Ring-construction/stereoselective functionalization cascade: Total synthesis of pachastrissamine (Jaspine B) through palladium-catalyzed bis-cyclization of propargyl chlorides and carbonates

Article abstract of DOI:10.1021/jo100544v

Figure presented Palladium(0)-catalyzed cyclization of bromoallenes, propargyl chlorides, and carbonates bearing hydroxy and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran. Cyclization reactivity is dependent on the relative configuration of the benzamide and leaving groups, and on the nature of the leaving groups. This bis-cyclization was used as the key step in a short total synthesis of pachastrissamine, which is a biologically active marine natural product.

Full text of DOI:10.1021/jo100544v

pubs.acs.org/joc
Ring-Construction/Stereoselective Functionalization Cascade: Total
Synthesis of Pachastrissamine (Jaspine B) through Palladium-Catalyzed
Bis-cyclization of Propargyl Chlorides and Carbonates
Shinsuke Inuki, Yuji Yoshimitsu, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received March 22, 2010
Palladium(0)-catalyzed cyclization of bromoallenes, propargyl chlorides, and carbonates bearing hydroxy
and benzamide groups as internal nucleophiles stereoselectively provides functionalized tetrahydrofuran.
Cyclization reactivity is dependent on the relative configuration of the benzamide and leaving groups, and
on the nature of the leaving groups. This bis-cyclization was used as the key step in a short total synthesis of
pachastrissamine, which is a biologically active marine natural product.
Introduction
of a palladium(0) catalyst and alcohol.4,5 This reactivity is
extremely useful for synthesis of medium-sized heterocycles
3 along with their regioisomers 4 from bromoallenes 1 bear-
ing an oxygen, nitrogen, or carbon nucleophile (Scheme 1,
eq 1). More recently, we developed an intramolecular domino
cyclization of bromoallenes 5 bearing a dual nucleophilic
moiety, which produced bicyclic products 7 (Scheme 1, eq 2).5
Unfortunately, this reaction is limited in that it requires a
highly nucleophilic sulfamide group for NuA-NuB, which
might have an appropriate conformation for the 5-endo-type
second cyclization.
In recent years, transition-metal-catalyzed cyclization of
allenes1 or alkynes2 bearing a nucleophilic moiety has been
used extensively for construction of cyclic compounds. We
investigated the development of cyclization reactions of
allenic compounds3 and found that bromoallenes can func-
tion as synthetic equivalents of allyl dication in the presence
(1) For recent books and reviews of allenes, see: (a) Zimmer, R.; Dinesh,
C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3036–3125.
(b) Bates, R. W.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12–21. (c) Mandai,
T. In Modern Allene Chemistry; Krause, N., Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004; Vol. 2, pp 925-972. (d) Ohno, H. Chem. Pharm. Bull. 2005, 53,
1211–1226. (e) Ma, S. Chem. Rev. 2005, 105, 2829–2871. (f) Widenhoefer, R. A.
Chem.;Eur. J. 2008, 14, 5382–5391.
(2) For reviews on palladium-catalyzed reactions of propargylic com-
pounds, see: (a) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140–145.
(b) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J. J. Organomet. Chem.
1987, 334, 225–242. (c) Tsuji, J.; Mandai, T. Angew. Chem., Int. Ed. Engl.
1995, 34, 2589–2612.
(3) (a) Ohno, H.; Hamaguchi, H.; Tanaka, T. Org. Lett. 2001, 3, 2269–
2271. (b) Ohno, H.; Ando, K.; Hamaguchi, H.; Takeoka, Y.; Tanaka, T.
J. Am. Chem. Soc. 2002, 124, 15255–15266. (c) Ohno, H.; Miyamura, K.;
Takeoka, Y.; Tanaka, T. Angew. Chem., Int. Ed. 2003, 42, 2647–2650.
(d) Ohno, H.; Mizutani, T.; Kadoh, Y.; Miyamura, K.; Tanaka, T. Angew.
Chem., Int. Ed. 2005, 44, 5113–5115. (e) Ohno, H.; Aso, A.; Kadoh, Y.; Fujii,
N.; Tanaka, T. Angew. Chem., Int. Ed. 2007, 46, 6325–6328. (f) Okano, A.;
Mizutani, T.; Oishi, S.; Tanaka, T.; Ohno, H.; Fujii, N. Chem. Commun.
2008, 3534–3536. (g) Inuki, S.; Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008,
10, 5239–5242.
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Int. Ed. 2003, 42, 1749–1753. (b) Ohno, H.; Hamaguchi, H.; Ohata, M.;
Kosaka, S.; Tanaka, T. J. Am. Chem. Soc. 2004, 126, 8744–8754.
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Int. Ed. 2005, 44, 1513–1517. (b) Hamaguchi, H.; Kosaka, S.; Ohno, H.;
Fujii, N.; Tanaka, T. Chem.;Eur. J. 2007, 13, 1692–1708.
The palladium-catalyzed reaction of propargylic compounds
developed by Tsuji et al. has become a useful tool for formation
of two carbon-carbon or carbon-heteroatom bonds.2,6,7
Bromoallenes 11 can be considered as a synthetic equivalent
(6) For pioneering works, see: (a) Tsuji, J.; Watanabe., H.; Minami, I.;
Shimizu, I. J. Am. Chem. Soc. 1985, 107, 2196–2198. (b) Minami, I.; Yuhara,
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M.; Tsuji, J. Tetrahedron Lett. 1987, 28, 629–632. (b) Geng, L.; Lu, X.
Tetrahedron Lett. 1990, 31, 111–114. (c) Labrosse, J.-R.; Lhoste, P.; Sinou,
D. Tetrahedron Lett. 1999, 40, 9025–9028. (d) Labrosse, J.-R.; Lhoste, P.;
Sinou, D. Org. Lett. 2000, 2, 527–529. (e) Labrosse, J.-R.; Lhoste, P.; Sinou,
D. J. Org. Chem. 2001, 66, 6634–6642. (f) Zong, K.; Abboud, K. A.;
Reynolds, J. R. Tetrahedron Lett. 2004, 45, 4973–4975. (g) Yoshida, M.;
Higuchi, M.; Shishido, K. Tetrahedron Lett. 2008, 49, 1678–1681.
(h) Yoshida, M.; Higuchi, M.; Shishido, K. Org. Lett. 2009, 11, 4752–
4755. For related reactions, see: (i) Bi, H.-P.; Liu, X.-Y.; Gou, F.-R.;
Guo, L.-N.; Duan, X.-H.; Shu, X.-Z.; Liang, Y.-M. Angew. Chem., Int. Ed.
2007, 46, 7068–7071. (j) Ren, Z.-H.; Guan, Z.-H.; Liang, Y.-M. J. Org. Chem.
2009, 74, 3145–3147. (k) Gou, F.-R.; Huo, P.-F.; Bi, H.-P.; Guan, Z.-H.;
Liang, Y.-M. Org. Lett. 2009, 11, 3418–3421.
DOI: 10.1021/jo100544v
r
Published on Web 05/10/2010
J. Org. Chem. 2010, 75, 3831–3842 3831
2010 American Chemical Society

Inuki et al.
JOCArticle
SCHEME 1. Palladium(0)-Catalyzed Cyclization of Bromoallenes
and Propargyl Bromides
FIGURE 1. Structures of naturally occurring jaspines.
SCHEME 2. Construction of Bicyclic Structures by Palladium(0)-
Catalyzed Cascade Cyclization of Bromoallenes 14 and
Propargyl Compounds 15
of propargylic compounds 12,8 both of which can work
as allyl dication equivalents 13 (Scheme 1). Considerable
research in this area has revealed that a combination of nucleo-
philic attacks by an internal nucleophilic functional group
and an appropriate external nucleophile can be an efficient
approach to various cyclic compounds, such as carbapenems,9
furans,10 indoles,11 indenes,12 and cyclic carbonates.13 Re-
cently, we also developed a palladium(0)-catalyzed domino
cyclization of propargyl bromides 8 with two nucleophilic
sites, which produced bicyclic products 10 (Scheme 1, eq 3).14
However, it should be noted that the attempted domino
cyclization for bicyclic furan synthesis was unsuccessful, and
instead formation of monocyclization products occurred
via β-elimination of the type 9 intermediate followed by
aromatization. The difficulty in the second cyclization is
partially due to the endo-type reaction.
We turned our attention to domino cyclization of type 14
bromoallenes or type 15 propargyl compounds bearing
nucleophilic groups at both ends of a branched alkyl group,
which would directly lead to bicyclic products such as 18 or
19 (Scheme 2). This bis-cyclization also enables a cyclization/
functionalization cascade, which creates a new chiral center
on the exo-type second cyclization and utilizes the chiral
center at the branched position. The key to success of this
domino reaction would be controlled successive nucleophilic
attacks by NuA and NuB in the desired order. First cycliza-
tion by NuA or NuB will produce intermediate 16 or 17,
respectively. These would be converted to the cyclic products
18 or 19, respectively, by the second intramolecular reaction.
