Approach to the homoerythrina alkaloids using a tandem N-alkylation/ azomethine ylide cycloaddition

Article abstract of DOI:10.1021/jo0703799

(Chemical Equation Presented) Synthetic efforts toward the homoerythrina alkaloids 1-3 are described. Two separate model systems guided the pivotal [3 + 2] azomethine ylide cycloaddition cascade to form the A-C rings of these alkaloids. The cycloaddition

Full text of DOI:10.1021/jo0703799

Approach to the Homoerythrina Alkaloids Using a Tandem
N-Alkylation/Azomethine Ylide Cycloaddition
,†
William H. Pearson,* Jeffrey E. Kropf, Allison L. Choy, Ill Young Lee, and
Jeff W. Kampf‡
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109-1055
wpearson@berryassoc.com
ReceiVed February 24, 2007
Synthetic efforts toward the homoerythrina alkaloids 1-3 are described. Two separate model systems
guided the pivotal [3 + 2] azomethine ylide cycloaddition cascade to form the A-C rings of these alkaloids.
The cycloaddition precursors 63 and 68, prepared in nine and ten steps, respectively, from alkyne 47,
each contain an enolizable ketone, a tethered electrophile, and an electron-poor dipolarophile. Heating
63 and 68 with the stannyl amine 17 generated demethoxyschelhammeridine 65 and demethoxyschel-
hammericine 70, the products of intramolecular azomethine ylide cycloadditions. Subsequent attempts
to install the C-3 methoxy group of 1-3 are also described.
Introduction
an azacyclohexene C-ring rather than the azacycloheptene C-ring
found in the homoerythrina alkaloids (4b). Many of the
Erythrina alkaloids (though few homoerythrina alkaloids) have
demonstrated biological activity including curare and hypnotic
effects. There are no reports on pharmacological effects of
either homoerythratine (1) or 3-epi-schelhammeridine (2),
although in two separate studies isolated alkaloids that were
extracted from leaves of the genus Dysoxylum lenticellare, which
includes 3-epi-schelhammericine (3), are shown to have both
The homoerythrina alkaloids are comprised of over 70 natural
products that are widely distributed in the plant kingdom and
have been isolated from six plant genera (Athrotaxis, Cephal-
2
a
1
otaxus, Dysoxylum, Lagarostrobos, Phelline, and Schelham-
2
mera). The alkaloids possess an intriguing azatetracyclic
framework and are grouped structurally into aromatic or
nonaromatic D-ring categories. The former category is predomi-
nant and includes homoerythratine (1), 3-epi-schelhammeridine
5
6
cardiac effects in rats and molluscicidal activity.
Numerous synthetic strategies have led to the successful
3
(
2), and 3-epi-schelhammericine (3).4 The homoerythrina
alkaloids are structurally similar and biosynthetically related to
the Erythrina alkaloids as the Erythrina alkaloids (4a) contain
2
a
construction of the erythrinan ring system. Specifically, we
note that Livinghouse and co-workers used an intramolecular
3 + 2] azomethine ylide cycloaddition to generate the
erythrinan framework (Scheme 1). Alkylation of dihydroiso-
2a
7
8
[
†
Current address: Berry & Associates, Inc., 2434 Bishop Circle East, Dexter,
MI 48130.
‡
To whom the correspondence for the crystal structure determinations should
be addressed.
(4) For total synthesis, see: (a) Tsuda, Y.; Ohshima, T.; Hosoi, S.;
Kaneuchi, S.; Kiuchi, F.; Toda, J.; Sano, T. Chem. Pharm. Bull. 1996, 44,
500-508. (b) Tsuda, Y.; Hosoi, S.; Ohshima, T.; Kaneuchi, S.; Murata,
M.; Kiuchi, F.; Toda, J.; Sano, T. Chem. Pharm. Bull. 1985, 33, 3574-
3577.
(5) Aladesanmi, A. J.; Ilesanmi, O. R. J. Nat. Prod. 1987, 50, 1041-
1044.
(6) Aladesanmi, A. J.; Adewunmi, C. O.; Kelley, C. J.; Leary, J. D.;
Bischoff, T. A.; Zhang, X.; Snyder, J. K. Phytochemistry 1988, 27, 3789-
3792.
(
1) Has also been classified as the genus Manoao: (a) Bloor, S. J.;
Benner, J. P.; Irwin, D.; Boother, P. Phytochemistry 1996, 41, 801-802.
b) Molloy, B. P. J. N. Z. J. Bot. 1995, 33, 183-201.
2) (a) Tsuda, Y.; Sano, T. Erythrina and Related Alkaloids. In The
Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 1996; Vol.
(
(
4
8, pp 249-337. (b) Bick, I. R. C.; Panichanun, S. Homoerythrina and
Related Alkaloids. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Springer-Verlag: New York, 1991; Vol. 7, pp 1-41.
(3) For total synthesis, see: (a) Tsuda, Y.; Murata, M.; Hosoi, S.; Ikeda,
M.; Sano, T. Chem. Pharm. Bull. 1996, 44, 515-524. (b) Tsuda, Y.; Hosoi,
S.; Murata, M. Heterocycles 1990, 30, 311-316.
(7) Westling, M.; Smith, R.; Livinghouse, T. J. Org. Chem. 1986, 51,
1159-1165.
1
0.1021/jo0703799 CCC: $37.00 © 2007 American Chemical Society
Published on Web 04/28/2007
J. Org. Chem. 2007, 72, 4135-4148
4135

Pearson et al.
SCHEME 1
quinoline 5 with trimethylsilylmethyl triflate (6) gave the
iminium ion 7, which was then desilylated with cesium fluoride
to form the azomethine ylide 8. An intramolecular cycloaddition
between the ylide and the terminal acetylenic dipolarophile of
8
resulted in the azatetracycle 9. A similar sequence was also
attempted by using dihydroisoquinoline 10, which bears eno-
9
lizable hydrogens. However, heating iminium 11 in the presence
of cesium fluoride resulted only in deprotonation to form
enamine 13. This result is not an isolated case, as a number of
literature reports demonstrate that generating an azomethine
ylide by desilylating an N-(trimethylsilyl)methyl iminium salt
10
is often not compatible with enolizable hydrogens.
In comparison to the erythrinans, far fewer synthetic reports
2
a,3,4,11
have appeared on the synthesis of the homoerythrinans.
The only reported total syntheses of homoerythrina alkaloids
have been accomplished by the Tsuda group, who have
constructed six natural products with the framework of 4b,
including 3-epi-schelhammeridine (2) and 3-epi-schelhammeri-
of the Tsuda group, only the recent literature examples described
by the Tu and Padwa groups have overcome this difficulty.
cine (3).3
,4,11f
Although these syntheses are lengthy (22-26
11a,b,d
steps), they use a synthetic strategy similar to that employed in
the synthesis of an Erythrina alkaloid.12 Despite the slight
structural difference between 4a and 4b, the utilization of a
common synthetic strategy to access both natural product
families has proven to be difficult.2 In addition to the work
Despite these recent examples, the synthesis of the intriguing
polycyclic architecture of the homoerythrina alkaloids remains
challenging and relatively unexplored. Herein, we describe a
full account of our synthetic studies on these alkaloids,
culminating in efficient syntheses of demethoxyschelham-
meridine 65 and demethoxyschelhammericine 70.
a,13
(
8) For reviews, see: (a) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105,
2
765-2810. (b) Harwood, L. M.; Vickers, R. J. Azomethine Ylides. In
Retrosynthetic Plan
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John
Wiley & Sons: New York, 2002; pp 169-252. (c) Padwa, A. Intermolecular
Our approach to the alkaloids 1-3 is retrosynthetically
outlined in Scheme 2. We envisioned that manipulating the
sulfoxide group of the advanced intermediate 14 would generate
1
,3-Dipolar Cycloadditions. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon: Oxford, UK, 1991; Vol. 4, pp 1069-
1
109. (d) Wade, P. A. Intramolecular 1,3-Dipolar Cycloadditions. In
1
and 2. Thus, a sulfoxide-sulfenate (Mislow-Evans) re-
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
1
4
Pergamon: Oxford, UK, 1991; Vol. 4, pp 1111-1168.
arrangement or a sulfoxide elimination of 14 would give the
alkaloids 1 and 2, respectively. Both of these compounds have
been independently converted to 3.
(
(
9) Smith, R.; Livinghouse, T. Tetrahedron 1985, 41, 3559-3568.
10) (a) Pearson, W. H.; Stoy, P.; Mi, Y. J. Org. Chem. 2004, 69, 1919-
15,16
The cornerstone of our
1
939. (b) Fishwick, C. W. G.; Jones, A. D.; Mitchell, M. B. Tetrahedron
approach involved a one-pot sequence that would efficiently
assemble the A-C rings of the azatetracycle 14 (cf. 4b). An
intramolecular [π4s + π2s] cycloaddition between the semi-
stabilized azomethine ylide and the terminal vinyl sulfide of
15 would complete the homoerythrina core by providing the
perhydroindole A and B rings. Ylide 15 may be generated in
Lett. 1989, 30, 4447-4448. (c) Tsuge, O.; Kanemasa, S.; Yamada, T.;
Matsuda, K. J. Org. Chem. 1987, 52, 2523-2530. (d) Smith, R.; Living-
house, T. J. Org. Chem. 1983, 48, 1554-1555.
(
11) (a) Gao, S.; Tu, Y. Q.; Hu, X.; Wang, S.; Hua, R.; Jiang, Y.; Zhao,
Y.; Fan, X.; Zhang, S. Org. Lett. 2006, 8, 2373-2376. (b) Cassidy, M.;
O¨ zdemir, A. D.; Padwa, A. Org. Lett. 2005, 7, 1339-1342. (c) Hart, J. B.;
Mason, J. M.; Gerard, P. J. Tetrahedron 2001, 57, 10033-10038. (d) Toda,
J.; Niimura, Y.; Sano, T.; Tsuda, Y. Heterocycles 1998, 48, 1599-1607.
(e) Le Dr e´ au, M. A.; Desma e¨ le, D.; Dumas, F.; d’Angelo, J. J. Org. Chem.
1
993, 58, 2933-2935. (f) Tsuda, Y.; Murata, M. Tetrahedron Lett. 1986,
(14) (a) Evans, D. A.; Andrews, G. C. Acc. Chem. Res. 1974, 7, 147-
155. (b) Tang, R.; Mislow, K. J. Am. Chem. Soc. 1970, 92, 2100-2104.
(15) For conversion of homoerythratine 1 to 3-epi-schelhammericine 3,
see: Panichanun, S.; Bick, I. R. C. Tetrahedron 1984, 40, 2677-2684.
(16) For conversion of 3-epi-schelhammeridine 2 to 3-epi-schelham-
mericine 3, see: Johns, S. R.; Lamberton, J. A.; Sioumis, A. A. Aust. J.
Chem. 1969, 22, 2219-2256.
2
7, 3385-3386.
(12) Sano, T.; Toda, J.; Ohshima, T.; Tsuda, Y. Chem. Pharm. Bull.
1
992, 40, 873.
13) (a) Chikaoka, S.; Toyao, A.; Ogasawara, M.; Tamura, O.; Ishibashi,
(
H. J. Org. Chem. 2003, 68, 312-318. (b) Toda, J.; Niimura, Y.; Takeda,
K.; Sano, T.; Tsuda, Y. Chem. Pharm. Bull. 1998, 46, 906-912.
4136 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
SCHEME 2
Results and Discussion
We began our approach to the homoerythrina alkaloids by
attempting to synthesize aldehyde 20. The known (Z)-vinyl
iodide 26, a key intermediate, may be readily obtained using
minor modifications of a route previously developed in our
19b
laboratories (Scheme 3). Hence, commercially available 1,3-
20
propanediol was monoprotected to give alcohol 21, which was
2
1
then oxidized to aldehyde 22 using a Swern oxidation. The
union of ethynylmagnesium bromide with aldehyde 22 gave the
propargylic alcohol 23. Following the formation of methyl ether
2
4, iodination of the alkyne terminus provided 25. Diimide
reduction of alkyne 25 selectively furnished (Z)-vinyl iodide
2
6 in excellent yield.
Next, we attempted a Negishi cross-coupling reaction22 to
access the phenylsulfanyl-functionalized diene 27. The phenyl-
sulfanyl substituent of 27 was sought because we have suc-
cessfully employed phenyl vinyl sulfide in an intermolecular
fashion as both an anionophile and a dipolarophile in [3 + 2]
1
7d,19a,23
cycloadditions with 2-azaallyl anions
and azomethine
1
0a
24
ylides, respectively. However, work by Negishi and Luo
describes the stereoselective formation of (E)-dienes by the Pd-
catalyzed cross-coupling of (E)-vinyl iodides solely with alkyl
vinyl sulfides. We sought to apply this selective sequence by
coupling (Z)-vinyl iodide 26 with the 1-(phenylsulfanyl)vinyl
zinc reagent, produced in situ by treating phenyl vinyl sulfide
with sec-butyllithium followed by zinc chloride. Unfortunately,
all efforts to form the cross-coupling product 27 failed presum-
ably due to the reported difficulty in cleanly forming the required
organolithium. A nearly 50-year-old literature report demon-
strates that the major product from the treatment of phenyl vinyl
sulfide with a variety of organolithiums is â-addition to the
2
5
double bond. Subsequent examples have appeared describing
conditions that improve the direct R-lithiation of phenyl vinyl
2
6
sulfide; however, in our hands these conditions either gave
unacceptable ratios of direct lithiation vs alkyllithium addition27
or were incompatible with the Negishi reaction conditions. In
sharp contrast, ethyl vinyl sulfide is cleanly lithiated with sec-
butyllithium, and thus coupling the corresponding vinyl zinc
of 26 afforded the ethylsulfanyl-functionalized diene 28 in
quantitative yield. Carrying on, aldehyde 30 was formed from
situ by destannylation of the N-(tributylstannyl)methyl iminium
ion 161 which, based on our earlier work, was expected to
tolerate the enolizable hydrogens, unlike work in the silicon
area (cf. Scheme 1). Formation of the azaheptene C ring along
with the iminium salt in 16 would be accomplished by heating
the ketone 18 together with (tributylstannyl)methylamine (17).
