h, and then the mixture
was transferred via cannula to a flask cooled to -42 °C. N-Boc
glycinal (12)23 (8.7 g, 55 mmol) in 18 mL of dry Et2O was added
dropwise over 20 min. The reaction mixture was warmed to 8
°C for 5 h and then poured into a cold saturated NH4Cl
solution, producing vigorous bubbling. The aqueous layer was
extracted with 3 × 10 mL of Et2O. The organic layers were
combined and dried over Na2SO4, filtered, and concentrated
in vacuo, and the residue was purified via flash chromatog-
raphy on silica gel (30-40% EtOAc/hexanes as eluent) to yield
3.56 g of 13 (32%) as a colorless oil. IR (CDCl3) 3598, 3458,
3308, 1709 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.95 (br s, 1H),
3.86 (m, 1H), 3.39 (br d, J ) 13.1 Hz), 3.18 (m, 1H), 2.38 (m,
2H), 2.14 (m, 1H), 1.42 (s, 9H); CIMS m/z (rel intensity) 200
(MH+, 9); HRMS Calcd for C10H18NO3 200.1287, found 200.1287.
This alkyne (66 mg, 0.28 mmol) was dissolved in 0.55 mL
of dry THF then cooled to -78 °C, and LiHMDS (0.28 mL of
a 1 M solution in THF, 0.28 mmol) was added over 30 min.
The mixture was stirred at -78 °C for 35 min, and then
tributyltin chloride (75 µL, 0.28 mmol) in 0.3 mL of dry THF
was added dropwise. The mixture was stirred at -78 °C for
45 min and then brought to room temperature for 2.5 h. After
concentrating in vacuo, the residue was purified via flash
chromatography on deactivated silica gel (4% EtOAc/hexanes
as eluent) to yield 120 mg of 14 (81%) as a colorless oil. IR
1
(CDCl3) 2150, 1692 cm-1; H NMR (300 MHz, CDCl3) δ 4.19
(m, 1H), 3.74 (m, 1H), 3.29 (m, 1H), 2.66 (dd, J ) 16.7, 4.5 Hz,
1H), 2.49 (dd, J ) 16.7, 7.8 Hz, 1H), 1.7-1.4 (m, 12H), 1.47 (s,
9H), 14-1.2 (m, 6H), 1.1-0.8 (m, 15H); 13C NMR (75 MHz,
CDCl3) δ 152.0, 105.5, 94.1, 84.7, 79.5, 72.4, 50.4, 28.8 (J C-Sn
) 11.4 Hz), 28.4, 26.9 (J C-Sn ) 29.5 Hz), 26.2, 25.5, 24.8, 13.7,
13
117
13
119
) 191.8 Hz); CIMS
C- Sn
10.9 (J
) 183.3 Hz and J
C- Sn
m/z (rel intensity) 530 (MH+, 100); HRMS Calcd. for C25H48
-
NO3118Sn+ 530.2661, found 530.2669.
Cyclop en ten e 17. Alkynylstannane 14 (0.12 g, 0.23 mmol)
was dissolved in 3 mL of dry CH2Cl2 then cooled to -42 °C,
and PhI(CN)OTf (84 mg, 0.22 mmol) was added in one portion.
The mixture was stirred at -42 °C for 2 h, and then half of
this solution was transferred via cannula to a flame-dried flask
and concentrated in vacuo with an aspirator and drying tube
at -42 °C. The residue was dissolved in 1.5 mL of dry DME
prechilled to -42 °C. The mixture was cooled to -78 °C, and
sodium p-toluenesulfinate (20 mg, 0.11 mmol) was added in
one portion. The mixture was stirred at -78 °C for 5 min and
then brought to reflux and held there for 15 min, cooled to
room temperature, and concentrated in vacuo. The crude
mixture was purified via flash chromatography on silica gel
(20-30% EtOAc/hexanes as eluent) to yield a mixture of
products. Resubjection of this mixture to flash chromatography
(32% EtOAc/hexanes as eluent) yielded an inseparable mixture
of 5.2 mg of 17 (2%) with small amounts of several byproducts
and 2.6 mg of 19 (7%) as a white solid.
17: IR (C6D6) 1705 cm-1; 1H NMR (300 MHz, d6-acetone) δ
7.77 (d, J ) 8.1 Hz, 2H), 7.47 (d, J ) 8.6 Hz, 2H), 6.59 (d, J )
1.3 Hz, 1H), 4.93 (d, J ) 5.5 Hz, 1H), 4.80 (apparent t, J ) 5.4
Hz, 1H), 2.84 (m, 1H), 2.48 (m, 1H), 2.44 (s, 3H), 1.48 (s, 9H),
1.40 (s, 3H), 1.38 (s, 3H); 13C NMR (75 MHz, d6-acetone) δ
145.9, 139.3, 130.8, 128.9, 128.5, 94.8, 77.7, 72.9, 67.3, 53.4,
48.8, 37.4, 28.5, 27.0, 24.1, 21.5; CIMS m/z (rel intensity) 394
(MH+, 2).
19: IR (C6D6) 3432, 1720 cm-1 1H NMR (400 MHz, d6-
;
acetone) δ 7.78 (d, J ) 8.4 Hz, 2H), 7.45 (d, J ) 8.5 Hz, 2H),
7.35 (s, 1H), 6.21 (s, 1H), 5.01 (m, 1H), 3.29 (m, 2H), 2.84 (m,
1H), 2.57 (ddd, J ) 14.3, 7.6, 1.8 Hz, 1H), 2.47 (s, 3H), 1.35 (s,
9H); 13C NMR (75 MHz, d6-acetone) δ 156.5, 144.7, 139.5,
130.7, 127.9, 118.2, 104.0, 86.1, 79.0, 44.5, 31.2, 28.5, 21.4;
CIMS m/z (rel intensity) 254 ([M - Boc + H2]+, 100).
Oxir a n e 21. Pyridine (7.3 mL, 90 mmol) and phenylchlo-
roformate (6.3 mL, 50 mmol) were successively added to
allylbenzylamine (6.6 g, 45 mmol) in 100 mL of CH2Cl2 at 0
°C over 10 min. The resulting mixture was allowed to stir at
0 °C for 1 h then at room temperature for 2 h. The reaction
mixture was diluted with 10 mL of H2O. The phases were
separated and the organic layer was washed with 25 mL of
brine, dried over Na2SO4, filtered, and concentrated in vacuo
to provide 13.9 g of an orange oil. Purification of this crude
Oxa zolid in e 14. Alcohol 13 (106 mg, 0.53 mmol) was
dissolved in 1.9 mL of acetone, and 2,2-dimethoxypropane (0.58
mL, 4.7 mmol) was added followed by 1 drop of BF3‚Et2O. The
mixture was stirred at room temperature for 130 min and then
concentrated in vacuo. The yellow oil was dissolved in CH2Cl2
and washed with aqueous NaHCO3. The aqueous layer was
(23) Bischofberger, N.; Waldmann, H.; Saito, T.; Simon, E. S.; Lees,
W.; Bednarski, M. D.; Whitesides, G. M. J . Org. Chem. 1988, 53, 3457-
3465.
7102 J . Org. Chem., Vol. 67, No. 20, 2002

Alkynyliodonium Salts in Organic Synthesis
material on silica gel (15% Et2O/hexanes to 25% Et2O/hexanes
as eluent) afforded 11.13 g (93%) of the allyl carbamate as a
Glacial acetic acid (2.1 mL, 36 mmol) and a 1.0 M THF
NF (36 mL, 36 mmol) were added to this
solution of Bu4
colorless oil. IR (film) 1724, 1714 cm-1 1H NMR (360 MHz,
;
oxazolidinone derivative (7.0 g, 24 mmol) in 60 mL of THF.
After 6 h, the mixture was diluted with 20 mL of H2O and
extracted with 150 mL of Et2O. The phases were separated
and the organic layer was washed with two 20-mL portions of
H2O and 20 mL of brine, dried over Na2SO4, filtered, and
concentrated in vacuo to afford a yellow oil. Purification of the
crude product by flash chromatography on silica gel (35%
EtOAc/hexanes, 40% EtOAc/hexanes, to 50% EtOAc/hexanes
as eluent) afforded 4.74 g (92%) of the terminal alkyne product
CDCl3, amide rotomers) δ 7.5-7.3 (m, 7H), 7.3-7.0 (m, 3H),
5.85 (m, 1H), 5.25 (m, 2H), 4.63/4.56 (each s, 1H), 3.98/3.96
(each s, 2H); 13C NMR (90 MHz, CDCl3, amide rotomers) δ
155.1, 154.6, 151.4, 137.2, 132.9, 132.8, 129.2, 128.6, 128.2,
127.5, 125.2, 121.7, 118.0, 117.1, 50.0, 49.7, 49.3, 48.8; CIMS
m/z (rel intensity) 268 (MH+, 100). Anal. Calcd for C17H17
-
NO2: C, 76.38; H, 6.71. Found: C, 76.53; H, 6.59.
m-CPBA (60%, 17.8 g, 62 mmol) was added to the allyl
carbamate (8.4 g, 31 mmol) in 250 mL of CH2Cl2 at 0 °C in
three portions over 15 min. After 5 h, an additional amount
of 60% m-CPBA (8.9 g, 32 mmol) was added and the solution
was allowed to stir for 12 h. The reaction mixture was diluted
carefully with saturated sodium bisulfite solution and then
saturated NaHCO3 solution was added. The phases were
separated and the organic layer was dried over Na2SO4,
filtered, and concentrated in vacuo to provide 7.9 g of a yellow
oil. Purification of the crude material on silica gel (15% EtOAc/
hexanes to 20% EtOAc/hexanes as eluent) afforded 6.52 g
as a colorless oil. IR (film) 3288, 2122, 1749 cm-1 1H NMR
;
(300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.60 (m, 1H), 4.47 (d, J
) 14.7 Hz, 1H), 4.39 (d, J ) 14.7 Hz, 1H), 3.54 (apparent t, J
) 9.0 Hz, 1H), 3.28 (dd, J ) 9.0, 6.0 Hz, 1H), 2.67-2.51 (m,
2H), 1.97 (t, J ) 2.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
157.7, 135.6, 128.8, 128.2, 128.0, 77.3, 71.5, 70.4, 48.3, 48.2,
24.7; CIMS m/z (rel intensity) 216 (MH+, 100). Anal. Calcd
for C13H13NO2: C, 72.54; H, 6.09. Found: C, 72.43; H, 6.26.
A 1.0 M solution of LiHMDS in THF (21.4 mL, 21.4 mmol)
was added to this terminal alkyne (4.6 g, 21.4 mmol) in 45
mL of THF at -78 °C over 1 h. The reaction mixture was
allowed to stir at -78 °C for 1.5 h before the addition of
tributyltin chloride (5.8 mL, 21.4 mmol). The solution was
allowed to warm to ambient temperature and stir for 2.5 h.
The mixture was diluted with 20 mL of saturated NH4Cl
solution and extracted with 200 mL of Et2O. The phases were
separated and the organic layer was washed with 50 mL of
brine, dried over Na2SO4, filtered, and concentrated in vacuo
to afford 11.5 g of the stannylated alkyne 22 as a yellow oil.
