A tandem metal carbene cyclization-cycloaddition approach to the pseudolaric acids

Article abstract of DOI:10.1021/jo026399m

An approach toward the synthesis of the antifungal and cytotoxic pseudolaric acids based on the tandem metal carbene cyclization-cycloaddition reaction is described. Using this strategy, the advanced intermediate 3a bearing three of the four stereocenters

Full text of DOI:10.1021/jo026399m

A Ta n d em Meta l Ca r ben e Cycliza tion -Cycloa d d ition Ap p r oa ch to
th e P seu d ola r ic Acid s
Bin Chen, Rebecca Y. Y. Ko, Mabel S. M. Yuen, Kin-Fai Cheng, and Pauline Chiu*
Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular
Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road,
Hong Kong, PR China
pchiu@hku.hk
Received September 4, 2002
An approach toward the synthesis of the antifungal and cytotoxic pseudolaric acids based on the
tandem metal carbene cyclization-cycloaddition reaction is described. Using this strategy, the
advanced intermediate 3a bearing three of the four stereocenters of the target molecules has been
synthesized. The substrate-controlled diastereoselectivity of the tandem carbene cyclization-
cycloaddition was preferential for the undesired diastereomer, but reagent control through the use
of Hashimoto’s chiral rhodium catalyst Rh2(S-BPTV)4 reversed the selectivity in favor of 3a . Ring
opening of the oxabicyclic nucleus to give a hydroxycycloheptene has been demonstrated in a model
study.
In tr od u ction
cal activities, the pseudolaric acids have been the targets
of a number of synthetic efforts.5-9
The root bark of Pseudolarix kaempferi Gordon (Pi-
naceae), a tree native to the Zhejiang province in China,
has been harvested as a traditional Chinese medicine
called tujinpi for the topological treatment of dermato-
logical fungal infections as early as the 17th century.1
From this preparation, a family of diterpenoids called the
pseudolaric acids have been isolated. Pseudolaric acid B
(1b) has been determined to be the main antifungal
principle and has been evaluated to have activity com-
parable to that of amphotericin B against a number of
strains of fungi.2 In vitro tests of pseudolaric acids A, B,
and C (1a -c) revealed their cytotoxicities to several
cancer cell lines at submicromolar levels with low toxicity
in vivo,1b,3 with pseudolaric acids A and B being the more
potent constituents.
Our aim was to develop a convergent strategy to all of
the members of the pseudolaric acid family. Previous
approaches to these molecules based on an aldol cycliza-
tion as the key ring-forming reaction suffered from being
unable to obtain the trans-fused 5,7-membered ring
system as the major product.5,8 Thus, alternative ap-
proaches that ensured the formation of this trans-ring
junction were examined. To this end, we retroanalyzed
these target molecules through a cleavage of the lactone
functionality, a disconnection of a vinyl nucleophile at
C11, back to a common enol triflate precursor 2 (Scheme
1). From this intermediate, pseudolaric acid A bearing a
methyl substituent will be accessible via methylcuprate
addition,10 while pseudolaric acids B and C with car-
bomethoxy groups at C7 can be synthesized via pal-
ladium-catalyzed carbonylation.11 This strategy permits
flexibility for variations at C7,12 and the methyl ketone
at C3 allows for the addition of different groups at C11
for the synthesis of pseudolaric acid analogues.
Pseudolaric acids A, B, and C all possess the same
characteristic perhydroazulene constitution with trans-
fused acetoxy or hydroxy and lactone groups at the
junctions, which is a rare arrangement for naturally
occurring hydroazulenes.4 Embedded in the common
structure are a tertiary and three quaternary stereo-
centers lodged in a contiguous array. The overall com-
pactness of the molecule also adds to the synthetic
challenge posed by these natural products. Owing to their
intriguing molecular architecture and promising biologi-
Enol triflate 2 can in turn be obtained via a reductive
elimination of oxatricyclic ketone 3, in which the acetate
of the tertiary alcohol at C4 has been masked as an
(5) Pan, B. C.; Chang, H. Y.; Cai, G. L.; Guo, Y. S. Pure Appl. Chem.
1989, 61, 389.
(6) Higuchi, R. I. Ph.D. Dissertation, Stanford University, Stanford,
CA, 1995.
* Corresponding author. Tel: (852) 2859-8949. Fax: (852) 2857-
1586.
(1) (a) Zhou, B. N.; Ying, B. P.; Song, G. Q.; Chen, Z. X.; Han, J .;
Yan, Y. F. Planta Med. 1983, 47, 35. (b) Hamburger, M. O.; Shieh, H.
L.; Zhou, B. N.; Pezzuto, J . M.; Cordell, G. A. Magn. Res. Chem. 1989,
27, 1025.
(2) Li, E.; Clark, A. M.; Hufford, C. D. J . Nat. Prod. 1995, 58, 57.
(3) Pan, D. J .; Li. Z. L.; Hu, C. Q.; Chen, K.; Chang, J . J .; Lee, K. H.
Planta Med. 1990, 56, 383.
(4) Beyer, J .; Becker, H.; Toyota, M.; Asakawa, Y. Phytochemistry
1987, 26, 1085.
(7) (a) Bonk, J . D. Ph.D. Dissertation, University of Mississippi, MS,
1997. (b) Wu, B.; Karle, J . M.; Watkins, E. B.; Avery, M. A. Tetrahedron
Lett. 2002, 43, 4095.
(8) (a) Chiu, P.; Chen, B.; Cheng, K. F. Tetrahedron Lett. 1998, 39,
9229. (b) Chiu, P.; Chen, B.; Cheng, K. F. Org. Lett. 2001, 3, 1721.
(9) (a) Hu, Y.; Ou L.; Bai, D. Tetrahedron Lett. 1999, 40, 545. (b)
Ou, L.; Hu, Y.; Song, G.; Bai, D. Tetrahedron 1999, 55, 13999.
(10) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1980, 21, 4313.
(11) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26,
1109.
(12) Ritter, K. Synthesis 1993, 735.
10.1021/jo026399m CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/25/2003
J . Org. Chem. 2003, 68, 4195-4205
4195