The expected cis-fused ring junction shown in 14 would be
consistent with previous work from our laboratories in which
28
7
2
8 by deprotection and Swern oxidation. It is worth noting that
aldehyde 30 was not stable to chromatography and decomposed
within days even when stored frozen in benzene; therefore, it
was made fresh and used immediately without purification.
10a
1
8
[
3 + 2] intramolecular cycloadditions of 2-azaallyllithiums
(20) McDougal, P. G.; Rico, J. G.; Oh, Y. I.; Condon, B. D. J. Org.
Chem. 1986, 51, 3388-3390.
19
gave solely cis-fused perhydroindoles. The C-3 methoxy
substituent was anticipated to prefer the equatorial conformation
in 15, which would lead to the desired relative configuration at
the methoxy group and the ring-junction stereocenters. The
cycloaddition precursor, iodoketone 18, should be available from
the addition of Grignard reagent 19 to the aldehyde 20.
(
21) Pirrung, M. C.; Webster, N. J. G. J. Org. Chem. 1987, 52, 3603-
3
613.
(22) (a) Negishi, E. -I.; Liu, F. In Metal-Catalyzed Cross-Coupling
Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH Verlag GmbH:
Weinheim, Germany, 1998; pp 0-47. (b) Erdik, E. Tetrahedron 1992, 48,
9
577-9648.
(23) (a) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004,
9, 9109-9122. (b) Pearson, W. H.; Ren, Y. J. Org. Chem. 1999, 64, 688-
89.
6
6
(
17) For generation of azomethine ylides by destannylation of N-(tri-n-
(24) Negishi, E. -I.; Luo, F. -T. J. Org. Chem. 1983, 48, 1560-1562.
butylstannyl)methyl iminiums, see: ref 10a; (a) Pearson, W. H.; Dietz, A.;
Stoy, P. Org. Lett. 2004, 6, 1005-1008. (b) Clark, R. B.; Pearson, W. H.
Org. Lett. 1999, 1, 349-351. (c) Pearson, W. H.; Clark, R. B. Tetrahedron
Lett. 1999, 40, 4467-4471. (d) Pearson, W. H.; Mi, Y. Tetrahedron Lett.
(25) Parham, W. E.; Motter, R. F. J. Am. Chem. Soc. 1959, 81, 2146-
2148.
(26) (a) Trost, B. M.; Lavole, A. C. J. Am. Chem. Soc. 1983, 105, 5075-
5090. (b) Ager, D. J. Tetrahedron Lett. 1981, 22, 587-590. (c) Cookson,
R. C.; Parsons, P. J. J. Chem. Soc., Chem. Commun. 1978, 821-822. (d)
Harirchian, B.; Magnus, P. J. Chem. Soc., Chem. Commun. 1977, 522-
523.
1
997, 38, 5441-5444.
18) For a recent review, see: Pearson, W. H.; Stoy, P. Synlett 2003,
(
9
03-921.
(
19) (a) Pearson, W. H.; Lovering, F. E. J. Org. Chem. 1998, 63, 3607-
(27) Determined by incorporating deuterium upon quenching with D2O;
see Table 1 in the Supporting Information.
(28) Oshima, K.; Shimoji, K.; Takahashi, H.; Yamamoto, H.; Nozaki,
H. J. Am. Chem. Soc. 1973, 95, 2694-2695.
3
5
617. (b) Pearson, W. H.; Postich, M. J. J. Org. Chem. 1994, 59, 5662-
671. (c) Pearson, W. H.; Walters, M. A.; Oswell, K. D. J. Am. Chem.
Soc. 1986, 108, 2769-2771.
J. Org. Chem, Vol. 72, No. 11, 2007 4137

Pearson et al.
SCHEME 3
SCHEME 4
Grignard reagent 19, a coupling partner for aldehyde 30, was
cyclization. However, when the structurally simpler and com-
mercially available model Grignard reagent 3,4-(methylene-
dioxy)phenylmagnesium bromide 35 was added to 30, alcohol
36 was formed in a much improved 84% yield.
accessible starting with a lithium aluminum hydride reduction
2
9
30
of 31 to give the known alcohol 32, which was then treated
with thionyl chloride to provide 33 (Scheme 4). Our initial
efforts to couple 19 with 30 drew upon similar work reported
by Parham and co-workers.31 Unfortunately, halogen-metal
exchange of aryl bromide 33 followed by addition of aldehyde
At this stage, we elected to continue with the model alcohol
36 to test the key cycloaddition step (Scheme 5). Thus, following
oxidation of the alcohol 36 to the ketone 37, the cyclization
cascade began by using an earlier method from our laboratory
3
0 did not yield the desired product. We then found that in situ
Grignard formation from the corresponding organolithium via
magnesium bromide at -78 °C did provide the desired alcohol
4 as a mixture of diastereomers, although in low yield. The
2
3,32
for the formation of ketone-derived (2-azaallyl)stannanes.
Condensing ketone 37 and (tributylstannyl)methylamine (17)1
in the presence of trimethylaluminum formed the (2-azaallyl)-
stannane 38 in situ as a mixture of (E)- and (Z)-isomers. Heating
0a
3
low temperature of the reaction was required to prevent
3
8 with benzyl bromide triggered alkylation, destannylation,
(
29) Ester 31 is readily available from a Wittig reaction of 6-bromopip-
azomethine ylide formation, and [3 + 2] cycloaddition. The
resulting cycloadduct 39 was isolated as a single diastereomer
in 28% yield. The structure of 39 was firmly established by
eronal. For a similar example, see: Arya, P.; Durieux, P.; Chen, Z. X.;
Joseph, R.; Leek, D. M. J. Comb. Chem. 2004, 6, 54-64.
(30) Tietze, L. F.; Schirok, H.; W o¨ hrmann, M.; Schrader, K. Eur. J. Org.
Chem. 2000, 13, 2433-2444.
31) Parham, W. E.; Jones, L. D.; Sayed, Y. A. J. Org. Chem. 1976, 41,
184-1186.
(
(32) Pearson, W. H.; Barta, N. S.; Kampf, J. W. Tetrahedron Lett. 1997,
38, 3369-3372.
1
4138 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
SCHEME 5
1
1
SCHEME 6
performing an H- H COSY experiment as well as a series of
NOE experiments. Ultimately, the relative configuration of 39
was unambiguously established by X-ray cyrstallography of the
N-benzenesulfonyl derivative 40. Several features of this cy-
cloaddition reaction are noteworthy. First, one of the few
correctly anticipated features of 39 was the cis-fused ring
junction of the perhydroindole. In addition to being consistent
with previous reports in our laboratory,19 inspection of molecular
models predicts that either the (E)- or the (Z)-(2-azaallyl)-
stannanes (38) can lead to this cis-fused ring junction. In
contrast, we are unable to provide a compelling explanation for
the unexpected relative configuration of the C-3 methoxy
substituent and the ring-junction stereocenters. Fortunately, not
33
only is the epimerization of this stereocenter possible but also
the homoerythrina alkaloids include numerous examples of both
C-3 methoxy epimers. Last, the isolation of the unconventional
N-unsubstituted rather than the N-benzyl cycloadduct 39 may
be rationalized via a mechanism proposed in a related example
by Imai and Achiwa,34 where a catalytic amount of tributyl-
stannyl bromide is formed in situ and acts as the electrophile
to form the iminium 41. The bromide counterion of 41
subsequently destannylates the iminium ion to regenerate
tributylstannyl bromide and N-stannylazomethine ylide, produc-
ing 39. Control experiments confirming this type of mechanism
(
n ) 1 or 2) should decrease the electron density of diene 43
10a
and narrow the HOMO(dipole)-LUMO(dipolarophile) gap. Second,
we felt that 43 may be more likely to withstand the cycloaddition
conditions by installing the sensitive C-3 methoxy group after
cycloaddition via allylic oxidation of 42. Such an allylic
oxidation seemed well-precedented; however, this presumption
would later prove problematic (vide infra). An additional change
included combining 45, which bears a protected hydroxypropyl
chain rather than the chloropropyl chain of 19 (cf. Scheme 4),
with aldehyde 46 to afford 44.
have been reported by our group.
Revised Strategy. Because of the suboptimal [3 + 2]
cycloaddition described above, we shifted to the modified
strategy outlined in Scheme 6. As compared with our initial
strategy, two structural variations to the cycloaddition precursor
were planned to increase the efficiency of the key cyclization
step. First, because azomethine ylide cycloadditions typically
favor electron-poor dipolarophiles, an oxidized sulfur moiety
The revised approach started by treating alkyne 4735 with
butyllithium and I2 to give iodoalkyne 48 (Scheme 7). Diimide
(
33) (a) Martin, S. F.; Davidsen, S. K. J. Am. Chem. Soc. 1984, 106,
6
1
431-6433. (b) White, J. D.; Chong, W. K. M.; Thirring, K. J. Org. Chem.
983, 48, 2300-2302. (c) Danishefsky, S.; Morris, J.; Mullen, G.; Gammill,
R. J. Am. Chem. Soc. 1980, 102, 2838-2840.
(
34) Imai, N.; Achiwa, K. Chem. Pharm. Bull. 1987, 35, 593-601.
(35) Guo, H.; O’Doherty, G. A. Org. Lett. 2005, 7, 3921-3924.
J. Org. Chem, Vol. 72, No. 11, 2007 4139

Pearson et al.
SCHEME 7
reduction of 48, similar to that used to reduce iodoalkyne 25
55 °C for 3 h to provide sulfoxide 57 in 59% yield. The structure
1
(cf. Scheme 3), resulted in 49 along with significant amounts
and configuration of 57 were confidently established using H
1
of starting material as well as trace amounts of the corresponding
overreduced alkane. However, reduction of 48 was cleanly
accomplished by hydroboration followed by acid hydrolysis of
the corresponding vinylborane36 to afford the cis-vinyl iodide
NMR decoupling experiments and focused H NOE enhance-
ments, including those between the methylene protons of the
sulfoxide moiety and the two indicated phenyl ring protons.
13
Furthermore, the C NMR spectrum closely correlated with
4
(
5
9. The Negishi cross-coupling reaction previously described
vide supra) once again used ethyl vinyl sulfide to provide diene
0 (not shown). Deprotection of 50 furnished 51 in 86% yield
the similar 39, whose structure was confirmed by X-ray. The
expected cis configuration of the hydroindole ring junction of
5
7 matched three separate hydroindole forming [3 + 2]
over two steps. It is noteworthy that intermediates 49-51 were
surprisingly prone to isomerization to a mixture of the trans-
and cis-dienes upon purification via silica gel chromatography
unless 1-3% triethylamine was included in the mobile phase.
The ethylsulfanyl group of 51 was oxidized with sodium
periodate to the sulfoxide 52, and Swern oxidation gave
aldehyde 53. As in the previous sequence (cf. Scheme 4), we
opted to test the forthcoming cycloaddition step by combining
model compound 35 with the aldehyde 53. The resulting benzyl
alcohol 54 (not shown) was then oxidized to give ketone 55.
With ketone 55 in hand, we reexamined the azomethine ylide
cycloaddition cascade. Thus, ketone 55 and (tributylstannyl)-
methylamine 17 were condensed to provide the (2-azaallyl)-
stannane 56 as a mixture of (E)- and (Z)-isomers. We were able
to follow the progress of this condensation using neutral alumina
TLC. Once the reaction appeared complete (about 90 min), 56
was subjected to an aqueous workup and combined without
further purification with an electrophile to initiate ylide forma-
tion. Although the choice of the electrophile was quite flexible
19
cycloaddition reactions reported by our group. If the same
reaction was heated at 65 °C for 14 h, a thermal elimination of
the sulfoxide group gave diene 58 without any detectable amount
of 57. A simple adjustment in the reaction length allowed us to
generate either of the alkene variants found in the A and B rings
of 1-3.
Synthesis of Demethoxyschelhammeridine 65 and De-
methoxyschelhammericine 70. On the basis of the success of
our revised model system, we sought to generate the fully
elaborated homoerythrina architecture and, we hoped, 1-3.
Toward this end (Scheme 8), protection of alcohol 32 gave the
thexyldimethylsilyl (TDS) ether 59. The corresponding orga-
nomagnesium was generated in situ and then combined with
aldehyde 53 to provide the benzyl alcohol 60. A Swern
oxidization of 60 to the ketone 61 was followed by desilylation
and iodination to furnish the cycloaddition precursor 63. Heating
6
3 with the amine 17 caused the key tandem N-alkylation/
azomethine ylide cycloaddition, presumably via the semistabi-
lized ylide 64, to give demethoxyschelhammeridine 65 in 56%
yield. The formation of the entire homoerythrina core by this
single-pot sequence extends the scope of [4πs + 2πs] azo-
methine ylide cycloadditions as the first example in which an
intramolecular electrophile and dipolarophile converged to form
(
BnBr, HF‚pyr, Sc(OTf)3, Bu3SnCl), the best results were
achieved when TMSCl and 56 were combined and heated at
(36) Corey, E. J.; Cashman, J. R.; Eckrich, T. M.; Corey, D. R. J. Am.
Chem. Soc. 1985, 107, 713-715.
