Catalytic asymmetric synthesis of the endo -6-Aryl-8-oxabicyclo[3.2.1]oct- 3-en-2-one natural product from ligusticum chuanxing via 1,3-dipolar cycloaddition of a formyl-derived carbonyl ylide using Rh2(S -TCPTTL)4

Article abstract of DOI:10.1021/jo101175b

The reaction of a six-membered cyclic formyl-carbonyl ylide derived from α-diazo-β-ketoester with phenylacetylene derivatives under the catalysis of dirhodium(II) tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh₂(S-TCPTTL)₄, provides cycloadducts containing an 8-oxabicyclo[3.2.1]octane ring system in up to 97% ee. This represents the first example of an enantioselective 1,3-dipolar cycloaddition of a cyclic formyl-carbonyl ylide. Using this catalytic process, an asymmetric synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product 1 from Ligusticum chuanxing Hort. has been achieved.

Full text of DOI:10.1021/jo101175b

pubs.acs.org/joc
reported concise total syntheses of natural products (()-
Catalytic Asymmetric Synthesis of the endo-6-Aryl-8-
oxabicyclo[3.2.1]oct-3-en-2-one Natural Product
from Ligusticum chuanxing via 1,3-Dipolar
Cycloaddition of a Formyl-Derived Carbonyl Ylide
Using Rh2(S-TCPTTL)4
1-3, in which the fully functionalized 8-oxabicyclo[3.2.1]-
octenone skeletons were efficiently constructed by a possibly
biomimetic [5 þ 2] cycloaddition of oxidopyrylium ion.4
Naoyuki Shimada,† Taiki Hanari,† Yasunobu Kurosaki,†
Koji Takeda,† Masahiro Anada,† Hisanori Nambu,†
Motoo Shiro,‡ and Shunichi Hashimoto*,†
†Faculty of Pharmaceutical Sciences, Hokkaido University,
Sapporo 060-0812, Japan, and Rigaku Corporation,
Akishima, Tokyo 196-8666, Japan
‡
The 8-oxabicyclo[3.2.1]octane skeleton is a key structural
unit found in a large and diverse array of biologically interesting
and medicinally important natural products.5 Although several
strategies have been developed to achieve the asymmetric
synthesis of this ring system,6,7 catalytic enantioselective var-
iants have been limited to date. Davies and co-workers devel-
oped an asymmetric entry to 8-oxabicyclo[3.2.1]octadienes by
using a tandem cyclopropanation/Cope rearrangement be-
tween vinylcarbenoides and furans in the presence of the chiral
dirhodium(II) catalyst Rh2(S-TBSP)4 (5) (Figure 1), in which
enantioselectivities up to 80% ee were achieved.8 The Harmata9
and Hsung10 groups recently reported that enantioselective
[4 þ 3] cycloaddition reactions of oxyallyl cation equivalents
with furans catalyzed by chiral amine or chiral Lewis acid gave
synthetically useful 8-oxabicyclo[3.2.1]oct-6-en-3-ones6a in up
to 90% and 99% ee, respectively.
hsmt@pharm.hokudai.ac.jp
Received June 16, 2010
The dirhodium(II) complex-catalyzed tandem cyclic car-
bonyl ylide formation/1,3-dipolar cycloaddition reaction
sequence represents one of the most efficient methods for
the rapid assembly of complex oxapolycyclic systems.11
The exceptional power of the carbonyl ylide cycloaddition
The reaction of a six-membered cyclic formyl-carbonyl ylide
derived from R-diazo-β-ketoester with phenylacetylene deri-
vatives under the catalysis of dirhodium(II) tetrakis[N-tetra-
chlorophthaloyl-(S)-tert-leucinate], Rh2(S-TCPTTL)4, pro-
vides cycloadducts containing an 8-oxabicyclo[3.2.1]octane
ring system in up to 97% ee. This represents the first example
of an enantioselective 1,3-dipolar cycloaddition of a cyclic
formyl-carbonyl ylide. Using this catalytic process, an asym-
metric synthesis of endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-
2-one natural product 1 from Ligusticum chuanxing Hort.
has been achieved.