Chen et al.
SCHEME 1. Retr osyn th etic An a lysis of
P seu d ola r ic Acid s A, B, a n d C
the bridgehead of the cycloadduct would be installed and
could be further oxidized to ultimately generate the
carboxylate at C20 of the pseudolaric acids. However, in
the previous studies of this reaction, many of which were
methodological in their aims, the olefins undergoing
cycloaddition with the carbene-derived ylides were rela-
tively simple; functionalized olefins, such as derivatives
of allylic alcohols, have rarely been used as dipolaro-
philes.18
Furthermore, there were few reports dealing with the
influence of preexisting stereocenters on the diastereo-
selectivity of the carbonyl ylide cycloaddition. Studies of
this reaction cascade for the construction of the tigliane
system by Dauben et al. showed that a number of
stereocenters on the tether had no bearing on the
stereochemistry of the carbonyl ylide cycloaddition.15b
However, Maier’s studies showed that cycloadditions of
related isomu¨nchnones generated from rhodium carbenes
gave products with the R-substituent trans to the bridge-
head substituent, a stereochemical result contrary to the
requirements for the pseudolaric acids.19
oxygen bridge. Oxatricyclic ketone 3 is envisioned as the
key intermediate that could be constructed by a reaction
cascade initiated by the decomposition of an appropri-
ately functionalized acyclic diazo ketone 4. This tandem
carbene cyclization-intramolecular cycloaddition reac-
tion13 has been studied extensively by Padwa and co-
workers.14 This reaction was known to generate exclu-
sively the cycloadduct with the oxygen bridge and the
side chain at C10 in a trans relationship, as the alterna-
tive cis-fused adduct was extremely high in energy. Some
applications of this powerful reaction for the synthesis
of natural products have appeared.15,16 Recently, a highly
enantioselective tandem carbene cyclization intramolecu-
lar cycloaddition reaction using a chiral rhodium BINOL
phosphate catalyst has been achieved.17
In this approach, the metal carbene derived from diazo
ketone 4 would undergo intramolecular cyclization with
the carbonyl group to form a six-membered cyclic carbo-
nyl ylide, followed by a [3 + 2] cycloaddition with the 1,1-
disubstituted olefin to give the oxatricyclic intermediate.
Two aspects of this reaction in the context of the total
synthesis have not been adequately explored in previous
studies. According to our strategy, the carbonyl ylide is
required to accomplish a dipolar cycloaddition with a
tethered allylic ether, so that an alkoxy substituent at
Resu lts a n d Discu ssion
Mod el Stu d ies.
To address the first issue, a model substrate 12a was
prepared to ascertain the viability of an allylic ether as
the dipolarophile in this tandem carbene cyclization-
cycloaddition reaction (Scheme 2). Zinc homoenolate 5a
was alkylated with chloride 6a 20 to give the homologated
ester 7a in 50% yield.21 The use of bromide analogue 6b,
which was obtained efficiently from 6a , escalated the
yield of the allylation to 88%. Chain extension via a
second homoenolate reaction with 5a was initially planned,
but neither the acid chloride nor the thioester derivative
of 7a gave good yields of coupled product under palladium
catalysis.22 However, conversion of ester 7a to Weinreb
amide 8a allowed homologation via reaction with Nor-
mant’s Grignard reagent 923 to give hydroxy ketone 10a .
Oxidation to afford acid 11a , followed by activation and
treatment with diazomethane, produced the desired
model diazo ketone substrate 12a . Gratifyingly, the
rhodium-catalyzed decomposition to the carbene and its
subsequent cyclization-cycloaddition produced the ex-
pected trans cycloadduct 13 in 61% yield without inci-
dent.
(13) Reviews: (a) Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991,
91, 263. (b) Padwa, A. Acc. Chem. Res. 1991, I, 22. (c) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223. (d) Chiu, P.; Lautens,
M. Top. Curr. Chem. 1997, 190, 3. (e) Doyle, M. P.; McKervey, M. A.;
Ye, T. Modern Catalytic Methods for Organic synthesis with Diazo
Compounds; J . Wiley & Sons: New York, 1998; Chapter 7, pp 397-
416. (f) Hodgson, D. M.; Pierard, F. Y. T. M.; Stupple, P. A. Chem.
Soc. Rev. 2001, 30, 50.
(14) (a) Padwa, A.; Fryxell, G. E.; Zhi, L. J . Org. Chem. 1988, 53,
2875. (b) Padwa, A.; Hornbuckle, S. F.; Fryxell, G. E.; Stull, P. D. J .
Org. Chem. 1989, 54, 817. (c) Padwa, A.; Hornbuckle, S. F.; Fryxell,
G. E.; Zhang, Z. J . J . Org. Chem. 1992, 57, 5747.
(15) Examples of carbene cyclization intramolecular cycloaddition:
(a) McMills, M. C.; Zhuang L.; Wright, D. L. Watt, W. Tetrahedron
Lett. 1994, 35, 8311. (b) Dauben, W. G.; Dinges, J .; Smith, T. C. J .
Org. Chem. 1993, 58, 7635.
(16) Examples of carbene cyclization intermolecular cycloaddition.
Illudins and ptaquilosins: (a) Padwa, A.; Sandanayaka, V. P.; Curtis,
E. A. J . Am. Chem. Soc. 1994, 116, 2667. (b) Padwa, A.; Curtis, E. A.;
Sandanayaka, V. P. J . Org. Chem. 1996, 61, 73. Zaragozic acids: (c)
Koyama, H.; Ball, R. G.; Berger, G. D. Tetrahedron Lett. 1994, 35, 9185.
(d) Hodgson, D. M.; Bailey, J . M.; Harrison, T. Tetrahedron Lett. 1996,
37, 4623. Brevicomin: (e) Padwa, A.; Fryxell, G. E. Zhi, L. J . Am. Chem.
Soc. 1990. 112, 3100.
Another model substrate 12b with a substituent at C3
was prepared in an analogous manner. Starting from
ester 7b, an R-methyl group was appended by alkylation
to give methylated substrate 7c (Scheme 2). Following
the analogous sequence of reactions employed for the
preparation of 12a , ester 7c was homologated and
(18) There is one example of a cycloaddition of an isomu¨nchnone
with a propargyl ether: Maier, M. E.; Schoffling, B. Chem. Ber. 1989,
122, 1081.
(19) Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988, 29, 1677.
(20) van der Louw, J .; van der Baan, L. L.; de Kanter, F. J . J .;
Bickelhaupt, F.; Klumpp, G. W. Tetrahedron 1992, 48, 6087.
(21) Ochiai, H.; Tamaru, Y.; Tsubaki, K.; Yoshida, Z. J . Org. Chem.
1987, 52, 4420.
(22) (a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Org.
Synth. Coll. Vol VIII, 274. (b) Tamaru, Y.; Ochiai, H.; Nakamura, T.;
Tsubaki, K.; Yoshida, Z. Tetrahedron Lett. 1985, 26, 5559. (c) Tokuya-
ma, H.; Yokoshima, S.; Yamashita, T.; Fukuyama, T. Tetrahedron Lett.
1998, 39, 3189.
(17) Hodgson, D. M.; Stupple, P. A.; J ohnstone, C. Chem. Commun.
1999, 2185.
(23) Normant, J . F.; Cahiez, G.; Alexakis, A. Tetrahedron Lett. 1978,
33, 3013.
4196 J . Org. Chem., Vol. 68, No. 11, 2003

