Development of an enantioselective route toward the lycopodium alkaloids: Total synthesis of lycopodine

Article abstract of DOI:10.1021/jo100916x

(Figure presented) Synthesis of a C₁₅-desmethyl tricycle core of lycopodine has been accomplished. Key steps in the synthetic sequence include organocatalytic, intramolecular Michael addition of a keto sulfone and a tandem 1,3-sulfonyl shift/Mannich cyclization to construct the tricyclic core ring system. Synthetic work toward this natural product family led to the development of N-(p-dodecylphenylsulfonyl)-2-pyrrolidinecarboxamide, an organocatalyst which facilitiates enantioselective, intramolecular Michael additions. A detailed mechanistic discussion is provided for both the intramolecular Michael addition and the sulfone rearrangement. Finally, the application of these discoveries to the enantioselective total synthesis of alkaloid lycopodine is described.

Full text of DOI:10.1021/jo100916x

pubs.acs.org/joc
Development of an Enantioselective Route toward the Lycopodium
Alkaloids: Total Synthesis of Lycopodine
Hua Yang and Rich G. Carter*
Department of Chemistry, Oregon State University, 153 Gilbert Hall, Corvallis, Oregon 97331
rich.carter@oregonstate.edu
Received May 12, 2010
Synthesis of a C15-desmethyl tricycle core of lycopodine has been accomplished. Key steps in the
synthetic sequence include organocatalytic, intramolecular Michael addition of a keto sulfone and a
tandem 1,3-sulfonyl shift/Mannich cyclization to construct the tricyclic core ring system. Synthetic
work toward this natural product family led to the development of N-(p-dodecylphenylsulfonyl)-2-
pyrrolidinecarboxamide, an organocatalyst which facilitiates enantioselective, intramolecular Mi-
chael additions. A detailed mechanistic discussion is provided for both the intramolecular Michael
addition and the sulfone rearrangement. Finally, the application of these discoveries to the
enantioselective total synthesis of alkaloid lycopodine is described.
Introduction
anticholinesterase activity7 have been attributed to lycopo-
dine (1) and other lycopodium alkaloids. Chinese folk med-
icine has historically used species of the Lycopodium (s. l.)
(club mosses) for the treatment of muscle bruising, strains,
and swelling as well as schizophrenia.1 Recently, additional
excitement has been generated by the revelation that these
alkaloids have positive effects for learning and memory.1
In 2008, our laboratory reported a preliminary account of
the enantioselective total synthesis of lycopodine (1).8 Prior
to our work, seven racemic total syntheses (two formal
The Lycopodium alkaloids have garnered considerable
attention over the years because of their wide-ranging bio-
logical activity and structural complexity.1 There are four
major subclasses of Lycopodium alkaloids shown in Figure 1,
as defined by Gang:1b lycopodine (1), lycodine (2), fawcetti-
mine (3), and phlegmarine (4). Lycopodine (1) was isolated
€
2
125 years ago by Bodeker. Over 50 years later, Achmato-
wicz and Uzieblo assigned the correct molecular formula to
lycopodine as well as identified two additional alkaloids
present in Lycopodium clavatum L., clavatine and
clavatoxine.3 The final structure and stereochemistry was
determined by Ayer and Iverach in 1962.4 The absolute
configuration was later established by Rodgers and Haque.5
Beneficial medicinal properties such as antipyretic6 and
(8) For a preliminary account, see: Yang, H.; Carter, R. G.; Zakharov,
L. N. J. Am. Chem. Soc. 2008, 130, 9238–9239.
(9) (a) Stork, G.; Kretchmer, R. A.; Schlessinger, R. H. J. Am. Chem. Soc.
1968, 90, 1647–1648. (b) Ayer, W. A.; Bowman, W. R.; Joseph, T. C.; Smith,
P. J. Am. Chem. Soc. 1968, 90, 1648–1650. (c) Kim, S.; Bando, Y.; Horii, Z.
Tetrahedron Lett. 1978, 2293–2294. (d) Heathcock, C. H.; Kleinman, E. F.;
Binkly, E. S. J. Am. Chem. Soc. 1982, 104, 1054–1068. (e) Schumann, D.;
Mueller, H. J.; Naumann, A. Lebigs Ann. Chem. 1982, 1700–5. (f ) Kraus,
G. A.; Hon, Y. S. Heterocycles 1987, 25, 377–386. (g) Grieco, P. A.; Dai, Y.
J. Am. Chem. Soc. 1998, 120, 5128–5129. (h) For formal syntheses of
lycopodine, see: Padwa, A.; Brodney, M. A.; Marino, J. P., Jr.; Sheehan,
S. M. J. Org. Chem. 1997, 62, 78–87. (i) Mori, M.; Hori, K.; Akashi, M.; Hori,
M.; Sato, Y.; Nishida, M. Angew. Chem., Int. Ed. 1998, 37, 637–638. ( j) For
synthetic efforts towards lycopodine, see: Colvin, E. W.; Martin, J.; Parker,
W.; Raphael, R. A.; Shroot, B.; Doyle, M. J. Chem. Soc., Perkin Trans. 1
1972, 860–870. (k) Wenkert, E.; Broka, C. A. J. Chem. Soc., Chem. Commun.
1984, 714–715.
(1) (a) Kobayashi, J.; Morita, H. Alkaloids 2005, 61, 1–57. (b) Ma, X.;
Gang, D. R. Nat. Prod. Rep. 2004, 21, 752–772.
€
(2) Bodeker, K. Justus Liebigs Ann. Chem. 1881, 208, 363–367.
(3) Achmatowicsz, O.; Uzieblo, W. Rocz. Chem. 1938, 18, 88–95.
(4) Ayer, W. A.; Iverach, G. G. Tetrahedron Lett. 1962, 3, 87–92.
(5) (a) Rogers, D.; Quick, A.; Hague, M. Acta Crystallogr. 1974, B30,
552–553. Hague, M.; Rogers, D. J. Chem. Soc., Perkin Trans. 2 1975, 93–98.
(6) Nikonorow, M. Acta Polon. Pharm. 1939, 3, 23–56.
(7) Ortega, M. G.; Agnese, A. M.; Cabrera, J. L. Phytomedicine 2004, 11,
539–543.
DOI: 10.1021/jo100916x
r
Published on Web 06/29/2010
J. Org. Chem. 2010, 75, 4929–4938 4929
2010 American Chemical Society

Yang and Carter
SCHEME 1. Retrosynthetic Strategy for Lycopodine
JOCFeatured Article
FIGURE 1. Four major subclasses of the Lycopodium alkaloids.
racemic syntheses) of 1 had been reported.9 The Evans
laboratory recently reported an elegant total synthesis of a
similar alkaloid ring system (clavolonine).10 Additionally,
numerous other total syntheses of structural different Lyco-
podium alkaloids have been reported over the past decade
by Bosch,11 Chang,12 Comins,13 Dake,14 Johnston,15 Liao,16
Mukai,17 Overman,18 Sarpong,19 Siegel,20 Toste,21 Takahashi22,
and Takayama.23 Herein, we disclose a full account of our work
toward the alkaloid lycopodine.
thereby speeding up the key cyclization step. The imine 6
should in turn be accessible from an organocatalyzed, in-
tramolecular Michael addition of a keto sulfone moiety 8,
which in turn would be available from a cross-metathesis
with alkene 9.