(4) (a) Snider, B. B.; Grabowski, J. F. Tetrahedron Lett. 2005, 46, 823–
825. (b) Snider, B. B.; Grabowski, J. F. Tetrahedron 2006, 62, 5171–5177.
(5) (a) Aoki, S.; Watanabe, Y.; Sanagawa, M.; Setiawan, A.; Kotoku, N.;
Kobayashi, M. J. Am. Chem. Soc. 2006, 128, 3148–3149. (b) Singh, S. B.;
Jayasuriya, H.; Ondeyka, J. G.; Herath, K. B.; Zhang, C.; Zink, D. L.; Tsou,
N. N.; Ball, R. G.; Basilio, A.; Genilloud, O.; Diez, M. T.; Vicente, F.;
Pelaez, F.; Young, K.; Wang, J. J. Am. Chem. Soc. 2006, 128, 11916–11920.
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Wang, H.; Gu, Q. Eur. J. Org. Chem. 2009, 3045–3051. (e) Thuong, P.-T.;
Dao, T.-T.; Pham, T.-H.-M.; Nguyen, P.-H.; Le, T.-V.-T.; Lee, K.-Y.; Oh,
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Chem., Int. Ed. 2004, 43, 1934–1949. (b) Harmata, M. Adv. Synth. Catal.
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In 1986, Wen, He, Xue, and Cao reported isolation of
the endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural
product 1 from Ligusticum chuanxing Hort.,1 which is much
used as a traditional Chinese medicine to promote blood
circulation. Descurainin (2)2 and cartorimine (3),3 possessing
the same ring system, were isolated from Descurainia sophia
(L.) Webb ex Prantl and Carthamus tinctorius L. by the Li and
He groups, respectively. Recently, Snider and Grabowski
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DOI: 10.1021/jo101175b
r
Published on Web 08/11/2010
J. Org. Chem. 2010, 75, 6039–6042 6039
2010 American Chemical Society

Shimada et al.
SCHEME 1. Retrosynthetic Analysis of Natural Product 1
JOCNote
FIGURE 1. Chiral dirhodium(II) complexes.
strategy has recently been demonstrated by an increasing
number of syntheses of diverse natural products.12,13 Over
the past decade, an enantioselective version of this sequence
catalyzed by chiral dirhodium(II) complexes has also been
realized in some selected reactions.14-16 Recently, we reported
that catalytic enantioselective cycloadditions of 2-diazo-3,6-
diketoester-derived carbonyl ylides with arylacetylene,
alkoxyacetylene, and styrene dipolarophiles using dirhodium(II)
tetrakis[N-tetrachlorophthaloyl-(S)-tert-leucinate], Rh2(S-
TCPTTL)4 (4),17,18 provide 8-oxabicyclo[3.2.1]octane deri-
vatives in good to high yields and with enantioselectivities
of up to 99% ee as well as with perfect exo diastereoselec-
tivity for styrenes.19 In order to demonstrate the utility of
this catalytic process, we addressed asymmetric synthesis of
natural product 1, focusing on the cycloaddition of a formyl-
derived cyclic carbonyl ylide with phenylacetylene derivatives
under the catalysis of Rh2(S-TCPTTL)4 (4).