We are also interested in the stereochemical course of the
domino cyclization, i.e., the effect of the axial or central
chirality in the allenic/propargylic moiety of 14/15 on the
reactivity and selectivity. We chose pachastrissamine 20
(Figure 1), which bears three contiguous stereogenic centers
on its tetrahydrofuran core structure, to evaluate this work-
ing hypothesis on the ring-construction/stereoselective func-
tionalization cascade.
(8) The reactivities of allenic and propargylic compounds are not neces-
sarily the same. For example, propargyl bromides and carbonates are
more reactive than bromoallenes toward SN2 reactions and alcoholysis,
respectively.4b
(9) (a) Kozawa, Y.; Mori, M. Tetrahedron Lett. 2001, 42, 4869–4873.
(b) Labrosse, J.-R.; Lhoste, P.; Sinou, D. J. Org. Chem. 2001, 66, 6634–6642.
(c) Kozawa, Y.; Mori, M. J. Org. Chem. 2003, 68, 8068–8074. (d) Kozawa,
Y.; Mori, M. Tetrahedron Lett. 2002, 43, 1499–1502.
(10) Yoshida, M.; Morishita, Y.; Fujita, M.; Ihara, M. Tetrahedron Lett.
2004, 45, 1861–1864.
(11) (a) Ambrogio, I.; Cacchi, S.; Fabrizi, G. Org. Lett. 2006, 8, 2083–
2086. (b) Ambrogio, I.; Cacchi, S.; Fabrizi, G.; Prastaro, A. Tetrahedron
2009, 65, 8916–8929. (c) Cacchi, S.; Fabrizi, G.; Filisti, E. Synlett 2009, 1817–
1821.
(12) (a) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M.
Org. Lett. 2006, 8, 5777–5780. (b) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538–1540. (c) Bi, H.-P.; Guo,
L.-N.; Gou, F.-R.; Duan, X.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem.
2008, 73, 4713–4716.
(13) (a) Yoshida, M.; Ihara, M. Angew. Chem., Int. Ed. 2001, 40, 616–619.
(b) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem. Soc. 2003, 125,
4874–4881.
Pachastrissamine 20 (Figure 1), an anhydrophytosphin-
gosine derivative, was isolated by Higa et al. from Okinawan
marine sponge Pachastrissa sp. in 2002.15 Debitus et al. then
isolated the same compound from Vanuatuan marine sponge
Jaspis sp. and named this jaspine B.16 Other structurally rela-
ted analogues have also been isolated from the same species,
(14) (a) Ohno, H.; Okano, A.; Kosaka, S.; Tsukamoto, K.; Ohata, M.;
Ishihara, K.; Maeda, H.; Tanaka, T.; Fujii, N. Org. Lett. 2008, 10, 1171–
1174. (b) Okano, A.; Tsukamoto, K.; Kosaka, S.; Maeda, H.; Oishi, S.; Tanaka, T.;
Fujii, N.; Ohno, H. Chem.;Eur. J. 2010, 16, in press (chem.201000653).
(15) Kuroda, I.; Musman, M.; Ohtani, I.; Ichiba, T.; Tanaka, J.; Garcia-
Gravalos, D.; Higa, T. J. Nat. Prod. 2002, 65, 1505–1506.
(16) Ledroit, V.; Debitus, C.; Lavaud, C.; Massoit, G. Tetrahedron Lett.
2003, 44, 225–228.
3832 J. Org. Chem. Vol. 75, No. 11, 2010

Inuki et al.
JOCArticle
including jaspine A and 2-epi-jaspine B. Pachastrissamine 20
displays remarkable cytotoxic activity against several tumor
cell lines. In 2009, Delgado et al. reported that dihydro-
ceramides mediated autophagy might be involved in the
cytotoxicity.17 Andrieu-Abadie et al. indicated that pachas-
trissamine induces apoptotic cell death in melanoma cells by
a caspase-dependent pathway.18 Because of its biological
importance, pachastrissamine has attracted considerable
interest from the synthetic community. A number of syn-
theses of pachastrissamine have been reported.19 More
recently, we communicated a pachastrissamine synthesis
by palladium-catalyzed bis-cyclization of bromoallene
(Scheme 3).20a Herein we describe divergent synthesis of
various pachastrissamine derivatives through our original
synthetic route using bromoallenes and a novel short-step
total synthesis of pachastrissamine using several propargyl
compounds. We also present a mechanistic consideration based
on stereochemical investigations of palladium-catalyzed cycli-
zation of propargylic substrates.
SCHEME 3. Total Synthesis of Pachastrissamine (Jaspine B)
through Palladium-Catalyzed Bis-cyclization of Bromoallenes
Results and Discussion
Divergent Synthesis of Various Pachastrissamine Deriva-
tives by Bis-cyclization of Bromoallenes. Our previous study
of pachastrissamine synthesis by palladium-catalyzed bis-
cyclization of bromoallene is shown in Scheme 3. The requi-
site bromoallene 22 bearing hydroxy and benzamide groups21
for palladium-catalyzed reaction was easily accessible from
(S)-Garner’s aldehyde 21.22,23 Among the several bases and
solvents investigated, we found that reaction of 22 with 5 mol %
of Pd(PPh3)4 and Cs2CO3 in THF/MeOH (10:1) at 50 °C suc-
cessfully produced the desired functionalized tetrahydro-
furan 23 in 89% yield. The undesired cyclization initiated by
nucleophilic attack of the benzamide group was not pro-
moted. Hydroboration-oxidation of the exo-olefin of 23
afforded primary alcohol 24 with the desired configuration
as the sole diastereomer.24 Triflation of the alcohol 24,
followed by copper-catalyzed alkylation with Grignard re-
agent, gave tetrahydrofuran 25 bearing all the requisite func-
tionalities.25 Finally, pachastrissamine 20 was obtained by
hydrolysis of 25 with 20% aqueous H2SO4.26
This synthetic route was characterized by the late-stage
introduction of the long alkyl side chain into the tetrahy-
drofuran ring at the C-2 position by copper-catalyzed reac-
tion. The use of various organocopper reagents derived from
Grignard reagents should make it possible to achieve a diver-
gent synthesis of pachastrissamine derivatives. Consequently,
we investigated the copper-catalyzed alkylation of the triflate
prepared from 24 (Table 1). Reaction with Grignard reagents
containing a primary alkyl group such as tridecyl, phenyl-
ethyl, and methyl in the presence of a copper salt (20 mol %)
afforded the desired alkylation products in good yields
(entries1-3).25,27 Changing the Grignard reagents to i-PrMgCl
or CH2dC(CH3)MgBr gave moderate yields of the corres-
ponding products 26c or 26d (entries 4 and 5), respectively,
containing a secondary alkyl or alkenyl group.28 We next
examined introduction of an allyl group, which can be read-
ily used for further manipulation (Table 2). However, treat-
ment of the triflate with allylMgBr and catalytic CuBr27
ꢀ
(17) Canals, D.; Mormeneo, D.; Fabrias, G.; Llebaria, A.; Casas, J.;
Delgado, A. Bioorg. Med. Chem. 2009, 17, 235–241.
ꢁ
(18) Salma, Y.; Lafort, E.; Therville, N.; Carpentier, S.; Bonnafe, M.-J.;
Levade, T.; Genisson, Y.; Andrieu-Abadie, N. Biochem. Pharmacol. 2009,
ꢁ
78, 477–485.
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A.; Jagadeesh, B.; Rao, B. V. Tetrahedron Lett. 2005, 46, 325–327.
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Sato, S.; Yoshimoto, Y. Chem. Pharm. Bull. 2007, 55, 1284–1286.
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TABLE 1. Copper-Catalyzed Alkylation of Triflatesa
entry
RMgX
CuX cat.
CuI
CuI
solvent
temp (°C)
products (% yield)b
1
2
3
4
5
C13H27MgBr
Ph(CH2)2MgCl
MeMgBr
i-PrMgCl
CH2dC(CH3)MgBr
THF
THF
-78 to -10
-78 °C to rt
-30 °C to rt
-20 to 0
25 (78)
26a (76)
26b (82)
26c (54)
26d (66)
CuBr
CuBr SMe2
CuBr SMe2
THF/Et2O (9:1)
THF/Me2S (30:1)
THF/Me2S (30:1)
3
3
-20 to 0
aReactions were carried out with RMgX (2.7-7.0 equiv) and CuX (20 mol %) for 1-4.5 h. bIsolated yields.
TABLE 2. Copper-Catalyzed Allylation of Triflates and Formation of 2-Oxa-5-azabicyclo[2.2.1]heptane
yielda,b (%)
entry
conditions
26e
27
90
91
ca. 5
1c
2c
3d
allylMgBr, CuBr (20 mol %) THF/Et2O (3:1), -30 °C
allylMgBr, THF/Et2O (3:1), -30 °C
(allyl)2Cu(CN)Li2, THF, -78 °C
ND
ND
32
aIsolated yields. bND = not detected. cReactions were carried out with allylMgBr (5.0 equiv) for 1.5 h. dReactions were carried out with
(allyl)2Cu(CN)Li2 (4.0 equiv) for 30 min.
provided the unanticipated product oxaazabicycloheptane
27 in 90% yield (entry 1).29 The reaction in the absence of a
copper catalyst also afforded 27 in 91% yield (entry 2). In
comparison, use of (allyl)2Cu(CN)Li230 resulted in 32% yield
of the desired product 26e along with a small amount of the
side product 27 (entry 3).