4140 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
SCHEME 8
SCHEME 9
three rings.37 Both the H and 13C NMR spectra of 65 are
consistent with those of diene 58 as well as 3-epi-schelham-
meridine (2). Interestingly, under these conditions, sulfoxide
elimination occurred rapidly without any measurable quantities
of the putative parent sulfoxide cycloadduct (not shown) that
would be analogous to the sulfoxide 57. Although efforts to
install a C-3 methoxy group by allylic oxidation of 65 were
unsuccessful, a more thorough investigation of this transforma-
tion focused on a subsequent analogue (vide infra).
1
meridine (2). To access the A ring olefin arrangement found in
homoerythratine (1) and 3-epi-schelhammericine (3), we used
the thermally more stable sulfone derivative which would not
be expected to eliminate under the reaction conditions because
sulfones are generally more endothermic than sulfoxides
(
(
Scheme 9). Thus, sulfoxide 61 was oxidized to the sulfone 66
not shown) with m-chloroperbenzoic acid. The cycloaddition
precursor 68 was then prepared following desilylation and
iodination of 67. Once again, the tandem N-alkylation/azo-
methine ylide cycloaddition proceeded smoothly upon heating
68 with the amine 17 in toluene for 2 h to provide the
cycloadduct 69 in 56% yield. The cis configuration of the A
and B rings, which has been consistent throughout, was
unequivocally established by X-ray crystallography of the
corresponding picrate of 69.
The spontaneous elimination of the sulfoxide moiety in the
cycloaddition of 63 furnished the adduct 65 bearing the 1,6-
diene arrangement of the A and B rings of 3-epi-schelham-
(
37) For examples of an intramolecular N-alkylation and an intermo-
lecular azomethine ylide cycloaddition via a three-component single-pot
sequence, see refs 10a and 17d. For examples of an intramolecular
N-alkylation followed by an azomethine ylide generation and afterwards
an intramolecular cycloaddition, see: Hassner, A.; Fischer, B. J. Org. Chem.
1
992, 57, 3070-3075. Vedejs, E.; Naidu, B. N.; Klapars, N. A.; Warner,
D. L.; Li, V.; Na, Y.; Kohn, H. J. Am. Chem. Soc. 2003, 125, 15796-
5806.
The previously described cycloadditions of the model ketones
7 and 55 (cf. Schemes 5 and 7) began with a dehydrative
3
1
J. Org. Chem, Vol. 72, No. 11, 2007 4141

Pearson et al.
condensation step that required trimethylaluminum to promote
the otherwise sluggish formation of the corresponding imines,
whereas the cycloadditions of 63 and 68 proceed smoothly
without trimethylaluminum. We believe this provides strong
evidence that the sequence of events in the cycloaddition
cascades of 63 and 68 is intermolecular N-alkylation of 17 with
the tethered electrophile followed by intramolecular dehydrative
condensation. Thus, using an intramolecular condensation of
ketones 63 and 68 has the advantage of milder reaction
conditions over the intermolecular condensation of ketones 37
and 55 by not requiring a strong Lewis acid despite all of the
ketones being similarly hindered and electron rich.
mericine (70), are presented. A key feature of the syntheses
involves the successful formation of the A-C rings of the
alkaloids using a tandem N-alkylation/azomethine ylide
[3 + 2] cycloaddition. This key step features both an intra-
molecular N-alkylation of a tethered electrophile and an
intramolecular cycloaddition of a tethered dipolarophile. Two
separate model systems guided our approach by demonstrating
improved yields of the key cascade sequence with the incor-
poration of an electron-poor vinyl sulfoxide dipolarophile and
removal of an allylic methoxy group. Unfortunately, subsequent
efforts to install the methoxy group via an allylic oxidation of
the advanced intermediate 69 were unsuccessful. The synthesis
of 65 and 70 nicely complements the construction of the
Erythrina ring system by Livinghouse and co-workers by
demonstrating that an azomethine ylide [3 + 2] cycloaddition
can generate the core ring system of both the homoerythrina
and Erythrina alkaloids. This adaptability represents an ac-
complishment that has proven to be challenging in previous
We then focused on installing a methoxy group at the C-3 of
6
9 via an allylic oxidation followed by methylation of the
38
corresponding alcohol. Papers by the Muxfeldt and Mori
groups39 reported successful allylic oxidations of a closely
related tetrahydroindole with SeO2. Unfortunately, these condi-
tions resulted in recovered starting material when applied to
2
a,11c,d
6
9. Allylic oxidations of five- and six-membered ring alkenes
approaches.
In addition, our method of generating azo-
40
are generally difficult, and we suspected that the basic nitrogen
methine ylides from 2-(azaallyl)stannanes was tolerant to the
presence of enolizable hydrogens with no detectable enamine
formation and thereby addresses a shortcoming of prior work
in the organosilane area.
41
of 69 might be a further interfering factor. Therefore, we also
explored the reaction under acidic conditions3 as well as on
the corresponding HCl salt of 69. We investigated alternative
allylic oxidants including the use of 2,2′-dipyridyldiselenide and
iodoxybenzene to generate 2-pyridineseleninic anhydride in situ
8,42
Experimental Section
4
3
44
(Crich ), SeO2 with t-butyl hydroperoxide (Sharpless ), and
For general experimental procedures, see the Supporting Infor-
mation.
palladium-catalyzed oxidation with t-butyl hydroperoxide (Co-
45
rey ). Ultimately, despite considerable effort, we were not able
to oxidize the C-3 position of 69.
3
-[(t-Butyldimethylsilyl)oxy]-propan-1-ol (21). Prepared by a
20
modification of the published procedure. Sodium hydride (6.0 g,
150 mmol) was washed with hexanes and combined with THF (200
mL) at room temperature. A solution of distilled 1,3-propanediol
(11.9 mL, 165 mmol) in THF (40 mL) was added in a dropwise
fashion, and the resultant mixture was stirred for 1 h. The mixture
was cooled to 0 °C, and a solution of t-butyldimethylsilylchloride
Despite the fact that the allylic oxidation precluded us from
functionalizing the C-3 position of 69, we were able to
successfully achieve desulfonylation of 69 by a palladium-
catalyzed LiBHEt3 reduction46 to generate demethoxyschel-
hammericine 70 in 84% yield. This compound has previously
(
22.6 g, 150 mmol) in THF (50 mL) was added in a dropwise
manner. After stirring overnight at room temperature, 10% (w/w)
aqueous K CO was added and the mixture was concentrated in
vacuo. Et O was added, and the organic layer was separated, washed
with 10% K CO and brine, dried (Na SO ), and concentrated in
been isolated as a minor component of the platinum oxide
1
6
catalyzed hydrogenolysis of natural schelhammeridine. The
2
3
1
H NMR spectrum of 70 compares and, not surprisingly,
2
improves upon the quality of that shown in ref 16 from 1969.
2
3
2
4
In addition, the 13C NMR olefin resonances in the A ring of 70
vacuo. The residue was chromatographed (gradient, 100% hexane-
(142.6 and 118.4 ppm) compare with those of 1 (145 and 121
20% EtOAc/hexane) to afford 25.4 g (89%) of the title compound
1
ppm).
as an oil. The H NMR spectrum was consistent with the reported
data.20
5
-[(t-Butyldimethylsilyl)oxy]-1-pentyn-3-ol (23). Prepared by
Summary
19b,21
a modification of the published procedure.
Dimethyl sulfoxide
(
4.7 mL, 66 mmol) in CH
fashion to a solution of oxalyl chloride (2.0 M in CH
mL, 33 mmol) in CH Cl (100 mL) at -78 °C. After stirring for
5 min, alcohol 21 (5.7 g, 30 mmol) in CH Cl (20 mL) was then
2
Cl
2
(20 mL) was added in a dropwise
Synthetic efforts directed at the total synthesis of the
homoerythrina alkaloids 1-3, including the synthesis of
demethoxyschelhammeridine (65) and demethoxyschelham-
2
Cl , 16.5
2
2
2
1
2
2
added in a dropwise fashion. After stirring for another 15 min,
triethylamine (21 mL, 150 mmol) was added in a dropwise manner,
and the resulting mixture was then stirred for 15 min. The reaction
was allowed to warm to 15 °C and then was washed successively
with water, ice-cold 0.1 M aqueous HCl, water, saturated aqueous
(
38) Muxfeldt, H.; Schneider, R. S.; Mooberry, J. B. J. Am. Chem. Soc.
1
1
966, 88, 3670-3671.
(
(
39) Nichimata, T.; Mori, M. J. Org. Chem. 1998, 63, 7586-7587.
40) (a) Warpehoski, M. A.; Chadaud, B.; Sharpless, K. B. J. Org. Chem.
982, 47, 2897-2900. (b) Sharpless, K. B.; Verhoeven, T. R. Aldrichimica
Acta 1979, 12, 63-74.
NaHCO
concentrated in vacuo. The resultant oil was diluted with Et
filtered through a pad of Celite to remove NEt
2 4
, and water. The organic layer was dried (Na SO
) and
O,
‚HCl salts, and
3
(41) For allylic oxidations performed on six-membered ring substrates
2
that also contain basic amines, see: ref 38. Campos, O.; Cook, J. M.
Tetrahedron Lett. 1979, 19, 1025-1028. Cain, M.; Comapos, O.; Guzman,
F.; Cook, J. M. J. Am. Chem. Soc. 1983, 105, 907.
3
concentrated in vacuo to provide aldehyde 2221 which was used
immediately without further purification. Aldehyde 22 (4.7 g, 25
mmol) in THF (23 mL) was added in a dropwise fashion to a
solution of ethynylmagnesium bromide (0.5 M in THF, 50 mL, 25
mmol) in THF (250 mL) at 0 °C. After complete addition, saturated
(
42) (a) Snider, B. B.; Shi, B. Tetrahedron 1999, 55, 14823-14828. (b)
Shibuya, K. Synth. Commun. 1994, 24, 2923-2941.
43) Barton, D. H. R.; Crich, D. Tetrahedron 1985, 41, 4359-4364.
Crich, D.; Zou, Y. Org. Lett. 2004, 6, 775-777.
(
(
44) Umbreit, M. A.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 5526-
aqueous NH
vacuo. Et O was added, and the layers were separated. The aqueous
layer was extracted with Et
O (3×), and the combined organic
layers were dried (Na SO ) and concentrated in vacuo. The residue
4
Cl was added and the mixture was concentrated in
5
528.
2
(
(
45) Yu, J. Q.; Corey, E. J. Org. Lett. 2002, 4, 2727-2730.
46) Orita, A.; Watanabe, A.; Tsuchiya, H.; Otera, J. Tetrahedron 1999,
2
5
5, 2889-2898.
2
4
4142 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
+
was chromatographed (gradient, 100% hexanes-10% EtOAc/
hexanes) to afford 4.5 g (80% from 23) of the title compound. The
H NMR spectrum was consistent with the reported data.
NH
[(M - OCH
NH
Anal. Calcd for C10
H, 8.89.
3
) m/z (rel intensity) 203.1 [(M + H) , 60], 186.2 (100), 171.1
+
+
3
) , 89], 141.1 [(M - SCH
2
CH
3
) , 61]; HRMS (CI,
1
19b
+
3
) calcd for C10
H O
19 2
S [(M + H) ] 203.1106, found 203.1095.
3
-Methoxy-5-[(t-butyldimethylsilyl)oxy]-1-pentyne (24). Pre-
H
18
O
2
S: C, 59.37; H, 8.97. Found: C, 59.39;
19b
pared by a modification of the published procedure. Sodium
hydride (0.92 g, 23.0 mmol) was washed with hexanes, suspended
in 80 mL of THF, and cooled to 0 °C. Alcohol 23 (4.48 g, 20.9
mmol) in THF (20 mL) was added in a dropwise fashion, and after
complete addition, the ice bath was removed. Methyl iodide (2 mL,
(Z)-6-Ethylsulfanyl-3-methoxy-4,6-heptadienal (30). Dimethyl
sulfoxide (0.46 mL, 6.5 mmol) in CH Cl (0.5 mL) was added in
a dropwise fashion to a solution of oxalyl chloride (2.0 M in CH
Cl , 1.6 mL, 3.3 mmol) in CH Cl (15 mL) at -78 °C. After stirring
for 15 min, alcohol 29 (600 mg, 2.96 mmol) in CH Cl (1.0 mL)
2
2
2
-
2
2
2
3
1.4 mmol) was added, and the reaction was stirred overnight.