Our synthetic strategy for 1 based on the enantioselec-
tive 1,3-dipolar cycloaddition is outlined retrosynthetically
in Scheme 1. We envisaged that natural product 1 would
be accessible from bicyclic compound 6 bearing all of the
stereogenic centers of 1. It was anticipated that 6 might be
formed by a catalytic hydrogenation of appropriately pro-
tected 8-oxabicyclo[3.2.1]oct-6-en-2-ones 7 in a stereocon-
trolled manner.20 As mentioned above,19 we envisioned that
Rh2(S-TCPTTL)4-catalyzed reaction of tert-butyl 2-diazo-
5-formyl-3-oxopentanoate (8) with phenylacetylene deriva-
tive 9 would provide cycloadducts 7. While a variety of
1,3-dipolar cycloadditions of keto- or ester-derived cyclic
carbonyl ylides have been reported,11 only one example of a
cyclic formyl-carbonyl ylide cycloaddition has been reported
so far. Padwa and co-workers reported that the cycloaddi-
tion of benzannulated formyl-carbonyl ylide with dimethyl
acetylenedicarboxylate in the presence of dirhodium(II) tet-
rakis(trifluoroacetate), Rh2(tfa)4, provided cycloadduct in
82% yield.21 However, the use of Rh2(OAc)4 as the catalyst
gave an unusual dimer as the sole product in 63% yield. The
authors suggested that the Rh2(OAc)4-catalyzed reaction
produces a mixture of both the six-membered ring dipole
and the C-H aldehydic insertion product. Consequently, the
(11) For books and reviews on 1,3-dipolar cycloadditions of carbonyl
ylides, see: (a) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223–269.
(b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for
Organic Synthesis with Diazo Compounds; Wiley-Interscience: New York,
1998; Chapter 7. (c) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A.
Chem. Soc. Rev. 2001, 30, 50–61. (d) Mehta, G.; Muthusamy, S. Tetrahedron
2002, 58, 9477–9504. (e) Savizky, R. M.; Austin, D. J. In Modern Rhodium-
Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim,
2005; Chapter 19.
(12) For a book and reviews on the syntheses of natural products by a
carbonyl ylide cycloaddition strategy, see: (a) McMills, M. C.; Wright, D. In
Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward
Heterocycles and Natural Products; Padwa, A., Pearson, W. H., Eds.; John
Wiley & Sons: Hoboken, 2003; Chapter 4. (b) Padwa, A. Helv. Chim. Acta
2005, 88, 1357–1374. (c) Padwa, A. J. Organomet. Chem. 2005, 690, 5533–
5540. (d) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247–12275. (e) Singh,
V.; Krishna, U. M.; Vikrant; Trivedi, G. K. Tetrahedron 2008, 64, 3405–3428.
(f) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072–3081.
(13) For other more recent works, see: (a) Geng, Z.; Chen, B.; Chiu, P.
Angew. Chem., Int. Ed. 2006, 45, 6197–6201. (b) Hirata, Y.; Nakamura, S.;
Watanabe, N.; Kataoka, O.; Kurosaki, T.; Anada, M.; Kitagaki, S.; Shiro,
M.; Hashimoto, S. Chem.;Eur. J. 2006, 12, 8898–8925. (c) England, D. B.;
Padwa, A. Org. Lett. 2007, 9, 3249–3252. (d) England, D. B.; Padwa, A.
J. Org. Chem. 2008, 73, 2792–2802. (e) Lam, S. K.; Chiu, P. Chem.;Eur. J.
2007, 13, 9589–9599. (f) Kim, C. H.; Jang, K. P.; Choi, S. Y.; Chung, Y. K.;
Lee, E. Angew. Chem., Int. Ed. 2008, 47, 4009–4011.
(14) (a) Hodgson, D. M.; Stupple, P. A.; Johnstone, C. Tetrahedron Lett.
1997, 38, 6471–6472. (b) Hodgson, D. M.; Stupple, P. A.; Johnstone, C.
Chem. Commun. 1999, 2185–2186. (c) Hodgson, D. M.; Stupple, P. A.;
Pierard, F. Y. T. M.; Labande, A. H.; Johnstone, C. Chem.;Eur. J. 2001, 7,
4465–4476. (d) Hodgson, D. M.; Glen, R.; Grant, G. H.; Redgrave, A. J.