Purification of the crude product on silica gel (20% EtOAc/
hexanes to 25% EtOAc/hexanes as eluent) afforded 8.53 g
(81%) of 22 as a pale yellow oil. IR (film) 2154, 1765 cm-1; 1H
NMR (300 MHz, C6D6) δ 7.07 (s 5H), 4.30 (d, J ) 14.7 Hz,
1H), 4.02 (d, J ) 14.7 Hz, 1H), 3.94 (m, 1H), 2.82 (dd, J )
10.5, 8.6 Hz, 1H), 2.80 (dd, J ) 12.1, 8.7 Hz, 1H), 2.3-2.2 (m,
2H), 1.7-1.5 (m, 6H), 1.4-1.2 (m, 6H), 1.0-0.8 (m, 15H); 13C
(74%) of 21 as a colorless oil. IR (film) 1730, 1714 cm-1 1H
;
NMR (360 MHz, CDCl3, amide rotomers) δ 7.6-7.4 (m, 7H),
7.3-7.1 (m, 3H), 4.9-4.6 (m, 2H), 3.8-3.6 (m, 1H), 3.3-3.0
(m, 2H) superimposed by 3.2-3.1 (m, 1H), 2.77 (apparent t, J
) 4.1 Hz, 1H), 2.52 (d, J ) 4.6 Hz, 1H); 13C NMR (90 MHz,
CDCl3, amide rotomers) δ 154.9, 151.2, 137.2, 137.1, 129.3,
128.7, 128.3, 127.6, 127.4, 125.4, 121.6, 51.7, 50.5, 50.4, 49.2,
48.5, 45.3, 45.1; CIMS m/z (rel intensity) 284 (MH+, 100). Anal.
Calcd for C17H17NO3: C, 72.06; H, 6.05. Found: C, 71.67; H,
5.64.
Alk yn ylsta n n a n e 22. A 2.5 M solution of n-BuLi in hexane
(16 mL, 39 mmol) was added to trimethylsilylacetylene (5.5
mL, 39 mmol) in 92 mL of THF at -78 °C over 25 min. After
15 min, BF3‚Et2O (4.9 mL, 39 mmol) was added over 5 min.
The reaction mixture was allowed to stir at -78°C for 20 min
before the addition of a solution of the epoxide (7.4 g, 26 mmol)
in 40 mL of THF over 25 min. After 1 h at -78 °C, the mixture
was poured into 20 mL of saturated NH4Cl solution and diluted
with 150 mL of EtOAc. The phases were separated and the
organic layer was washed with 40 mL of brine, dried over Na2-
SO4, filtered, and concentrated in vacuo to afford 11.4 g of an
orange oil. Purification of the crude product by flash chroma-
tography on silica gel (15% EtOAc/hexanes, 20% EtOAc/
hexanes, to 25% EtOAc/hexanes as eluent) afforded 9.54 g
(96%) of the expected homopropargyl alcohol as a light yellow
NMR (75 MHz, CDCl3) δ 157.6, 135.7, 128.8, 128.1, 128.0,
119
103.3, 86.3, 71.3, 48.5, 48.3, 28.8 (J C-
) 11.6 Hz), 26.9
Sn
119
119
117
(J C- Sn ) 29.1 Hz), 26.3, 13.7, 11.0 (J C- Sn ) 191.1 Hz, J C-
Sn
) 183.1 Hz). APCIMS m/z (rel intensity) 506 (Sn120) (MH+,
80); APCI-HRMS Calcd for C25H40NO2120Sn 506.2086, found
506.2056.
Cyclop en ten e 24. Cyano(phenyl)iodonium triflate (0.11 g,
0.29 mmol) was added to a -42 °C solution of the alkynyl-
stannane 22 (0.15 g, 0.29 mmol) in 3.5 mL of CH2Cl2. After 1
h, the solvent was removed in vacuo at -42 °C and the white
residue was used immediately (assuming quantitative yield).
This alkynyl(phenyl)iodonium triflate (0.15 g, 0.29 mmol) in
18 mL of THF prechilled to -42 °C was added via cannula to
a refluxing suspension of anhydrous TolO2SNa (52 mg, 0.29
mmol) in 1.1 mL of THF. An additional 1 mL of THF was used
to rinse over any residual iodonium salt. The yellow suspension
was held at reflux for 30 min and then stirred at room
temperature for 10 min. The reaction mixture was poured into
brine and extracted with 50 mL of EtOAc. The organic layer
was washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo to afford 0.14 g of a yellow oil. Purifica-
tion of the crude material by flash chromatography on deac-
tivated silica gel (30% EtOAc/hexanes, 40% EtOAc/hexanes,
to 50% EtOAc/hexanes as eluent) afforded 44 mg (41%) of the
1,5 C-H insertion product 24 as a white solid, 31 mg (31%) of
the formal oxygen/lone-pair insertion product 25, and 9 mg
(6%) of the (bis)sulfone/conjugate addition product 26.
oil. IR (film) 2175, 1715 cm-1 1H NMR (360 MHz, CDCl3,
;
amide rotomers) δ 7.5-7.3 (m, 7H), 7.3-7.1 (m, 3H), 4.8-4.6
(m, 2H), 4.06 (br s, 1H), 3.53 (m, 2H), 2.48 (apparent t, J )
5.2 Hz, 2H), 0.15 (s, 9H); 13C NMR (90 MHz, CDCl3, amide
rotomers) δ 156.6, 155.2, 151.2, 151.1, 137.2, 137.0, 129.3,
128.7, 128.2, 127.7, 127.4, 125.5, 125.3, 121.6, 102.5, 101.8,
88.2, 87.7, 69.8, 68.6, 52.5, 52.4, 51.7, 51.0, 26.5, 0.0; CIMS
m/z (rel intensity) 382 (MH+, 24). Anal. Calcd for C22H27NO3-
Si: C, 69.26; H, 7.13. Found: C, 69.09; H, 6.84.
A 60% dispersion of sodium hydride (0.97 g, 24 mmol) was
added in three portions over 15 min to this homopropargyl
alcohol (9.3 g, 24 mmol) in 200 mL of THF at 0 °C. After 1 h
at 0 °C, the mixture was diluted with 40 mL of H2O and
extracted with 200 mL of EtOAc. The phases were separated
and the organic layer was washed with 5 × 50 mL of cold 1 N
NaOH solution, 2 × 50 mL of H2O, and brine, dried over Na2-
SO4, filtered, and concentrated in vacuo to afford 7.0 g of the
oxazolidinone product as a white solid (100%). Mp 73-74 °C;
IR (film) 2178, 1760 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.4-
7.2 (m, 5H), 4.59 (m, 1H), 4.54 (d, J ) 15.1 Hz, 1H), 4.34 (d, J
) 14.7 Hz, 1H), 3.52 (apparent t, J ) 9.0 Hz, 1H), 3.29 (dd, J
) 9.0, 6.0 Hz, 1H), 2.7-2.5 (m, 2H), 0.13 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 157.7, 135.7, 129.0, 128.2, 128.1, 99.4, 88.5,
70.9, 48.4, 48.3, 26.0, 0.0; CIMS m/z (rel intensity) 288 (MH+,
100). Anal. Calcd for C16H21NO2Si: C, 66.85; H, 7.36. Found:
C, 66.56; H, 7.35.
24: mp 124 °C; IR (film) 1747 cm-1
;
1H NMR (360 MHz,
CDCl3) δ 7.69 (d, J ) 8.2 Hz, 2H), 7.4-7.2 (m, 7H), 6.33 (s,
1H), 5.11 (apparent t, J ) 6.8 Hz, 1H), 4.61 (d, J ) 15.0 Hz,
1H), 4.57 (d, J ) 7.7 Hz, 1H), 4.30 (d, J ) 15.0 Hz, 1H), 3.03
(dd, J ) 18.2, 6.8 Hz, 1H), 2.79 (d, J ) 17.8 Hz, 1H), 2.48 (s,
3H); 13C NMR (90 MHz, CDCl3) δ 157.6, 147.7, 145.6, 135.5,
134.8, 134.7, 130.2, 129.1, 128.5, 128.3, 76.0, 64.3, 47.6, 37.9,
J . Org. Chem, Vol. 67, No. 20, 2002 7103

Feldman et al.
21.7; CIMS m/z (rel intensity) 370 (MH+, 100); CI-HRMS Calcd
for C20H20NO4S 370.1113, found 370.1108.
concentrated in vacuo and the residue was purified via flash
chromatography on silica gel (20% EtOAc/hexanes as eluent)
to yield 102 mg of 31 (67%) as a yellow oil. IR (CDCl3) 1797,
25: IR (film) 3468 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.72
(d, J ) 8.0 Hz, 2H), 7.55 (s, 1H), 7.4-7.2 (m, 7H), 4.37 (d, J )
15.1 Hz, 1H), 4.29 (d, J ) 15.1 Hz, 1H), 4.11 (br s, 1H), 3.02
(d, J ) 12.6 Hz, 1H), 2.93 (dd, J ) 12.8, 3.3 Hz, 1H), 2.42 (m,
4H), 2.20 (dd, J ) 15.6, 4.0 Hz, 1H), 1.80 (br s, 1H); 13C NMR
(100 MHz, CDCl3) δ 143.6, 142.7, 139.2, 136.0, 129.5, 128.9,
128.2, 127.6, 126.9, 98.9, 62.4, 59.8, 50.8, 28.6, 21.9. FABMS
m/z (rel intensity) 370 (MH+, 2).
1750, 1709 cm-1 1H NMR (360 MHz, CDCl3) δ 7.37 (t, J )
;
7.9, Hz, 2H), 7.24 (m, 1H), 7.16 (m, 2H), 4.04 (dd, J ) 14.7,
4.6 Hz, 1H), 3.93 (dd, J ) 14.7, 4.6 Hz, 1H), 3.24 (dd, J ) 4.1,
2.6 Hz, 1H), 2.80 (apparent t, J ) 4.4 Hz, 1H), 2.67 (dd, J )
4.9, 2.6 Hz, 1H), 1.54 (s, 9H); 13C NMR (90 MHz, CDCl3) δ
152.4, 151.7, 150.6, 129.3, 125.9, 121.3, 83.7, 49.7, 47.6, 45.7,
27.8; ESIMS m/z (rel intensity) 294 (MH+, 59).
P yr r ole Ca r boxa m id e 29. Benzylamine (0.32 mL, 2.9
mmol) was added to the bicyclic cyclopentene 24 (0.18 g, 0.49
mmol) in 5 mL of absolute EtOH. After 24 h at reflux, the
reaction mixture was cooled and concentrated in vacuo to
afford an oil. Purification of the crude product by flash
chromatography on silica gel (50% EtOAc/hexanes, 60% EtOAc/
hexanes, to 70% EtOAc/hexanes as eluent) afforded 0.19 g
(81%) of the secondary amine product as a white solid. Mp
Oxa zolid in on e 32. Trimethylsilylacetylene (2.12 mL, 15
mmol) was dissolved in 20 mL of THF, and the mixture was
cooled to -78 °C. n-Butyllithium (6 mL of a 2.5 M solution in
hexanes, 15 mmol) was added over 18 min. This mixture was
stirred at -78 °C for 15 min, and then boron trifluoride
etherate (1.9 mL, 15 mmol) was added over 6 min. This
mixture was stirred at -78 °C for 20 min and then epoxide
31 (2.94 g, 10 mmol) was added as a solution in 10 mL of THF
over 20 min. This mixture was stirred at -78 °C for 2.5 h,
saturated NH4Cl was added to the solution, and the mixture
was allowed to warm to room temperature. The mixture was
extracted with EtOAc. The organic layer was washed with
brine, dried over Na2SO4, filtered, and adsorbed onto silica gel.