Saturated aqueous NH Cl was added, and the mixture was
concentrated in vacuo. After diluting with Et O, the mixture was
extracted with Et
O (3×). The combined organic layers were
washed with brine, dried (Na SO ), and concentrated in vacuo. The
2
2
4
was added in a dropwise fashion. Upon stirring for another 15 min,
triethylamine (2.1 mL, 14.8 mmol) was added over the course of
5 min. The reaction was warmed to room temperature and washed
successively with water, ice-cold 0.1 M aqueous HCl, water,
2
2
2
4
residue was chromatographed (gradient, 100% hexanes-5% EtOAc/
saturated aqueous NaHCO
(Na SO ) and concentrated in vacuo. The resultant oil was diluted
with Et O, filtered through a pad of Celite to remove NEt ‚HCl
3
, and water. The organic layer was dried
1
hexanes) to afford 4.3 g (90%) of the title compound. The H NMR
2
4
spectrum was consistent with the reported data.1
9b
2
3
(
Z)-5-Methoxy-7-[(t-butyldimethylsilyl)oxy]-2-ethylsulfanyl-
salts, and concentrated in vacuo to provide 540 mg (91%) of the
1
,3-heptadiene (28). sec-Butyllithium (1.3 M in cyclohexane, 2.7
title compound. Aldehyde 30 was used immediately without further
47
1
mL, 3.5 mmol) was added in a dropwise fashion to a solution of
ethyl vinyl sulfide (0.39 mL, 3.8 mmol) in THF-HMPA (9:1, 16.0
mL) at -78 °C. After stirring for 1 h, a solution of anhydrous ZnCl
purification: R
CDCl
f
) 0.38 (20% EtOAc/hexanes); H NMR (500 MHz,
3
) δ 9.78 (dd, J ) 3.0, 1.9 Hz, 1 H), 6.19 (d, J ) 11.5 Hz, 1
2
H), 5.50 (dd, J ) 11.5, 9.3 Hz, 1 H), 5.08 (d, J ) 1.4 Hz, 1 H),
5.05 (s, 1 H), 4.83-4.77 (m, 1 H), 3.29 (s, 3 H), 2.74 (q, J ) 7.4
Hz, 2 H), 2.68 (ddd, J ) 16.2, 8.8, 3.0 Hz, 1 H), 2.51 (ddd, J )
(
0.87 M in THF, 4.1 mL, 3.6 mmol) was added in a dropwise
fashion, and the resultant mixture was then warmed to 0 °C. A
solution of vinyl iodide 26 (1.14 g, 3.2 mmol) and Pd(PPh (185
13
3
)
4
16.2, 4.0, 1.9 Hz, 1 H), 1.32 (t, J ) 7.4 Hz, 3 H); C NMR (100
MHz, C ) δ 199.0, 140.6, 133.9, 131.6, 111.0, 72.4, 56.2, 49.5,
25.9, 13.5; IR (neat) 1726 (s), 1588, 1450 cm
3-[6-Bromo-3,4-(methylenedioxy)phenyl]-1-propanol (32). Pre-
mg, 0.16 mmol) in THF (8 mL) was added in a dropwise fashion,
and the resultant mixture was then warmed to room temperature.
After stirring for 18 h in the dark, the reaction was treated with
6 6
D
-
1
.
3
0
saturated aqueous NH
was washed with saturated aqueous NH
aqueous NaHCO . The combined aqueous layers were then
extracted with Et O until the aqueous layer was clear and colorless.
The combined organic layers were washed with brine, dried (Na
SO ), and concentrated in vacuo. The residue was chromatographed
gradient, 100% hexanes-3% EtOAc/hexanes) to afford 1.0 g
100%) of the title compound as a yellow oil: R ) 0.36 (5%
) δ 6.07 (dt, J ) 11.7,
.1 Hz, 1 H), 5.44 (dd, J ) 11.7, 9.5 Hz, 1 H), 5.11 (d, J ) 1.1
Hz, 1 H), 5.04 (s, 1 H), 4.40 (td, J ) 9.5, 4.4 Hz, 1 H), 3.77-3.62
m, 2 H), 3.23 (s, 3 H), 2.70 (q, J ) 7.3 Hz, 2 H), 1.78-1.62 (m,
H), 1.27 (t, J ) 7.3 Hz, 3 H), 0.87 (s, 9 H), 0.03 (s, 3 H), 0.02
s, 3 H); 13C NMR (100 MHz, CDCl
) δ 139.8, 135.3, 130.6, 111.5,
4
Cl and diluted with Et
2
O. The organic layer
pared by a modification of the published procedure. Lithium
4
Cl, water, and saturated
aluminum hydride (1.6 g, 42.1 mmol) in Et O (40 mL) was added
2
to a solution of ester 3129 (5.3 g, 17.6 mmol) in Et O/THF (2:1, 75
3
2
2
mL) at 0 °C. After stirring for 1 h at 0 °C, water (1.6 mL), aqueous
NaOH (2 M, 1.6 mL), and water (4.8 mL) were each carefully
added to the mixture. The resulting slurry was filtered through a
pad of Celite and concentrated in vacuo. The residue was chro-
matographed (40% EtOAc/hexanes) to afford 4.1 g (90%) yield of
2
-
4
(
(
f
1
1
EtOAc/hexane); H NMR (400 MHz, CDCl
3
the title compound. The H NMR spectrum was consistent with
the reported data.30
1
(Z)-1-[3,4-(Methylenedioxy)phenyl]-3-methoxy-6-ethylsul-
fanyl-4,6-heptadien-1-ol (36). Aldehyde 30 (400 mg, 2.0 mmol)
was diluted with THF (3 mL) and added in a dropwise fashion to
a solution of 3,4-(methylenedioxy)phenylmagnesium bromide (35,
1.0 M in 50:50 THF/toluene, 2.1 mL, 2.1 mmol) in THF (7 mL) at
0 °C. The reaction was stirred for 30 min at 0 °C and then stirred
for 1 h at room temperature. The mixture was treated with half-
saturated aqueous NH Cl and diluted with Et O. The organic layer
(
2
(
3
13
7
3.1, 59.1, 56.3, 38.9, 25.9, 25.8, 18.2, 13.6, -5.4, -5.5; C NMR
(100 MHz, C
6 6
D
) δ 140.8, 136.3, 130.8, 111.2, 73.4, 59.5, 56.3,
-1
3
9.5, 26.1, 26.0, 18.4, 13.7, -5.2, -5.3; IR (neat) 1588, 1471 cm ;
+
MS (CI, NH
3
) m/z (rel intensity) 317.1 [(M + H) , 13], 287.1 [(M
4
2
+
+
+
-
1
3
CH
00]; HRMS (CI, NH
17.1971, found 317.1959.
Z)-6-Ethylsulfanyl-3-methoxy-4,6-heptadien-1-ol (29). Tet-
2
CH
3
) , 14], 203.1 [(M - C
6
H
13Si) , 30], 110.0 [(C
7
H
10O) ,
was separated and washed with half-saturated aqueous NH Cl and
4
+
3
) calcd for C16
H O
33 2
SSi [(M + H) ]
brine. The aqueous layer was re-extracted with Et O (3×), and the
2
combined organic layers were dried (Na SO ) and concentrated in
2
4
(
vacuo. The residue was chromatographed (gradient, 100% hexanes-
rabutylammonium fluoride (1.0 M in THF, 3.5 mL) was added to
a solution of silyl ether 28 (1.0 g, 3.2 mmol) in THF (16 mL) at
room temperature. After stirring for 2.5 h in the dark, the mixture
was treated with water and concentrated in vacuo. The mixture was
diluted with EtOAc, and the organic layer was separated and washed
with water and brine, dried (Na
The residue was chromatographed (gradient, 100% hexanes-30%
EtOAc/hexanes) to afford 600 mg (93%) of the title compound as
an oil: R
CDCl
1
4
20% EtOAc/hexanes) to afford 540 mg (84%) of two diastereomers
1
(1:1 by H NMR) of the title compound as a viscous, yellow oil.
The diastereomers were separated only for characterization pur-
poses, and the relative configuration was not determined. Less polar
1
diastereomer: R ) 0.26 (20% EtOAc/hexanes); H NMR (400
f
2 4
SO ), and concentrated in vacuo.
MHz, CDCl ) δ 6.85 (d, J ) 1.5 Hz, 1 H), 6.81-6.73 (m, 2 H),
3
6.11 (d, J ) 11.7 Hz, 1 H), 5.92 (s, 2 H), 5.55 (dd, J ) 11.7, 9.4
Hz, 1 H), 4.95-4.90 (m, 3 H), 4.52-4.45 (m, 1 H), 3.52 (d, J )
4.8 Hz, 1 H), 3.25 (s, 3 H), 2.67 (qd, J ) 7.3, 1.5 Hz, 2 H), 2.02-
1.86 (m, 2 H), 1.24 (t, J ) 7.3 Hz, 3 H); 13C NMR (100 MHz,
1
f
) 0.23 (30% EtOAc/hexanes); H NMR (400 MHz,
3
) δ 6.13 (d, J ) 11.7 Hz, 1 H), 5.47 (dd, J ) 11.7, 9.2 Hz,
H), 5.04 (d, J ) 1.5 Hz, 1 H), 5.01 (s, 1 H), 4.46 (td, J ) 9.2,
CDCl ) δ 147.6, 146.5, 139.9, 138.7, 134.0, 131.2, 118.7, 111.1,
3
.4 Hz, 1 H), 3.75 (app q, J ) 5.5 Hz, 2 H), 3.26 (s, 3 H), 2.72
108.0, 106.3, 100.9, 74.9, 71.2, 56.4, 44.0, 25.9, 13.5; IR (neat)
-
1
(
(
(
qd, J ) 7.3, 1.5 Hz, 2 H), 2.62 (t, J ) 5.7 Hz, 1 H), 1.92-1.80
3
3437 (br), 1588, 1502, 1487, 1442, 1245 cm ; MS (CI, NH ) m/z
13
+
+
m, 1 H), 1.75-1.65 (m, 1 H), 1.28 (t, J ) 7.3 Hz, 3 H); C NMR
100 MHz, C ) δ 140.7, 135.4, 131.1, 111.0, 76.0, 60.1, 56.2,
8.8, 25.9, 13.6; IR (neat) 3402 (br), 1589, 1449 cm ; MS (CI,
(rel intensity) 323.1 [(M + H) , 12], 305.1 [(M - OH) , 43], 273.1
+
+
D
6 6
[(M - CH O ) , 100], 261.1 [(M - SCH CH ) , 22]; HRMS (CI,
5
2
2
3
-
1
+
3
NH ) calcd for C H O S ([M + H] ) 323.1317, found 323.1308.
1
3
17 23
4
More polar diastereomer: R
f
) 0.20 (20% EtOAc/hexanes); H
(47) Titrated with diphenylacetic acid: Kofron, W. G.; Baclawshi, L.
NMR (400 MHz, CDCl ) δ 6.87 (d, J ) 1.8 Hz, 1 H), 6.81-6.72
3
M. J. Org. Chem. 1976, 41, 1879-1880.
(m, 2 H), 6.12 (d, J ) 11.4 Hz, 1 H), 5.91 (s, 2 H), 5.42 (dd, J )
J. Org. Chem, Vol. 72, No. 11, 2007 4143

Pearson et al.
1
1.7, 9.2 Hz, 1 H), 4.99 (app s, 2 H), 4.82 (dd, J ) 9.5, 1.8 Hz, 1
H), 4.51 (td, J ) 9.7, 3.3 Hz, 1 H), 3.84 (d, J ) 1.1 Hz, 1 H), 3.29
s, 3 H), 2.71 (qd, J ) 7.3, 1.3 Hz, 2 H), 1.99 (dt, J ) 14.7, 9.7
Hz, 1 H), 1.71 (dt, J ) 14.7, 3.3 Hz, 1 H), 1.28 (t, J ) 7.3 Hz, 3
H); 13C NMR (100 MHz, CDCl
) δ 147.6, 146.6, 140.0, 138.5,
34.0, 131.2, 119.0, 110.8, 107.9, 106.4, 100.8, 77.2, 73.2, 56.3,
the mixture was extracted with EtOAc (3×). The combined organic
layers were washed with 1 M aqueous HCl, water, saturated aqueous
(
3 2 4
NaHCO , and brine, dried (Na SO ), and concentrated in vacuo.
The residue was chromatographed (30% EtOAc/hexanes) to afford
7 mg (49%) of the title compound as a white solid: mp ) 161-
3
1
1
4
162 °C; R
δ 7.58-7.54 (m, 2 H, SO
6.84 (m, 2 H, SO Ph), 6.48 (br s, 1 H, Ar-H), 6.43 (d, J ) 8.3 Hz,
1 H, Ar-H), 6.37 (br d, J ) 7.6 Hz, 1 H, Ar-H), 5.97 (dt, J ) 10.0,
1.7 Hz, 1 H, CHdCH, H-5), 5.25 (AB , J ) 1.5 Hz, ∆νAB ) 10.0
Hz, 2H, OCH O), 5.19 (dd, J ) 10.0, 2.1 Hz, 1 H, CHdCH, H-4),
f
) 0.28 (30% EtOAc/hexane); H NMR (500 MHz, C
6 6
D )
-1
5.0, 25.9, 13.5; IR (neat) 3435 (br), 1653, 1488, 1443, 1245 cm
;
2
Ph), 6.96-6.92 (m, 1 H, SO Ph), 6.88-
2
+
MS (CI, NH
3
) m/z (rel intensity) 323.1 [(M + H) , 31], 296.2 (72),
2
+
+
2
61.1 [(M - SCH
2
CH
3
3 7
) , 32], 247.1 [(M - C H S) , 100]; HRMS
+
(CI, NH
3
) calcd for C17
H O
23 4
S [(M + H) ] 323.1317, found
q
3
23.1304.