J. Org. Chem. 2003, 68, 581–586. (e) Hodgson, D. M.; Labande, A. H.;
ꢀ
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Pierard, F. Y. T. M.; Exposito Castro, M. A. J. Org. Chem. 2003, 68, 6153–
6159. (f) Hodgson, D. M.; Bruckl, T.; Glen, R.; Labande, A. H.; Selden,
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D. A.; Dossetter, A. G.; Redgrave, A. J. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5450–5454. (g) Hodgson, D. M.; Glen, R.; Redgrave, A. J. Tetrahedron:
Asymmetry 2009, 20, 754–757.
(15) (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda, C.;
Watanabe, N.; Hashimoto, S. J. Am. Chem. Soc. 1999, 121, 1417–1418. (b)
Kitagaki, S.; Yasugahira, M.; Anada, M.; Nakajima, M.; Hashimoto, S.
Tetrahedron Lett. 2000, 41, 5931–5935. (c) Tsutsui, H.; Shimada, N.; Abe, T.;
Anada, M.; Nakajima, M.; Nakamura, S.; Nambu, H.; Hashimoto, S. Adv.
Synth. Catal. 2007, 349, 521–526. (d) Nambu, H.; Hikime, M.; Krishna-
murthi, J.; Kamiya, M.; Shimada, N.; Hashimoto, S. Tetrahedron Lett. 2009,
50, 3675–3678. (e) Kurosaki, Y.; Shimada, N.; Anada, M.; Nambu, H.;
Hashimoto, S. Bull. Korean Chem. Soc. 2010, 31, 694–696.
(16) Suga and co-workers reported enantioselective 1,3-dipolar cycload-
ditions of carbonyl ylides using chiral Lewis acid catalysts: (a) Suga, H.;
Inoue, K.; Inoue, S.; Kakehi, A. J. Am. Chem. Soc. 2002, 124, 14836–14837.
(b) Suga, H.; Inoue, K.; Inoue, S.; Kakehi, A.; Shiro, M. J. Org. Chem. 2005,
70, 47–56. (c) Suga, H.; Ishimoto, D.; Higuchi, S.; Ohtsuka, M.; Arikawa, T.;
Tsuchida, T.; Kakehi, A.; Baba, T. Org. Lett. 2007, 9, 4359–4362. (d) Suga,
H.; Highchi, S.; Ohtsuka, M.; Ishimoto, D.; Arikawa, T.; Hashimoto, Y.;
Misawa, S.; Tsuchida, T.; Kakehi, A.; Baba, T. Tetrahedron 2010, 66, 3070–
3089.
(17) For the effective use of Rh2(S-TCPTTL)4 (4) in enantioselective
aminations, see: (a) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.;
Hashimoto, S. Tetrahedron Lett. 2002, 43, 9561–9564. (b) Tanaka, M.;
Kurosaki, Y.; Washio, T.; Anada, M.; Hashimoto, S. Tetrahedron Lett.
2007, 48, 8799–8802. (c) Anada, M.; Tanaka, M.; Shimada, N.; Nambu, H.;
Yamawaki, M.; Hashimoto, S. Tetrahedron 2009, 65, 3069–3077.
(18) Charette and co-workers recently reported the highly efficient asym-
metric cyclopropanation with R-nitro diazoacetophenones using Rh2(S-
TCPTTL)4 (4), where the X-ray crystal structure of 4 was determined.
Lindsay, V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131,
16383–16385.
(19) Shimada, N.; Anada, M.; Nakamura, S.; Nambu, H.; Tsutsui, H;
Hashimoto, S. Org. Lett. 2008, 10, 3603–3606.
(20) Hodgson and co-workers reported exo-selective alkene hydrogena-
tion of 8-oxabicyclo[3.2.1]oct-6-en-2-one derivatives. (a) Hodgson, D. M.;
Avery, T. D.; Donohue, A. C. Org. Lett. 2002, 4, 1809–1811. (b) Hodgson,
€
D. M.; Le Strat, F.; Avery, T. D.; Donohue, A. C.; Bruckl, T. J. Org. Chem.
2004, 69, 8796–8803.