SCHEME 4. Formation of 2-Oxa-5-azabicyclo[2.2.1]heptane 27
The rationale for formation of the oxaazabicycloheptane
27 is depicted in Scheme 4. The addition of allylMgBr to
imine followed by intramolecular attack of the resulting
nitrogen anion to triflate would generate monoallylated inter-
mediate 30. The second nucleophilic attack of allylMgBr to
iminium cation derived from 30 would proceed to give the
oxaazabicycloheptane 27.31 Servi et al. also reported that
2-phenyloxazolines bearing a tosylate leaving group with
allyl Grignard reagent gave bicyclic compounds similar
to the intermediate 30.32 In contrast, the reaction with the
other Grignard reagents did not afford the oxaazabicyclo-
heptane-type products (Table 1). The formation of the
oxaazabicycloheptane 27 with allylMgBr would be caused
by the first addition step to imine 28 proceeding through six-
membered transition state.
Novel Strategy for Short-Step Synthesis of Pachastrissa-
mine. Based on the above flexible synthetic route using
bromoallenes, we decided to explore a shorter total synthesis
of pachastrissamine. This would introduce the alkyl side chain
at the beginning. We expected that palladium(0)-catalyzed
cyclization of type 33 internal bromoallenes or type 34
propargylic substrates, bearing hydroxy and benzamide groups
(29) The structure of 27 was confirmed by NMR analysis and comparison
€
with structurally related compounds; see: Hummer, W.; Dubois, E.; Gracza,
€
T.; Jager, V. Synthesis 1997, 634–642.
(30) (a) Lipshutz, B. H.; Crow, R.; Dimock, S. H.; Ellsworth, E. L. J. Am.
Chem. Soc. 1990, 112, 4063–4064. (b) Lipshutz, B. H.; Ellsworth, E. L.;
Dimock, S. H.; Smith, R. A. K. J. J. Am. Chem. Soc. 1990, 112, 4404–4410.
(31) Reaction of triflate 28 with 1.0 equiv of the allyl Grignard reagents
gave the oxaazabicycloheptane 27 in 13% yield along with the recovery of the
unchanged triflate 28 in 73% yield, without isolation of the intermediate 30.
This is presumably due to a highly strained aminal structure of 30 and facile
Grignard reaction to the iminium moiety of 31.
(32) Fronza, G.; Mele, A.; Pedrocchi-Fantoni, G.; Pizzi, D.; Servi, S.
J. Org. Chem. 1990, 55, 6216–6219.
3834 J. Org. Chem. Vol. 75, No. 11, 2010

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JOCArticle
SCHEME 5. Retrosynthetic Analysis of Pachastrissamine 20
TABLE 3. Chlorination of Propargyl Alcoholsa
entry substrate
additive
solvent yieldb (%) dr (syn/anti)c
1
2
3
4
5
6
7
8
syn-35
syn-35
syn-35
syn-35
syn-35
syn-35
syn-35
anti-35
DMF
MeCN
THF
9
15
22
30
48
8
>95:5
93:7
>95:5
>95:5
55:45
>95:5
>95:5
5:>95
CH2Cl2
toluene
CH2Cl2
SCHEME 6. Synthesis of Propargyl Carbonates syn- and anti-37
LiCld
(n-Bu)4NCld CH2Cl2
14
47
CH2Cl2
aReactions were carried out with Ph3PCl2 (4.0 equiv) and imidazole
(4.0 equiv) for 2-8 h. bIsolated yields. cDetermined by 1H NMR
analysis. d4.0 equiv.
and MeOH followed by acylation with BzCl and (i-Pr)2NEt
gave the benzamide syn-37. The isomeric benzamide anti-37
was obtained in the same manner via the alkynol anti-3535
derived from (S)-Garner’s aldehyde 21.
Synthesis of Propargyl Chlorides. We next examined pre-
paration of the required propargyl chloride by chlorination of
propargyl alcohol 35 (Table 3).36 Contrary to our expectations,
the reaction of syn-35 with Ph3PCl2 and imidazole in DMF
afforded propargyl chloride syn-38 in only 9% yield (entry 1).
The syn-configuration of chloride, determined by cyclization
of the corresponding benzamide 41 (vide infra, Scheme 7),
demonstrates that the reaction proceeds with net retention
of configuration.37,38 Changing the solvent from DMF to
MeCN, THF, or CH2Cl2 increased the yields of the desired
as nucleophilic functional groups, could regio- and stereo-
selectively provide the desired bicyclic tetrahydrofuran 32
(Scheme 5). Further hydrogenation of the olefin in 32 from
the convex face would allow creation of the C-2 chiral center.
Initial examination has revealed that chemoselective pre-
paration of type 33 1,3-disubstituted bromoallenes and type
34 propargyl tosylates/bromides is difficult.33,34 Therefore, we
chose type 34 propargyl carbonates and chlorides as poten-
tial substrates for the palladium(0)-catalyzed bis-cyclization
reaction.
(36) Fluorination reaction of a similar alkynol is known to proceed with
inversion of configuration; see: De Jonghe, S.; Van Overmeire, I.; Van
Calenbergh, S.; Hendrix, C.; Busson, R.; De Keukeleire, D.; Herdewijin, P.
Eur. J. Org. Chem. 2000, 3177–3183.
(37) The observed stereoretention in the chlorination can be rationalized
by the double inversion pathway. Activation of syn-35 by Ph3PCl2 followed
by initial intramolecular nucleophilic attack of a Boc group to the activated
propargylic position would form bicyclic intermediate 40 through inversion
of configuration. The second intermolecular nucleophilic attack of chloride
anion via stereoinversion then gives syn-38.
Synthesis of Propargyl Carbonates. Initially, we planned to
synthesize the diastereomeric propargyl carbonates syn- and
anti-37 to investigate the difference in reactivity between the
diastereoisomers (Scheme 6). Alkynol syn-35 was prepared
from (S)-Garner’s aldehyde 21 following the literature.23
The alkynol syn-35 was converted into the corresponding
carbonate syn-36 by treatment with ClCO2Me, pyridine, and
DMAP. Removal of the Boc and acetal groups with TFA
(33) For example, treatment of propargyl mesylates with CuBr SMe2 in
3
the presence of LiBr gave a mixture of allenyl/propargyl bromides in low
yield.
(34) For example, treatment of propargyl tosylates and propargyl bro-
mides with TFA and MeOH followed by acylation with BzCl and DIPEA did
not afford the desired benzamide.
(38) For related examples of Mitsunobu-type reaction with net retention of
configuration by participation of a vicinal nitorogen functionality, see: (a)
Roush, D. M.; Patel, M. M. Synth. Commun. 1985, 15, 675–679. (b) Freedman,
J.; Vaal, M. J.; Huber, E. W. J. Org. Chem. 1991, 56, 670–672. (c) Lipshutz,
B. H.; Miller, T. A. Tetrahedron Lett. 1990, 31, 5253–5256. (d) Okuda, M.;
Tomioka, K. Tetrahedron Lett. 1994, 35, 4585–4586.
(35) According to the literature,23 anti-35 was produced in 71% yield.
However, in our study, the desired product was obtained in low yield (37%)
along with unidentified side products, and the optical rotation of alkynol
anti-35 was slightly decreased: [R]25 -33.6 (c 1.33, CHCl3) [lit.23 [R]25
D
D
-40.1 (c 1.0, CHCl3)].
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JOCArticle
TABLE 4. Palladium-Catalyzed Cascade Cyclization of Propargyl Chloridesa
44
42
entry
substrate
base (equiv)
solvent
MeOH
THF
THF/MeOH (10:1)
THF/MeOH (10:1)
THF/MeOH (10:1)
THF/MeOH (10:1)
THF/MeOH (10:1)
yieldb (%)
E/Zc,d
yieldb (%)
cis/transc,d
1
2
syn-41
syn-41
syn-41
syn-41
syn-41
syn-41
anti-41
NaH (2.5)
NaH (2.5)
NaH (2.5)
K2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
Cs2CO3 (1.2)
49
ca. 12
21
92:8
ND
54:46
>95:5
95:5
ca. 12
18
10
<18
<18
trace
32
80:20
>95:5
69:31
77:22
74:26
ND
3
4e
5
24
73
89
55
6f
>95:5
13:87
7f
55:45
c
aReactions were carried out with Pd(PPh3)4 (5 mol %) at 0.1 M for 1-1.5 h. bIsolated yields. Determined by 1H NMR analysis. dND = not
determined. e46% of syn-41 was recovered. fReactions were carried out using 10 mol % of Pd(PPh3)4.