Results and Discussion
Our synthetic approach to the lycopodine subclass is
shown in Scheme 1. Our first major disconnection was an
intramolecular Mannich cyclization to form the tricyclic core
5. Prior work by both Heathcock9d and Schumann9e has
exploited a related cyclization strategy. In Heathcock’s
work, they noted that the key Mannich cyclization step
required extended reaction times in most cases.9d We hypo-
thesized that the placement of an R-sulfonyl moiety at C8
should help to activate the imine to Mannich reaction,
Des-methyl Series. Key to this strategy was the successful
execution of the intramolecular Michael addition/Mannich
reaction sequence. As we were unsure as to the controlling
influence of the stereochemistry at C15, we felt it was prudent
to first explore a des-methyl keto sulfone series to test the
validity of this concept (Scheme 2). One observation that
became readily apparent to us was that the nature of R was
critical to the stereochemical outcome of the transformation.
If a small R group (RS) was used such as H, one would expect
the top pathway A to be favored.24 In contrast, if a larger R
group (RL) was present, one would expect the diastereo-
selectivity to switch in the conjugate addition on the basis of
the pioneering work by Stork.25 Interestingly, the primary
stereochemical difference between paths A and B resides in
the placement of the ketone in either the top or right-hand
ring. An organocatalyzed protocol would appear to be
ideally suited for this transformation; however, we are un-
aware of any direct examples for accomplishing this type of
enantioselective reaction.26 A somewhat related example by
Jørgensen had been reported using β-keto sulfones in a
tandem Michael/aldol organocatalyzed process.27
(10) Evans, D. A.; Scheerer, J. R. Angew. Chem., Int. Ed. 2005, 44, 6038–
42.
(11) Amat, M.; Griera, R.; Fabregat, R.; Bosch, J. Tetrahedron: Asym-
metry 2008, 19, 1233–1236.
(12) Sha, C.-K.; Lee, F.-K.; Chang, C.-J. J. Am. Chem. Soc. 1999, 121,
9875–9876.
(13) (a) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J. J. Org.
Chem. 1999, 64, 2184–2185. (b) Comins, D. L.; Brooks, C. A.; Al-awar, R. S.;
Goehring, R. R. Org. Lett. 1999, 1, 229–231.
(14) Linghu, X.; Kennedy-Smith, J.-J.; Toste, F. D. Angew. Chem., Int.
Ed. 2007, 46, 7671–7673.
(15) Chandra, A.; Pigza, J. A.; Han, J-.S.; Mutnick, D.; Johnston, J. N.
J. Am. Chem. Soc. 2009, 131, 3470–3471.
(16) Yen, C.-F.; Liao, C.-C. Angew. Chem., Int. Ed. 2002, 41, 4090–4093.
(17) Kozaka, T.; Miyakoshi, N.; Mukai, C. J. Org. Chem. 2007, 72,
10147–10154.
(18) Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M. J.
Am. Chem. Soc. 2008, 130, 11297–11299.
(19) (a) Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130,
7222–7223. (b) West, S. P.; Bisai, A.; Lim, A. D.; Narayan, R. R.; Sarpong,
R. J. Am. Chem. Soc. 2009, 131, 11187–11194. (c) Fischer, D. F.; Sarpong, R.
J. Am. Chem. Soc. 2010, 132, 5926–5927.
We first set out to probe the nature of the diastereoselec-
tivity in the key intramolecular Michael addition reaction
racemically (Scheme 3). The sulfone 18 was prepared in a
(20) Yuan, C.; Chang, C.-T.; Axelrod, A.; Siegel, D. J. Am. Chem. Soc.
2010, 132, 5924–5925.
(21) Kozak, J. A.; Dake, G. R. Angew. Chem., Int. Ed. 2008, 47, 4221–
4223.
(24) For an example, see: Grossman, R. B.; Pendharkar, D. S.; Patrick,
B. O. J. Org. Chem. 1999, 64, 7178–7183.
(22) Ishizaki, M.; Niimi, Y.; Hoshino, O.; Hara, H.; Takahashi, T.
Tetrahedron 2005, 61, 4053–4065.
(25) Stork, G.; Winkler, J. D.; Saccomano, N. A. Tetrahedron Lett. 1983,
24, 465–468.
(26) For a recent review of organocatalysis on sulfone substrates, see:
(23) (a) Katakawa, K.; Kitajima, M.; Aimi, N.; Seki, H.; Yamaguchi, K.;
Furihata, K.; Harayama, T.; Takayama, H. J. Org. Chem. 2005, 70, 658–663.
(b) Shigeyama, T.; Katakawa, K.; Kogure, N.; Kitajima, M.; Takayama, H.
Org. Lett. 2007, 9, 4069–4072. (c) Nishikawa, Y.; Kitajima, M.; Takayama,
H. Org. Lett. 2008, 10, 1987–1990.
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Alba, A.-N. R.; Companyo, X.; Rios, R. Chem. Soc. Rev. 2010, 39, 2018-
2033.
(27) Pulkkinen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv.
Synth. Catal. 2004, 346, 1077–1080.
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JOCFeatured Article
SCHEME 2. Key Michael/Mannich Sequence
SCHEME 3. Development of Racemic Protocol for Intramole-
cular, Keto Sulfone Michael Addition
the presence of an azide functionality (potential Staudinger
reduction by phosphine ligands from the transition metal
catalyst) and an internal nucleophile (keto sulfone) for the
electrophilic enone formed in the reaction. Consequently, we
screened a range of catalysts for this transformation and CM
partners. Both first- and second-generation Grubbs catalysts
were ineffective. Fortunately, second-generation Grubbs-
Hoveyda proved useful in this transformation. We also dis-
covered that the nature of the CM partner was also impor-
tant.29 Pentenone 22 proved more effective than MVK, gen-
erally leading to a 15-20% increase in chemical yield. One
possible explanation is that the increased steric hindrance
imparted by the β-methyl group on the enone 22 (as compared
to MVK) reduced the rate of deleterious side reactions. For the
key intramolecular Michael addition of 24, we initially tested
hydride (e.g., NaH, PhH) and alkoxide (e.g., Cs2CO3, EtOH)
conditions as they had proven effective in prior intramolecular
Michael additions with the desired relative configuration by
Stork25 and Evans.10 In both cases, we appeared to observe
overreaction to provide a product derived from attack of the
resultant methyl ketone (after conjugate addition) by an en-
olate at C14. Even more disheartening, the cyclization occurred
with the undesired C7,8 cis relationship in the initial Michael
addition. Fortunately, treatment of the keto sulfone 24 with
diisopropylamine [IPA/CH2Cl2 (1:1), rt, 76 h, 84%] cleanly
induced Michael addition to generate the desired C7,8 trans
diastereomer rac-25 (Table 1, entry 1). The stereochemical
outcome of this transformation was confirmed by X-ray
crystallographic analysis. The nature of the enolate geometry
is likely key in controlling the stereochemical outcome of the
Michael addition.10,25
With a working route to a diastereoselective, intramole-
cular Michael addition, we moved on to the enantioselective
variant of this transformation (Table 1). We hypothesized
that optimum levels of enantioselectivity would be best
obtained in nonpolar, chlorinated solvents. We initially
screened proline (26) but observed no reaction in CHCl3
(entry a). Sluggish reaction could be observed in more polar
media (e.g., DMSO), but the level of enantioselectivity was
minimal (<20% ee). It should be noted that extensive
attempts to use chiral HPLC to achieve chromatographic
separation of the enantiomers of 25 in order to obtain the
level of enantioselectivity from these reactions proved un-
successful. Fortunately, chiral shift reagent Eu(hfc)3 was able
to provide meaningful separation for analysis by NMR.30
one-pot procedure from dibromide 17. While this transfor-
mation could be conducted in two separate steps, the proce-
dural ease and the low cost of starting materials made this
one-pot approach more advantageous. Initially, we employed
a Julia coupling strategy followed by oxidation to access the
desired keto sulfone 21. This approach worked modestly well;