(21) Padwa, A.; Preccedo, L.; Semones, M. A. J. Org. Chem. 1999, 64,
4079–4088.
6040 J. Org. Chem. Vol. 75, No. 17, 2010

Shimada et al.
JOCNote
SCHEME 2. Preparation of Formyl-Derived Carbonyl Ylide
Precursor 8
SCHEME 3. Stereoselective Reduction of 7e
TABLE 1. Enantioselective 1,3-Dipolar Cycloaddition of Formyl-
Derived Carbonyl Ylide from 8 with 9a-e Using Rh2(S-TCPTTL)4 (4)
SCHEME 4. Determination of Absolute Configuration of 6a
methylsilyl (TBS)-protected phenylacetylene 9b resulted in
a noticeable drop in both product yield and enantioselec-
tivity (50% yield, 35% ee, entry 2). We found that switching
the dipolarophile to acetyl- or benzyl-protected phenylace-
tylenes 9c and 9d afforded the corresponding cycloadducts 7c
and 7d in higher yields (66% and 72%) and enantioselec-
tivities (81% and 88% ee, respectively) than those found with
9b (entries 3 and 4). Gratifyingly, the reaction with phenyl-
acetylene 9e bearing a free phenolic hydroxy group gave
cycloadduct 7e in 73% yield with 95% ee (entry 5). These
results suggest that the use of phenylacetylenes bearing
sterically less-demanding substituents at the para position
on the benzene ring is crucial for a high level of enantios-
electivity in this reaction.
Hydrogenation of 7e provided exclusively the desired
endo-bicyclic compound 6a as a single diastereomer in 99%
yield (Scheme 3).20 A single recrystallization of 6a from
ethanol-hexane produced optically pure material [mp
105.5-106.5 °C, [R]24D þ103.4 (c 1.02, CHCl3)] in 80% yield.
The absolute configuration of 6a was determined to be
(1R,5R,7R) by single-crystal X-ray analysis of the corre-
sponding carboxylic acid cinchonidine salt 13 (Scheme 4).25
With optically pure compound 6a in hand, the stage was
now set for completion of the asymmetric synthesis of
natural product 1 as illustrated in Scheme 5. Protection of
the phenolic hydroxy group in 6a as the tert-butyldiphenyl-
silyl (TBDPS) ether gave 6b in 99% yield. Treatment of
ketone 6b with NaHMDS at -78 °C followed by addition of
PhNTf2 and subsequent palladium-catalyzed reduction of
the resulting enol triflate26 furnished alkene 14 in 75% yield.
Reduction of tert-butyl ester 14 with LiAlH4 and subsequent
silylation provided bis-TBDPS ether 16 in 85% yield. Allylic
oxidation of 15 with SeO2 gave alcohol 16 as a single
diastereomer in 77% yield, which, upon oxidation with
MnO2, produced enone 17 in 83% yield. Finally, removal
dipolarophile
R1
product
entry
R2
yielda (%)
eeb (%)
1
2
3
4
5
9a
9b
9c
9d
9e
H
H
7a
7b
7c
7d
7e
75
50
66
72
73
97
35
81
88
95
OMe
OMe
OMe
OMe
OTBS
OAc
OBn
OH
aIsolated yield. bDetermined by HPLC. See the Supporting Informa-
tion for details.
development of an enantioselective cycloaddition of formyl-
derived cyclic carbonyl ylide with phenylacetylene deriva-
tives has become a challenging objective.