2
(
Z)-1-[3,4-(Methylenedioxy)phenyl]-3-methoxy-6-ethylsul-
4.53 (ddt, J ) 10.0, 5.1, 1.7 Hz, 1 H, H-6â), 3.57 (ddd, J ) 12.7,
5.1, 1.2 Hz, 1 H, H-7â), 3.40-3.34 (m, 1 H, H-2), 3.36 (s, 3 H,
fanyl-4,6-heptadienone (37). Manganese(IV) oxide (3.9 g) was
added to a solution of diastereomeric alcohols 36 (161 mg, 0.5
mmol) in Et
round-bottom flask fitted with a ground-glass stopper. After stirring
for 15 h in the dark, the mixture was filtered through a pad of
Celite and rinsed with several portions of Et
dried (Na SO ) and concentrated in vacuo to afford 150 mg (94%)
of the title compound as a yellow oil, which was used immediately
without further purification. A small portion was purified by
chromatography (gradient, 100% hexanes-5% EtOAc/hexanes) to
provide an analytical sample for characterization purposes: R
0
OCH
Hz, 1 H, H-7R), 2.02 (dq, J ) 11.2, 7.3 Hz, 1 H, SCH
1.75 (m, 2 H, SCH , H-3), 1.27 (dd, J ) 12.7, 6.6 Hz, 1 H, H-3),
3
), 3.22 (t, J ) 9.0 Hz, 1 H, H-2), 2.37 (dd, J ) 12.7, 10.0
O (50 mL). The reaction was performed in a 1-neck
2
), 1.86-
2
2
13
2 3 6 6
0.76 (t, J ) 7.6 Hz, 3 H, SCH CH ); C NMR (100 MHz, C D )
2
O. The filtrate was
δ 147.0, 146.7, 139.9, 136.5, 132.3, 131.0, 128.5, 127.5, 121.1,
108.6, 106.9, 101.1, 74.4, 73.9, 59.3, 56.5, 47.0, 34.8, 33.5, 23.2,
2
4
-
1
14.3; IR (CH
2 2
Cl ) 1335, 1157 cm ; MS (EI, 70 eV) m/z (rel
+
+
intensity) 473.4 [(M) , 6], 412.4 [(M - SCH
2
CH
3
) , 100]; HRMS
+
(ESI) calcd for C24H27NNaO S [(M + Na) ] 496.1228, found
5 2
1
)
496.1220. All H assignments were made from a two-dimensional
COSY experiment.
f
1
.18 (10% EtOAc/hexane); H NMR (400 MHz, CDCl
3
) δ 7.55
(
1
dd, J ) 8.3, 1.7 Hz, 1 H), 7.44 (d, J ) 1.7 Hz, 1 H), 6.82 (d, J )
1-[(t-Butyldimethylsilyl)oxy]-5-iodo-4-pentyne (48). n-Butyl-
47
.7 Hz, 1 H), 6.82 (d, J ) 8.3 Hz, 1 H), 6.14 (d, J ) 11.6 Hz, 1
lithium (2.0 M in hexanes, 38 mL, 77.4 mmol) was added to a
solution of alkyne 4735 (12.8 g, 64.5 mmol) in THF (230 mL) at
H), 6.02 (s, 2 H), 5.53 (dd, J ) 11.6, 9.5 Hz, 1 H), 5.10 (d, J ) 1.5
Hz, 1 H), 5.04 (s, 1 H), 4.88 (td, J ) 9.5, 3.7 Hz, 1 H), 3.31-3.26
2
-78 °C. After stirring for 1 h at -78 °C, a solution of I (19.7 g,
(m, 1 H), 3.24 (s, 3 H), 2.86 (dd, J ) 15.6, 3.7 Hz, 1 H), 2.72 (q,
77.4 mmol) in THF (100 mL) was added via cannula and the
resulting mixture was then warmed to room temperature. After
stirring for 1 h, the reaction was treated with water and concentrated
13
J ) 7.3 Hz, 2 H), 1.28 (t, J ) 7.3 Hz, 3 H); C NMR (100 MHz,
CDCl ) δ 195.4, 151.7, 148.1, 139.8, 133.9, 132.1, 131.3, 124.7,
11.1, 108.0, 107.7, 101.8, 73.3, 56.6, 44.3, 25.9, 13.5; IR (neat)
3
1
1
in vacuo. The mixture was extracted with Et
organic layers were washed with saturated aqueous Na
and brine, dried (MgSO ), and concentrated in vacuo. The residue
2
O (3×). The combined
-
1
677 (s), 1603, 1504, 1488, 1443, 1355, 1248 cm ; HRMS (ESI)
2 2 3
S O
(2×)
+
calcd for C17
H20NaO
4
S [(M + Na) ] 343.0980, found 343.0977.
4
(3aR,6R,7aR)-2,3,3a,6,7,7a-Hexahydro-3a-ethylsulfanyl-6-meth-
was chromatographed (gradient, 100% hexanes-3% EtOAc/hex-
anes) to afford 19.7 g (94%) of the title compound as a colorless
oxy-7a-[3,4-(methylenedioxy)phenyl]indole (39). A solution of
amine 171 (42 mg, 0.13 mmol) in toluene (0.3 mL) was cooled
to 0 °C. Trimethylaluminum (2.0 M in heptane, 66 µL, 0.13 mmol)
was added in a dropwise fashion, followed by the dropwise addition
of ketone 37 (28 mg, 0.09 mmol) in toluene (0.6 mL). After stirring
for 2 h, benzyl bromide (31 µL, 0.26 mmol) was added, and the
mixture was placed in an oil bath preheated to 110 °C and heated
to reflux for 4.5 h. Upon cooling to room temperature, EtOAc and
0a
1
oil: R
f
) 0.26 (2% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
)
δ 3.68 (t, J ) 6.1 Hz, 2 H), 2.46 (t, J ) 7.1 Hz, 2 H), 1.72 (ddd,
1
3
J ) 13.2, 6.8, 6.8 Hz, 2 H), 0.90 (s, 9 H), 0.06 (s, 6 H); C NMR
(125 MHz, CDCl ) δ 94.2, 61.3, 31.4, 25.9, 18.2, 17.2, -5.4, -7.1;
IR (neat) 2361 (w) cm ; MS (CI, NH
3
-
1
3
) m/z (rel intensity) 325.1
+
+
[(M + H) , 4], 267.0 [(M - C(CH
calcd for C11 22IOSi 325.0485, found 325.0481. Anal. Calcd for
21IOSi: C, 40.74; H, 6.63. Found: C, 40.60; H, 6.58.
(Z)-1-[(t-Butyldimethylsilyl)oxy]-5-iodo-4-pentene (49). BH
Me S (2.0 M in THF, 21 mL, 42.8 mmol) was added to a solution
3 3 3
) ) , 100]; HRMS (CI, NH )
H
saturated aqueous NH
The organic layer was washed with water, saturated aqueous
NaHCO , water, and brine. The aqueous layers were back-extracted
with EtOAc (3×). The combined organic layers were dried (Na
SO ) and concentrated in vacuo. The residue was chromatographed
gradient, 100% hexanes-50% EtOAc/hexanes) to afford 8 mg
28%) of the title compound as a single diastereomer: R ) 0.32
) δ 7.00 (d, J
2.0 Hz, 1 H), 6.94 (dd, J ) 8.3, 2.0 Hz, 1 H), 6.77 (d, J ) 8.3
4
Cl were added and the layers were separated.
11
C H
3
‚
3
2
2
-
of cyclohexane (8.6 mL, 85.1 mmol) in Et
2
O (280 mL) at 0 °C.
After stirring for 1 h at 0 °C, alkyne 48 in Et O (50 mL) was added
2
4
(
(
(
via cannula and the resulting mixture was allowed to warm to room
temperature. After stirring for 90 min, acetic acid (35 mL, 604
mmol) was added to the mixture. Upon stirring for another 30 min,
f
1
50% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
)
the mixture was carefully poured into saturated aqueous NaHCO
(200 mL) cooled to 0 °C. The mixture was extracted with Et
(3×). The combined organic layers were washed with saturated
4
aqueous NaHCO and brine. The organic layer was dried (MgSO )
3
Hz, 1 H), 5.96 (s, 2 H), 5.93 (dd, J ) 10.0, 2.0 Hz, 1 H), 5.60 (dd,
J ) 10.3, 2.0 Hz, 1 H), 4.15 (tt, J ) 8.1, 2.0 Hz, 1 H), 3.41 (s, 3
H), 3.26 (t, J ) 9.0 Hz, 1 H), 3.06 (dt, J ) 10.5, 6.8 Hz, 1 H), 2.37
2
O
3
(
(
(
1
5
dq, J ) 11.5, 7.3 Hz, 1 H), 2.20 (d, J ) 8.1 Hz, 2 H), 2.12-2.01
and concentrated in vacuo. The residue was chromatographed
m, 2 H), 1.76 (dd, J ) 12.7, 6.6 Hz, 1 H), 1.56 (br s, 1 H), 1.06
(gradient, 100% hexanes-2% EtOAc/hexanes) to afford 6.7 g
t, J ) 7.6 Hz, 3 H); 13C NMR (100 MHz, CDCl
1
3
) δ 147.0, 146.2,
(75%) of the title compound. The H NMR spectrum was consistent
with the reported data.48
41.8, 133.5, 128.4, 120.1, 108.1, 107.0, 101.0, 74.2, 68.3, 56.7,
-
1
6.1, 43.8, 36.1, 35.8, 23.5, 14.4; IR (neat) 3382 (br), 1607 cm
;
(Z)-6-Ethylsulfanyl-4,6-heptadien-1-ol (51). sec-Butyllithium
+
47
MS (EI, 70 eV) m/z (rel intensity) 272.2 [(M - SCH
2
CH
3
) , 100],
(1.1 M in cyclohexane, 20.1 mL, 22.6 mmol) was added to a
+
2
40.2 [(M - C
S [(M + H) ] 334.1477, found 334.1477.
3aR,6R,7aR)-2,3,3a,6,7,7a-Hexahydro-1-benzenesulfonyl-
a-ethylsulfanyl-6-methoxy-7a-[3,4-(methylenedioxy)phenyl]-
indole (40). Benzenesulfonyl chloride (50 µL, 0.4 mmol) and
-dimethylaminopyridine (1 mg, 0.01 mmol) were added to a
H
3 9
O) , 18], 147.1 (44); HRMS (ESI) calcd for
solution of ethyl vinyl sulfide (2.5 mL, 24.6 mmol) in THF-HMPA
+
18 3
C H24NO
(9:1, 103 mL) at -78 °C. After stirring for 1 h, a solution of
(
2
anhydrous ZnCl (0.9 M in THF, 25.7 mL, 23.1 mmol) was added
3
and the resultant mixture was then warmed to 0 °C. A solution of
vinyl iodide 49 (6.70 g, 20.5 mmol) and Pd(PPh (1.2 g, 1.0 mmol)
3 4
)
4
solution of amine 39 (10 mg, 0.03 mmol) in pyridine (0.10 mL) at
(48) Mukai, C.; Sugimoto, Y.; Ikeda, Y.; Hanaoka, M. Tetrahedron 1998,
room temperature. After stirring overnight, water was added and
54, 823-850.
4144 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
in THF (51 mL) was added via cannula. After stirring for 18 h in
the dark at room temperature, the reaction was treated with saturated
(Z)-1-[3,4-(Methylenedioxy)phenyl]-6-ethanesulfinyl-4,6-hep-
tadien-1-ol (54). 3,4-(Methylenedioxy)phenylmagnesium bromide
(35, 1.0 M in 50:50 THF/toluene, 0.6 mL, 0.46 mmol) was added
to a solution of aldehyde 53 (78 mg, 0.42 mmol) in THF (2 mL)
at -30 °C. After stirring for 30 min, the mixture was treated with
aqueous NH
extracted with Et
washed with saturated aqueous NaHCO
4
Cl and concentrated in vacuo. The mixture was
O (3×). The combined organic layers were
and brine, dried (Na SO ),
2
3
2
4
and concentrated in vacuo. The crude residue was then diluted with
THF (100 mL), and tetrabutylammonium fluoride (1.0 M in THF,
half-saturated aqueous NH
the mixture was extracted with Et
layers were washed with half-saturated aqueous NH
dried (Na SO ), and concentrated in vacuo. The residue was
4
Cl. After warming to room temperature,
O (3×). The combined organic
Cl and brine,
2
35 mL, 34.9) was added at room temperature. After stirring for 90
4
min, the mixture was treated with water and extracted with Et
2
O
2
4
(
(
3×). The combined organic layers were washed with brine, dried
Na SO ), and concentrated in vacuo. The residue was chromato-
N, 80% hexanes) to afford 3.0 g
86%) of the title compound as a colorless oil: R ) 0.17 (20%
) δ 5.87 (dd, J ) 11.2,
.5 Hz, 1 H), 5.54 (dt, J ) 11.2, 7.3 Hz, 1 H), 5.06 (d, 1.5 Hz, 1
chromatographed (100% EtOAc) to afford 73 mg (56%) of the title
compound as a colorless oil that contained two inseparable
2
4
graphed (17% EtOAc, 3% Et
(
EtOAc/hexanes); H NMR (500 MHz, CDCl
1
H), 5.03 (s, 1 H), 3.58 (t, J ) 6.3 Hz, 2 H), 2.66 (ddd, J ) 7.3,
7
3
diastereomers (1:1 by NMR): R
H NMR (500 MHz, CDCl
3
f
) 0.10 (33% EtOAc/CH
) δ 6.80 (s, 1 H), 6.72-6.68 (m, 2 H),
5.88 (app d, J ) 1.7 Hz, 2 H), 5.85 (d, J ) 3.4 Hz, 1 H), 5.83-
.71 (m, 2 H), 5.64 (d, J ) 3.4 Hz, 1 H), 4.54-4.49 (m, 1 H), 3.25
d, J ) 2.7 Hz, 0.5 H), 3.16 (d, J ) 2.5 Hz, 0.5 H), 2.76-2.67 (m,
H), 2.51-2.40 (m, 1 H), 2.30-2.13 (m, 2 H), 1.82-1.75 (m, 1
2 2
Cl );
1
f
1
3
5
(
1
.3, 7.3 Hz, 2 H), 2.32 (dt, J ) 7.6, 1.7 Hz, 2 H), 2.27 (br s, 1 H),
.61 (ddd, J ) 14.2, 6.6, 6.6 Hz, 2 H), 1.23 (t, J ) 7.3 Hz, 3 H);
13
H), 1.72-1.62 (m, 1 H), 1.11 (t, J ) 7.3 Hz, 3 H); C NMR (125
1
13
MHz, CDCl ) δ 147.6, 147.5, 147.1, 146.7, 146.6, 138.7, 138.6,
C NMR (125 MHz, CDCl
2.5, 25.7, 24.7, 13.7; IR (neat) 3340 (br), 1633 (w); MS (EI, 70
3
) δ 140.1, 133.9, 128.1, 110.8, 61.9,
3
138.4, 138.2, 131.9, 131.8, 128.4, 128.3, 119.5, 119.1, 119.0, 118.7,
3
+
+
107.84, 107.82, 106.16, 106.15, 100.79, 100.77, 73.2, 72.9, 44.32,
44.28, 38.6, 25.69, 25.57, 5.3, 5.2; IR (neat) 3378 (br), 1609, 1040
eV) m/z (rel intensity) 172.1 [(M) , 9], 143.0 [(M - CH
2
CH
O) , 100]; HRMS (EI, 70 eV)
16OS (M ) 172.0922, found 172.0924.