however, aldehyde 19 was not commercially available, and its
volatility during preparation hindered its practicality. Ulti-
mately, we found that the direct sulfone/ester coupling route
proved more effective. The choice of base for the sulfone/ester
coupling was key to the reaction yield; lithium tetramethylpi-
peridine (LiTMP) provided significantly higher yields than
LDA or n-BuLi. Our group has previously observed the diver-
gent behavior of different lithium bases in Julia couplings.28
The cross-metathesis (CM) step between 21 and an enone (e.g.,
methyl vinyl ketone (MVK) or pentenone 22) is also worthy of
additional comment. This transformation is challenging due to
(29) Carlson, E. C.; Rathbone, L. K.; Yang, H.; Collett, N. D.; Carter,
R. G. J. Org. Chem. 2008, 73, 5155–5158.
(28) Zhou, X.-T.; Carter, R. G. Angew. Chem., Int. Ed. 2006, 45, 1787–1790.
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TABLE 1. Optimization of Conditions for Enantioselective, Organocatalyzed Intramolecular Michael Addition
entry
catalyst
additive
conditionsa
% eeb (% yield)
a
b
c
d
e
f
g
h
i
26 (20 mol %)
27 (20 mol %)
27 (20 mol %)
27 (20 mol %)
27 (20 mol %)
28 (20 mol %)
29 (20 mol %)
30 (20 mol %)
31 (20 mol %)
31 (10 mol %)
CHCl3c, rt, 3 d
no reaction
no reaction
CHCl3c, rt, 3 d
piperidine (1 equiv)
piperidine (1 equiv)
CHCl3c, rt, 16 h
33% ee (82%)
42% ee (60%)
57% ee (72%)
64% ee (63%)
64% ee (73%)
53% ee (75%)
59% ee (71%)
88% ee (75%)
ClCH2CH2Cl, rt, 3 d
ClCH2CH2Cl, rt, 16 h
ClCH2CH2Cl, rt, 16 h
ClCH2CH2Cl, rt, 16 h
ClCH2CH2Cl, rt, 16 h
ClCH2CH2Cl, rt, 16 h
ClCH2CH2Cl (0.2 M), -20 °C, 72 h
piperidine (1 equiv), 1% EtOH
piperidine (1 equiv), 1% EtOH
piperidine (1 equiv), 1% EtOH
piperidine (1 equiv), 1% EtOH
piperidine (1 equiv), 1% EtOH
Piperidine (1 equiv.),1% EtOH
j
aThe reaction was performed at 0.1 M concentration of substrate unless otherwise noted. bThe enantiomeric excess was determined by chiral shift
NMR [50% Eu(hfc)3, C6D6]. cCommercial CHCl3 stabilized with 1% EtOH was used without further purification.
With a valid method for ascertaining the ee of the reaction, we
next screened the tetrazole catalyst 2731 which has also shown
enhanced activity compared to proline (24), particularly in
CHCl3. Interestingly, we again observed no reaction after 3 d
at room temperature (Entry b). Ley and co-workers have
recently shown that the addition of a stoichiometric secondary
amine base can affect the rate and enantioselectivity.32 We
were gratified to find that addition of piperidine (Entry c)
facilitated the desired transformation with a reasonable rate
(16 h), albeit with a modest enantioselectivity (33% ee). It is
important to note that the background reaction (piperidine,
CHCl3, rt) gave no product formation, even after prolonged
exposure to the reaction conditions. Use of ClCH2CH2Cl as
solvent led to a decrease in reaction rate but an increase in
enantiomeric excess (entry d). It turned out that the choice of
CHCl3 was quite fortuitous as 1% EtOH is typically added
commercially as a stabilizing agent for this solvent. This
additive turned out to be critical in our hands: use of 1%
EtOH in ClCH2CH2Cl gave a dramatic increase in rate and
enantioselectivity (entry e). We next explored the use of proline
sulfonamides as potential organocatalysts. While these ligands
have shown promise in certain organocatalyzed reactions,33
they have proven problematic in facilitating Michael addition
processes.33c We were gratified to find that these catalysts
performed well in our hands, providing improved enantio-
meric excess (ee) at room temperature (entries f-h). While
these sulfonamides 28-30 proved more soluble than the
analogous tetrazole 27, solubility at lower temperatures con-
tinued to be problematic. Other catalysts such as those devel-
oped by Jørgenson27 and MacMillian34 proved ineffective. We
also screened diphenylprolinol35 in this transformation with-
out success. Ultimately, we found that the previously unknown
sulfonamide derivative 31 gave greatly improved solubility
properties and continued high levels of enantiomeric excess
(entries i and j). This sulfonamide 31 is readily accessible from
the commercially available p-dodecylsulfonyl chloride (32)36,37
and Cbz-protected proline 34 in three steps (Scheme 4). We
have prepared over 100 mmol of this catalyst 31 through this
procedure. Our laboratory has gone on to show that this
catalyst is effective at facilitating a range of transformations
in high enantioselectivity.38 Cooling the reaction to -20 °C
with 10 mol % catalyst loading gave the optimum results
(Table 1, entry j). The absolute configuration of keto sulfone
(30) For a recent review of ee determination using NMR methods, see:
Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–118.
(31) (a) Cobb, A. J. A.; Shaw, D. M.; Ley, S. V. Synlett 2004, 558–560. (b)
Hartikka, A.; Arvidsson, P. I. Tetrahedron: Asymmetry 2004, 15, 1831–1834.
(c) Torii, H.; Nakadai, N.; Ishihara, K.; Saito, S.; Yamamoto, H. Angew.
Chem., Int. Ed. 2004, 43, 1983–1986. (d) Knudsen, K. R.; Mitchell, C. E. T.;
Ley, S. V. Chem. Commun. 2006, 66–68. (e) For a recent review, see:
Longbottom, D. A.; Franckevicius, V.; Kumarn, S.; Oelke, A. J.; Wascholowski,
V.; Ley, S. V. Aldrichim. Acta 2008, 41, 3–11.
(32) Mitchell, C. E. T.; Brenner, S. E.; Garcıa-Fortanet, J.; Ley, S. V. Org.
Biomol. Chem. 2006, 4, 2039–2049.
(33) (a) Berkessel, A.; Koch, B.; Lex, J. Adv. Synth. Catal. 2004, 346,
1141–1146. (b) Dahlin, N.; Bøegevig, A.; Adolfsson, H. Adv. Synth. Catal.
2004, 346, 1101–1105. (c) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.;
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Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84–96. (d) Sunden, H.;
Dahlin, N.; Ibrahem, I.; Adolfsson, H.; Cordova, A. Tetrahedron Lett. 2005,
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(34) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan, D. M. C. J. Am.
Chem. Soc. 2005, 127, 15051–15053.