SCHEME 7. Synthesis of Propargyl Chlorides syn- and anti-41
MeOH, followed by acylation with BzCl and (i-Pr)2NEt
(Scheme 7).39-42
Palladium-Catalyzed Cascade Cyclization of Propargyl
Chlorides. We investigated cascade cyclization of propargyl
chlorides syn-41 and anti-41 in the presence of palladium(0)
(Table 4). Reaction of syn-41 with Pd(PPh3)4 (5 mol %) and
NaH (2.5 equiv) in MeOH at 50 °C (standard conditions for
cyclization of propargyl bromide)14 afforded the desired
products to some extent with high diastereoselectivities
(entries 2-4). It should be noted that the use of toluene as
solvent provided the desired propargyl chloride in mode-
rate yield (48%) but with extremely low diastereoselecti-
vity (55:45, entry 5). Further screening of the reaction con-
ditions using the additives LiCl or (n-Bu)4NCl did not
enhance the yield of the desired product. When the alkynol
anti-35 was employed, propargyl chloride anti-38 was simi-
larly produced by net retention of configuration in 47%
yield.
(40) The relative configuration of cis-42 was confirmed by comparison
with the authentic sample prepared from the known alkynol syn-35.23
Next, we prepared benzamides syn- and anti-41 by
removal of the Boc and acetal groups with TFA and
(41) Therelativeconfigurationofcis-43 was determined using our JHab-based
configurational analysis: the observed Ha-Hb coupling constant (JHab=6.0 Hz)
indicates the 2,3-cis configuration of the aziridine; see: Ohno, H.; Toda, A.;
Takemoto, Y.; Fujii, N.; Ibuka, T. J. Chem. Soc., Perkin Trans. 1 1999, 2949–
2962.
(39) The relative configuration of syn- and anti-41 was determined by
derivatization to the corresponding oxazolines or aziridines. The chloride
syn-41 was subjected to NaH in DMF to give the oxazoline cis-4240 (7%) and
aziridine cis-4341 (69%). In contrast, the reaction of anti-41 gave the oxazo-
line trans-4242 in 36% yield.
(42) The relative configuration of trans-42 was confirmed by comparison
with the authentic sample prepared from the known alkynol anti-35.23
3836 J. Org. Chem. Vol. 75, No. 11, 2010

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JOCArticle
TABLE 5. Palladium-Catalyzed Cascade Cyclization of Propargyl Carbonates a
44
yieldc,d (%)
42
entry
substrate
baseb
additive
solvent
MeOH
THF
THF
THF:MeOH (10:1)
THF
THF
THF
THF
THF
E/Ze
yieldc,d (%)
cis/transe
1
syn-37
syn-37
syn-37
syn-37
syn-37
syn-37
anti-37
anti-37
anti-37
anti-37
anti-37
anti-37
2f
69
60
65
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
ND
ND
ND
ND
ND
ND
60
ND
ND
15
2
3g
4
5
Cs2CO3
Cs2CO3
67-78
14
<20
ND
ND
39
6g
7
82:18
8
9
10
11
12
(n-Bu)4NClh
LiCli
THF:MeOH (10:1)
THF
THF:MeOH (10:1)
13:87
42:58
16:84
>95:5
>95:5
Cs2CO3
Cs2CO3
<26
7
39
ND
aReactions were carried out with Pd(PPh3)4 (5 mol %) at 0.1 M for 2-4.5 h. b1.2 equiv of a base was used. cIsolated yields. dND = not detected.
eDetermined by 1H NMR analysis. fSolvolysis product was obtained. gReactions were carried out on 1 g scale. h0.3 equiv. i1.0 equiv.
bicyclic tetrahydrofuran 44 in 49% yield with high E-selec-
tivity (E/Z43 = 92:8, entry 1). Although the undesired
monocyclized furan derivatives were not obtained,14 SN2-
type oxazoline product 42 was observed (ca. 12%, cis/trans=
80:20).44 Changing the solvent from MeOH to THF or THF/
MeOH (10:1) did not enhance the yield of the desired
product (entries 2 and 3). Of the several bases investigated,
Cs2CO3 was the most effective, yielding 73% of 44 as a 95:5
E/Z mixture (entries 3-5). Furthermore, increased loading
of Pd(PPh3)4 (10 mol %) improved the yield to 89% and
suppressed formation of oxazoline 42 (entry 6). When anti-41
was subjected to the optimized reaction conditions (entry 6),
the desired bicyclic tetrahydrofuran 44 was obtained in
55% yield with moderate Z-selectivity (E/Z = 13:87),
along with oxazoline 42 (32%, cis/trans = 55:45, entry 7).
These results show utility of propargyl chlorides with syn-
configuration as a precursor of bicyclic products and a
clear difference in reactivity between the diastereomeric
substrates.
(Table 5). Treatment of syn-37 with Pd(PPh3)4 (5 mol %) in
MeOH at 50 °C afforded the desired bicyclic tetrahydrofuran
44 in low yield (2%) (entry 1). The main product was the
corresponding diol formed by alcoholysis of carbonate 37
(entry 1). When THF was used as the reaction solvent,
44 was obtained with a higher yield (69%) and excellent
E-selectivity (E/Z > 95:5, entry 2). Conducting the reaction
on a 1 g scale also gave the desired product in satisfactory
yield (60%, entry 3). According to our previous reports,4,5,14
solvents containing alcohol promote the palladium-catalyzed
reactions of bromoallenes or propargylic compounds. How-
ever, the addition of MeOH did not improve the yield (entry 4).
Although the reaction of syn-37 on a 40 mg scale in the
presence of Cs2CO3 gave 44 in 67-78% yield, this was not
reproducible on a 1 g scale (entries 5 and 6). Next, we reacted
the diastereomeric carbonates anti-37 under the above opti-
mized conditions (entry 2). This gave the desired product 44
in unexpectedly low yield (<20%) with >95:5 E-selectivity
and SN2 product 42 (60%, cis/trans= 82:18) (entry 7). This
result is quite different from the reaction using propargyl
chlorides (Table 4, entries 6 and 7). To achieve efficient
transformation, further screening was carried out on the
basis of the examination of propargyl chlorides (Table 4).
Addition of a chloride anion source such as (n-Bu)4NCl or
LiCl did not afford 44 (entries 8 and 9). Among the several
reaction conditions investigated (entries 10-12), the use of a
mixed solvent THF/MeOH (10:1) under base-free conditions
gave the most efficient conversion of anti-37 into the desired
product 44 in favor of Z-isomer (39%, E/Z=13:87, entry 10).
These results indicate that an alcoholic solvent plays an
important role in stereospecific cyclization of some pro-
pargylic systems.
Palladium-Catalyzed Cascade Cyclization of Propargyl
Carbonates. We next investigated the reaction of propargyl
carbonates syn-37 and anti-37 in the presence of palladium(0)
(43) The configuration of the bicyclic tetrahydrofuran 44 was determined
by NOE analysis.
(44) The minor isomer trans-42 could be produced by double inversion
pathway: anti-attack of benzamide group to propargyl/allenyl palladium
complex, formed by anti-attack of palladium(0) to syn-41, will produce the
net retention product trans-42.
Proposed Mechanism for the Cascade Reaction. Formation
of (E)-44 from the carbonate syn-37 or chloride syn-41 can
be explained as follows (Scheme 8). Initially, regio- and
J. Org. Chem. Vol. 75, No. 11, 2010 3837

Inuki et al.
JOCArticle
SCHEME 8. Proposed Mechanism for Cascade Reaction
stereoselective SN20 attack of palladium(0) to propargylic
compounds proceeds to yield the allenylpalladium intermedi-
ate A. First cyclization by the hydroxy group on the central
carbon of π-propargylpalladium complex B,45 which is
formed by rearrangement of A, would generate a fused
palladacyclobutene intermediate C.46 This is followed by
protonation to form complex D without loss of chirality.
After formation of the π-allylpalladium intermediate E,
isomerization to anti-type complex F is necessary for the
next anti-cyclization. Therefore, transformation into the
intermediate F through π-σ-π equilibration followed by
the second cyclization by the benzamide group then gives
(E)-44.47 The carbonate anti-37 or the chloride anti-41 would
be converted into π-propargylpalladium complex epi-B via
SN20 attack of palladium(0). Cyclization by hydroxy group
and subsequent protonation will form π-allylpalladium
intermediate epi-E, which gives (Z)-44 by anti attack of the
benzamide group. It should be noted that the reaction of syn-
propargylic compounds, which would have unfavorable
steric interaction between the palladium and the benzamide
group in the first cyclization step, proceeds more efficiently
than that of anti-compounds (entries 6 vs 7, Table 4; entries 2
vs 7, Table 5). This result suggests that coordination of the
benzamide group to palladium would promote the first
cyclization by stabilizing the reactive conformer as depicted
in B and/or the resulting palladacyclobutene intermediate
C . Although the exact reason for the lower Z-selectivities in
reaction of the anti-substrates (Table 5, entries 7 and 10-12)
is unclear, it can be attributed to epimerization of allenyl-
palladium or π-propargylpalladium complex epi-B due to
slower cyclization without assistance of a coordinating
effect.46b,48 Further studies to understand the stereoselecti-
vities and reactivities of these cyclization reactions are
currently underway in our laboratory.