Z)-6-Ethylsulfanyl-4,6-heptadien-1-ol (52). Sodium periodate
5.3 g, 24.6 mmol) followed by water (20 mL) was added to a
3
) ,
+
3
9], 125.0 [(M - CH
2
CH
3
- H
2
-
1
+
(s) cm ; HRMS (ESI) calcd for C16
31.0977.
Z)-1-[3,4-(Methylenedioxy)phenyl]-6-ethanesulfinyl-4,6-hep-
tadien-1-one (55). Dimethyl sulfoxide (3.5 M in CH Cl , 150 µL,
.52 mmol) was added in a dropwise fashion to a solution of oxalyl
chloride (2.0 M in CH Cl , 130 µL, 0.26 mmol) in CH Cl (0.8
mL) at -78 °C. Stirring for 10 min, alcohol 54 (73 mg, 0.24 mmol)
in CH Cl (0.4 mL) was then added in a dropwise fashion via
4
H20NaO S 331.0980, found
9
calcd for C H
3
(
(
(
2
2
solution of vinyl sulfide 51 (3.0 g, 17.6 mmol) in MeOH (150 mL)
at room temperature. After stirring for 1 h, the reaction was
0
2
2
2
2
concentrated in vacuo. The mixture was diluted with CH
saturated aqueous NaHCO
organic layers were washed with saturated aqueous NaHCO
brine, dried (Na SO
chromatographed (1% Et
title compound as a colorless oil: R
NMR (500 MHz, CDCl ) δ 5.86 (s, 1 H), 5.80 (dt, J ) 11.5, 7.3
2
Cl
2
and
3
and extracted (3×). The combined
2
2
3
and
cannula. After stirring for 30 min, triethylamine (0.17 mL, 1.2
mmol) was added. The reaction was warmed to room temperature,
2
4
), and concentrated in vacuo. The residue was
N/EtOAc) to afford 2.7 g (80%) of the
3
treated with water, and extracted with CH
organic layers were washed with saturated aqueous NaHCO
brine, dried (Na SO ), and concentrated in vacuo. The residue was
chromatographed (75% EtOAc/hexanes) to afford 61 mg (84%) of
the title compound as a colorless oil: R ) 0.31 (75% EtOAc/
) δ 7.54 (dd, J ) 8.1, 1.7
Cl
2 2
(3×). The combined
1
f
) 0.13 (100% EtOAc); H
3
and
3
2
4
Hz, 1 H), 5.73 (dd, J ) 11.7, 1.2 Hz, 1 H), 5.67 (s, 1 H), 3.52 (t,
J ) 6.4 Hz, 2 H), 3.23 (br s, 1 H), 2.74 (dq, J ) 14.9, 7.6 Hz, 1
H), 2.48 (dq, J ) 14.7, 7.3 Hz, 1 H), 2.29-2.16 (m, 2 H), 1.61-
f
1
hexanes); H NMR (500 MHz, CDCl
3
13
1
52 (m, 2 H), 1.11 (t, J ) 7.3 Hz, 3 H); C NMR (125 MHz,
Hz, 1 H), 7.42 (d, J ) 1.7 Hz, 1 H), 6.85 (d, J ) 8.3 Hz, 1 H),
CDCl ) δ 147.0, 138.7, 119.3, 118.9, 61.3, 44.2, 32.1, 25.5, 5.2;
IR (neat) 3410 (br), 1630, 1059 (s) cm ; MS (EI, 70 eV) m/z (rel
3
6
3
1
1
1
1
.04 (s, 2 H), 6.00 (s, 1 H), 5.91-5.84 (m, 2 H), 5.78 (s, 1 H),
-
1
.02 (t, J ) 7.1 Hz, 2 H), 2.82 (dddd, J ) 14.7, 7.3, 7.3, 7.3 Hz,
+
+
intensity) 189.1 [(M + H) , 4], 171.1 [(M - H
2
O) , 28], 111.1
H), 2.68-2.62 (m, 2H), 2.56 (dddd, J ) 14.7, 7.3, 7.3, 7.3 Hz,
+
[
(M - S(O)CH
for C
Z)-6-Ethylsulfanyl-4,6-heptadien-1-al (53). Dimethyl sulfoxide
0.39 mL, 5.6 mmol) in CH Cl (1.0 mL) was added in a dropwise
fashion to a solution of oxalyl chloride (2.0 M in CH Cl , 1.4 mL,
.8 mmol) in CH Cl (9 mL) via cannula at -78 °C. After stirring
for 10 min, alcohol 52 (476 mg, 2.5 mmol) in CH Cl (2.6 mL)
2
CH
3
) , 37], 77.0 (100); HRMS (EI, 70 eV) calcd
13
H), 1.22 (t, J ) 7.6 Hz, 3 H); C NMR (125 MHz, CDCl
3
) δ
+
9
17 2
H O S [(M + H) ] 189.0949, found 189.0953.
96.6, 151.8, 148.2, 147.5, 137.2, 131.4, 124.2, 120.4, 118.9, 107.8,
07.7, 101.8, 44.6, 37.7, 23.9, 5.4; IR (neat) 1675 (s), 1604, 1037
(
(
2
2
-1
+
cm ; HRMS (ESI) calcd for C16
found 329.0822.
4
H18NaO S [(M + Na) ] 329.0824,
2
2
2
2
2
(
3aR,7aR)-2,3,3a,6,7,7a-Hexahydro-3a-ethylsulfinyl-7a-[3,4-
2
2
(
methylenedioxy)phenyl]-1H-indole (57). Trimethylaluminum (2.0
was then added in a dropwise fashion via cannula. After stirring
for 30 min, triethylamine (1.8 mL, 12.6 mmol) was added. The
reaction was warmed to room temperature, treated with water, and
M, in heptane 0.22 mL, 0.45 mmol) was added to a solution of
10a
amine 17 (143 mg, 0.45 mmol) in toluene (1.4 mL) at room
temperature. After stirring for 5 min, a solution of ketone 55 (62
mg, 0.20 mmol) in toluene (0.6 mL) was added via cannula. After
stirring for an additional 90 min, the reaction was treated with
extracted with CH
washed successively with water, saturated aqueous NaHCO
brine, dried (Na SO ), and concentrated in vacuo. The resultant oil
was diluted with Et O, filtered through a pad of Celite to remove
triethylamine salts, and concentrated in vacuo to afford 140 mg
93%) of the title compound as a colorless oil. Aldehyde 53 was
used immediately without further purification: R ) 0.33 (100%
) δ 9.79 (d, J ) 1.0 Hz, 1 H),
.02 (d, J ) 1.0 Hz, 1 H), 5.88 (d, J ) 11.5 Hz, 1 H), 5.80 (dt, J
2
Cl
2
(3×). The combined organic layers were
3
, and
2
4
saturated aqueous NaHCO
combined organic layers were washed with brine, dried (Na SO ),
and extracted with Et
O (3×). The
3
2
2
2 4
and concentrated in vacuo. Without further purification, the crude
(
residue (R ) 0.38 (50% EtOAc/hexanes using neutral Alumina
f
f
plates)) was dissolved in toluene (10 mL) at room temperature.
1
EtOAc); H NMR (500 MHz, CDCl
3
Chlorotrimethylsilane (26 µL, 0.20 mmol) was added, and the
reaction was heated to 55 °C. After stirring for 3 h, the mixture
was cooled to room temperature and concentrated in vacuo. The
residue was chromatographed on neutral alumina (gradient, 2%-
10% MeOH/EtOAc) to afford 38 mg (59%) of the title compound
f
6
)
11.5, 7.1 Hz, 1 H), 5.76 (s, 1 H), 2.84 (dddd, J ) 14.9, 7.6, 7.6,
.6 Hz, 1 H), 2.62-2.51 (m, 5 H), 1.22 (dt, J ) 7.6, 1.2 Hz, 3 H);
7
13
C NMR (100 MHz, CDCl
3
) δ 200.6, 147.4, 136.2, 120.7, 118.9,
4
4.4, 43.1, 21.6, 5.2; IR (neat) 2828, 2727, 1721 (s), 1634, 1059
as a yellow oil containing two inseparable diastereomers: R )
-
1
+
1
(s) cm ; MS (EI, 70 eV) m/z (rel intensity) 186.1 [(M) , 2], 157.1
0.55 (5% MeOH/EtOAc, neutral alumina plate); H NMR (500
+
+
[
-
C
(M - CH
2
CH
CH
3
) , 9], 109.1 [(M - S(O)CH
3
2
CH
3
) , 79], 81.1 [(M
MHz, CDCl
3
) δ 7.05 (d, J ) 2.0 Hz, 1 H), 6.98 (dd, J ) 8.3, 2.0
+
S(O)CH
2
- CHO) , 100]; HRMS (EI, 70 eV) calcd for
S (M ) 186.0714, found 186.0708.
Hz, 1 H), 6.77 (d, J ) 8.3 Hz, 1 H), 6.14 (dt, J ) 10.3, 3.9 Hz, 1
H), 5.96 (AB
+
9
H
14
O
2
q
, J ) 1.5 Hz, ∆ν ) 8.6 Hz, 2 H), 5.75 (dt, J ) 10.3,
J. Org. Chem, Vol. 72, No. 11, 2007 4145

Pearson et al.
2
1
2
5
.0 Hz, 1 H), 3.29 (ddd, J ) 11.5, 9.8, 2.7 Hz, 1 H), 3.18 (dt, J )
1.2, 8.3 Hz, 1 H), 2.82 (dt, J ) 13.4, 9.0 Hz, 1 H), 2.67-2.52 (m,
H), 2.35-2.18 (m, 2 H), 2.02-1.91 (m, 2 H), 1.81 (dt, J ) 13.4,
.9 Hz, 1 H), 1.27 (t, J ) 7.6 Hz, 3 H); 13C NMR (100 MHz,
vacuo. The residue was chromatographed (60% EtOAc/hexanes)
to afford 620 mg (53%) of the title compound as a colorless oil
that contained two inseparable diastereomers (ratio not deter-
1
mined): R
CDCl
f
) 0.50 (50% EtOAc/CH
2
Cl
2
); H NMR (500 MHz,
CDCl
1
3
) δ 147.4, 146.5, 137.3, 132.7, 125.3, 120.2, 108.1, 107.5,
3
) δ 6.95 (d, J ) 0.7 Hz, 1 H), 6.61 (d, J ) 1.7 Hz, 1H), 5.96
01.0, 70.0, 67.8, 44.0, 41.3, 34.2, 31.7, 22.5, 7.8; IR (neat) 3343
(d, J ) 1.5 Hz, 1 H), 5.92 (d, J ) 2.2 Hz, 2 H), 5.90-5.79 (m, 2
H), 5.74 (d, J ) 4.9 Hz, 1 H), 4.92 (dddd, J ) 7.8, 7.8, 4.2, 4.2
Hz, 1 H), 3.65-3.55 (m, 2 H), 2.81 (dddd, J ) 14.7, 7.3, 7.3, 7.3
Hz, 1 H), 2.67 (dddd, J ) 15.1, 8.6, 8.6, 8.6 Hz, 1 H), 2.61-2.49
(m, 2 H), 2.45-2.25 (m, 2 H), 1.91-1.82 (m, 1 H), 1.78-1.64
(m, 3 H), 1.63 (dddd, J ) 13.2, 6.8, 6.8, 6.8 Hz, 1 H), 1.19 (t, J )
7.6 Hz, 3 H), 0.90 (d, J ) 6.8 Hz, 6 H), 0.85 (s, 6 H), 0.09 (d, J
-
1
20
(br), 1673, 1609, 1039 (s) cm ; HRMS (ESI) calcd for C17H -
+
NO
3
S [(M + H) ] 320.1320, found 320.1315.
2
,6,7,7a-Tetrahydro-7a-[3,4-(methylenedioxy)phenyl]-1H-in-
dole (58). Trimethylaluminum (2.0 M, in heptane, 75 µL, 0.15
mmol) was added to a solution of amine 171 (48 mg, 0.15 mmol)
in 0.4 mL of toluene at room temperature. After stirring for 5 min,
a solution of ketone 55 (21 mg, 0.07 mmol) in 0.3 mL of toluene
was added via cannula. After stirring an additional 90 min, the
reaction was treated with saturated aqueous NaHCO
with Et
O (3×). The combined organic layers were washed with
brine, dried (Na SO ), and concentrated in vacuo. Without further
purification, the crude residue (R ) 0.38 (50% EtOAc/hexanes
using neutral Alumina plates)) was dissolved in toluene (1.7 mL)
and placed in a sealed tube at room temperature. Chlorotrimeth-
ylsilane (8.7 µL, 0.07 mmol) was added, and the reaction was heated
to 65 °C. After stirring for 14 h, the mixture was cooled to room
temperature and concentrated in vacuo. The residue was chromato-
0a
) 4.4 Hz, 6 H); 13C NMR (125 MHz, CDCl
3
) δ 147.4, 146.7, 146.6,
146.10, 146.07, 138.3, 138.2, 135.5, 135.4, 132.4, 132.3, 119.83,
119.78, 119.2, 118.8, 109.3, 109.2, 105.77, 105.75, 100.80, 100.78,
69.0, 68.7, 61.81, 61.77, 69.0, 68.7, 61.81, 61.77, 44.44, 44.42,
38.03, 38.02, 34.8, 34.7, 34.1, 28.4, 26.2, 26.0, 25.1, 20.3, 18.5,
3
and extracted
2
2
4
-
1
f
5.4, 5.3, -3.37, -3.41; IR (neat) 3389 (s), 1623, 1041 (s) cm ;
+
HRMS (ESI) calcd for C27
found 531.2578.