The crude product was purified via flash chromatography on
silica gel (18%, 25%, then 50% EtOAc, hexanes as eluent) to
yield 1.75 g of the crude oxazolidinone which was recrystallized
from 20 mL of Et2O and 150 mL of hexanes to yield pure 32
(1.41 g, 47%) as a white solid. Mp 116-117 °C; IR (CDCl3)
3692, 3604, 2181, 1816, 1720 cm-1; 1H NMR (400 MHz, CDCl3)
δ 4.60 (m, 1H), 4.03 (dd, J ) 10.4, 8.6 Hz, 1H), 3.81 (dd, J )
10.4, 5.8 Hz, 1H), 2.66 (d, J ) 5.6 Hz, 2H), 1.54 (s, 9H), 0.14
(s, 9H); 13C NMR (90 MHz, CDCl3) δ 151.5, 149.5, 98.6, 89.2,
83.9, 70.1, 47.6, 28.1, 26.1, -0.1; APCIMS m/z (rel intensity)
320 ([MNa]+, 9). Anal. Calcd for C14H23NO4Si: C, 56.54; H,
7.79. Found: C, 56.40; H, 7.84.
1
138 °C; IR (film) 3322, 1748 cm-1; H NMR (300 MHz, C6D6)
δ 7.56 (d, J ) 8.3 Hz, 2H), 7.2-6.9 (m, 11H), 6.73 (d, J ) 7.9
Hz, 1H), 4.83 (d, J ) 15.4 Hz, 1H), 3.98 (dd, J ) 15.8, 7.1 Hz,
1H), 3.90 (d, J ) 15.8 Hz, 1H), 3.81 (dd, J ) 7.5, 3.4 Hz, 1H),
3.5-3.2 (m, 3H), 2.83 (d(apparent)t, J ) 10.6, 7.4 Hz, 1H), 2.14
(ddd, J ) 17.4, 10.6, 6.8 Hz, 1H), 1.87 (s, 3H), 1.8-1.6 (m, 1H),
1.40 (br s, 1H); 13C NMR (75 MHz, C6D6) δ 157.0, 144.7, 139.9,
136.6, 136.1, 130.0, 129.0, 128.9, 128.7, 128.5, 128.2, 127.9,
127.5, 74.5, 65.9, 64.6, 63.9, 51.1, 46.4, 34.7, 21.2; CIMS m/z
(rel intensity) 477 (MH+, 100). Anal. Calcd for C27H28N2O4S:
C, 68.05; H, 5.92. Found: C, 68.35; H, 5.94.
Following general procedure B, this secondary amine (31
mg, 0.065 mmol) was acylated with 28. The crude product was
purified by flash chromatography on silica gel (45% EtOAc/
hexanes, 50% EtOAc/hexanes, to 60% EtOAc/hexanes as
eluent) to afford 28 mg (76%) of amide 29 as a white solid. Mp
1
206-207 °C; IR (film) 3354, 1755 cm-1; H NMR (360 MHz,
CDCl3) δ 9.35 (br s, 1H), 7.74 (d, J ) 8.2 Hz, 2H), 7.4-7.1 (m,
11H), 6.95 (t, J ) 1.8 Hz, 1H), 6.9-6.8 (m, 2H), 6.52 (br s,
1H), 6.19 (dd, J ) 6.4, 2.7 Hz, 1H), 5.4-5.2 (m, 2H), 4.65 (d,
J ) 17.3 Hz, 1H), 4.39 (d, J ) 8.2 Hz, 1H), 4.27 (d, J ) 16.4
Hz, 1H), 4.16 (br s, 1H), 4.00 (ddd, J ) 10.5, 6.8, 4.1 Hz, 1H),
3.40 (d, J ) 16.4 Hz, 1H), 2.87 (ddd, J ) 17.8, 9.8, 8.0 Hz,
1H), 2.46 (s, 3H), 2.32 (ddd, J ) 15.1, 6.4, 4.1 Hz, 1H); 13C
NMR (90 MHz, CDCl3) δ 163.3, 157.0, 145.5, 136.0, 135.3,
134.2, 130.2, 129.4, 128.8, 128.5, 128.3, 127.5, 127.4, 127.2,
123.5, 122.2, 113.3, 110.8, 79.1, 70.7, 68.1, 65.3, 54.3, 45.7, 37.4,
21.7; CIMS m/z (rel intensity) 570 (MH+, 100); CI-HRMS Calcd
for C32H32N3O5S 570.2063, found 570.2057.
Sta n n yla lk yn e 33. Oxazolidinone 32 (600 mg, 2.0 mmol)
was dissolved in 5.3 mL of dry THF, and then bis(tributyltin)
oxide (0.54 mL, 1 mmol) and Bu4NF (42 µL of a 1 M solution
of Bu4NF in THF, 0.4 mmol) were added. The flask was sealed
and heated to 60 °C for 4 h. Bu4NF (10 µL of a 1 M solution of
Bu4NF in THF, 0.1 mmol) was added and the mixture was
heated for an additional 50 min. The solution was concentrated
in vacuo, and the residue was purified via flash chromatog-
raphy with deactivated silica gel (12-20% EtOAc/hexanes as
eluent) to yield 0.47 g of 33 (45%) as a colorless oil. IR (CDCl3)
2153, 1821, 1721 cm-1 1H NMR (300 MHz, CDCl3) δ 4.59
;
(apparent tdd, J ) 10.7, 6.3, 4.4 Hz, 1H), 4.03 (dd, J ) 10.4,
8.4 Hz, 1H), 3.85 (dd, J ) 10.4, 6.3 Hz, 1H), 2.77 (ddd, J )
16.7, 9.2, 4.7 Hz, 1H), 2.63 (dd, J ) 16.7, 8.0 Hz, 1H), 1.6-1.4
(m, 6H), 1.56 (s, 9H), 1.3-1.2 (m, 6H), 1.1-0.8 (m, 15H); 13C
NMR (90 MHz, CDCl3) δ 151.2, 149.1, 102.2 (J C-Sn ) 29.5 Hz),
86.7, 83.3, 70.3, 47.4, 28.6 (J C-Sn ) 11.6 Hz), 27.7, 26.6 (J C-Sn
Oxir a n e 31. Phenyl-N-allylcarbamate (30)24 (3.0 g, 17
mmol) was dissolved in 430 mL of CH2Cl2 and cooled to 4 °C.
m-CPBA (77%, 5.9 g, 26 mmol) was added in one portion. After
2 min, the solution was warmed to room temperature and held
there with stirring for 60 h. The mixture was poured into 300
mL of ice cold 10% Na2SO3. The organic layer was washed with
3 × 300 mL of saturated NaHCO3, water, and then brine, dried
over Na2SO4, and filtered, and the residue was concentrated
in vacuo to yield 3.3 g of the oxirane product (100%) as a yellow
13
117
13
119
) 29.6 Hz), 25.8, 13.4, 10.7 (J
) 183.0 Hz and J
C- Sn
C- Sn
) 191.4 Hz); ESIMS m/z (rel intensity) 533 ([M + Na]+, 32);
HRMS Calcd for C23H41NO4118Sn 516.2140, found 516.2133.
Cyclop en ten e 35. Alkynylstannane 33 (1.21 g, 2.35 mmol)
was dissolved in 28 mL of dry CH2Cl2 then cooled to -50 °C,
and PhI(CN)OTf (883 mg, 2.33 mmol) was added in one
portion. The mixture was stirred at -42 °C for 2 h, and then
concentrated in vacuo at -42 °C at aspirator pressure through
a drying tube. The residue was dissolved in 9.4 mL of dry DME
prechilled to -42 °C and poured into a refluxing suspension
of TolO2SNa (427 mg, 2.35 mmol) in 22 mL of dry DME. The
mixture was held at reflux for 15 min, cooled to room
temperature, and concentrated in vacuo. The crude mixture
was purified via flash chromatography on silica gel (40-50%
EtOAc/hexanes as eluent) to yield 365 mg of 35 (41%) and 116
mg of alkyne 34 (13%) as white solids. A sample of 35 was
recrystallized from 3:5 CHCl3/hexanes for characterization.
1
oil. IR (CHCl3) 1732 cm-1; H NMR (360 MHz, CDCl3) δ 7.36
(apparent t, J ) 7.9 Hz, 2H), 7.20 (t, J ) 7.4 Hz, 1H), 7.12 (d,
J ) 7.7 Hz, 2H), 3.70 (d(apparent)t, J ) 14.7, 3.1 Hz, 1H),
3.31 (d(apparent)t, J ) 14.7, 5.7 Hz, 1H), 3.18 (m, 1H), 2.83
(apparent t, J ) 4.2 Hz, 1H), 2.67 (apparent t, J ) 3.2 Hz,
1H); 13C NMR (90 MHz, CDCl3) δ 154.8, 150.8, 129.3, 125.4,
121.5, 50.5, 45.1, 42.4; ESMS m/z (rel intensity) 194 (MH+,
100).
This oxirane (100 mg, 0.52 mmol) was dissolved in 5 mL of
dry THF. Triethylamine (87 µL, 0.62 mmol) followed by
4-DMAP (13 mg, 0.1 mmol) mixed with di-tert-butyl dicarbon-
ate (147 mg, 0.67 mmol) were added. The orange solution was
stirred at room temperature for 18 h. The solution was
35: mp 145 °C (decomposes with gas evolution); IR (CDCl3)
3690, 3607, 1818, 1723 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.73 (d, J ) 8.2 Hz, 2H), 7.35 (d, J ) 8.3 Hz, 2H), 6.64 (d, J )
(24) Patonay, T.; Patonay-Peli, E.; Mogyorodi, F. Synth. Commun.
1990, 20, 2865-2885.
7104 J . Org. Chem., Vol. 67, No. 20, 2002

Alkynyliodonium Salts in Organic Synthesis
1.6 Hz, 1H), 5.20 (d, J ) 7.2 Hz, 1H), 5.10 (apparent t, J ) 6.7
Hz, 1H), 3.01 (ddd, J ) 18.0, 6.4, 2.3 Hz, 1H), 2.77 (d, J )
18.0 Hz, 1H), 2.43 (s, 3H), 1.52 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 150.4, 148.4, 147.6, 145.6, 134.9, 134.4, 130.2, 128.2,
84.7, 75.1, 64.0, 37.5, 27.8, 21.6; APCIMS m/z (rel intensity)
397 ([M + H3O]+, 3). Anal. Calcd for C18H21NO6S: C, 56.98; H
5.58. Found: C, 56.80; H, 5.56.
34: IR (CCl4) 2213, 1805 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.85 (d, J ) 8.4 Hz, 2H), 7.36 (d, J ) 8.4, Hz, 2H), 4.65 (m,
1H), 4.06 (dd, J ) 10.9, 10.2 Hz, 1H), 3.70 (dd, J ) 10.9, 5.5
Hz, 1H), 2.82 (m, 2H), 2.46 (s, 3H), 1.54 (s, 9H); 13C NMR (90
MHz, CDCl3) δ 150.9, 149.2, 146.0, 138.4, 130.3, 127.7, 88.4,
84.7, 81.5, 69.1, 47.8, 28.2, 25.3, 22.0; APCIMS m/z (rel
intensity) 402 (MNa+, 3).
ee). Enantiomeric excess was determined by chiral HPLC with
a Chiralcel OD-H column (5% PrOH/hexanes as eluent at 1
i
mL/min), detecting at λ ) 205 nm. Retention times were 33.10
and 44.20 min for the two enantiomers. IR (CDCl3) 3475, 3314,
1
2174 cm-1; H NMR (360 MHz, CDCl3) δ 7.59 (m, 2H), 7.4-
7.1 (m, 8H), 5.03 (t, J ) 5.6 Hz, 1H), 4.57 (s, 1H), 4.45 (s, 2H),
3.86 (m, 1H), 3.53 (ddd, J ) 14.3, 6.1, 2.8 Hz, 1H), 3.30 (ddd,
J ) 14.3, 6.7, 5.4 Hz, 1H), 2.82 (s, 3H), 2.50 (dd, J ) 16.9, 5.9
Hz, 1H), 2.41 (dd, J ) 16.9, 7.4 Hz, 1H), 0.38 (s, 6H); 13C NMR
(50 MHz, CDCl3) δ 159.7, 137.3, 137.1, 133.5, 129.3, 128.6,
127.8, 127.3, 127.1, 105.0, 85.0, 70.5, 52.2, 46.0, 34.3, 26.1,
-0.9; ESMS m/z (rel intensity) 381 (MH+, 100).