(45) (a) Ogoshi, S.; Tsutsumi, K.; Nishiguchi, S.; Kurosawa, H.
J. Organomet. Chem. 1995, 493, C19–C21. (b) Tsutsumi, K.; Ogoshi, S.;
Nishiguchi, S.; Kurosawa, H. J. Am. Chem. Soc. 1998, 120, 1938–1939.
(c) Tsutsumi, K.; Kawase, T.; Kakiuchi, K.; Ogoshi, S.; Okada, Y.;
Kurosawa, H. Bull. Chem. Soc. Jpn. 1999, 72, 2687–2692.
(46) (a) Casey, C. P.; Nash, J. R.; Yi, C. S.; Selmeczy, A. D.; Chung, S.;
Powell, D. R.; Hayashi, R. K. J. Am. Chem. Soc. 1998, 120, 722–733.
(b) Ogoshi, S.; Kurosawa, H. J. Synth. Org. Chem. Jpn. 2003, 61, 14–23.
Formation of a palladacyclobutene intermediate in a related reaction has
been well rationalized by DFT calculation: (c) Labrosse, J.-R.; Lhoste, P.;
Delbecq, F.; Sinou, D. Eur. J. Org. Chem. 2003, 2813–2822.
(47) For related chirality transfer in the reaction of the propargylic
compounds via palladacyclobutene intermediates, see: Yoshida, M.; Fujita,
M.; Ihara, M. Org. Lett. 2003, 5, 3325–3327.
(48) (a) Mikami, K.; Yoshida, A. Angew. Chem., Int. Ed. Engl. 1997, 36,
858–860. (b) Ogoshi, S.; Nishida, T.; Shinagawa, T.; Kurosawa, H. J. Am.
Chem. Soc. 2001, 123, 7164–7165. (c) Yoshida, M.; Gotou, T.; Ihara, M.
Tetrahedron Lett. 2004, 45, 5573–5575. (d) Molander, G. A.; Sommers,
E. M.; Baker, S. R. J. Org. Chem. 2006, 71, 1563–1568. (e) Yoshida, M.;
Hayashi, M.; Shishido, K. Org. Lett. 2007, 9, 1643–1646. (f) Yoshida, M.;
Okada, T.; Shishido, K. Tetrahedron 2007, 63, 6996–7002. (g) Vaz, B.;
ꢁ
ꢁ
Pereira, R.; Perez, M.; Avarez, R.; De Lera, A. R. J. Org. Chem. 2008, 73,
6534–6541.
3838 J. Org. Chem. Vol. 75, No. 11, 2010

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TABLE 6. Hydrogenation of (E)-Olefin 44a
SCHEME 9. Cleavage of Oxazoline Ring
difference was observed between the diastereomeric syn- or
anti-substrates. Reaction of the syn-propargylic isomer pro-
ceeded more efficiently than the corresponding anti-isomer.
We have achieved a short total synthesis of pachastrissamine
using propargylic carbonates. This synthetic route furnishes
pachastrissamine in 26% overall yield in seven steps (final
deprotection by hydrolysis) or 28% overall yield in eight
steps (reductive deprotection) starting from Garner’s alde-
hyde as the sole chiral source (Scheme 10).
entry catalyst (mol %)
solvent
EtOAc
EtOAc
EtOAc
EtOAc
temp (°C) time (h) yieldb (%)
1
2
3
4
5
6
7
10% Pd/C (5)
Pd(OH)2/C (5)
PtO2 (5)
rt
rt
1
16
22
25
27
25
21
45
5
rt
ca. 5
28
62
82
Ir-black (10)
50
50
50
70
(Ph3P)3RhCl (5) C6H6/EtOH
(Ph3P)3RhCl (10) C6H6/EtOH
Crabtree cat. (10) DCEc
30
aReactions were carried out with pure (E)-olefin 44. bIsolated yields.
cDCE = 1,2-dichloroethane.
Experimental Section
Hydrogenation of (E)-Olefin 44. We next investigated
hydrogenation of (E)-olefin 44, which enabled creation of
the C-2 stereogenic center (Table 6). When 10% Pd/C was
used, the desired product 25 was obtained in 45% yield as the
sole diastereomer. Heterogeneous catalysts (Pd(OH)2/C,
PtO2, and Ir-black entries 2-4) were screened further, but
the yield of the desired product decreased with a prolonged
reaction time. On examination of the homogeneous catalyst,
we found 5 mol % of (Ph3P)3RhCl enhanced the yield (62%).
When the catalyst loading was increased to 10 mol %, the
desired product 25 was isolated in a higher yield (82%, entry 6).
In contrast, use of Crabtree catalyst49 decreased the yield of
25 to 30% (entry 7).
Cleavage of Oxazoline Ring. After synthesis of the pachas-
trissamine derivative 25 bearing the requisite functionalities,
we tested cleavage of the oxazoline ring. Previously, we re-
ported the hydrolysis under harsh conditions (20% H2SO4,
CH2Cl2, sealed tube, 120 °C) led to the desired conversion in
80% yield (Scheme 3).20 We decided to develop an alter-
native approach for oxazoline group cleavage and used a
two-step reduction under mild conditions.50 Treatment of 25
with DIBAL-H successfully produced the desired benzyl
protected pachastrissamine 45 quantitatively.50c Finally,
removal of the benzyl group with Pd(OH)2/C led to pachas-
trissamine 20 in 86% yield (Scheme 9).
(3aS,6S,6aS)-2-Phenyl-6-(3-phenylpropyl)-3a,4,6,6a-tetrahydro-
furo[3,4-d]oxazole (26a) (Table 1, Entry 2). To a stirred mixture
of 24 (40 mg, 0.18 mmol) and Et3N (0.065 mL, 0.47 mmol) in
CH2Cl2 (1.8 mL) was added Tf2O (0.055 mL, 0.32 mmol) at -78 °C,
and the mixture was stirred for 30 min at this temperature.
The mixture was quenched by addition of saturated NH4Cl at
-78 °C, and the whole was extracted with CH2Cl2. The extract
was washed with H2O and brine and was dried over Na2SO4.
Concentration of the filtrate under reduced pressure followed by
rapid filtration through a short pad of silica gel with Et2O-
CH2Cl2 (1:1) gave a crude triflate, which was used without
further purification. To a suspension of CuI (6.9 mg, 0.036 mmol)
in THF (0.9 mL) was added dropwise a solution of Ph(CH2)2-
MgCl in THF (1.0 M; 0.90 mL, 0.90 mmol) at -78 °C under
argon. The mixture was allowed to warm to 0 °C and was stirred
for 10 min at this temperature. To the mixture of the resulting
cuprate was added dropwise a solution of the above triflate in
THF (1.3 mL) at -78 °C, and the mixture was allowed to warm
to room temperature. After being stirred for 1.5 h at this
temperature, the mixture was quenched by addition of saturated
NH4Cl and 28% NH4OH. The whole was extracted with Et2O,
and the extract was washed with H2O and brine and dried over
Na2SO4. Concentration under reduced pressure followed by
flash chromatography over silica gel with n-hexane-EtOAc
(1:1) and then over Chromatorex with n-hexane-AcOEt (2:1)
gave 26a as a colorless oil (42.2 mg, 76% yield): Rf 0.35
(n-hexane/EtOAc = 2:3); [R]26 þ97.7 (c 1.49, CHCl3); IR
D
(neat) 1650 (CdN); 1H NMR (500 MHz, CDCl3) δ 1.77-1.83
(m, 2H), 1.81-1.89 (m, 2H), 2.63-2.70 (m, 1H), 2.71-2.77 (m,
1H), 3.60-3.64 (m, 1H), 3.70 (dd, J=9.7, 5.4 Hz, 1H), 4.09 (d,
J=9.7 Hz, 1H), 4.81 (dd, J=7.7, 5.4 Hz, 1H), 4.96 (dd, J=7.7,
3.7 Hz, 1H), 7.17-7.23 (m, 3H), 7.28 (dd, J=7.4, 7.4 Hz, 2H),
7.38 (dd, J=7.7, 7.7 Hz, 2H), 7.46 (t, J=7.7 Hz, 1H), 7.85 (d,
J=7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 27.8, 28.4, 35.9,
72.7, 73.2, 83.5, 83.8, 125.8, 127.2, 128.3 (4C), 128.5 (4C), 131.4,
142.1, 164.3; HRMS (FAB) calcd for C20H22NO2 (MHþ)
308.1651, found 308.1655.