Toward this end, the formyl-derived cyclic carbonyl ylide
precursor 8 was prepared from γ-butyrolactone (10) as
shown in Scheme 2. Claisen condensation of 10 with the
lithium enolate of tert-butyl acetate in THF gave an equilib-
rium mixture of hemiketal and keto tautomers 11 and 110 in
89% yield,22 which, upon diazo transfer with methanesulfo-
nyl azide, produced R-diazo-β-ketoester 12 in 76% yield.23
Oxidation of 12 with Dess-Martin periodinane afforded
aldehyde 8 in 93% yield.24
On the basis of our previous work,19 we initially evaluated
the reaction of R-diazo-β-ketoester 8 with phenylacetylene
(9a) (3 equiv) as a model system using 1 mol % of Rh2(S-
TCPTTL)4 (4). The reaction in R,R,R-trifluorotoluene at
23 °C proceeded smoothly to give cycloadduct 7a in 75%
yield (Table 1, entry 1). The enantiomeric excess of 7a was
determined to be 97% by HPLC using a Chiralcel OD-H
column. Encouraged by this result, we next examined the
reaction of 8 with a variety of 4-hydroxy-3-methoxypheny-
lacetylenes 9b-e as dipolarophiles. The use of tert-butyldi-
(22) (a) Duggan, A. J.; Adams, M. A.; Brynes, P. J.; Meinwald, J.
Tetrahedron Lett. 1978, 4323–4326. (b) Kobayashi, K.; Minakawa, H.;
Sakurai, H.; Kujime, S.; Suginome, H. J. Chem. Soc., Perkin Trans. 1
1993, 3007–3010.
(23) Taber, D. F.; Ruckle, R. E., Jr.; Hennessy, M. J. J. Org. Chem. 1986,
51, 4077–4078.
(24) For an example of the oxidation with PCC, see: Padwa, A.; Dean,
D. C.; Osterhout, M. H.; Precedo, L.; Semones, M. A. J. Org. Chem. 1994, 59,
5347–5357.
(25) CCDC-778842 (for 13) 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.
(26) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25, 4821–
4824.
J. Org. Chem. Vol. 75, No. 17, 2010 6041

Shimada et al.
JOCNote
SCHEME 5. Synthesis of Natural Product 1
8-oxabicyclo[3.2.1]oct-6-en-2-one derivatives in up to 97% ee.
This is the first example of an enantioselective cycloaddition
of a formyl-derived cyclic carbonyl ylide. Using this catalytic
methodology, we have achieved the asymmetric synthesis of
endo-6-aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one natural product
1 in 13 steps and 11% overall yield from γ-butyrolactone (10).
This represents the first example of a total synthesis of a
natural product using a catalytic enantioselective carbonyl
ylide cycloaddition strategy. Further application of this metho-
dology to asymmetric synthesis of biologically active natural
products containing an 8-oxabicyclo[3.2.1]octane skeleton is
currently in progress.30
Experimental Section
Representative Procedure for the Tandem Carbonyl Ylide
Formation/1,3-Dipolar Cycloaddition (Table 1, Entry 5). A solu-
tion of 8 (452 mg, 2.0 mmol) and 9e (889 mg, 6.0 mmol) in
CF3C6H5 (10 mL) was added via syringe pump over 1 h to a
stirred solution of Rh2(S-TCPTTL)4 (4) (39.5 mg, 0.020 mmol,
1 mol %) in CF3C6H5 (10 mL) at 23 °C. After the addition was
complete, the reaction mixture was concentrated in vacuo, and
the residue was purified by column chromatography (silica gel,
3:1 hexane/EtOAc) to give 7e (505.0 mg, 73%) as a pale yellow
amorphous liquid: Rf = 0.45 (1:1 hexane/AcOEt); [R]22D þ147.1
(c 1.10, CHCl3) for 95% ee; IR (KBr) ν 3437, 2979, 1743, 1208
cm-1; 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 9H), 1.89 (m, 1H),
2.56-2.68 (m, 2H), 2.85 (m, 1H), 3.87 (s, 3H), 5.14 (br d, J = 4.1
Hz, 1H), 5.67 (br, 1H), 6.33 (d, 1H, J = 1.5 Hz), 6.84-6.89 (m,
3H); 13C NMR (100 MHz, CDCl3) δ 27.7, 27.8, 33.7, 55.7, 79.1,
82.8, 93.0, 109.2, 113.8, 119.8, 124.4, 130.0, 143.2, 145.4, 145.6,
163.5, 198.6; HRMS (EI) calcd for C19H22O6 (Mþ) 346.1416,
found 346.1416. The enantiomeric excess of 7e was determined to
be 95% by HPLC with a Chiralpak IA column (9:1 hexane/
i-PrOH, 1.0 mL/min): tR (major) = 17.8 min for (1R,5R)-7e; tR
(minor) = 22.9 min for (1S,5S)-7e.