Hyd r oxy Ur ea 39c. Benzyldimethylchlorosilane (10.9 g, 59
mmol) was added rapidly dropwise to ethynylmagnesium
bromide (130 mL of a 0.5 M solution in THF, 65 mmol). The
brown solution was heated at reflux for 18 h and cooled to 4
°C for 20 min, then water and Et2O were added. The organic
layer was washed with water and brine. The aqueous layers
were washed twice with Et2O. The combined organic layers
were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by distillation at 99 °C/22 Torr to
yield benzylethynyldimethylsilane (8.8 g, 86%) as a colorless
liquid. IR (KBr plates) 2034 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.21 (m, 2H), 7.1-7.0 (m, 3H), 2.38 (s, 1H), 2.21 (s, 2H), 0.14
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 138.5, 128.3, 128.2,
124.5, 94.4, 88.5, 25.9, -2.3. Anal. Calcd for C11H14Si: C, 75.79;
H, 8.10. Found: C, 75.48; H, 8.33.
This silane (8.0 g, 46 mmol) was added rapidly dropwise to
ethylmagnesium bromide (55 mL of a 1 M solution in THF,
55 mmol). This mixture was heated at 50 °C for 1 h then cooled
to room temperature, and CuBr (66 mg, 0.46 mmol) was added.
Allyl bromide (6.0 mL, 69 mmol) was added over 1 h, and the
exotherm raised the temperature to 55 °C. The mixture was
heated at 55 °C for 1.5 h, and then saturated NH4Cl, water,
and Et2O were added. The organic layer was washed with
water and brine, and the aqueous layers were washed twice
with Et2O. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo to provide a yellow
liquid. This liquid was distilled at 58-60 °C/0.05 Torr to yield
9.3 g of 37c (95%) as a colorless liquid. IR (KBr plates) 2176
cm-1; 1H NMR (200 MHz, CDCl3) δ 7.20 (m, 2H), 7.1-7.0 (m,
3H), 5.79 (ddt, J ) 17.0, 10.0, 5.1 Hz, 1H), 5.30 (d(apparent)q,
J ) 17.0, 1.7 Hz, 1H), 5.12 (d(apparent)q, J ) 10.0, 1.7 Hz,
1H), 2.99 (dt, J ) 5.2, 1.8 Hz, 2H), 2.19 (s, 2H), 0.12 (s, 6H);
13C NMR (50 MHz, CDCl3) δ 139.1, 131.9, 128.4, 128.1, 124.2,
116.3, 104.8, 85.5, 26.4, 24.1, -2.0; EIMS m/z (rel intensity)
214 (M+, 10). Anal. Calcd for C14H18Si: C; 78.44, H; 8.46.
Found: C; 78.44, H; 8.52.
Cyclop en tylca r ba m a te 36. Cyclopentene 35 (107 mg, 0.28
mmol) was suspended in 3.8 mL of absolute EtOH and
benzylamine (159 µL, 1.8 mmol) was added. The mixture was
heated at reflux for 3 h. Additional benzylamine (42 µL, 0.5
mmol) was added and the mixture was held at reflux for an
additional 16 h. The brown solution was cooled to room
temperature and concentrated in vacuo, and the residue was
purified via flash chromatography on silica gel (40-50%
EtOAc/hexanes as eluent) to yield 36 (26.5 mg, 19%) as a
yellow solid. Mp 154-158 °C; IR (C6D6) 3681, 3424, 1732 cm-1
;
1H NMR (300 MHz, CDCl3, 60 °C) δ 7.69 (d, J ) 7.8 Hz, 2H),
7.4-7.2 (m, 12H), 5.08 (m, 1H), 5.02 (m, 1H), 4.35 (m, 2H),
4.12 (m, 1H), 3.81 (m, 2H), 3.65 (m, 1H), 3.51 (m, 1H), 2.4-
2.0 (m, 6H), 1.43 (s, 9H); 13C NMR (75 MHz, CDCl3, 60 °C) δ
155.6, 155.4, 144.9, 135.8, 130.0, 129.5, 128.8, 128.73, 128.68,
128.4, 128.0, 127.6, 127.2, 126.1, 80.2, 73.4, 65.5, 62.5, 58.3,
50.7, 45.4, 30.7, 28.4, 21.5; APCIMS m/z (rel intensity) 594
(MH+, 100).
Hyd r oxy Ur ea 39a . Following general procedure A, pen-
tenyne 37a 22a (55 mg, 0.40 mmol) and urea 38 were combined.
Purification of the crude reaction product by flash chromatog-
raphy on silica gel (1% MeOH, 19% Et2O, CH2Cl2 as eluent)
yielded 56 mg of hydroxy urea 39a (44%, 8% ee) as a yellow
oil. Enantiomeric excess was determined by chiral HPLC with
i
a Chiralcel OD-H column (5% PrOH/hexanes at 1 mL/min),
detecting at λ ) 205 nm. Retention times were 20.25 and 26.84
min for the two enantiomers. IR (CHCl3) 2181, 1775, 1679
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.3-7.0 (m, 5H), 5.34 (t, J
) 5.5 Hz, 1H), 4.80 (br s, 1H), 4.45 (s, 2H), 3.82 (m, 1H), 3.5
(ddd, J ) 14.1, 6.0, 2.8 Hz, 1H), 3.26 (ddd, J ) 14.1, 6.9, 5.4
Hz, 1H), 2.82 (s, 3H), 2.43 (dd, J ) 16.9, 5.9 Hz, 1H), 2.34 (dd,
J ) 16.9, 7.1 Hz, 1H), 0.13 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 159.7, 137.5, 128.7, 127.3, 127.2, 103.2, 86.9, 70.3, 52.2, 46.1,
34.3, 26.1, 0.1; ESMS m/z (rel intensity) 319 (MH+, 100).
Hyd r oxy Ur ea 39b. Ethynyldimethylphenylsilane22b (10.4
g, 65 mmol) was added rapidly dropwise to ethylmagnesium
bromide (78 mL as a 1 M solution in THF, 78 mmol) in 10 mL
of THF. This mixture was heated at 50 °C for 1 h then cooled
to room temperature, and CuBr (93 mg, 0.65 mmol) was added.
Allyl bromide (8.4 mL, 98 mmol) was added over 1 h, and the
exotherm raised the temperature to about 62 °C. The mixture
was heated at 55 °C for 1.5 h, and then saturated NH4Cl, Et2O,
and water were added. The organic layer was washed with
water and brine, and the aqueous layers were washed twice
with Et2O. The combined organic layers were dried over Na2-
SO4, filtered, and concentrated in vacuo to provide 13.6 g of a
yellow liquid. This crude product was distilled at 61 °C/0.03
Torr to yield 12.4 g of 37b (95%) as a colorless liquid. IR (KBr
Following general procedure A, pentenyne 37c (91 mg, 0.42
mmol) and urea 38 were combined. Urea alcohol 39c was
isolated after flash chromatography on silica gel (50-60%
EtOAc/hexanes as eluent) as 64 mg of a colorless oil (39%, 20%
ee). Enantiomeric excess was determined by chiral HPLC with
i
a Chiralcel OD-H column (5% PrOH/hexanes as eluent at 1
mL/min), detecting at λ ) 205 nm. Retention times were 39.00
and 43.70 min for the two enantiomers. IR (CDCl3) 3475, 3318,
1629 cm-1; 1H NMR (360 MHz, CDCl3) δ 7.4-7.1 (m, 7H), 7.1-
7.0 (m, 3H), 4.90 (br s, 1H), 4.48 (s, 2H), 3.85 (m, 2H), 3.44 (d,
J ) 13.2 Hz, 1H), 3.24 (m, 1H), 2.87 (s, 3H), 2.45 (dd, J )
16.9, 5.9 Hz, 1H), 2.34 (dd, J ) 16.9, 7.4 Hz, 1H), 2.16 (s, 2H),
0.12 (s, 6H); 13C NMR (50 MHz, CDCl3) δ 159.7, 139.1, 137.4,
128.7, 128.3, 128.0, 127.4, 127.1, 124.2, 104.5, 85.4, 70.6, 52.2,
45.9, 34.4, 26.2, 26.0, -2.0; ESIMS m/z (rel intensity) 417
(MNa+, 100).
Sta n n yla lk yn e 40. Urea alcohol 39a (5.6 g, 17 mmol) was
dissolved in 174 mL of dry THF. Diisopropylethylamine (10
mL, 58 mmol) and triphosgene (5.69 g, 19 mmol) were added,
and the reaction mixture was stirred for 20 min under a partial
aspirator vacuum such that there was mild bubbling of the
solution. Saturated NaHCO3 was poured into the reaction
mixture and the resulting solution was extracted with EtOAc.
The organic layer was washed with water and then brine, dried
1
plates) 2177 cm-1; H NMR (200 MHz, CDCl3) δ 7.7-7.5 (m,
2H), 7.4-7.3 (m, 3H), 5.89 (ddt, J ) 17.0, 10.0, 5.1 Hz, 1H),
5.42 (dq, J ) 17.0, 1.8 Hz, 1H), 5.21 (dq, J ) 10.0, 1.8 Hz,
1H), 3.12 (dt, 5.2, 1.8 Hz, 1H), 0.50 (s, 6H); 13C NMR (50 MHz,
CDCl3) δ 137.4, 133.6, 131.9, 129.3, 127.8, 116.4, 105.3, 85.0,
24.2, -0.7; EIMS m/z (rel intensity) 200 (M+, 22).
Following general procedure A, pentenyne 37b (93 mg, 0.46
mmol) and urea 38 were combined. Urea alcohol 39b was
isolated after flash chromatography on silica gel (50-60%
EtOAc/hexanes as eluent) as 75 mg of a yellow oil (43%, 4%
J . Org. Chem, Vol. 67, No. 20, 2002 7105

Feldman et al.
over Na2SO4, filtered, and concentrated in vacuo. The residue
was purified via flash chromatography on silica gel (30-40%
EtOAc/hexanes as eluent) to furnish 4.4 g of the oxazolidinone
product (73%) as a yellow oil. IR (CHCl3) 2181, 1775, 1679
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.68 (m,
1H), 4.60 (s, 2H), 4.07 (dd, J ) 9.8, 8.1 Hz, 1H), 3.87 (dd, J )
9.9, 6.5 Hz, 1H), 2.96 (s, 3H), 2.75 (dd, J ) 16.9, 4.8 Hz, 1H),
2.64 (dd, J ) 16.9, 7.5 Hz, 1H), 0.14 (s, 9H); 13C NMR (90 MHz,
C6D6) δ 154.0, 153.3, 137.2, 128.8, 128.1, 127.6, 100.2, 88.4,
71.6, 53.2, 48.1, 35.8, 25.4, -0.1; APCIMS m/z (rel intensity)
345 (MH+, 100). Anal. Calcd for C18H24N2O3Si: C, 62.76; H,
7.02. Found: C, 62.67; H, 7.12.
This oxazolidinone (680 mg, 1.97 mmol) was dissolved in 2
mL of THF, and glacial acetic acid (172 µL, 3 mmol) followed
by Bu4NF (3 mL as a 1 M solution in THF, 3 mmol) were
added. The reaction was complete by TLC after 4 h at room
temperature. The solution was poured into saturated aqueous
NaHCO3 and extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo. The crude dark yellow oil (612 mg) was
purified via flash chromatography on silica gel (40-50%
EtOAc/hexanes as eluent) to furnish 427 mg of the terminal
alkyne (80%). IR (CHCl3) 3307, 1776, 1679 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.4-7.2 (m, 5H), 4.71 (m, 1H), 4.63 (d, J )
15.4 Hz, 1H), 4.57 (d, J ) 15.3 Hz, 1H), 4.10 (dd, J ) 9.9, 8.0
Hz, 1H), 3.84 (dd, J ) 9.9, 6.3 Hz, 1H), 2.96 (s, 3H), 2.66 (m,
2H), 2.04 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 153.9, 153.4,
136.4, 128.8, 127.84, 127.78, 77.1, 72.1, 71.8, 53.4, 48.4, 36.1,
24.3; ESIMS m/z (rel intensity) 295 (MNa+, 100). Anal. Calcd
for C15H16N2O3: C, 66.16; H, 5.92. Found: C, 65.94; H, 6.00.