Conclusion
We have developed a novel ring-construction/stereoselec-
tive functionalization cascade by palladium(0)-catalyzed bis-
cyclization of bromoallenes and propargylic carbonates/
chlorides. The bromoallene cyclization was expanded to
divergent synthesis of various pachastrissamine derivatives
with different alkyl groups at the pachastrissamine C-2
position. When using propargylic compounds, a reactivity
(1S,4S,7S)-5-(4-Phenylhepta-1,6-dien-4-yl)-2-oxa-5-azabicyclo-
[2.2.1]heptan-7-ol (27) (Table 2, Entry 2). By a procedure iden-
tical with that described for synthesis of 26a from 24, the alcohol
24 (40 mg, 0.18 mmol) was converted into the corresponding
crude triflate, which was used without further purification. To a
mixture of allylMgBr in Et2O (1.0 M; 0.90 mL, 0.90 mmol) in
THF (1.6 mL) was added dropwise a solution of the above
triflate in THF (1.1 mL) at -30 °C under argon. After being
stirred for 1.5 h at this temperature, the mixture was quenched
(49) (a) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem.
1977, 141, 205–215. (b) Crabtree, R. H.; Davis, M. W. J. Org. Chem. 1986, 51,
2655–2661.
(50) (a) Nordin, I. C. J. Heterocycl. Chem. 1966, 3, 531–532. (b) Wilson,
S. R.; Mao, D. T.; Khatri, H. N. Synth. Commun. 1980, 10, 17–23. (c) Meyers,
A. I.; Himmelsbach, R. J.; Reuman, M. J. Org. Chem. 1983, 48, 4053–4058.
(d) Nagamitsu, T.; Sunazuka, T.; Tanaka, H.; Omura, S.; Sprengeler, P. A.;
Smith, A. B., III. J. Am. Chem. Soc. 1996, 118, 3584–3590. (e) Feldman, K. S.;
Cutarelli, T. D; Florio, R. D. J. Org. Chem. 2002, 67, 8528–8537.
J. Org. Chem. Vol. 75, No. 11, 2010 3839

Inuki et al.
JOCArticle
SCHEME 10. Straightforward Total Synthesis of Pachastrissamine (20)
with saturated NH4Cl. The whole was extracted with Et2O, and
the extract was washed with H2O and brine and dried over
Na2SO4. Concentration under reduced pressure followed by
flash chromatography over silica gel with n-hexane-EtOAc
(3:2) gave 27 as a colorless oil (46.5 mg, 91% yield): Rf 0.88 (n-
164.3; HRMS (FAB) calcd for C15H18NO2 (MHþ) 244.1338,
found 244.1338.
tert-Butyl (S)-4-[(S)-1-Hydroxyhexadec-2-yn-1-yl]-2,2-dimethyl-
oxazolidine-3-carboxylate (syn-35). To a solution of pentadec-
1-yne (562 mg, 2.70 mmol) in Et2O (5 mL) was added dropwise
n-BuLi in hexane (1.6 M; 1.64 mL, 2.61 mmol) at -20 °C. After
the resulting white suspension was stirred for 1 h at this
temperature, a solution of ZnBr2 in Et2O (ca. 1.0 M; 2.78 mL,
2.78 mmol) was added at 0 °C. After being stirred for 1 h at this
temperature and for 1 h at room temperature, a solution of
Garner’s aldehyde 21 (200 mg, 0.87 mmol) in Et2O (0.75 mL)
was added dropwise at -78 °C. The mixture was allowed to
warm to room temperature. After being stirred for 12 h at this
temperature, the mixture was quenched by addition of saturated
NH4Cl at -20 °C. After dilution with H2O, the aqueous layer
was separated and extracted with Et2O. The combined Et2O
extracts were washed with brine and dried over MgSO4. The
filtrate was concentrated under reduced pressure to give a color-
less oil, which was purified by flash chromatography over silica
gel with n-hexane-EtOAc (7:1) to give syn-35 as a colorless oil
(315 mg, 83% yield, dr > 95:5): Rf 0.48 (n-hexane/EtOAc=4:1);
[R]25D -32.3 (c1.29, CHCl3) [lit.23 [R]25D -32.4 (c1.3, CHCl3)]. All
of the spectral data were in agreement with those reported by
Herold.23
hexane/EtOAc = 1:2); [R]25 þ35.9 (c 1.61, CHCl3); IR (neat)
D
3445 (OH); 1H NMR (500 MHz, CDCl3) δ 2.79 (dd, J=14.6, 8.6
Hz, 2H), 2.85 (dd, J=14.6, 8.3 Hz, 2H), 2.97 (d, J=9.5 Hz, 1H),
2.90-2.99 (m, 1H), 3.13 (d, J = 8.0 Hz, 1H), 3.16 (dd, J = 9.5,
2.3 Hz, 1H), 3.38-3.40 (m, 1H), 3.52 (dd, J=8.0, 1.7 Hz, 1H),
3.96 (dd, J = 2.3, 2.3 Hz, 1H), 4.02-4.04 (m, 1H), 5.09 (d,
J= 10.3 Hz, 1H), 5.12 (d, J= 10.3 Hz, 1H), 5.17 (d, J= 16.6 Hz,
2H), 5.68-5.79 (m, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.36 (dd,
J = 7.4, 7.4 Hz, 2H), 7.46 (d, J = 7.4 Hz, 2H); 13C NMR (125
MHz, CDCl3) δ 39.3, 39.6, 49.0, 59.0, 60.4, 70.5, 73.8, 77.9,
118.3, 118.5, 126.6 (2C), 127.3, 128.5 (2C), 133.8 (2C), 141.7;
HRMS (FAB) calcd for C18H24NO2 (MHþ) 286.1807, found
286.1805.
(3aS,6S,6aS)-6-(But-3-enyl)-2-phenyl-3a,4,6,6a-tetrahydrofuro-
[3,4-d]oxazole (26e) (Table 2, Entry 3). By a procedure identical
with that described for synthesis of 26a from 24, the alcohol 24
(40 mg, 0.18 mmol) was converted into the corresponding crude
triflate, which was used without further purification. To a sus-
pension of CuCN (71.6 mg, 0.72 mmol) in THF (2.0 mL) was
added dropwise a solution of MeLi in Et2O (1.06 M; 1.36 mL,
1.44 mmol) at -78 °C under argon. The mixture was allowed to
warm to 0 °C and was stirred for 10 min at this temperature. To
the mixture was added dropwise allyltributylstannane (0.45 mL,
1.44 mmol) at -78 °C, and the mixture was allowed to warm to
room temperature. The mixture was stirred for 30 min at this
temperature. To the mixture of the resulting cuprate was added
dropwise a solution of the above triflate in THF (1.1 mL) at
-78 °C. After being stirred for 30 min at this temperature, the
mixture was quenched with saturated NH4Cl and 28% NH4OH.
The whole was extracted with Et2O, and the extract was washed
with H2O and brine and dried over Na2SO4. Concentration
under reduced pressure followed by flash chromatography over
silica gel with n-hexane-EtOAc (10:1 to 2:3) gave 26e as a white
waxy solid (14.0 mg, 32% yield): Rf 0.70 (n-hexane/EtOAc =
3:1); mp 55-56 °C; [R]24D þ91.7 (c 0.50, CHCl3); IR (neat) 1651
(CdN); 1H NMR (500 MHz, CDCl3) δ 1.82-1.94 (m, 2H),
2.22-2.35 (m, 2H), 3.65 (ddd, J = 6.9, 6.9, 3.4 Hz, 1H), 3.72
(dd, J=9.7, 5.4 Hz, 1H), 4.12 (d, J=9.7 Hz, 1H), 4.84 (dd, J=7.7,
5.4 Hz, 1H), 5.00 (dd, J=7.7, 3.4 Hz, 1H), 5.02 (d, J=10.3 Hz,
1H), 5.10 (d, J=16.6 Hz, 1H), 5.88 (ddd, J=16.6, 10.3, 6.8 Hz,
1H), 7.41 (dd, J=7.7, 7.7 Hz, 2H), 7.48 (t, J=7.7 Hz, 1H), 7.93
(d, J=7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 28.0, 30.3,
72.8, 73.2, 83.2, 83.5, 115.1, 127.3, 128.3 (4C), 131.4, 138.0,
tert-Butyl (S)-4-[(S)-1-(Methoxycarbonyloxy)hexadec-2-yn-1-yl]-
2,2-dimethyloxazolidine-3-carboxylate (syn-36). To a stirred solu-
tion of syn-35 (1.00 g, 2.28 mmol) in CH2Cl2 (8.0 mL) were added
pyridine (1.11 mL, 13.7 mmol), DMAP (55.7 mg, 0.46 mmol), and
ClCO2Me (1.06 mL, 13.7 mmol) at 0 °C, and the mixture was
stirred for 1.5 h at room temperature, followed by quenching with
saturated NH4Cl. The whole was extracted with EtOAc. The
extract was washed with H2O and brine, dried over MgSO4, and
concentrated under pressure to give an oily residue, which was
purified by column chromatography over silica gel with n-hexane-
EtOAc (11:1) to give syn-36 as a colorless oil (1.06 g, 94% yield):
Rf 0.78 (n-hexane/EtOAc = 4:1); [R]25 -23.4 (c 1.10, CHCl3);
D
IR (neat) 2247 (CtC), 1757 (CdO), 1705 (CdO); 1H NMR (500
MHz, DMSO, 100 °C) δ 0.86 (t, J= 6.9 Hz, 3H), 1.22-1.38 (m,
20H), 1.43 (s, 3H), 1.43 (s, 9H), 1.44-1.47 (m, 2H), 1.52 (s, 3H),
2.20 (td, J = 6.9, 2.3 Hz, 2H), 3.72 (s, 3H), 3.98 (dd,
J = 9.2, 3.4 Hz, 1H), 3.99-4.02 (m, 1H), 4.02-4.07 (m, 1H),
5.59 (dt, J=5.1, 2.3 Hz, 1H); 13C NMR (125 MHz, CDCl3; as a
mixture of amide rotamers) δ 14.1, 18.8, 22.6, 23.4, 24.7, 26.0, 26.8,
28.2, 28.3, 28.8, 29.0, 29.3 (2C), 29.4, 29.6 (3C), 31.8, 54.9, 58.7
(0.5C), 59.3 (0.5C), 64.4 (0.5C), 64.7 (0.5C), 68.0 (0.5C), 68.4
(0.5C), 73.9, 80.5, 88.6 (0.5C), 89.0 (0.5C), 94.3 (0.5C), 94.9 (0.5C),
151.7, 154.5 (0.5C), 154.6 (0.5C). Anal. Calcd for C28H49NO6: C,
67.84; H, 9.96; N, 2.83. Found: C, 67.90; H, 9.68; N, 2.79.