(35) Kobahashi, S.; Ogawa, C.; Kawamura, M.; Sugiura, M. Synlett
2001, 983–985.
(36) Wako Chemicals catalog no. 040-19872.
(37) Compound 32 is sold as a mixture of isomers on the C12H25 alkyl
chain. No attempt was made to separate the isomers in this sequence, and the
isomeric mixture does not appear to adversely affect the reactivity.
(38) (a) Yang, H.; Carter, R. G. Org. Lett. 2008, 10, 4649–4652. (b) Yang, H.;
Carter, R. G. J. Org. Chem. 2009, 74, 2246–2249. (c) Yang, H.; Carter, R. G.
J. Org. Chem. 2009, 74, 5151–5156. (d) Yang, H.; Carter, R. G. Tetrahedron 2010,
66, 4854-4859. (e) Yang, H.; Carter, R. G. Org. Lett. 2010, 12, 3108-3111.
46, 3385–3389. (e) Bellis, E.; Vasiatou, K.; Kokotos, G. Synthesis 2005, 2407–
13. (f ) Wu, Y.; Zhang, Y.; Yu, M.; Zhao, G.; Wang, S. Org. Lett. 2006, 8,
4417–4420. (g) Silva, F.; Sawicki, M.; Gouverneur, V. Org. Lett. 2006, 8,
5417–19. (h) Vogt, H.; Baumann, T.; Nieger, M.; Braese, S. Eur. J. Org.
Chem. 2006, 2006, 5315–5338. (i) Hayashi, Y.; Sumiya, T.; Takahashi, J.;
Gotoh, H.; Urushima, T.; Shoji, M. Angew. Chem., Int. Ed. 2006, 45, 958–
961. ( j) Aratake, S.; Itoh, T.; Okano, T.; Nagae, N.; Sumiya, T.; Shoji, M.;
Hayashi, Y. Chem.;Eur. J. 2007, 13, 10246–10256. (k) Huang, J.; Zhang, X.;
Armstrong, D. W. Angew. Chem., Int. Ed. 2007, 46, 9073–9077. (l) Wang,
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4932 J. Org. Chem. Vol. 75, No. 15, 2010

Yang and Carter
JOCFeatured Article
SCHEME 4. Synthesis of Novel Sulfonamide 31
TABLE 2. Exploration of Scope for Enantioselective, Organocatalyzed
Intramolecular Michael Addition
entry
n
R (reaction time)
% eea (% yield, dr)
a
b
c
d
e
2
2
2
2
1
CH2CH2CH2N3 (72 h)
Me (5 d)
CH2CH2OTBS (72 h)
CH2Ph (72 h)
Me (6 d)
88% ee (75%, 20:1 dr)
83% ee (80%, 20:1 dr)
83% ee (76%, 20:1 dr)
81% ee (89%, 20:1 dr)
84% ee (58%, 20:1 dr)
SCHEME 5. Enantioselective Synthesis of the Lycopodine
Tricyclic Core 37
aThe enantiomeric excess was determined by chiral shift NMR [50%
Eu(hfc)3, C6D6].
SCHEME 6. Synthesis of the Key Enone Intermediate
25 was conclusively established via X-ray crystallographic
analysis.39 Resubmission of the highly enantioenriched pro-
duct 25 (88% ee) to conditions which provided reduced
enantioselectivity (e.g., 10 mol % of 31, rt, 16 h) did not result
in any erosion in enantioselectivity. This experiment indicates
that the reaction is likely not operating under reversible
conditions. Note that the product 25 from this reaction is
enantiomeric to the natural series of lycopodine.
Application of this technology to the tricyclic core of
lycopodine is shown in Scheme 5. Use of the enantiomeric
catalyst ent-31 gave comparable results (71% yield, 88% ee).
A single recrystallization provided material ent-25 that was
enantiomerically pure (>95% ee, 60-65% yield). This series
was required for the synthesis of the correct enantiomer of
lycopodine. Subsequent Staudinger reduction with in situ
imine generation followed by silyl enol ether formation
provided the cyclization precursor 36. Treatment of enol
ether 36 with Zn(OTf )2 cleanly generated a cyclization
product which was ultimately established to be the rear-
ranged tricyclic product 37 via X-ray crystallographic anal-
ysis (Supporting Information).40 Interestingly, none of the
expected tricycle 37a was observed under the reaction con-
ditions. Product 37 is the result of a net 1,3-rearrangement of
the sulfone moiety from the expected C8 position to the C14
position. Padwa and several other researchers have reported
limited examples of 1,3-rearrangements of allylic sulfones;41
however, we believe this is the first example of an R-sulfonyl
imine undergoing such a shift. A detailed discussion of a
possible mechanistic explanation for this transformation is
provided later in this manuscript.
We also briefly explored the scope of our novel organo-
catalyzed, intramolecular Michael reaction (Table 2). It is
important to emphasize that this type of intramolecular, keto
sulfone Michael addition has not been previously reported
using organocatalysis prior to our work (entry a). We were
pleased to observe good tolerance of different moieties on the
keto sulfone side arm. The level of diastereoselectivity in each
case was excellent (20:1 dr). Additionally, reasonable enan-
tioselectivities were observed (81-88% ee). Finally, the
(39) This crystal structure was determined using the ent-31 catalyst
derived from D-proline. CCDC-663,290 (ent-25) contains the supplementary
crystallographic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
(40) CCDC-663,289 (37) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
(41) (a) Padwa, A.; Bullock, W. H.; Dyszlewski, A. D. Tetrahedron Lett.
1987, 28, 3193–3196. (b) Ogura, K.; Iihama, T.; Kiuchi, S.; Kajiki, T.;
Koshikawa, O.; Takahashi, K.; Iida, H. J. Org. Chem. 1986, 51, 700–705.
(c) Lin, P.; Whitman, G. H. J. Chem. Soc., Chem. Commun. 1983, 1102–1103.
(d) Baechler, R. D.; Bentley, P.; Deuring, L.; Fisk, S. Tetrahedron Lett. 1982,
23, 2269–2272. (e) For palladium-catalyzed methods, see: Jagusch, T.; Gais,
H.-J.; Bondarev, O. J. Org. Chem. 2004, 69, 2731–2736. and references cited
therein.
J. Org. Chem. Vol. 75, No. 15, 2010 4933

Yang and Carter
JOCFeatured Article
SCHEME 7. Possible Mechanistic Pathway for Diastereoselective Michael Addition
cyclization could be extended to the analogous 5-membered
series (entry e) with good success (58% yield, 84% ee).42
Application to Total Synthesis of Lycopodine. With the
basis for the tricycle formation established, we sought to
apply this approach to the total synthesis of lycopodine. Syn-
thesis of the C15 methyl series is outlined in Scheme 6. The
sulfone component 18 was dilithiated with LiTMP, and the
known ester 4243 was added to the solution to generate after
workup the keto sulfone 44 in good yield (74%) as an incon-
sequential mixture of diastereomers at C8. Cross-metathesis
using second-generation Grubbs-Hoveyda provided the
desired enone 8.44
We next set out to explore the key intramolecular keto
sulfone Michael addition (Scheme 7). Initial inspection of the
stereochemistry required in this cyclization would indicate
that at least two substituents must be placed axial in a chair
transition state. This observation leads to two possible chair
transition states 45 and 46, which would generate the desired
stereochemistry. The immediate products from these two
pathways would be interconvertable chair conformations of
each other. We were concerned that a third chair transition
state 47, which places the maximum number of substituents
in the equatorial position, might prove to be the preferred
reaction pathway. One possible destabilizing force in this third
transition state would be disruptive 1,2-diequatorial steric
interactions. While 1,2-diequatorial substitution on cyclohex-
anes is normally viewed as the thermodynamically more stable
conformation, large substituents in both those positions can
complicate the preferences.45 An alternative explanation would
invoke a stabilizing hydrogen-bonding interaction between the
methyl ketone and an enol derived from the keto sufone in
SCHEME 8. Diastereoselective Michael Addition of 8
transition state 45. A similar stabilizing interaction does not
appear to be accessible in alternative pathways 46 and 47.