2.3, 1.0 Hz, 1H), 2.90 (s, 3H), 2.86 (d(apparent)q, J ) 17.9, 1.7
Hz, 1H), 2.43 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 153.0, 152.0,
147.1, 145.5, 136.4, 136.1, 134.9, 130.2, 128.8, 128.3, 127.7,
127.6, 77.2, 65.1, 53.5, 37.1, 36.3, 21.6; APCIMS m/z (rel
intensity) 427 (MH+, 98). Anal. Calcd for C22H22N2O5S: C,
61.96; H 5.20. Found: C, 61.78; H, 5.22.
42: IR (CDCl3) 2213, 1790, 1682 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.85 (d, J ) 8.4 Hz, 2H), 7.7-7.1 (m, 7H), 4.74 (m,
1H), 4.59 (s, 2H), 4.11 (apparent t, J ) 9.0 Hz, 1H), 3.70 (dd,
J ) 10.0, 6.2 Hz, 1H), 2.97 (s, 3H), 2.84 (m, 2H), 2.46 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 153.3, 152.6, 145.6, 138.0, 136.0,
129.9, 128.5, 127.5, 127.2, 102.9, 88.9, 80.8, 70.4, 53.1, 48.0,
36.0, 24.5, 21.5; ESMS m/z (rel intensity) 427 (MH+, 100).
P yr r ole Ca r boxa m id e 43a . Cyclopentene 41 (0.60 g, 1.4
mmol) and 2-nitrobenzylamine (426 mg, 2.8 mmol) were added
to 14 mL of ethanol, and the mixture was heated at reflux for
15 h. Additional 2-nitrobenzylamine (444 mg, 2.9 mmol) in 5.1
mL of EtOH was added. The mixture was held at reflux an
additional 2 d. The crude mixture was concentrated in vacuo
and then purified via flash chromatography on silica gel (30-
34% EtOAc/CH2Cl2 as eluent) to yield 657 mg of the secondary
amine (81%) as an orange solid. Mp 82-84 °C; IR (CHCl3)
1780, 1678 cm-1; 1H NMR (300 MHz, CDCl3, 60 °C) δ 7.89 (dd,
J ) 8.1, 1.2 Hz, 1H), 7.62 (d, J ) 8.2 Hz, 2H), 7.6-7.3 (m,
8H), 7.21 (d, J ) 8.1 Hz, 2H), 5.05 (dd, J ) 13.9, 7.2 Hz, 1H),
4.78 (d, J ) 7.8 Hz, 1H), 4.62 (br s, 1H), 4.16 (d, J ) 14.1 Hz,
1H), 3.96 (d, J ) 14.1 Hz, 1H), 3.62 (d, J ) 4.4 Hz, 1H), 3.42
(m, 1H), 2.95 (s, 3H), 2.56 (m, 1H), 2.4-2.2 (m, 4H), 1.95 (br
s, 1H); 13C NMR (75 MHz, CDCl3) δ 153.4, 152.9, 149.1, 145.5,
136.3, 134.4, 134.3, 133.4, 131.8, 130.2, 128.8, 128.6, 128.4,
127.9, 127.7, 125.1, 77.4, 68.8, 66.2, 64.1, 53.2 (br), 48.8, 36.2
(br), 33.8, 21.7; ESMS m/z (rel intensity) 601 (MNa+, 100).
Anal. Calcd for C29H30N4O7S: C, 60.19; H 5.23. Found: C,
60.26; H, 5.16.
Following general procedure B, this secondary amine (317
mg, 0.55 mmol) was acylated with 28 and purified via flash
chromatography on silica gel (50-60% EtOAc/hexanes as
eluent) to yield 207 mg of 43a (56%) as a white solid. Mp 109-
111 °C; IR (CDCl3) 3450, 1775, 1678 cm-1; 1H NMR (300 MHz,
CDCl3, 60 °C) δ 9.48 (br s, 1H), 8.18 (dd, J ) 8.1, 0.9 Hz, 1H),
7.85 (d, J ) 7.4 Hz, 1H), 7.75 (t, J ) 7.3 Hz, 1H), 7.68 (dd, J
) 3.1, 1.5 Hz, 1H), 7.59 (m, 2H), 7.47 (t, J ) 7.7 Hz, 1H), 7.33
(dd, J ) 3.6, 1.5 Hz, 1H), 7.3-7.0 (m, 6H), 6.9-6.8 (m, 3H),
6.44 (t, J ) 3.4 Hz, 1H), 6.08 (m, 2H), 5.53 (m, 2H), 5.37 (d, J
) 7.8 Hz, 1H), 4.75 (br s, 2H), 4.38 (d, J ) 15.1 Hz, 1H), 4.00
(m, 1H), 3.89 (s, 1H), 3.01 (m, 1H), 2.91 (s, 3H), 2.51 (br d, J
) 14.0 Hz, 1H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3, 60 °C)
δ 164.3, 153.1, 152.8, 147.4, 145.7, 136.1, 134.7, 134.2, 131.6,
129.9, 129.3, 128.4, 128.3, 127.22, 127.16, 125.3, 123.3, 122.9,
122.7, 113.0, 110.3, 80.5, 71.1, 68.2, 67.5, 53.1, 36.6, 35.2, 21.3;
ESIMS m/z (rel intensity) 672 (MH+, 100); ES-HRMS Calcd
for C34H34N5O8S 672.2128, found 672.2109.
Cyclop en ta n ol 44. Oxazolidinone 43a (259 mg, 0.38 mmol)
was dissolved in 2.9 mL of dry MeOH and 0.9 mL of dry CH2-
Cl2. Cesium carbonate (74 mg, 0.23 mmol) was added and the
mixture was stirred at room temperature overnight. The
mixture was treated with citric acid monohydrate (192 mg,
0.91 mmol) and diluted with water and EtOAc. The organic
layer was washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The crude mixture was purified via
flash chromatography on silica gel (4% MeOH/CH2Cl2 as
eluent) to yield 200 mg of 44 (81%) as a pale yellow solid. Mp
214-215 °C; IR (CHCl3) 3603, 3451, 1734 cm-1; 1H NMR (300
MHz, MeOD, 60 °C) δ 8.01 (dd, J ) 8.0, 1.5 Hz, 1H), 7.70 (d,
J ) 8.3 Hz, 2H), 7.57 (dd, J ) 7.0, 1.6 Hz, 1H), 7.4-7.0 (m,
10H), 6.88 (dd, J ) 2.6, 1.3 Hz, 1H), 6.15 (br s, 1H), 6.01 (dd,
J ) 3.7, 2.6 Hz, 1H), 5.12 (d, J ) 18.9 Hz, 1H), 4.97 (br s, 1H),
4.78 (d, J ) 18.9 Hz, 1H), 4.68 (br s, 1H), 4.36 (m, 3H), 4.12
(d(apparent)t, J ) 7.3, 2.2 Hz, 1H), 2.69 (s, 3H), 2.49 (ddd, J
) 15.3, 10.4, 5.2 Hz, 1H), 2.35 (s, 3H), 2.17 (ddd, J ) 15.1,
5.3, 2.3 Hz, 1H); 13C NMR (75 MHz, MeOD, 60 °C) δ 162.3,
157.8, 147.9, 145.5, 137.8, 134.4, 133.4, 133.0, 130.1, 129.8,
This terminal alkyne (427 mg, 1.57 mmol) was dissolved in
3 mL of dry THF and cooled to -78 °C, then LiHMDS (1.54
mL as a 1 M solution in THF, 1.54 mmol) was added via
syringe pump over 30 min. Tributyltin chloride (0.47 mL, 1.73
mmol) was dissolved in 1 mL of THF to prevent freezing and
added over 10 min via syringe pump 5 min after completing
the LiHMDS addition. The reaction solution was warmed to
room temperature over 1 h, stirred at room temperature 1 h,
and then was concentrated in vacuo. Purification of the residue
via flash chromatography on silica gel (1% Et3N/CH2Cl2 as
eluent) afforded 759 mg of 40 (86%) as a colorless oil. IR
1
(CHCl3) 2153, 1774, 1679 cm-1; H NMR (360 MHz, C6D6) δ
7.4-6.9 (m, 5H), 4.45 (d, J ) 15.2 Hz, 1H), 4.40 (d, J ) 15.2
Hz, 1H), 3.94 (m, 1H), 3.69 (dd, J ) 9.6, 6.7 Hz, 1H), 3.54
(apparent t, J ) 8.8 Hz, 1H), 2.71 (s, 3H), 2.20 (dd, J ) 17.2,
6.3 Hz, 1H), 2.13 (dd, J ) 17.2, 5.1 Hz, 1H), 1.61 (m, 6H), 1.35
(m, 6H), 0.93 (m, 15H); 13C NMR (90 MHz, C6D6) δ 154.1,
153.4, 137.2, 128.8, 128.1, 127.6, 103.9, 86.4, 72.0, 53.1, 48.2,
35.8, 29.2 (J C-Sn ) 11.5 Hz), 27.3 (J C-Sn ) 29 Hz), 35.6, 13.8,
11.2 (J C-Sn ) 183.0 Hz); ESIMS m/z (rel intensity) 563 (MH+,
9); HRMS Calcd for C27H43N2O3118Sn+ 563.2295, found 563.2292.
Cyclop en ten e 41. Urea alkynylstannane 40 (5.36 g, 9.54
mmol) was dissolved in 96 mL of dry CH2Cl2 and cooled to
-42 °C. PhI(CN)OTf (3.58 g, 9.44 mmol) was added in one
portion, the solution was stirred at -42 °C for 1 h, and then
the mixture was concentrated in vacuo at -42 °C. The white
solid iodonium salt (∼9.4 mmol) was dissolved in 38 mL of
dry DME that was prechilled to -42 °C. The flask was briefly
removed from the cold bath to warm and dissolve residual
solids, and the solution was poured rapidly into a refluxing
suspension of TolO2SNa (1.7 g, 9.6 mmol) in 153 mL of DME.
This mixture turned clear yellow immediately after addition.
The reaction mixture was held at reflux for 5 min, cooled to
room temperature, and concentrated in vacuo. Purification of
the residue via flash chromatography on silica gel (40-60%
EtOAc/hexanes as eluent) afforded 1.43 g of 41 (35%) and 565
mg of 42 (14%), both as off-white solids.