3840 J. Org. Chem. Vol. 75, No. 11, 2010

Inuki et al.
JOCArticle
(2S,3S)-2-Benzamido-1-hydroxyoctadec-4-yn-3-yl Methyl Carbo-
nate (syn-37). To a stirred solution of syn-36 (963 mg, 1.94 mmol)
in MeOH (6.5 mL) at 0 °C was added trifluoroacetic acid (18 mL),
and the mixture was stirred for 1.5 h at 50 °C. The mixture was
concentrated under reduced pressure, and the residue was dissolved
in CH2Cl2 (18 mL). The solution was made neutral with
(i-Pr)2NEt at 0 °C. (i-Pr)2NEt (1.18 mL, 6.79 mmol) and BzCl
(0.248 mL, 2.13 mmol) were added to the mixture under stirring at
0°C. The mixture was stirred for 2.5 h at this temperature, followed
by addition of H2O. The whole was extracted with EtOAc. The
extract was washed successively with 1 N HCl, H2O and brine and
dried over Na2SO4. The filtrate was concentrated under reduced
pressure to give an oily residue, which was purified by flash chro-
matography over silica gel with n-hexane-EtOAc (3:2) to give syn-
37 as a pale yellow oil (664 mg, 74% yield): Rf 0.55 (n-hexane/
EtOAc=1:1); [R]25D þ33.3 (c 1.43, CHCl3); IR (neat) 3380 (OH),
0.095 mmol) in THF/MeOH (1.0 mL, 10:1) were added Pd(PPh3)4
(11.0 mg, 0.0095 mmol) and Cs2CO3 (37.1 mg, 0.114 mmol) at room
temperature under argon. The mixture was stirred for 1.0 h at 50 °C
and filtered through a short pad of SiO2 with EtOAc. The filtrate
was concentrated under reduced pressure to give a yellow oil, which
was purified by flash chromatography over silica gel with n-hex-
ane-EtOAc (4:1) to give (E)-44 as a white solid (32.4 mg, 89%
yield): Rf 0.45 (n-hexane/EtOAc = 2:1); mp 79-80 °C; [R]24
D
1
þ253.32 (c 1.38, CHCl3); IR (neat) 1647 (CdN); H NMR (500
MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H), 1.20-1.47 (m, 22H),
2.13-2.26 (m, 2H), 4.19 (dd, J=9.5, 6.3 Hz, 1H), 4.27 (dd, J=9.5,
1.7 Hz, 1H), 4.91 (ddd, J=8.0, 6.3, 1.7 Hz, 1H), 5.09 (t, J=8.0 Hz,
1H), 5.58 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.4, 7.4 Hz, 2H), 7.48 (t,
J = 7.4 Hz, 1H), 7.93 (d, J = 7.4 Hz, 2H); 13C NMR (125 MHz,
CDCl3) δ 14.1, 22.7, 27.0, 29.2, 29.4, 29.6, 29.7 (5C), 30.4, 31.9, 70.6,
74.9, 79.0, 105.0, 127.2, 128.3 (2C), 128.5 (2C), 131.6, 154.2, 164.2.
Anal. Calcd for C25H37NO2: C, 78.28; H, 9.72; N, 3.65. Found: C,
77.99; H, 9.80; N, 3.67.
1
2237 (CtC), 1755 (CdO), 1650 (CdO); H NMR (500 MHz,
CDCl3) δ0.88 (t, J=6.6 Hz, 3H), 1.19-1.35 (m, 20H), 1.47 (tt, J=
7.2, 7.2 Hz, 2H), 2.20 (td, J=7.2, 1.7 Hz, 2H), 2.55 (br s, 1H), 3.80
(dd, J=11.5, 5.2 Hz, 1H), 3.81 (s, 3H), 4.02 (dd, J=11.5, 4.6 Hz,
1H), 4.45-4.52 (m, 1H), 5.60-5.66 (m, 1H), 6.66 (d, J=8.0 Hz,
1H), 7.44 (dd, J=7.4, 7.4 Hz, 2H), 7.52 (t, J=7.4 Hz, 1H), 7.80 (d,
J=7.4 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 14.1, 18.7, 22.7,
28.2, 28.8, 29.1, 29.3, 29.4, 29.6 (3C), 29.7, 31.9, 54.4, 55.2, 61.8,
67.5, 74.3, 89.7, 127.1, 128.6 (2C), 131.8 (2C), 133.9, 154.9, 167.8;
HRMS (FAB) calcd for C27H42NO5 (MHþ) 460.3063, found
460.3068.
General Procedure for Palladium-Catalyzed Cascade Cycliza-
tion of Propargyl Carbonates: Synthesis of (3aS,6aS,E)-2-Phenyl-
6-tetradecylidene-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazole ((E)-44)
from syn-37 (Table 5, Entry 2). To a stirred mixture of syn-37
(40 mg, 0.087 mmol) in THF (0.9 mL) was added Pd(PPh3)4
(5.03 mg, 0.0044 mmol) at room temperature under argon. After
the mixture was stirred for 2.0 h at 50 °C, concentration under
reduced pressure gave a yellow oil, which was purified by flash
chromatography over silica gel with n-hexane-EtOAc (4:1) to
give (E)-44 as a white solid (23.1 mg, 69% yield).
tert-Butyl (S)-4-[(R)-1-Chlorohexadec-2-yn-1-yl]-2,2-dimethyloxa-
zolidine-3-carboxylate (syn-38) (Table 3, Entry 4). To a stirred
solution of syn-35 (2.00 g, 4.57 mmol) and imidazole (1.25 g, 18.3
mmol) in CH2Cl2 (8.0 mL) was added a solution of Ph3PCl2
(6.09 g, 18.3 mmol) in CH2Cl2 (12 mL) at 0 °C. After the solution
was stirred for 1.0 h at this temperature, concentration under
reduced pressure gave an oily residue, which was purified by
flash chromatography over silica gel with n-hexane-EtOAc
(30:1) to give syn-38 as a colorless oil (618 mg, 30% yield);
Rf 0.83 (n-hexane/EtOAc = 4:1); [R]24D -96.7 (c 1.17, CHCl3);
IR (neat): 2246 (CtC), 1694 (CdO); 1H NMR (500 MHz,
DMSO, 100 °C) δ 0.86 (t, J = 6.9 Hz, 3H), 1.20-1.38 (m, 20H),
1.43 (s, 3H), 1.44 (s, 9H), 1.45-1.48 (m, 2H), 1.53 (s, 3H), 2.23
(td, J=6.9, 2.3 Hz, 2H), 4.05-4.12 (m, 3H), 5.02-5.09 (m, 1H);
13C NMR (125 MHz, CDCl3; as a mixture of amide rotamers) δ
14.1, 18.9, 22.7, 23.5, 24.9, 25.9, 26.5, 28.2, 28.3, 28.4, 28.8, 29.1,
29.3, 29.5, 29.6 (2C), 29.7, 31.9, 48.1 (0.5C), 49.0 (0.5C), 61.9
(0.5C), 62.2 (0.5C), 64.5 (0.5C), 64.9 (0.5C), 75.0 (0.5C), 75.4
(0.5C), 80.6 (0.5C), 80.8 (0.5C), 89.0 (0.5C), 89.5 (0.5C), 94.8
(0.5C), 95.5 (0.5C), 151.5 (0.5C), 152.5 (0.5C); HRMS (FAB)
calcd for C26H47ClNO3 (MHþ) 456.3244, found 456.3248.