of two TBDPS protecting groups with TBAF in THF com-
pleted the asymmetric synthesis of 1. The synthetic material 1
exhibited spectroscopic data (1H and 13C NMR, IR, HRMS)
consistent with those reported for natural product 1, except
for their circular dichroism (CD) spectra. The absolute maxi-
mal molar CD of synthetic 1 (Δε - 3.81 at 348 nm) displayed
a startling difference in magnitude to that of natural 1
(Δε þ0.01 at 355 nm).1 This observation suggests that natu-
ral product 1 might be biosynthesized in near-racemic form
like polygalolides A and B.27,28 Our result provides experi-
mental support for the biogenetic hypothesis by Snider’s
group.4b,29
In summary, we have developed an enantioselective inter-
molecular 1,3-dipolar cycloaddition of a six-membered cyclic
formyl-carbonyl ylide derived from tert-butyl 2-diazo-5-
formyl-3-oxopentanoate with phenylacetylene dipolaro-
philes under the influence of Rh2(S-TCPTTL)4 to provide
Acknowledgment. This research was supported, in part,
by a Grant-in-Aid for Scientific Research on Innovative
Areas (Project No. 2105: Organic Synthesis Based on Reac-
tion Integration) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan. We thank S. Oka,
M. Kiuchi, and T. Hirose of the Center for Instrumental
Analysis at Hokkaido University for mass measurements
and elemental analysis.
Supporting Information Available: Full experimental and
characterization data and copies of 1H and 13C NMR spectra for
all new compounds, as well as X-ray crystallographic data (CIF)
for 13. This material is available free of charge via the Internet at
http://pubs.acs.org.
(27) The enantiomeric purity of synthetic 1 was determined to be >99%
ee by comparison of HPLC retention time with a racemic sample of 1, which
was prepared according to the literature. See ref 4b.
(28) (a) Nakamura, S.; Sugano, Y.; Kikuchi, F.; Hashimoto, S. Angew.
Chem., Int. Ed. 2006, 45, 6532–6535. (b) Snider, B. B.; Wu, X.; Nakamura, S.;
Hashimoto, S. Org. Lett. 2007, 9, 873–874.
(29) Recently, Peterson and co-workers reported that compound 1 could
be produced from glucose, glycine, and ferulic acid in 3% yield in a simulated
baking model system (10% moisture at 200 °C for 15 min). Jiang, D.; Chiaro,
C.; Maddali, P.; Prabhu, K. S.; Peterson, D. G. J. Agric. Food Chem. 2009,
57, 9932–9943. We thank one of the reviewers for pointing out the reference,
which provides further support for the proposed biosynthesis.
(30) After submission of this manuscript, a catalytic asymmetric synthesis
of 8-oxabicyclo[3.2.1]octane derivatives via enantio- and diastereoselective
[3 þ 2]-cycloaddition of platinum-containing carbonyl ylides with vinyl
ethers was published by Iwasawa and co-workers. Ishida, K.; Kusama,
H.; Iwasawa, N. J. Am. Chem. Soc. 2010, 132, 8842–8843.
6042 J. Org. Chem. Vol. 75, No. 17, 2010