1
41: mp 131-132 °C; IR (CCl4) 1791, 1685 cm-1; H NMR
(360 MHz, CDCl3) δ 7.74 (d, J ) 8.2 Hz, 2H), 7.4-7.1 (m, 7H),
6.89 (apparent q, J ) 1.8 Hz, 1H), 5.19 (d(apparent)q, J ) 7.1,
1.3 Hz, 1H), 5.12 (td, J ) 6.6, 1.1 Hz, 1H), 4.57 (d, J ) 15.3
Hz, 1H), 4.52 (d, J ) 15.3 Hz, 1H), 2.98 (dddd, J ) 17.9, 6.1,
7106 J . Org. Chem., Vol. 67, No. 20, 2002

Alkynyliodonium Salts in Organic Synthesis
128.5 (2 overlapping signals), 127.9, 127.6, 127.2, 124.8, 124.1,
122.0, 112.9, 110.2, 71.0, 66.1, 65.0, 58.2, 52.3, 51.8, 34.0, 33.1,
21.4; ESMS m/z (rel intensity) 646 (MH+, 100); ES-HRMS
Calcd for C33H36N5O7S 646.2335, found 646.2275; Anal. Calcd
for C33H35N5O7S: C, 61.38; H, 5.46. Found: C, 61.24; H, 5.46.
(apparent t, J ) 12.6 Hz, 1H); 13C NMR (75 MHz, CD3OD) δ
161.4, 161.1, 124.1, 116.0, 113.8, 107.2, 95.7, 67.4, 62.2, 54.4,
40.0, 24.2. ESMS m/z (rel intensity) 285.1 (MNa+, 24), 245.1
(M - OH, 100).
1
2: IR (CH2Cl2) 1722, 1678 cm-1; H NMR (300 MHz, CD3-
Tr icyclic Cyclop en ta n on e 45. Following general proce-
dure C, cyclopentanol 44 (124 mg, 0.19 mmol) was oxidized
and cyclized, and the resulting solid was purified to yield 62
mg of 45 (67%) as a yellow solid. Mp 110-114 °C; IR (CHCl3)
OD) δ 6.96 (s, 1H), 4.60 (d(apparent)t, J ) 11.8, 6.0 Hz, 1H),
4.11 (d, J ) 5.5 Hz, 1H), 3.88 (s, 1H), 2.81 (s, 3H), 2.68 (dd, J
) 13.1, 6.5 Hz, 1H), 2.12 (apparent t, J ) 12.6 Hz, 1H); 13C
NMR (75 MHz, CD3OD) δ 161.4, 159.6, 117.0, 111.0, 108.6,
101.8, 95.6, 67.6, 62.1, 55.5, 40.0, 24.2; APCIMS m/z (rel
intensity) 421 (MH-, 84).
3687, 1764, 1719, 1651 cm-1 1H NMR (300 MHz, CDCl3) δ
;
8.00 (dd, J ) 8.1, 1.2 Hz, 1H), 7.55 (dt, J ) 7.5, 1.1 Hz, 1H),
7.4-7.3 (m, 2H), 7.3-7.1 (m, 5H), 6.90 (dd, J ) 3.9, 1.5 Hz,
1H), 6.76 (dd, J ) 2.6, 1.5 Hz, 1H), 6.39 (d, J ) 6.6 Hz, 1H),
6.25 (dd, J ) 3.9, 2.7 Hz, 1H), 5.64 (d, J ) 16.8 Hz, 1H), 4.9-
4.8 (m, 3H), 4.43 (s, 2H), 3.54 (dd, J ) 9.1, 6.8 Hz, 1H), 3.18
(dd, J ) 18.6, 5.5 Hz, 1H), 3.04 (d, J ) 18.4 Hz, 1H), 2.84 (s,
3H); 13C NMR (90 MHz, CDCl3) δ 207.3, 158.5, 157.5, 148.6,
137.2, 133.8, 133.1, 129.3, 128.9, 128.5, 127.5, 127.2, 125.3,
123.6, 122.5, 115.8, 111.8, 61.8, 60.1, 52.2, 51.3, 46.8, 42.3, 34.4;
APCIMS m/z (rel intensity) 488.3 (MH+, 100).
(8a R)-Oxa zolid in on e 50. A flask equipped with an over-
head stirrer was charged with alkynyl epoxide 4916 (9.7 g, 63
mmol), sodium azide (20.5 g, 315 mmol), ammonium chloride
(17 g, 310 mmol), and 630 mL of 95% ethanol. The white
suspension was stirred at room temperature for 39 h. The
mixture was diluted with 400 mL of EtOAc then filtered, and
the filtrate was concentrated in vacuo. The resulting white
solid was dissolved with 250 mL of EtOAc and 250 mL of H2O.
The aqueous layer was washed with 2 × 75 mL of EtOAc, and
the organic layers were washed with brine, dried over Na2-
SO4, filtered, and concentrated in vacuo to give 11.9 g of (4R)-
5-azido-4-hydroxy-1-(trimethylsilyl)pent-1-yne (84%) as a yel-
low oil. 1H NMR (360 MHz, CDCl3) δ 3.97 (br s, 1H), 3.48 (dd,
J ) 12.8, 3.8 Hz, 1H), 3.40 (dd, J ) 12.8, 6.9 Hz, 1H), 2.50 (m,
2H), 2.28 (br s, 1H), 0.16 (s, 9H). The crude azide was dissolved
in 530 mL of dry THF and, after cooling to -78 °C, n-
butyllithium (5.3 mL of a 2.5 M solution of n-BuLi in hexanes,
13 mmol) was added dropwise. After 10 min, dry ice was
allowed to sublime through drierite into the solution for 40
min, and then trimethylphosphine (74 mL of a 1 M solution
in THF, 74 mmol) was added. The solution was stirred at -78
°C for 20 min, and then the bath was removed and the mixture
warmed gradually with vigorous bubbling to room tempera-
ture. The mixture was stirred under a balloon pressure of 1
atm of carbon dioxide at room temperature for 4 h. Phosphate
buffer (pH 7.0, 250 mL) was poured into the reaction mixture
which then was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo to yield 10.6 g of a yellow tacky solid. 160 mg
of this residue was purified via flash chromatography on silica
gel (70 to 75% EtOAc/hexanes as eluent) to yield 126 mg of
(R)-50 (67% from epoxide 49) as a white solid. An analytical
Tr icyclic Cyclop en ta n on es 46/47. Cyclopentanone 45 (60
mg, 0.12 mmol) was dissolved in 19.3 mL of THF and 3.4 mL
of water. The solution was dispersed with glass beads and
suspended in a Rayonet photochemical reactor with 350-nm
bulbs, then the mixture was irradiated for 6 h. The mixture
was then filtered and the beads were washed with EtOAc and
water. The organic layer was washed with brine, dried over
Na2SO4, filtered, concentrated in vacuo, and purified via
preparatory plate chromatography (5% MeOH, CH2Cl2 as
eluent) to yield 46 and its C(5b) epimer 47 (42 mg, 96%) in a
3.2:1 ratio. IR (CDCl3) 3689, 3419, 1762, 1661, 1552, 1514 cm-1
;
1H NMR (360 MHz, CDCl3 for the major product 46) δ 7.5-
7.0 (m, 6H), 6.78 (dd, J ) 2.6, 1.4 Hz, 1H), 6.30 (dd, J ) 3.9,
2.7 Hz, 1H), 4.81 (d, J ) 15.5 Hz, 1H), 4.50 (m, 1H), 4.31 (br
s, 1H), 4.05 (d, J ) 15.9 Hz, 1H), 3.29 (br s, 1H), 3.16 (dd, J )
18.6, 6.0 Hz, 1H), 2.95 (d, J ) 18.6 Hz, 1H), 2.89 (s, 3H); 13C
NMR (75 MHz, CDCl3 for the major product 46) δ 207.0, 160.1,
157.5, 137.3, 128.7, 128.5, 127.4, 127.1, 122.9, 115.2, 111.6,
62.2, 55.7, 54.5, 51.8, 50.5, 42.3, 34.0; APCIMS m/z (rel
intensity) 375.2 (MNa+, 100), 353.2 (MH+, 76).
(()-Debr om oa gela sta tin A (11). A mixture of cyclopen-
tanones 46/47 (90 mg, ∼0.22 mmol of 46) was dissolved in 2.5
mL of dry THF, and palladium hydroxide on carbon (dried,
53 mg) was added. The mixture was stirred under a balloon
of hydrogen gas for 16 h, and then the mixture was loaded
directly onto two 1 mm thick silica gel prep plates and
developed with 18% MeOH/EtOAc to yield 34 mg of 11 (57%)
as a white solid, [partially mixed at low Rf with C(5b)-
epidebromoagelastatin A (12 mg)]. IR (CH2Cl2) 3284, 1716,
1671 cm-1; 1H NMR (360 MHz, CD3OD) 7.02 (dd, J ) 2.6, 1.5
Hz, 1H), 6.88 (dd, J ) 3.9, 1.5 Hz, 1H), 6.22 (dd, J ) 3.9, 2.6
Hz, 1H), 4.64 (dt, J ) 9.9, 5.8 Hz, 1H), 4.00 (dd, J ) 6.1, 1.5
Hz, 1H), 3.80 (d, J ) 1.3 Hz, 1H), 2.79 (s, 3H), 2.61 (dd, J )
13.3, 6.4 Hz, 1H), 2.27 (dd, J ) 13.3, 10.3 Hz, 1H); 13C NMR
(90 MHz, CD3OD) δ 162.2, 161.5, 125.7, 123.0, 115.6 (d, J )
22.3 Hz), 111.2, 96.0, 68.1, 63.0, 55.8, 41.8, 24.4; ESMS m/z
(rel intensity) 285 (MNa+, 24).
sample was sublimed at 100 °C/0.1 Torr. [R]20 -58.8° (c 1.0,
D
CHCl3); mp 70-71 °C; IR (CDCl3) 3469, 2180, 1765 cm-1; H
1
NMR (300 MHz, CDCl3) δ 5.83 (br s, 1H), 4.74 (apparent tdd,
J ) 8.2, 6.0, 4.9 Hz, 1H), 3.74 (apparent t, J ) 8.6 Hz, 1H),
3.50 (dd, J ) 8.7, 6.1 Hz, 1H), 2.73 (dd, J ) 16.8, 4.9 Hz, 1H),
2.65 (dd, J ) 16.8, 7.6 Hz, 1H), 0.15 (s, 9H); 13C NMR (90 MHz,
CDCl3) δ 159.9, 99.4, 88.1, 73.9, 44.8, 25.8, -0.3; APCMS m/z
(rel intensity) 198 (MH+, 100). Anal. Calcd for C9H15NO2Si:
C, 54.79; H, 7.66. Found: C, 54.46; H, 7.60.
(8a R)-Sta n n yla lk yn e 51. Crude oxazolidinone 50 (9.4 g,
42 mmol, purity 87%) was dissolved in 430 mL of dry THF,
and the solution was cooled to -78 °C. Lithium hexamethyl-
disilazide (42 mL as a 1 M solution in THF, 42 mmol) was
added over 30 min. The mixture was stirred at -78 °C for 2
h, and then methyl (2-nitrobenzyl)carbamoyl chloride25 (12 g,
54 mmol) was transferred via cannula as a solution in 100 mL
of dry THF. The mixture was warmed with the bath for 6 h to
room temperature, and then the bath was removed and the
solution was stirred at room temperature overnight. The
solution was cooled in an ice-water bath and then diluted with
500 mL of 1 M HCl. The organic layer was washed with water
and brine. The aqueous layers were extracted with 400 mL of
EtOAc. The combined organic layers were dried over Na2SO4,
filtered, and concentrated in vacuo to yield 19 g of an orange
gum. A 280-mg portion of this gum was purified via flash
(()-Agela sta tin A (1) a n d (()-Agela sta tin B (2). Debro-
moagelastatin A (11) (6.9 mg, 26 µmol) was suspended in 1.0
mL of THF and 1.0 mL of CH3OH, and NBS (4.7 mg, 26 µmol)
was added. The suspension was stirred at room temperature
under irradiation from a 500 W halogen spotlight and a 250
W GE infrared heat lamp for 1 h, at which time the mixture
was concentrated in vacuo. 1H NMR analysis of the crude
reaction mixture indicated a ca. 1.3:1 mixture of (()-1 to (()-
2. This mixture was purified via prep plate chromatography
(24% EtOH/CH2Cl2) to yield 3.8 mg of (()-1 and (()-2 in a 1.1:1
ratio (38%).