N-[(2S,3R)-3-Chloro-1-hydroxyoctadec-4-yn-2-yl]benzamide
(syn-41). By a procedure identical with that described for the syn-
thesis of the benzamide syn-37 from syn-36, the carbamate syn-
38 (49.1 mg, 0.108 mmol) was converted into syn-41 (31.3 mg,
69% yield): white waxy solid; Rf 0.68 (n-hexane/EtOAc =1:1);
(3aS,6aS,Z)-2-Phenyl-6-tetradecylidene-3a,4,6,6a-tetrahydrofuro-
[3,4-d]oxazole ((Z)-44) (Table 4, Entry 3). To a stirred mixture of
syn-41 (40 mg, 0.095 mmol) in THF/MeOH (1.0 mL, 10:1) was
added Pd(PPh3)4 (5.03 mg, 0.0048 mmol) at room temperature
under argon. After the mixture was stirred for 1.5 h at 50 °C,
concentration under reduced pressure gave a yellow oil, which
was purified by flash chromatography over silica gel with
n-hexane-EtOAc (4:1) to give an isomeric mixture 44 (E/Z =
54:46) as a white solid (7.7 mg, 21% yield). This mixture was
separated by PTLC with hexane-EtOAc (2:1) to give (Z)-44 in a
pure form: pale yellow oil; Rf 0.55 (n-hexane/EtOAc = 2:1);
[R]24 þ143.68 (c 0.36, CHCl3); IR (neat) 1646 (CdN); 1H
D
NMR (500 MHz, CDCl3) δ 0.88 (t, J=6.9 Hz, 3H), 1.20-1.40
(m, 22H), 2.02-2.20 (m, 2H), 4.25 (dd, J=9.5, 6.3 Hz, 1H), 4.32
(dd, J=9.5, 2.0 Hz, 1H), 4.81 (t, J=7.2 Hz, 1H), 4.89 (ddd, J=
8.6, 6.3, 2.0 Hz, 1H), 5.37 (d, J=8.6 Hz, 1H), 7.41 (dd, J=7.4,
7.4 Hz, 2H), 7.48 (t, J=7.4 Hz, 1H), 7.94 (d, J=7.4 Hz, 2H); 13C
NMR (125 MHz, CDCl3) δ 14.1, 22.7, 25.4, 29.3, 29.5 (2C), 29.6
(5C), 29.7, 31.9, 70.2, 75.9, 82.3, 106.0, 127.3, 128.3 (2C), 128.5
(2C), 131.5, 153.7, 164.3; HRMS (FAB) calcd for C25H38NO2
(MHþ) 384.2903, found 384.2900.
(3aS,6S,6aS)-2-Phenyl-6-tetradecyl-3a,4,6,6a-tetrahydrofuro-
[3,4-d]oxazole (25) (Table 6, Entry 6). Amixtureof(E)-44 (50.0 mg,
0.13 mmol) and (Ph3P)3RhCl (12.1 mg, 0.013 mmol) in C6H6/
EtOH (1.3 mL, 1:1) was stirred for 25 h at 50 °C under H2 and
then filtered through a short pad of SiO2 with EtOAc. The
filtrate was concentrated under reduced pressure to give a
brown solid, which was purified by flash chromatography
over silica gel with n-hexane-EtOAc (3:1) to give 25 as a
white solid (41.1 mg, 82% yield): Rf 0.40 (n-hexane/EtOAc =
1:3); [R]24D þ65.4 (c 1.38, CHCl3) [lit.20a [R]24D þ60.9 (c 1.05,
CHCl3)]. All of the spectral data were in agreement with those
of our previous report.20a
mp 60-61 °C; [R]24 -22.7 (c 1.20, CHCl3); IR (neat) 3335
D
(OH), 2237 (CtC), 1653 (CdO); 1H NMR (500 MHz, CDCl3) δ
0.88 (t, J=6.9 Hz, 3H), 1.19-1.35 (m, 20H), 1.47 (tt, J=7.4, 7.4
Hz, 2H), 2.22 (td, J=7.4, 1.1 Hz, 2H), 3.85 (dd, J=11.7, 5.7 Hz,
1H), 4.16 (dd, J = 11.7, 4.3 Hz, 1H), 4.42-4.49 (m, 1H),
5.03-5.07 (m, 1H), 6.72 (d, J = 7.4 Hz, 1H), 7.46 (dd, J = 8.0,
8.0 Hz, 2H), 7.54 (t, J=8.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 2H); 13
C
NMR (125 MHz, CDCl3) δ 14.1, 18.8, 22.7, 28.2, 28.8, 29.1,
29.3, 29.4, 29.6 (3C), 29.7, 31.9, 49.2, 55.8, 61.9, 76.0, 89.9, 127.1,
128.7 (2C), 131.9 (2C), 133.8, 167.8; HRMS (FAB) calcd for
C25H39ClNO2 (MHþ) 420.2669, found 420.2671.
General Procedure for Palladium-Catalyzed Cascade Cycliza-
tion of Propargyl Chlorides: Synthesis of (3aS,6aS,E)-2-Phenyl-
6-tetradecylidene-3a,4,6,6a-tetrahydrofuro[3,4-d]oxazole ((E)-44)
from syn-41 (Table 4, Entry 6). To a stirred mixture of syn-41 (40mg,
(2S,3S,4S)-4-(Benzylamino)-2-tetradecyltetrahydrofuran-3-ol
(N-Benzylpachastrissamine) (45). To a stirred solution of 25 (120mg,
0.31 mmol) in CH2Cl2 (6.0 mL) was added DIBAL-H in toluene
(1.01 M; 1.24 mL, 1.24 mmol) at 0 °C. After being stirred for 20 min
at this temperature, the mixture was allowed to warm to room
temperature. The mixture was stirred for 2.0 h at this temperature
and quenched with 2 N Rochelle salt. After being stirred for 3.0 h, the
J. Org. Chem. Vol. 75, No. 11, 2010 3841

Inuki et al.
JOCArticle
whole was extracted with EtOAc. The extract was washed with brine
and dried over Na2SO4. Concentration under reduced pressure
followed by flash chromatography over silica gel with CHCl3-
MeOH (15:1) gave 45 as a white solid: Rf 0.63 (CHCl3/MeOH=9:1);
mp 72-73 °C; [R]25D þ14.5 (c0.99, CHCl3);IR(neat) 3334(NHand
86% yield): Rf 0.55 (EtOAc/MeOH=9:1); [R]25D þ18.9 (c 0.77,
EtOH) [lit.20a [R]25 þ19.7 (c 0.62, EtOH)]. All of the spectral
D
data were in agreement with those of our previous report.20a
1
Acknowledgment. This work was supported by a Grant-in-
Aid for Encouragement of Young Scientists (A) (H.O.) and
Targeted Proteins Research Program from the Ministry
of Education, Culture, Sports, Science and Technology of
Japan, as well as the Program for Promotion of Fundamen-
tal Studies in Health Sciences of the National Institute of
Biomedical Innovation (NIBIO). S.I. is grateful for Research
Fellowships from the Japan Society for the Promotion of
Science (JSPS) for Young Scientists.
OH); H NMR (500 MHz, CDCl3) δ 0.88 (t, J = 6.9 Hz, 3H),
1.22-1.43 (m, 24H), 1.62-1.75 (m, 2H), 2.39-2.90 (m, 2H), 3.44
(ddd, J=7.4, 7.4, 4.6 Hz, 1H), 3.55 (dd, J=8.6, 7.4 Hz, 1H), 3.70
(ddd, J=6.9, 6.9, 2.9 Hz, 1H), 3.77 (d, J=13.2 Hz, 1H), 3.84 (d, J=
13.2 Hz, 1H), 3.89-3.92 (m, 1H), 3.91-3.94 (m, 1H), 7.26-7.37 (m,
5H); 13C NMR (125 MHz, CDCl3) δ 14.1, 22.7, 26.3, 29.3, 29.4, 29.6
(5C), 29.7 (2C), 29.8, 31.9, 52.7, 61.2, 69.7, 70.4, 83.5, 127.5, 128.1
(2C), 128.6(2C), 139.2;HRMS(FAB) calcdforC25H44NO2 (MHþ)
390.3372, found 390.3372.
(2S,3S,4S)-4-Amino-2-tetradecyltetrahydrofuran-3-ol (Pacha-
strissamine) (20). A mixture of 45 (20.0 mg, 0.051 mmol) and
20% w/w Pd(OH)2/C (3.6 mg, 0.0051 mmol) in EtOAc (0.8 mL)
was stirred at 50 °C under H2. After the mixture was stirred for
12 h, further EtOAc (0.4 mL) was added to stirred mixture. The
mixture was stirred for 9 h at 50 °C and filtered through a short
pad of Celite with EtOAc. The filtrate was concentrated under
reduced pressure to give a white solid, which was purified by
flash chromatography over silica gel with CHCl3-MeOH-
28% NH4OH (95:4:1) to give 20 as a white solid (13.1 mg,
Note Added after ASAP Publication. Scheme 1 was incorrect
in the version published ASAP May 10, 2010; the correct version
reposted May 12, 2010.
Supporting Information Available: Experimental proce-
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
3842 J. Org. Chem. Vol. 75, No. 11, 2010