5
H44NaO SSi [(M + Na) ] 531.2576,
(Z)-1-(6-{3-[Dimethyl(1,1,2-trimethylpropyl)silyloxy]propyl}-
3,4-(methylenedioxy)phenyl)-6-ethanesulfinyl-4,6-heptadien-1-
one (61). Dimethyl sulfoxide (0.48 mL, 6.8 mmol) was added in a
dropwise fashion to a solution of oxalyl chloride (0.30 mL, 3.4
mmol) in CH Cl (12 mL) at -78 °C. After stirring for 10 min,
graphed (3% Et
3
N, 2% MeOH/EtOAc) to afford 8.0 mg (48%) of
) 0.42 (15% MeOH/EtOAc);
) δ 6.88 (d, J ) 1.7 Hz, 1 H), 6.84 (dd,
J ) 8.1, 1.7 Hz, 1 H), 6.74 (d, J ) 8.1 Hz, 1 H), 6.41 (dd, J ) 9.8,
the title compound as a yellow oil: R
f
2
2
1
H NMR (500 MHz, CDCl
3
2 2
alcohol 60 (1.6 g, 3.1 mmol) in CH Cl (4 mL) was then added via
cannula. After stirring for an additional 30 min, triethylamine (2.1
mL, 15 mmol) was added. The reaction was warmed to room
temperature, treated with water, and extracted with CH Cl (3×).
2
5
2
1
q
.7 Hz, 1 H), 5.93 (AB , J ) 1.5 Hz, ∆νAB ) 1.9 Hz, 2 H), 5.81-
.75 (m, 2 H), 3.63 (dd, J ) 21.5, 15.4 Hz, 2 H), 2.95-2.62 (m,
H), 2.47 (dd, J ) 12.5, 4.9 Hz, 1 H), 2.14 (dt, J ) 18.8, 5.1 Hz,
2
2
The combined organic layers were washed with saturated aqueous
NaHCO and brine, dried (Na SO ), and concentrated in vacuo.
1
3
H), 1.94 (dt, J ) 12.2, 4.9 Hz, 1 H), 1.81-1.72 (m, 1 H);
C
3
2
4
NMR (125 MHz, CDCl
1
3
3
) δ 147.6, 146.4, 141.8, 131.6, 122.5, 122.3,
19.3, 108.0, 106.9, 100.9, 77.2, 69.6, 50.7, 36.1, 24.7; IR (neat)
299, 1676, 1607 cm ; MS (EI, 70 eV) m/z (rel intensity) 241.1
The residue was chromatographed (gradient, 33-50% EtOAc/
hexanes) to afford 1.2 g (76%) of the title compound as a colorless
-
1
1
oil: R ) 0.29 (50% EtOAc/hexanes); H NMR (500 MHz, CDCl )
f
3
+
+
[
2
(M) , 100]; HRMS (ESI) calcd for C15
42.1181, found 242.1185.
-[6-Bromo-3,4-(methylenedioxy)phenyl]-1-[dimethyl-1,1,2-
trimethylpropyl)silyloxy]propane (59). Triethylamine (0.63 mL,
H16NO
2
[(M + H) ]
δ 7.08 (s, 1 H), 6.72 (s, 1 H), 5.99 (s, 1 H), 5.98 (s, 2 H), 5.86-
5.83 (m, 2 H), 5.76 (s, 1 H), 3.59 (t, J ) 6.4 Hz, 2 H), 2.92 (t, J
) 7.3 Hz, 2 H), 2.87-2.76 (m, 3 H), 2.63-2.58 (m, 2 H), 2.57-
2.50 (m, 1 H), 1.76-1.69 (m, 2 H), 1.61 (dddd, J ) 13.7, 13.7,
6.8, 6.8 Hz, 1 H), 1.20 (t, J ) 7.3 Hz, 3 H), 0.87 (d, J ) 6.8 Hz,
3
(
4
4
.6 mmol), dimethylthexylsilyl chloride (0.86 mL, 4.1 mmol) and
-dimethylaminopyridine (15 mg, 0.12 mmol) were each added to
6 H), 0.83 (s, 6 H), 0.07 (s, 6 H); 13C NMR (125 MHz, CDCl ) δ
3
a solution of alcohol 32 (1.1 g, 4.1 mmol) in CH
2
Cl
2
(8.3 mL) at
200.2, 149.9, 147.5, 145.5, 139.3, 137.1, 130.4, 120.4, 118.9, 111.3,
108.5, 101.6, 62.2, 44.6, 40.7, 34.7, 34.1, 30.7, 25.0, 24.1, 20.3,
room temperature. After stirring for 14 h, the mixture was filtered
through a pad of Celite and concentrated in vacuo. The residue
was chromatographed (2% EtOAc/hexanes) to afford 1.6 g (95%)
of the title compound as a colorless oil: R
hexanes); H NMR (400 MHz, CDCl
H), 5.94 (s, 2 H), 3.62 (t, J ) 6.2 Hz, 2 H), 2.73-2.67 (m, 2 H),
1
7
CDCl
3
-
1
18.5, 5.3, -3.4; IR (neat) 1682 (s), 1610, 1061 (s) cm ; HRMS
+
(ESI) calcd for C H NaO SSi [(M + Na) ] 529.2420, found
27
42
5
f
) 0.29 (2% EtOAc/
529.2419.
1
3
) δ 6.98 (s, 1 H), 6.72 (s, 1
(Z)-1-[6-(3-Hydroxypropyl)-3,4-(methylenedioxy)phenyl]-6-
ethanesulfinyl-4,6-heptadien-1-one (62). Hydrogen fluoride-py-
ridine (0.1 mL) was added to a solution of silyl ether 61 (90 mg,
.80-1.71 (m, 2 H), 1.64 (septet, J ) 7.0 Hz, 1 H), 0.90 (d, J )
13
.0 Hz, 6 H), 0.86 (s, 6 H), 0.95 (s, 6 H); C NMR (100 MHz,
) δ 147.2, 146.5, 134.7, 114.3, 112.6, 110.0, 101.5, 61.9,
4.2, 33.0, 32.6, 25.1, 20.4, 18.6, -3.4; IR (neat) 1503, 1477, 830
0.18 mmol) in CH CN (1.4 mL) at room temperature. After stirring
3
3
for 3 h, the mixture was carefully neutralized with solid NaHCO3,
dried (Na SO ), and concentrated in vacuo. The residue was
2
4
-
1
cm ; MS (EI, 70 eV) m/z (rel intensity) 316.9 [(M + 2 - C(CH
CH(CH
3
)
2
-
chromatographed (gradient, 100% EtOAc-3% MeOH/EtOAc) to
+
+
3
)
2
) , 100], 314.9 [(M - C(CH
CH(CH , 37]; HRMS (ESI) calcd for
Si [(M + Na) ] 423.0967, found 423.0958.
Z)-1-(6-{3-[Dimethyl(1,1,2-trimethylpropyl)silyloxy]propyl}-
,4-(methylenedioxy)phenyl)-6-ethanesulfinyl-4,6-heptadien-1-
3
)
2
CH(CH
3
)
2
) , 100], 236.0
afford 60 mg (93%) of the title compound as colorless oil: R )
f
1
[
(M - Br - C(CH
3
)
2
3
)
2
0.25 (100% EtOAc); H NMR (400 MHz, CDCl ) δ 7.08 (s, 1 H),
3
7
9
+
BrC18
(
H
29NaO
3
6.73 (s, 1 H), 5.99 (s, 2 H), 5.98 (s, 1 H), 5.87-5.83 (m, 2 H),
5.76 (s, 1 H), 3.56 (t, J ) 5.9 Hz, 2 H), 2.94 (t, J ) 7.0 Hz, 2 H),
2.87-2.78 (m, 3 H), 2.63-2.51 (m, 4 H), 1.82 (dddd, J ) 5.9,
5.9, 5.9, 5.9 Hz, 2 H), 1.20 (t, J ) 7.8 Hz, 3 H); 13C NMR (100
3
ol (60). tert-Butyllithium (1.73 M in pentane, 2.8 mL, 4.9 mmol)
was added to a solution of bromide 59 (930 mg, 2.3 mmol) in THF
MHz, CDCl ) δ 201.4, 150.3, 147.4, 145.7, 138.7, 137.1, 130.6,
3
49
(10 mL) at -78 °C. After stirring for 10 min, MgBr
2
(0.2 M in
120.5, 119.1, 111.1, 108.5, 101.7, 61.2, 44.6, 40.8, 34.5, 29.6, 24.1,
-
1
THF, 16 mL, 3.2 mmol) was added to the mixture, and after an
additional 15 min, a solution of aldehyde 53 (430 mg, 2.3 mmol)
in THF (2 mL) was added via cannula. Following another 15 min,
5.4; IR (neat) 3400 (s), 1683 (s), 1609, 1038 cm ; MS (EI, 70
+
eV) m/z (rel intensity) 347.1 [(M - H O) , 5], 287.1 [(M - S(O)-
2
+
CH CH ) , 42], 207.0 [(M - C H OS), 100]; HRMS (ESI) calcd
for C H NaO S [(M + Na) ] 387.1242, found 387.1237.
Z)-1-[6-(3-Iodopropyl)-3,4-(methylenedioxy)phenyl]-6-ethane-
sulfinyl-4,6-heptadien-1-one (63). Triphenylphosphine (150 mg,
.58), imidazole (63 mg, 0.92 mmol), and I (105 mg, 0.42 mmol)
were sequentially added to a solution of alcohol 62 (84 mg, 0.23
mmol) in CH Cl (3.9 mL) in the dark at 0 °C. After stirring for
2
3
8
13
+
the mixture was treated with half-saturated aqueous NH
warming to room temperature, the mixture was extracted with Et
3×). The combined organic layers were washed with half-saturated
aqueous NH Cl and brine, dried (Na SO ), and concentrated in
4
Cl. After
19
24
5
2
O
(
(
4
2
4
0
2
(49) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702-5703.
2
2
4146 J. Org. Chem., Vol. 72, No. 11, 2007

Approach to the Homoerythrina Alkaloids
1
5 min, the mixture was warmed to room temperature. Upon stirring
for an additional 30 min, the mixture was treated with 5% (w/w)
aqueous Na and extracted with CH Cl
(3×). The combined
organic layers were washed with 5% aqueous Na and brine,
dried (Na SO ), and concentrated in vacuo. The residue was
chromatographed (gradient, 33%-66% EtOAc/hexanes) to afford
0 mg (73%) as a colorless oil: R ) 0.31 (66% EtOAc/hexanes);
) δ 7.15 (s, 1 H), 6.76 (s, 1 H), 6.02 (s,
H), 6.01 (s, 1 H), 5.90-5.83 (m, 2 H), 5.78 (s, 1 H), 3.21 (t, J
6.8 Hz, 2 H), 2.95 (t, J ) 7.1 Hz, 2 H), 2.89-2.81 (m, 3 H),
(s, 2 H), 5.96-5.90 (m, 2 H), 3.56 (t, J ) 5.9 Hz, 2 H), 3.01-2.96
(m, 4 H), 2.83 (t, J ) 7.3 Hz, 2 H), 2.69 (br s, 1 H), 2.61 (dddd,
J ) 7.1, 7.1, 7.1, 2.0 Hz, 2 H), 1.82 (dddd, J ) 7.3, 7.3, 6.1, 6.1
2
S
2
O
4
2
2
S O
2 2 4
Hz, 2 H), 1.29 (t, J ) 7.6 Hz, 3 H); 13C NMR (125 MHz, CDCl
3
)
2
4
δ 201.2, 150.4, 145.7, 143.7, 138.7, 138.3, 130.5, 127.1, 120.9,
111.2, 108.5, 101.7, 61.1, 46.7, 40.5, 34.4, 29.6, 23.4, 6.8; IR (neat)
-
1
8
f
3524 (br), 1679 (s), 1609, 1112 cm ; MS (EI, 70 eV) m/z (rel
1
+
+
H NMR (500 MHz, CDCl
3
intensity) 380.2 [(M) , 16], 362.2 [(M - H
2
O) , 9], 287.2 [(M -
+
+
2
)
2
SO
2
CH
2
CH
3
) , 100], 269.2 [(M - C
2
H
7
O
3
S) , 26]; HRMS (ESI)
+
calcd for C19
H O
24 6
S [(M) ] 380.1294, found 380.1290.
.66-2.53 (m, 3 H), 2.09 (q, J ) 7.1 Hz, 2 H), 1.23 (t, J ) 7.3
(Z)-1-[6-(3-Iodopropyl)-3,4-(methylenedioxy)phenyl]-6-ethane-
sulfinyl-4,6-heptadien-1-one (68). Triphenylphosphine (123 mg,
1
3
Hz, 3 H); C NMR (125 MHz, CDCl
3
) δ 200.0, 150.2, 147.6,
1
4
45.9, 137.8, 137.0, 130.2, 120.6, 119.0, 111.4, 108.9, 101.8, 44.7,
0.6, 35.4, 35.2, 24.2, 6.6, 5.5; IR (neat) 1679 (s), 1609, 1038 cm
0.47), imidazole (35 mg, 0.52 mmol), and I (142 mg, 0.56 mmol)
2
-1
;
were sequentially added to a solution of alcohol 67 (89 mg, 0.23
+
MS (EI, 70 eV) 397.0 [(M - S(O)CH
C
Na) ] 497.0260, found 497.0266.