1
1: IR (CH2Cl2) 1724, 1673 cm-1; H NMR (300 MHz, CD3-
OD) δ 6.90 (d, J ) 4.1 Hz, 1H), 6.32 (d, J ) 4.1 Hz, 1H), 4.59
(d(apparent)t, J ) 11.6, 6.0 Hz, 1H), 4.07 (d, J ) 5.7 Hz, 1H),
3.88 (s, 1H), 2.80 (s, 3H), 2.64 (dd, J ) 13.2, 6.6 Hz, 1H), 2.09
(25) Yoakim, C.; Ogilvie, W. W.; Cameron, D. R.; Chabot, C.; Guse,
I.; Hache´, B.; Naud, J .; O’Meara, J . A.; Plante, R.; De´ziel, R. J . Med.
Chem. 1998, 41, 2882-2891.
J . Org. Chem, Vol. 67, No. 20, 2002 7107

Feldman et al.
chromatography on silica gel (36-40% EtOAc/hexanes as
eluent) to yield 206 mg (87%) of oxazolidinone urea as a yellow
gum. [R]20D -29.0° (c 1.0, CHCl3); IR (CDCl3) 2181, 1774, 1683
cm-1; 1H NMR (300 MHz, CDCl3, 60 °C) δ 8.04 (d, J ) 7.9 Hz,
1H), 7.7-7.5 (m, 2H), 7.43 (t, J ) 7.4 Hz, 1H), 5.04 (d, J )
17.2 Hz, 1H), 4.97 (d, J ) 17.1 Hz, 1H), 4.71 (m, 1H), 4.08
(dd, J ) 9.9, 8.0 Hz, 1H), 3.90 (dd, J ) 9.9, 6.6 Hz, 1H), 3.05
(s, 3H), 2.77 (dd, J ) 17.0, 4.9 Hz, 1H), 2.68 (dd, J ) 17.0, 7.3
Hz, 1H), 0.14 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 153.9, 153.3,
147.9, 133.9, 131.9, 128.1 (2 overlapping signals), 125.0, 98.6,
88.7, 72.0, 50.9, 48.0, 37.2, 25.3, -0.3; APCMS m/z (rel
intensity) 390 (MH+, 100). Anal. Calcd for C18H23N3O5Si: C,
55.51; H, 5.95. Found: C, 55.63; H, 5.92.
The crude oxazolidinone urea from above (18.9 g, 36 mmol)
was dissolved in 70.5 mL of dry THF. Acetic acid (4.05 mL,
70.7 mmol) and Bu4NF (70.5 mL of a 1 M solution in THF,
70.5 mmol) were added. The mixture was stirred at room
temperature for 6 h. Saturated NaHCO3 and EtOAc were
added to the reaction mixture. The organic layer was washed
with 1 M H3PO4 and then brine, dried over Na2SO4, filtered,
and concentrated in vacuo. The orange gum was purified via
flash chromatography on silica gel (46-50% EtOAc/hexanes
as eluent) to yield 10.9 g of the terminal alkyne (97%) as a
yellow tacky solid. IR (CDCl3) 3308, 1775, 1683 cm-1; 1H NMR
(300 MHz, CDCl3) δ 8.09 (d, J ) 8.2 Hz, 1H), 7.67 (d, J ) 4.6
Hz, 1H), 7.46 (m, 2H), 5.03 (s, 2H), 4.78 (m, 1H), 4.14 (dd, J )
9.9, 8.0 Hz, 1H), 3.90 (dd, J ) 9.9, 6.4 Hz, 1H), 3.07 (s, 3H),
2.73 (dd, J ) 5.7, 2.7 Hz, 2H), 2.10 (t, J ) 2.7 Hz, 1H); 13C
NMR (90 MHz, CDCl3) δ 153.9, 153.3, 147.9, 133.9, 131.8,
128.1 (2 overlapping signals), 125.0, 76.8, 71.9, 71.8, 51.0, 48.0,
37.2, 23.9; APIMS m/z (rel intensity) 318 (MH+, 100).
53: [R]20 +137.8° (c 1.0, CHCl3); mp 88-90 °C; IR (CDCl3)
D
1776, 1682 cm-1; H NMR (300 MHz, CDCl3) δ 8.07 (dd, J )
1
7.6, 1.1 Hz, 1H), 7.78 (d, J ) 8.3 Hz, 2H), 7.7-7.5 (m, 2H),
7.47 (t, J ) 7.6 Hz, 1H), 7.37 (d, J ) 8.4 Hz, 2H), 6.91 (d, J )
1.6 Hz, 1H), 5.27 (m, 2H), 5.07 (d, J ) 17.1 Hz, 1H), 4.87 (d,
J ) 17.2 Hz, 1H), 3.1-2.8 (m, 5H), 2.45 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 153.2, 152.1, 148.0, 147.0, 145.4, 136.1, 134.7,
133.9, 131.6, 130.1, 128.4 (2 overlapping signals), 128.2, 125.2,
77.3, 65.0, 51.3, 37.2 (br), 36.9, 21.5; ESMS m/z (rel intensity)
472 (MH+, 2).
52: [R]20 +6.3° (c 1.0, CHCl3); mp 114-117 °C; IR (CDCl3)
D
2213, 1779, 1686, 1599 cm-1
;
1H NMR (300 MHz, CDCl3) δ
8.09 (d, J ) 8.1 Hz, 1H), 7.85 (d, J ) 8.3 Hz, 2H), 7.7-7.6 (m,
2H), 7.46 (td, J ) 7.4, 2.1 Hz, 1H), 7.38 (d, J ) 8.1 Hz, 2H),
5.04 (d, J ) 17.2 Hz, 1H), 4.96 (d, J ) 17.3 Hz, 1H), 4.81 (m,
1H), 4.16 (dd, J ) 10.1, 8.2 Hz, 1H), 3.75 (dd, J ) 10.1, 6.1
Hz, 1H), 3.05 (s, 3H), 2.92 (m, 2H), 2.46 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 153.6, 152.9, 148.1, 145.7, 138.1, 134.1, 131.8,
130.0, 128.3 (2 overlapping signals), 127.4, 125.2, 88.6, 81.0,
70.6, 51.2, 48.1, 37.6, 24.7, 21.7; ESI+ MS m/z (rel intensity)
489.2 ([M + H2O]+, 100), 472.1 (MH+, 13). Anal. Calcd for
C
22H21N3O7S: C, 56.04; H, 4.49; N, 8.91; S, 6.80. Found: C,
56.32; H, 4.63; N, 8.87; S, 6.82.
(5bS,8a R,5a S,9a S)-P yr r ole Ca r boxa m id e 54. Cyclopen-
tene 53 (543 mg, 1.15 mmol) was suspended in 15.7 mL of
absolute ethanol containing 2-nitrobenzylamine (877 mg, 5.76
mmol). The mixture was heated at reflux for 5 d. At that time,
the solution was cooled to room temperature and then con-
centrated in vacuo. The residue was purified via flash chro-
matography with silica gel (60-65% EtOAc/hexanes as eluent)
to yield 608 mg of pure secondary amine (85%) as a yellow
1
The alkyne from above (1.6 g, 5.0 mmol) was dissolved in
10 mL of dry THF then cooled to -78 °C, and LiHMDS (5 mL
as a 1 M solution in THF, 5 mmol) was added over 30 min.
The mixture was stirred at -78 °C for 30 min, and then
tributyltin chloride (1.41 mL, 5.2 mmol) dissolved in 3 mL of
dry THF was added. The mixture was allowed to warm with
the bath to room temperature overnight. Saturated NH4Cl and
EtOAc were added to the reaction mixture. The organic layer
was washed with brine, dried over Na2SO4, filtered, and
concentrated in vacuo. The orange oil was purified via flash
chromatography with deactivated silica gel (40% EtOAc/
hexanes as eluent) to yield 2.3 g of the alkynylstannane 51
solid. [R]20 +14.2° (c 1.0, CHCl3); mp 80 °C ; H NMR (300
D
MHz, CDCl3) δ 8.09 (d, J ) 8.1, Hz, 1H), 7.90 (d, J ) 7.8 Hz,
1H), 7.70 (d, J ) 8.2 Hz, 2H), 7.6-7.4 (m, 6H), 7.31 (d, J ) 8.1
Hz, 2H), 5.33 (d, J ) 18.1 Hz, 1H), 5.16 (dd, J ) 13.2, 7.4 Hz,
1H), 4.82 (m, 2H), 4.78 (d, J ) 16.3 Hz, 1H), 4.13 (d, J ) 14.2
Hz, 1H), 3.94 (d, J ) 14.2 Hz, 1H), 3.75 (d, J ) 3.6 Hz, 1H),
3.50 (apparent td, J ) 8.0, 4.2 Hz, 1H), 3.14 (s, 3H), 2.61, (m,
1H), 2.45 (m, 1H), 2.42 (s, 3H), 2.03 (br s, 1H); 13C NMR (75
MHz, CDCl3) δ 153.4, 152.8, 148.7, 147.8, 145.2, 134.3, 134.04,
133.95, 133.0, 131.9, 131.4, 129.9, 128.1, 128.0, 125.1, 124.7,
122.2, 112.4, 77.6, 68.7, 65.8, 63.7, 51.0, 48.3, 37.4, 33.4, 21.4;
APCMS m/z (rel intensity) 624 (MH+, 38); HRMS Calcd for
(76%) as a viscous yellow oil. [R]20 -29.8° (c 1.0, CHCl3); IR
C
29H30N5O9S 624.1764, found 624.1744.
Pyrrole-2-carboxylic acid (564 mg, 5.0 mmol, 3 equiv) was
D
1
(CCl4) 2154, 1782, 1690 cm-1; H NMR (360 MHz, CDCl3) δ
8.08 (d, J ) 8.2 Hz, 1H), 7.65 (m, 2H), 7.46 (t, J ) 7.3 Hz,
1H), 5.03 (s, 2H), 4.74 (m, 1H), 4.10 (dd, J ) 10.0, 7.8 Hz, 1H),
3.94 (dd, J ) 9.9, 6.7 Hz, 1H), 3.08 (s, 3H), 2.83 (dd, J ) 16.7,
4.7 Hz, 1H), 2.72 (dd, J ) 16.7, 8.0 Hz, 1H), 1.6-1.4 (m, 6H),
1.3-1.1 (m, 6H), 1.1-0.8 (m, 6H), 0.90 (m, 9H); 13C NMR (90
MHz, CDCl3) δ 154.2, 153.7, 148.2, 134.1, 132.1, 128.6, 128.3,
suspended in 24.4 mL of dry benzene. Oxalyl chloride (885 µL,
10.1 mmol) and 2 drops of DMF were added. The mixture was
stirred until a colorless solution was formed and gas evolution
ceased (45 min). The mixture was concentrated, and the beige
solid residue (28) was dissolved in 4.8 mL of dry 1,2-dichlo-
roethane (DCE). The secondary o-nitrobenzylamine (1.06 g,
1.69 mmol) prepared above was dissolved in 12.2 mL of dry
DCE. Pyridine (0.82 mL, 10.14 mmol) and 4-(dimethylamino)-
pyridine (41 mg, 0.34 mmol) were added to the amine solution,
and the mixture was slowly heated. The acid chloride 28 was
added in 3 portions with 30-min intervals between additions
when the amine mixture was at 30, 40, and 50 °C. The mixture
was stirred between 45 and 55 °C for 2 days. The solution was
diluted with CH2Cl2 and poured into saturated aqueous
NaHCO3. The organic layer was washed with 1 M H3PO4,
saturated. NaHCO3, and brine, filtered, and concentrated in
vacuo. The residue was purified via flash chromatography (40,
45, and 50% EtOAc/hexanes as eluent) to provide 988 mg of
125.3, 102.5, 87.2, 72.7, 51.2, 48.5, 37.5 (br), 28.8 (J C-Sn ) 11.5
119
Hz), 26.9 (J C-Sn ) 30.2 Hz), 25.7, 13.6, 11.0 (J C-
) 191.4
Sn
Hz, J C-
) 182.9 Hz); ESMS m/z (rel intensity) 608 (M+,
117
Sn
100); HRMS Calcd for C27H41N3O5116Sn+ 606.2147, found
606.2153. Anal. Calcd for C27H41N3O5Sn: C, 53.48; H, 6.82;
N, 6.93. Found: C, 53.47; H, 6.72; N, 7.15.