The cyclization of enone 8 is detailed in Scheme 8. In order
to probe the exact nature of this cyclization, we first con-
ducted the experiment using a simple (achiral) secondary
catalyst, diispropylamine. This amine was selected in part
due to the steric hindrance imparted by the two isopropyl
moieties attached to the nitrogen. We had previously utilized
this system on the desmethyl series 24 (Scheme 3). We were
gratified to discover that a single stereoisomer had arisen
from these reaction conditions. Through X-ray crystallo-
graphic analysis, we were able to determine that the desired
stereochemistry 7 from this transformation had been
formed.46 Interestingly, the chair conformation 7a observed
in the crystallographic analysis was the one that placed the
sulfone and methyl ketone moieties in the axial position and
the C15 methyl moiety in the equatorial position. This
crystallographic data would appear to indicate that the 1,2-
steric interaction between these two substituents is mini-
mized in conformation 7a as compared to chair conforma-
tion 7b. Furthermore, this data would appear to support
transition state 45 as the favored pathway.47 The amine
(42) Absolute and relative configuration of product 39e were assigned
based on analogy to the 6-membered series.
(46) The CIF containing the supplementary crystallographic data for
compound 7 has been previously reported. These data can be obtained free of
charge from the American Chemical Society via http://pubs.acs.org/doi/
suppl/10.1021/ja803613w/suppl_file/ja803613w-file006.cif.
(47) Attempts to switch the diastereoselectivity of this reaction through
the use of sulfonamide catalyst 31 conditions led to a formation the same
diastereomer 7; however, use of enantiomeric sulfamide catalyst ent-31 gave
what we have tentatively assigned as the alternate trans-disatereomer 48 in
modest diastereosectivity (1.5:1 dr).
(43) (a) Boulet, S. L.; Paquette, L. A. Synthesis 2002, 895–900. (b)
Lipshutz, B. H.; Hackmann, C. J. Org. Chem. 1994, 59, 7437–7444.
(44) It should be noted that the C15 methyl series appears to perform
slightly better in the CM than the desmethyl series. We are unsure as to the
exact explanation for that difference.
(45) (a) Golan, O.; Goren, Z.; Biali, S. E. J. Am. Chem. Soc. 1990, 112,
9300–9307. (b) Weiser, J.; Golan, O.; Fitjer, L.; Biali, S. E. J. Org. Chem.
1996, 61, 8277–8284.
4934 J. Org. Chem. Vol. 75, No. 15, 2010

Yang and Carter
JOCFeatured Article
SCHEME 9. Enantioselective Total Synthesis of Lycopodine
be noted that the C15 methyl series does require slightly
higher reaction temperatures (96 °C) to proceed effectively.
Subsequent desulfurization of tricycle 49 using Na/Hg
amalgam provided the intermediate 50. This amine 50 was
converted into lycopodine (1) in three chemical transfor-
mations.8 Comparison of the literature values for lycopodine
(1H, 13C NMR, [R]D)9f,49,50 as well as an authentic sample
provided by Heathcock matched nicely with the synthesized
material. Because of the basicity of lycopodine’s nitrogen,
care must be taken to remove any extraneous DCl present in
the CDCl3 (e.g., base washing solvent with basic alumina,
avoiding exposure to light).
Probe of Mechanism for Tandem Sulfone Rearrangement/
Mannich Cyclization. The mechanism for the key Mannich
cyclization to form the tricyclic core of lycopodine is worthy
of additional discussion. A possible explanation for this
transformation is outlined in Scheme 10. After initial com-
plexation of the imine nitrogen, complex 54 likely tauto-
merizes to metallo-enamine 55. We believe that it is this
intermediate which undergoes a net 1,3-transposition of the
sulfonyl moiety to C14. This rearrangement could occur via
several possible pathways: (a)/(b) heterolytic cleavage of the
C-S bond to a tight ion pair or homolytic cleavage followed
by recombination at C14 to arise as the axial sulfone 56, (c)
2,3-sigmatropic rearrangement to the sulfinate ester fol-
lowed by reorganization to the sulfone 5651 or (d) forma-
tion of an intermediate 1,1-dioxothietane followed by ring-
opening. Diastereoselective protonation of the enamine and
epimerzation at C14 would generate the penultimate inter-
mediate 57 which can undergo intramolecular Mannich
cyclization to yield the tricycles 37 or 49. This net 1,3-shift
of the phenyl sulfone moiety may facilitate a more reactive
intermediate for the key Mannich cyclization.
In order to probe what possible pathway is facilitating the
net 1,3-transposition, we have conducted a series of experi-
ments (Scheme 11). Exclusion of light from the reaction
appears to have no impact on the product formation (eq 1).
Photolysis of the imino-sulfone 6 at room temperature does
not appear to induce the 1,3-shift (eq 2). Most interestingly,
submission of ketone 58 to the reaction conditions does not
appear to lead to the formation of any new compounds (eq 3).
This experiment seems to imply that the rearrangement is
reversible and that the Mannich cyclization drives the reaction
to completion. In order to probe a possible crossover process
with a sulfonate anion, compound 6 was treated under the
standard cyclization but in the presence of NaSO2-p-tol.
Unfortunately, this experiment only led to complex mixture
of products. Ion exchange with Zn(OTf )2 likely generates a
catalyst which is less effective at facilitating the transforma-
tion. Interestingly, when the reaction was performed under the
standard conditions but in the presence of the radical initiator
TEMPO, an alternate product was observed (eq 5). This
product corresponds to the Mannich cyclization product 5
without 1,3-migration of the sulfone moiety. Conversion of 5
additive could participate in the transformation through one
or more ways: (a) enamine formation with the keto sulfone
moiety, (b) deprotonation of the keto sulfone to generate an
enolate, and/or (c) iminium ion activiation of the methyl
ketone. While not depicted in Scheme 8, enamine formation
might explain the high level of diastereoselectivity (syn/anti
between C7-C8) through strong E selectivity in the enamine,
likely due to steric hindrance of the isopropyl groups on
nitrogen. Stork showed that enolate geometry is often corre-
lated to syn/anti selectivity, although it is important to note
that Stork’s cases required aprotic media to obtain good
levels of diastereoselectivity.25 If iminium ion activiation of
the methyl ketone occurs, the increased steric bulk of the
iminium ion would likely aid in favoring transition state 45.
The completion of the total synthesis of lycopodine is
detailed in in Scheme 9. Staudinger reduction and TBS enol
ether formation generated the cyclization precursor 6. As
demonstrated in the desmethyl series, treatment with Zn-
(OTf )2 in DCE at elevated temperatures in a sealed tube
induced the tandem 1,3-sulfone rearrangement and intra-
molecular Mannich cyclization to yield amine 49.48 It should
(49) Nakashima, T. T.; Singer, P. P.; Browne, L. M.; Ayer, W. A. Can. J.