2
CH
3
) , 86], 317.0 [(M -
mmol) in Et O and CH CN (1:1, 4 mL) in the dark at 0 °C. After
2
3
+
8
H
13OS) , 100]; HRMS (ESI) calcd for C19
H
23INaO S [(M +
4
stirring for 15 min, the mixture was warmed to room temperature.
Upon stirring for an additional 30 min, the mixture was treated
+
Demethoxyschelhammeridine (65). Iodide 63 (11 mg, 0.02
with 5% (w/w) aqueous Na
The combined organic layers were washed with brine, dried (Na
SO ), and concentrated in vacuo. The residue was chromatographed
(gradient, 25%-33% EtOAc/hexanes) to afford 103 mg (90%) as
2
S
2
O
4
and extracted with EtOAc (3×).
mmol) in toluene (0.4 mL) was added to a solution of amine 171
(
0a
-
2
18 mg, 0.06 mmol) in toluene (0.4 mL) at 85 °C. After stirring
4
for 5 h, the reaction was treated with EtOH, dried (Na SO ), and
2
4
1
concentrated in vacuo. The residue was chromatographed (5%
MeOH/EtOAc) to afford 4 mg (56%) of the title compound as a
a colorless oil: R
f
) 0.25 (33% EtOAc/hexanes); H NMR (500
MHz, CDCl ) δ 7.16 (s, 1 H), 6.75 (s, 1 H), 6.43 (s, 1 H), 6.17
3
1
yellow oil: R
CDCl
H), 5.89 (AB
f
) 0.23 (5% MeOH/EtOAc); H NMR (500 MHz,
(dddd, J ) 11.5, 1.7, 1.7, 1.7 Hz, 1 H), 6.02 (s, 2 H), 5.97-5.92
(m, 2 H), 3.20 (t, J ) 7.1 Hz, 2 H), 3.00 (q, J ) 7.3 Hz, 2 H), 2.98
(t, J ) 7.1 Hz, 2 H), 2.85 (app t, J ) 7.6 Hz, 2 H), 2.62 (dddd, J
) 7.1, 7.1, 7.1, 1.7 Hz, 2 H), 2.11-2.03 (m, 2 H), 1.30 (t, J ) 7.6
3
) δ 6.61 (s, 1 H), 6.53 (s, 1 H), 6.40 (dd, J ) 9.8, 2.6 Hz, 1
, J ) 1.5 Hz, ∆νAB ) 8.3 Hz, 2 H), 5.80-5.74 (m,
q
2
H), 3.66 (dd, J ) 14.4, 2.2 Hz, 1 H), 3.27 (ddd, J ) 15.6, 95, 5.4
Hz, 1 H), 3.13 (d, J ) 14.4 Hz, 1 H), 3.04 (ddd, J ) 12.5, 6.4, 2.0
Hz, 1 H), 2.81-2.73 (m, 2 H), 2.43 (t, J ) 11.2 Hz, 1 H), 2.12-
Hz, 3 H); 13C NMR (125 MHz, CDCl
3
) δ 199.7, 150.3, 145.9,
143.7, 138.4, 137.8, 130.1, 127.1, 120.9, 111.4, 108.9, 101.8, 46.7,
-1
1
.91 (m, 3 H), 1.81 (dt, J ) 12.5, 4.4 Hz, 1 H), 1.67-1.57 (m, 1
40.3, 35.3, 35.2, 23.4, 6.9, 6.5; IR (neat) 1681 (s), 1610, 1112 cm ;
13
+
+
H); C NMR (125 MHz, CDCl
3
) δ 145.9, 145.4, 143.7, 132.3,
MS (EI, 70 eV) 490.1 [(M) , 11], 397.1 [(M - SO
2
CH
2
CH
3
) ,
+
+
1
3
31.1, 123.5, 121.5, 111.5, 109.9, 100.7, 77.2, 70.9, 59.2, 49.4,
100], 362.2 [(M - I) , 10], 317.0 [(M - C
8
H
13
O
2
S) , 45]; HRMS
-1
+
4.2, 32.8, 24.5, 23.3; IR (neat) 1683, 1618, 1484, 1241, 1038 cm ;
(EI, 70 eV) calcd for C19
H
23IO
5
S [(M) ] 490.0311, found 490.0316.
+
MS (EI, 70 eV) m/z (rel intensity) 281.1 [(M) , 100]; HRMS (ESI)
6R-Ethanesulfonyldemethoxycomosine (69). Iodide 68 (8.5 mg,
+
calcd for C18
Z)-1-(6-{3-[Dimethyl(1,1,2-trimethylpropyl)silyloxy]propyl}-
,4-(methylenedioxy)phenyl)-6-ethanesulfonyl-4,6-heptadien-1-
H
20NO
2
[(M + H) ] 282.1494, found 282.1494.
0.02 mmol) in toluene (0.5 mL) was added to a solution of amine
10a
(
17 (11 mg, 0.04 mmol) in toluene (0.3 mL) at 85 °C. After stirring
for 2 h, the reaction was treated with EtOH, dried (Na SO ), and
concentrated in vacuo. The residue was chromatographed with basic
alumina (gradient, 5%-10% Et O/toluene) to afford 4 mg (63%)
of the title compound as a white solid: mp ) 142-144 °C; R
3
2
4
one (66). m-Chloroperbenzoic acid (77%, w/w water, 177 mg, 0.69
mmol) was added to a solution of sulfoxide 61 (232 mg, 0.46 mmol)
2
in CH
the mixture was treated with saturated aqueous NaHCO
extracted with CH Cl
(3×). The combined organic layers were
washed with brine, dried (Na SO ), and concentrated in vacuo. The
2
Cl
2
(20 mL) at room temperature. After stirring for 15 min,
f
)
1
3
and
0.33 (33% EtOAc/hexanes); H NMR (500 MHz, CDCl
(s, 1 H), 6.55 (s, 1 H), 6.22 (dddd, J ) 8.3, 2.9, 2.9, 2.9 Hz, 1 H),
5.95 (dt, J ) 10.3, 2.2 Hz, 1 H), 5.91 (AB , J ) 1.5 Hz, ∆νAB )
3
) δ 7.24
2
2
2
4
q
residue was chromatographed (gradient, 20%-25% EtOAc/hex-
10.5 Hz, 2 H), 3.13 (dt, J ) 9.0, 2.0 Hz, 1 H), 3.05-2.95 (m, 2
H), 2.87 (ddd, J ) 14.4, 8.3, 3.9 Hz, 1 H), 2.81-2.69 (m, 2 H),
2.61 (dt, J ) 12.7, 9.0 Hz, 1 H), 2.44-2.36 (m, 2 H), 2.27-2.09
(m, 4 H), 1.93 (ddd, J ) 12.7, 7.1, 1.0 Hz, 1 H), 1.81 (dt, J )
13.4, 5.1 Hz, 1 H), 1.70-1.60 (m, 1 H), 1.15 (t, J ) 7.3 Hz, 3 H);
anes) to afford 182 mg (76%) of the title compound as a colorless
1
oil: R
f
) 0.49 (50% EtOAc/hexanes); H NMR (500 MHz, CDCl
3
)
δ 7.11 (s, 1 H), 6.74 (s, 1 H), 6.43 (s, 1 H), 6.17 (dddd, J ) 11.5,
.7, 1.7, 1.7 Hz, 1 H), 6.00 (s, 2 H), 5.97-5.91 (m, 2 H), 3.60 (t,
J ) 6.4 Hz, 2 H), 3.00 (q, J ) 7.3 Hz, 2 H), 2.97 (t, J ) 6.8 Hz,
1
1
3
C NMR (125 MHz, CDCl
3
) δ 146.4, 145.8, 135.8, 133.9, 133.7,
2
1
7
H), 2.82-2.77 (m, 2 H), 2.62 (ddd, J ) 7.1, 7.1, 2.0 Hz, 2 H),
.78-1.70 (m, 2 H), 1.62 (septet, J ) 6.8 Hz, 1 H), 1.30 (t, J )
.3 Hz, 3 H), 0.89 (d, J ) 6.8 Hz, 6 H), 0.85 (s, 6 H), 0.08 (s, 6
124.2, 112.0, 110.9, 101.1, 77.4, 70.1, 46.6, 44.6, 41.5, 33.4, 33.0,
30.5, 26.2, 23.0, 5.4; IR (CH
eV) m/z (rel intensity) 375.2 [(M) , 2]; 282.2 [(M - SO
100]; HRMS (ESI) calcd for C20H26NO S [(M + H) ] 376.1583,
-
1
2 2
Cl ) 1622, 1129 cm ; MS (EI, 70
+
+
2
CH
2
CH
3
) ,
1
3
+
H); C NMR (125 MHz, CDCl
3
) δ 200.0, 149.9, 145.5, 143.7,
39.2, 138.4, 130.3, 126.9, 120.7, 111.3, 108.5, 101.6, 62.1, 46.6,
0.4, 34.7, 34.1, 30.7, 25.0, 23.4, 20.3, 18.4, 6.8, -3.5; IR (neat)
4
1
4
1
4
2
found 376.1581. The relative configuration was determined by an
X-ray crystal structure of the corresponding picrate salt. See
Supporting Information for details.
-
1
681 (s), 1610, 1113 (s) cm ; MS (EI, 70 eV) m/z (rel intensity)
+
37.1 [(M - C(CH
3
)
2
CH(CH
3
)
2
) , 33], 343.1 [(M - C
H
8 18
O
2
S),
Demethoxyschelhammericine (70). Lithium triethylborohydride
(1 M in THF, 46 µL, 0.05 mmol) was slowly added over a period
2], 161.0 (100); HRMS (ES) calcd for C27
H
42NaO
6
SSi [(M +
+
Na) ] 545.2370, found 545.2369.
of 15 min to a mixture of PdCl dppp (1.3 mg, 0.002 mmol) and
2
(
Z)-1-[6-(3-Hydroxypropyl)-3,4-(methylenedioxy)phenyl]-6-
sulfone 69 (8 mg, 0.2 mmol) in THF (0.4 mL) at 0 °C. After stirring
ethanesulfonyl-4,6-heptadien-1-one (67). Hydrogen fluoride-py-
ridine (0.12 mL) was added to a solution of silyl ether 66 (131
for an additional 30 min, the mixture was treated with 10% (w/w)
aqueous KCN and extracted with Et
layers were washed with water and brine, dried (Na
concentrated in vacuo. The residue was chromatographed (3% Et
2
O (3×). The combined organic
SO ), and
N/
mg, 0.25 mmol) in CH
stirring for 3 h, the mixture was carefully neutralized with solid
NaHCO , dried (Na SO ), and concentrated in vacuo. The residue
was chromatographed (60% EtOAc/hexanes) to afford 93 mg (98%)
of the title compound as a colorless oil: R ) 0.13 (50% EtOAc/
) δ 7.11 (s, 1 H), 6.74 (s, 1
H), 6.42 (s, 1 H), 6.15 (dddd, J ) 11.5, 1.7, 1.7, 1.7 Hz, 1 H), 6.00
3
CN (2 mL) at room temperature. After
2
4
3
3
2
4
2% EtOAc/hexanes) to afford 5 mg (84%) of the title compound
as a white solid. Although this compound has been previously
reported,16 it has not been fully characterized: mp ) 119-120 °C;
f
1
1
hexanes); H NMR (500 MHz, CDCl
3
R
CDCl
f
) 0.30 (3% Et
3
N/5% EtOAc/hexanes); H NMR (500 MHz,
3
) δ 6.83 (s, 1 H), 6.62 (s, 1 H), 5.89 (AB
q
, J ) 1.5 Hz, ∆νAB
J. Org. Chem, Vol. 72, No. 11, 2007 4147

Pearson et al.
)
7.6 Hz, 2 H), 5.57 (s, 1 H), 3.54 (ddd, J ) 14.9, 12.7, 2.2 Hz,
H), 3.26 (dddd, J ) 14.9, 2.9, 2.9, 2.9 Hz, 1 H), 3.12 (ddd, J )
Acknowledgment. We thank the National Institutes of
Health (GM-52491) for financial support of this work and
Patrick Stoy for helpful discussions.
1
1
2
2
4.9, 12.9, 1.5 Hz, 1 H), 2.76-2.67 (m, 3 H), 2.53-2.44 (m, 2 H),
.32-2.24 (m, 1 H), 2.13-2.07 (m, 2 H), 1.88 (qdd, J ) 12.7,
13
.7, 1.5 Hz, 1 H), 1.67-1.45 (m, 3 H), 1.33-1.20 (m, 1 H);
C
Supporting Information Available: Table surveying deproto-
NMR (100 MHz, CDCl
3
) δ 145.4, 144.7, 142.6, 135.7, 135.4, 118.4,
nation of phenyl vinyl sulfide. General experimental methods.
1
1
12.4, 111.3, 100.8, 67.1, 50.1, 45.7, 37.6, 32.4, 28.0, 25.3, 23.2,
8.1; IR (CH Cl ) 1618, 1484, 1235, 1039 cm ; MS (EI, 70 eV)
2 2
1
13
Copies of H and/or C spectra of compounds without elemental
analysis. ORTEP plots and cif files for 40 and 69. This material is
available free of charge via the Internet at http://pubs.acs.org.
-
1
+
m/z (rel intensity) 283.2 [(M + H) , 30]; 254.1 (100), 148.1 (84);
HRMS (EI, 70 eV) calcd for C18
found 283.1574.
+
2
H21NO [(M + H) ] 283.1572,
JO0703799
4148 J. Org. Chem., Vol. 72, No. 11, 2007