(5bS,8a R)-Cyclop en ten e 53. Stannylalkyne 51 (3.45 g, 5.7
mmol) was dissolved in 57 mL of dry CH2Cl2 then cooled to
-42 °C, and PhI(CN)OTf (2.13 g, 5.6 mmol) was added in one
portion. The mixture was stirred at -42 °C for 60 min, and
then concentrated in vacuo at -42 °C. The crude alkynyliodo-
nium salt was dissolved in 23 mL of dry DME at ∼0 °C, and
then transferred via cannula to a refluxing suspension of
TolO2SNa (998 mg, 5.6 mmol) in 89 mL of dry DME. The
mixture immediately became a clear yellow solution that
slowly darkened over 5 min at reflux. After cooling to -78 °C,
the mixture was concentrated in vacuo, and the residue was
purified via flash chromatography on silica gel (60% EtOAc/
hexanes as eluent) to yield 900 mg of cyclopentene 53 (34%)
as a yellow solid and 1.14 g of alkynyl sulfone 52 (41%) as a
yellow solid.
amide 54 (82%) as a yellow-orange solid. [R]20 +15.5° (c 1.0,
D
CHCl3); mp 140-142 °C; IR (CHCl3) 3451, 1772, 1681, 1610
1
cm-1; H NMR (300 MHz, CDCl3, 60 °C) δ 9.39 (s, 1H), 8.13
(dd, J ) 8.1, 1.2 Hz, 1H), 8.01 (d, J ) 7.8 Hz, 1H), 7.82 (dd, J
) 7.9, 1.0 Hz, 1H), 7.72 (d, J ) 8.1 Hz, 2H), 7.7-7.4 (m, 5H),
7.34 (d, J ) 8.0 Hz, 2H), 6.91 (td, J ) 2.7, 1.2 Hz, 1H), 6.16
(ddd, J ) 3.8, 2.5, 1.3 Hz, 1H), 6.09 (dt, J ) 3.9, 2.6 Hz, 1H),
5.6-5.4 (m, 2H), 5.29 (d, J ) 8.0 Hz, 1H), 5.16 (d, J ) 17.3
Hz, 1H), 5.05 (d, J ) 19.1 Hz, 1H), 4.61 (d, J ) 17.3 Hz, 1H),
7108 J . Org. Chem., Vol. 67, No. 20, 2002

Alkynyliodonium Salts in Organic Synthesis
4.00 (m, 2H), 3.09 (s, 3H), 2.97 (ddd, J ) 16.4, 8.2, 7.1 Hz,
1H), 2.45 (s, 3H), 2.43 (m, 1H); 13C NMR (75 MHz, CDCl3 at
60 °C) δ 164.6, 153.6, 153.0, 148.4, 147.9, 145.8, 134.7, 134.6,
133.8, 132.1, 131.6, 130.2, 129.6, 128.6, 128.2, 128.0, 125.5,
125.1, 123.3, 122.7, 113.4, 110.8, 80.6, 71.2, 67.9, 67.4, 64.2,
53.2, 51.1, 37.3, 21.5; ESI+ MS m/z (rel intensity) 717.2 (MH+,
44).
(-)-Debr om oa gela sta tin A (11). Cyclopentanone 55 (13
mg, 25 µmol) was dissolved in 3.9 mL of THF, and 0.7 mL of
water was added. The solution was dispersed with glass beads
and suspended in a Rayonet photochemical reactor. Irradiation
with 350-nm bulbs was continued for 6.5 h. The mixture was
then filtered and the beads were washed with MeOH. The
filtrate was concentrated in vacuo, and purified via silica gel
preparatory plate chromatography (20% MeOH/EtOAc as the
developing solvent) to yield 5.4 mg of (-)-11 (82%) as a white
(5bS,5a S,9a R)-Tr icyclic Cyclop en ta n on e 55. Amide 54
(130 mg, 0.18 mmol) was suspended in 3.6 mL of methanol at
room temperature, and then Cs2CO3 (36 mg, 0.11 mmol) was
added. The mixture was stirred at room temperature for 18
h. The clear orange solution was treated with citric acid
monohydrate (91 mg, 0.43 mmol) and then diluted with water
and CH2Cl2. The organic layer was washed with brine, dried
over Na2SO4, filtered, and concentrated in vacuo to yield 117
mg of the product cyclopentanol (94%) as a yellow-orange solid.
solid. [R]20 -68.4° (c 0.5, CH3OH); mp 244-245 °C.
D
(-)-Agela sta tin A (1). (-)-Debromoagelastatin A (11) (5.7
mg, 22 µmol) was dissolved in 0.5 mL of CH3OH and 1.0 mL
of THF, and 2.1 mg of NBS (11 µmol, 0.5 equiv) was added.
The solution was stirred at room temperature for 3 h, at which
time a sample was removed, concentrated in vacuo, and
assayed for conversion by 1H NMR. The remainder of NBS
required to complete 1 equiv was added (2.2 mg), and the
mixture was stirred at room temperature overnight. The
mixture was concentrated in vacuo, and the brown residue was
purified via silica gel preparatory plate chromatography (14%
MeOH/CH2Cl2 as developing solvent) to yield 5.1 mg of (-)-1
(73%) as an off-white solid. 1H NMR (300 MHz, MeOD) and
TLC Rf matches an authentic sample of the natural product
[R]20 -2.9° (c 1.0, CHCl3); mp 124-125 °C; IR (CHCl3) 3635,
D
3446,1650 cm-1
;
1H NMR (300 MHz, 10:1 MeOD/CDCl3, 60
°C) δ 8.02 (dd, J ) 7.8, 1.7 Hz, 1H), 7.96 (dd, J ) 8.1, 1.3 Hz,
1H), 7.67 (d, J ) 8.3 Hz, 2H), 7.61 (d, J ) 7.4 Hz, 1H), 7.5-
7.2 (m, 4H), 6.89 (dd, J ) 2.6, 1.3 Hz, 1H), 6.17 (br s, 1H),
6.01 (dd, J ) 3.8, 2.6 Hz, 1H), 5.77 (d, J ) 8.8 Hz, 1H), 5.16
(d, J ) 18.9 Hz, 1H), 4.97 (br s, 1H), 4.81 (d, J ) 18.9 Hz, 1H),
4.78 (d, J ) 17.7 Hz, 1H), 4.67 (br s, 1H), 4.64 (d, J ) 17.7 Hz,
1H), 4.33 (br s, 1H), 4.14 (m, 1H), 2.78 (s, 3H), 2.45 (ddd, J )
15.3, 10.3, 5.2 Hz, 1H), 2.34 (s, 3H), 2.15 (ddd, J ) 15.2, 5.1,
2.3 Hz, 1H); 13C NMR (75 MHz, 10:1 MeOD/CDCl3, 60 °C) δ
165.9, 159.6, 149.6, 149.2, 146.6, 136.2, 134.6, 134.5, 134.3,
134.1, 130.9, 130.3, 129.4, 129.2, 129.1, 128.9, 125.82, 125.76,
125.0, 123.1, 144.0, 110.5, 69.6, 64.7, 62.8, 58.9, 58.8, 50.8, 35.3,
33.6, 21.6; APCMS m/z (rel intensity) 691 (MH+, 7); HRMS
Calcd for C33H35N6O9S 691.2186, found 691.2174.
kindly supplied by Dr. D’Ambrosio: [R]20 -65.5° (c 0.5, CH3-
D
OH).
(-)-Agela sta tin B (2). (-)-Debromoagelastatin A (11) (25
mg, 95 µmol) was dissolved in 2.1 mL of MeOH and 4.2 mL of
dry THF, and NBS (35.5 mg, 200 µmol, 2.1 equiv) was added.
The solution was stirred at room temperature for 18 h. The
mixture was concentrated in vacuo, and the yellow residue was
purified via chromatography (10-15% MeOH/CH2Cl2) to yield
(-)-2 (17.8 mg, 45%) as an off-white solid. [R]20D -60.3° (c 0.5,
MeOH); mp 220-221 °C dec.
Following general procedure C, this cyclopentanol (86 mg,
0.12 mmol) was oxidized and cyclized, and the resulting solid
was purified (72-80% EtOAc/hexanes as eluent) to yield 40
mg of 55 (63%) as a yellow solid. [R]20 -31.4° (c 1.0, CHCl3);
D
mp 154-160 °C; IR (CDCl3) 3531, 3461, 1765, 1652 cm-1; H
1
Ack n ow led gm en t. Financial support from the Na-
tional Institutes of Health (GM 37681) is gratefully
acknowledged, as is the sample of authentic agelastatin
A provided by Dr. D’Ambrosio of the Universita` di
Trento.
NMR (400 MHz, CDCl3) δ 8.05 (d, J ) 8.0 Hz, 1H), 7.92 (d, J
) 8.0 Hz, 1H), 7.64 (apparent t, J ) 7.6 Hz, 2H), 7.48 (m, 2H),
7.35 (m, 2H), 7.02 (d, J ) 5.8 Hz, 1H), 6.72 (s, 1H), 6.65 (d, J
) 2.7 Hz, 1H), 6.17 (t, J ) 3.0 Hz, 1H), 5.61 (d, J ) 16.7 Hz,
1H), 5.0-4.7 (m, 5H), 3.37 (br s, 1H), 3.14 (dd, J ) 18.6, 5.4
Hz, 1H), 3.00 (d, J ) 18.6 Hz, 1H), 2.99 (s, 3H); 13C NMR (90
MHz, CDCl3) δ 206.5, 158.4, 157.3, 148.4, 147.9, 134.1, 133.8,
133.5, 132.6, 129.2, 128.5, 127.9, 127.5, 125.2, 125.1, 122.8,
122.5, 115.5, 111.8, 61.5, 59.7, 51.1, 50.4, 46.5, 42.2, 35.2; ESI+
MS m/z (rel intensity) 533.2 (MH+, 100).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for 1, 2, 11, 14, 17, 19, 22, 24, 25, 29, 31, 33,
34, 36, 39a -c, 40, 42, 43a , 45, 53, 54, and 55. This material is
available free of charge via the Internet at http://pubs.acs.org.
Detailed spectral data for (-)-11, (-)-1, and (-)-2 can be
found in the description of the racemic series earlier in the
Experimental Section.
J O026287V
J . Org. Chem, Vol. 67, No. 20, 2002 7109