Chem. 1975, 53, 1936–1942.
(50) Douglas, B.; Lewis, D. G.; Marion, L. Can. J. Chem. 1953, 31, 272–
276.
(51) One example of such a [2,3]-sigmatropic rearrangement has been
reported: (a) Hatanaka, N.; Ozaki, O.; Matsumoto, M. Tetrahedron Lett.
1986, 27, 3169–3172. See also: (b) Knight, D. J.; Whitman, G. H.; Williams,
J. G. J. Chem. Soc., Perkin Trans. 1 1987, 2149–2152. (c) Ball, D. B.;
Hernandez, L. S. 232nd ACS National Meeting, San Francisco 2006, CHED-329.
(48) The CIF containing the supplementary crystallographic data for
compound 49 has been previously reported. These data can be obtained free
of charge from the American Chemical Society via http://pubs.acs.org/doi/
suppl/10.1021/ja803613w/suppl_file/ja803613w-file007.cif.
J. Org. Chem. Vol. 75, No. 15, 2010 4935

Yang and Carter
JOCFeatured Article
SCHEME 10. Possible Mechanistic Pathway for Tricycle Formation
SCHEME 11. Probing the Mechanistic Pathway for Sulfone
Rearrangement/Mannich Cyclization
involving imines have been documented.52-54 Magnus utilized
TEMPO and hypervalent iodine reagents to functionalize the
allylic position of silyl enol ethers.55 Renaud and Studer
recently demonstrated the TEMPO-mediated oxidation of
catecholboron enolates which is proposed to go through a
radical intermediate.56 As a complement to TEMPO experi-
ment, a radical inhibitor was added to the standard cyclization
conditions, but only complex mixture of products was ob-
tained (eq 6).57
Conclusion
The first enantioselective synthesis of lycopodine has been
accomplished. Key steps include an organocatalyzed, intra-
molecular Michael addition of keto sulfone 8 and a tandem
1,3-sulfonyl shift/intramolecular Mannich reaction. Ex-
ploration of the mechanism for the tandem sulfonyl shift/
Mannich sequence revealed an alternative reaction pathway
which generated C8-sulfonyl product 5. Additionally, a novel
proline-based sulfonamide organocatalyst 31 has been de-
veloped. The utility of catalyst 31 at facilitating enantio-
selective, intramolecular Michael additions has been demon-
strated.
Experimental Section
Sulfonamide 33. To a solution of p-dodecylbenzenesulfonyl
chloride (32) (48.7 g, 150 mmol) in CHCl3 (1.5 L) was NH4OH
(313 mL, 78.9 g, 2.25 mol) at rt. After being stirred vigorously for
4 h, the reaction mixture was extracted with CHCl3 (2 ꢀ 300 mL).
(53) (a) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran,
E. N. Org. Lett. 2001, 3, 1009–1011. (b) Prabhakaran, E. N.; Nugent, B. M.;
Williams, A. L.; Nailor, K. E.; Johnston, J. N. Org. Lett. 2002, 4, 4197–4200.
(c) Viswanathan, R.; Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N. J. Am.
Chem. Soc. 2003, 125, 163-EOA. (d) Nugent, B. M.; Williams, A. L.; Prabhakaran,
E. N.; Johnston, J. N. Tetrahedron 2003, 59, 8877–8888. (e) Srinivasan, J. M.;
Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston, J. N. Synthesis 2005,
330–333.
(54) Miyabe, H.; Yamaoka, Y.; Takemoto, Y. J. Org. Chem. 2006, 71,
2099–2106.
to tricycle 50 (Na/Hg, Na2HPO4, MeOH, THF, -10 °C, 45%)
provided additional evidence for the structural assignment.
TEMPO appears to initiate a secondary reaction pathway for
the cyclization. It should be noted that radical cyclizations
(55) (a) Magnus, P.; Roe, M. B.; Hulme, C. J. Chem. Soc., Chem.
Commun. 1995, 263–265. (b) Magnus, P.; Lacour, J.; Evans, P. A.; Roe,
M. B.; Hulme, C. J. Am. Chem. Soc. 1996, 118, 3406–3418.
(56) Pouliot, M.; Renaud, P.; Schenk, K.; Studer, A.; Vogler, T. Angew.
Chem., Int. Ed. 2009, 48, 6037–6040.
(57) Preparation of LiTMP: To a solution of 2,2,6,6-tetramethylpiper-
idine (283 mg, 340 μL, 2.0 mmol) in THF (0.86 mL) was added n-BuLi (0.8
mL, 2.0 mmol, 2.5 M in hexanes). The reaction was warmed to -10 °C and
stirred for 30 min prior to use.
(52) For a recent review, see: Pastori, N.; Gambarotti, C.; Punta, C. Mini-
Rev. Org. Chem. 2009, 6, 184–195.
4936 J. Org. Chem. Vol. 75, No. 15, 2010

Yang and Carter
JOCFeatured Article
The organic layer was dried over MgSO4 and concentrated
under reduced pressure to give the product 33 (47.8 g, 147 mmol,
98%). Compound 32 is sold as a mixture of isomers on the C12H25
alkyl chain. No attempt was made to separate the isomers in this
sequence, and the isomeric mixture does not appear to adversely
affect the reactivity: 1H NMR (400 MHz, CDCl3) 7.86-7.88 (m,
CDCl3) δ 7.82-7.84 (m, 2H), 7.69-7.72 (m, 1H), 7.56-7.60 (m,
2H), 3.48 (tq, J = 10.8, 2.0 Hz, 1H), 3.20-3.40 (m, 3H), 2.89 (dt,
J = 15.2, 7.2 Hz, 1H), 2.53 (dd, J = 17.6, 10.8 Hz, 1H), 2.41 (dt,
J = 15.2, 7.2 Hz, 1H), 2.26 (s, 3H), 1.85-2.18 (m, 5H), 1.57-1.69
(m, 2H), 1.38-1.47 (m, 1H);13C NMR (100 MHz, CDCl3) δ206.0,
205.8, 135.9, 134.3, 130.6, 128.8, 78.9, 51.5, 44.6, 39.4, 35.0, 30.5,
27.6, 27.1, 24.5, 21.5; HRMS (FABþ) calcd for C18H24N3O4S (M
þ H) 378.1488, found 378.1497.
2H), 7.29-7.35 (m, 2H), 5.03 (s, 2H), 0.78-1.68 (m, 25H); 13
C
NMR (100 MHz, CDCl3) δ 139.2, 128.4, 127.8, 126.5, 47.9, 46.1,
40.0, 38.1, 36.7, 31.9, 29.7, 29.5, 29.2, 27.5, 22.7, 14.1.
Determination of the Enantiomeric Excess. Product 25 (3 mg)
in C6D6 (0.55 mL) with 40 mol % (þ)-Eu(hfc)3 (3.8 mg) at
400 MHz. The 1H NMR difference of R-methylene protons
(doublet at 3.31 ppm) on C6 for two enantiomers is 18.8 Hz. The
enantiomeric excess can be obtained on the basis of the calcula-
tion of ratio for two sets of doublets.
Cbz-sulfonamide 35. To a solution of (Z)-L-proline 34 (36.6 g,
147 mmol) in CH2Cl2 (735 mL) were added sulfonamide 33
(47.8 g, 147 mmol), DMAP (3.71 g, 30.4 mmol), and EDCI
(28.2 g, 147 mmol) respectively. The reaction mixture was stirred
at room temperature for 72 h before being partitioned between
EtOAc (500 mL) and aq HCl (200 mL, 1 N). The organic layer
was washed with half-saturated brine (2 ꢀ 300 mL). The dried
(Na2SO4) extract was concentrated in vacuo and purified by
chromatography over silica gel, eluting with 10% EtOAc/
CH2Cl2, to give 35 (76.1 g, 137 mmol, 93%) as a colorless liquid.
Compound 35 is a mixture of isomers on the C12H25 alkyl
chain. No attempt was made to separate the isomers in this
sequence and the isomeric mixture does not appear to adversely
affect the reactivity: [R]23D = þ90 (c = 2.2, CHCl3); IR (neat)
3148, 2955, 2925, 2856, 1720, 1677, 1449, 1411, 1355, 1174, 1131,
Cyclohexanone 39b. To a solution of 38b (25 mg, 0.0812
mmol) in EtOH/DCE (1:99, 0.4 mL) were added sulfonamide
31 (3.4 mg, 0.00812 mmol) and piperidine (6.9 mg, 8 μL, 0.0812
mmol) at -20 °C. After being stirred at the same temperature for
72 h, the reaction was loaded directly onto silica gel and was
purified by chromatography, eluting with 10-30% EtOAc/
hexanes, to give the product 39b (20 mg, 0.0649 mmol, 80%,
82% ee) as colorless oil: [R]23D = þ63.3 (c = 1.3, CHCl3); IR
(neat) 2949, 2884, 1713, 1446, 1375, 1310, 1364, 1141, 1108,
1
1075, 972, 754, 721, 629 cm-1; H NMR (400 MHz, C6D6) δ
1
1088, 826, 692 cm-1; H NMR (300 MHz, CDCl3) 10.4 (br s,
7.84-7.86 (m, 2H), 7.00-7.09 (m, 3H), 3.84-3.90 (m, 1H), 3.15
(dt, J = 14.4, 9.6 Hz, 1H), 2.87 (dd, J = 17.2, 3.2 Hz, 1H),
2.18-2.32 (m, 2H), 1.34-1.87 (m, 6H), 2.15 (s, 3H), 0.94-1.02
(m, 1H); 13C NMR (100 MHz, C6D6) δ 205.1, 204.2, 136.4,
133.5, 130.4, 128.4, 75.9, 44.7, 38.2, 34.8, 29.4, 26.0, 20.9, 15.2;
HRMS (EIþ) calcd for C16H20O4S (Mþ) 308.1082, found
308.1078.
1H), 7.93-7.95 (m, 2H), 7.26-7.40 (m, 7H), 5.23 (s, 2H), 4.31
(br s, 1H), 3.42 (m, 2H), 2.45-2.57 (m, 1H), 0.85-1.87 (m, 28H);
13C NMR (100 MHz, CDCl3) δ 169.0, 157.2, 135.9, 128.6, 128.4,
128.3, 128.1, 127.5, 68.1, 60.8, 47.2, 46.2, 38.8, 38.1, 36.6, 31.8,
29.6, 29.3, 27.5, 27.2, 26.7, 24.3, 22.7, 14.1; HRMS (EIþ) calcd
for C31H45N2O5S (M þ 1) 557.3049, found 557.3067.
Sulfonamide 31. To a solution of (Z)-L-sulfamide 35 (76.1 g,
137 mmol) in MeOH (685 mL) was added Pd/C (7.60 g, 10%).
The mixture was stirred at rt for under an atmosphere of
hydrogen. After 24 h, the reaction was filtered through Celite
and silica gel pad, and the filtrate was concentrated in vacuo to
give a white solid. The crude product was recrystallized from
MeOH to give the product 35 (43.2 g, 102 mmol, 74%) as a white
solid. Compound 31 is a mixture of isomers on the C12H25
alkyl chain. No attempt was made to separate the isomers in this
sequence and the isomeric mixture does not appear to adversely
affect the reactivity: mp 184-186 °C; [R]23D = þ94 (c = 0.95,
CHCl3); IR (neat) 3135, 2955, 2920, 2852, 1626, 1458, 1372,
1308, 1144, 1084, 843 cm-1; 1H NMR (400 MHz, CDCl3) 8.73
(br s, 1H), 8.06 (br s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.22-7.26
(m, 2H), 4.33 (t, J = 8.0 Hz, 1H), 3.23-3.43 (m, 2H), 2.33-2.40
(m, 1H), 0.82-2.05 (m, 28H); 13C NMR (100 MHz, CDCl3) δ
173.8, 140.4, 127.8, 127.2, 126.4, 62.8, 47.8, 39.9, 38.2, 36.8, 31.9,
31.8, 30.1, 29.7, 29.6, 29.3, 29.2, 27.6, 27.2, 24.5, 22.7, 14.1;
HRMS (EIþ) calcd for C23H39N2O3S (M þ 1) 423.2681, found
423.2701.
Cyclohexanone 39c. To a solution of 38c (35 mg, 0.077 mmol)
in EtOH/DCE (1:99, 0.39 mL) were added sulfonamide 31 (3.3
mg, 0.0077 mmol) and piperidine (6.6 mg, 7.7 μL, 0.077 mmol)
at -20 °C. After being stirred at the same temperature for
5 days, the reaction was loaded directly onto silica gel and was
purified by chromatography, eluting with 10-20% EtOAc/
hexanes, to give the product 39c (26.6 mg, 0.0588 mmol, 76%,
83% ee) as a colorless oil: [R]23D = þ35 (c = 0.8, CHCl3); IR
(neat) 2922, 2851, 1718, 1364, 1299, 1255, 1075, 836, 716,
689 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.2 Hz,
2H), 7.67 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 3.74 (t,
J = 6.4 Hz, 1H), 3.46 (d, J = 17.6 Hz, 1H), 3.37 (t, J = 7.6 Hz,
1H), 2.45-2.72 (m, 4H), 2.18-2.32 (m, 5H), 1.74-1.96 (m, 3H),
1.40-1.50 (m, 1H), 0.87 (s, 9H), 0.03 (s, 3H), 0.02 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 206.3, 205.4, 136.3, 134.0, 131.0,
128.6, 78.5, 59.3, 45.3, 39.6, 35.3, 32.9, 30.5, 29.7, 27.7, 25.9,
21.9, 18.3, -5.51; HRMS (ESþ) calcd for C23H36O5NaSSi (M þ
Na) 475.1950, found 475.1959.
Cyclohexanone 39d. To a solution of 38d (32 mg, 0.0833
mmol) in EtOH/DCE (1:99, 0.4 mL) were added sulfonamide
31 (3.5 mg, 8.33 μmol) and piperidine (7.1 mg, 8.2 μL, 0.0833
mmol) at -20 °C. After being stirred at the same temperature for
72 h, the reaction mixture was loaded directly onto silica gel and
was purified by chromatography, eluting with 10-30% EtOAc/
hexanes, to give the product 39d (28.6 mg, 0.0745 mmol, 89%,
81% ee) as colorless oil: [R]23D = þ44.4 (c = 1.1, CHCl3); IR
Cyclohexanone 25. Racemic Protocol. To a solution of 24 (8.0
mg, 0.0212 mmol) in CH2Cl2/2-propanol (1:1, 0.2 mL) was
added diisopropylamine (2.2 mg, 3.0 μL, 0.0212 mmol) at room
temperature. After 76 h, the reaction was loaded directly onto
silica gel and was purified by chromatography, eluting with
10-30% EtOAc/hexanes, to give the product cyclohexanone 25
(6.7 mg, 0.0178 mmol, 84%) as a white solid.
1
(neat) 2922, 1718, 1696, 1304, 1141, 689 cm-1; H NMR (400
Enantioselective Protocol. To a solution of 24 (82.0 mg, 0.217
mmol) in EtOH/DCE (1:99, 1.1 mL) were added ent-sulfonam-
ide 31 (9.2 mg, 0.0217 mmol) and piperidine (18.5 mg, 21 μL,
0.217 mmol) at -20 °C. After being stirred at the same tem-
perature for 72 h, the reaction was loaded directly onto silica gel
and was purified by chromatography, eluting with 10-30%
EtOAc/hexanes, to give the product cyclohexanone 25 (58 mg,
MHz, CDCl3) δ 7.57-7.84 (m, 5H), 7.14-7.29 (m, 5H),
3.63-3.77 (m, 3H), 3.20 (d, J = 13.6 Hz, 1H), 2.72 (dt, J =
15.6, 8.8 Hz, 1H), 2.58-2.65 (m, 1H), 2.18-2.26 (m, 4H),
1.72-1.81 (m, 1H), 1.53-1.61 (m, 1H), 1.41-1.49 (m, 1H),
0.56-0.61 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 207.1, 206.2,
135.5, 135.2, 134.2, 131.2, 130.5, 128.68, 128.65, 127.5, 79.9,
45.6, 39.1, 35.7, 33.2, 30.3, 26.5, 19.3; HRMS (ESþ) calcd for
C22H24O4SNa (Mþ) 407.1293, found 407.1288.
0.154 mmol, 71%, 88% ee) as a white solid: mp 95-96 °C; [R]23
=
D
þ101 (c = 0.78, CHCl3); IR (neat) 2925, 2099, 1716, 1699, 1445,
Cyclopentanone 39e. To a solution of 38e (40 mg, 0.137 mmol)
in EtOH/DCE (1:99, 0.68 mL) were added sulfonamide 31
1355, 1303, 1140, 1088, 723, 688 cm-1 1H NMR (300 MHz,
;
J. Org. Chem. Vol. 75, No. 15, 2010 4937

Yang and Carter
JOCFeatured Article
(5.7 mg, 0.0137 mmol) and piperidine (11.6 mg, 13 μL, 0.137
mmol) at -20 °C. After being stirred at same temperature for 6
days, the reaction mixture was loaded directly onto silica gel and
was purified by chromatography, eluting with 10-30% EtOAc/
hexanes, to give the product 39e (23.2 mg, 0.0792 mmol, 58%,
84% ee) as a colorless oil: [R]23D = -22 (c = 0.3, CHCl3); IR
(neat) 2960, 2916, 2845, 1745, 1713, 1446, 1299, 1146, 1130,
116.9, 74.7, 74.4, 51.8, 51.6, 50.8, 40.9, 40.6, 28.3, 28.0, 26.3,
24.7, 24.6, 19.60, 19.57; HRMS (ESþ) calcd for C17H23N3O3-
NaS (M þ Na) 372.1358, found 372.1333.
Acknowledgment. Financial support was provided by the
National Institutes of Health (NIH) (GM63723). The Na-
tional Science Foundation (CHE-0722319) and the Mur-
dock Charitable Trust (2005265) are acknowledged for their
support of the NMR facility. We thank Dr. Lev N. Zakharov
(OSU and University of Oregon) for X-ray crystallographic
analysis of compounds 7a, 25, 37, and 39, Professor Clayton
Heathcock (UC Berkeley) for providing an authentic sample
1086, 759, 721, 689 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.57-7.86 (m, 5H), 3.49-3.56 (m, 1H), 3.08 (dd, J = 17.2, 2.0
Hz, 1H), 2.30-2.49 (m, 4H), 2.22 (s, 3H), 1.24-1.45 (m, 4H);
13C NMR (100 MHz, CCl3) δ 210.1, 206.0, 135.3, 134.3, 130.8,
128.8, 72.5, 44.9, 38.6, 36.3, 30.3, 25.6, 14.1; HRMS (ESþ) calcd
for C15H18O4NaS (M þ Na) 317.0824, found 317.0834.
ꢀ
Keto Sulfone 44. To a stirred solution of 18 (2.52 g, 10.55
mmol) in THF (120 mL) at -78 °C was added lithium 2,2,6,6-
tetramethylpiperidine54 (21.1 mL, 21.1 mmol, 1.0 M in THF)
dropwise. After 5 min, a solution of 42 (3.00 g, 21.1 mmol) in
precooled THF (5 mL) was added via cannula to the sulfone
solution. After being stirred at -78 to -20 °C for 90 min, the
reaction mixture was removed from the cooling bath, quenched
with satd aq NH4Cl (40 mL), and extracted with diethyl ether
(3 ꢀ 50 mL). The dried (Na2SO4) extract was concentrated in
vacuo and purified by chromatography over silica gel, eluting
with 5-20% EtOAc/hexanes, to give 44 (2.72 g, 7.79 mmol,
74%) as a colorless oil: IR (neat) 2959, 2929, 2873, 2095, 1712,
1449, 1320, 1153, 1084, 912, 748, 688 cm-1; 1H NMR (400 MHz,
CDCl3, two diastereomers) δ 7.80-7.82 (m, 2H), 7.71-7.75 (m,
1H), 7.59-7.61 (m, 2H), 5.73-5.79 (m, 1H), 5.03-5.08 (m, 2H),
4.11-4.16 (m, 1H), 3.26-3.30 (m, 2H), 2.93 (dd, J = 18.4, 5.2
Hz, 1H), 2.62-2.80 (m, 1H), 2.48 (dd, J = 18.4, 7.2 Hz, 1H),
1.87-2.15 (m, 5H), 1.46-1.80 (m, 2H), 0.97 (d, J = 6.4 Hz, 3H),
0.94 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 201.6,
201.4, 136.34, 136.25, 136.20, 136.1, 134.5, 129.45, 129.43, 129.2,
of 1, Professor Max Deinzer and Dr. Jeff Morre (OSU) for
mass spectra data, and Synthetech, Inc., for the generous gift
of compound 34. The reviewers of this manuscript are
acknowledged for their suggestions with regard to the stereo-
chemical outcome of the cyclization of keto sulfone 8.
Finally, the authors are grateful to Professor James D. White
(OSU), Professor Paul R. Blakemore (OSU), Professor Paul
Ha-Yeon Cheong (OSU), and Dr. Roger Hanselmann (Rib-
X Pharmaceuticals) for their helpful discussions.
Note Added after ASAP Publication. Schemes 5, 9, and 11
contained errors in the version published ASAP June 29, 2010;
the correct version reposted July 9, 2010.
Supporting Information Available: Complete experimental
1
procedures are provided, including H and 13C spectra, of all
new compounds. X-ray crystallographic data (CIF) for com-
pounds 7a, 25, 37, and 49 are also provided. This material is
available free of charge via the Internet at http://pubs.acs.org.
4938 J. Org. Chem. Vol. 75, No. 15, 2010