Metal Carbene Approach to the Pseudolaric Acids
SCHEME 2. Syn th esis of Mod el Dia zo P r ecu r sor s 12a a n d 12ba
a
Reagents and Conditions: (a) LiBr, Aliquat 336, 60 °C, 97%; (b) IZnCH2CH2CO2Et 5a , CuCN, THF, DMA, rt, 88% for 7a ,
IZnCH2CH2CO2Me 5b, 86% for 7b; (c) (i) LDA, THF, -78 °C, (ii) MeI, 88%; (d) MeONHMe‚HCl, Me3Al, CH2Cl2, 92% for 8a , 75% for 8b;
(e) ClMg(CH2)3OMgCl 9, CuI, THF, 92% for 10a , 94% for 10b; (f) PDC, DMF, H2O, 71% for 11a , 45% for 11b; (g) (i) i-BuOCOCl, Et3N,
THF, -10 °C, (ii) CH2N2, Et2O, 0 °C, 74% for 12a , 68% for 12b; (h) cat. Rh2(OAc)4, 61% for 13, 63% total yield of (()-14a :(()-14b, 4:1.
SCHEME 3. Syn th esis of Dia zo P r ecu r sor 4a
a
Reagents and Conditions: (a) NaOH, MeOH, 98%; (b) t-BuCOCl, Et3N, DMAP, (S)-4-benzyl-2-oxazolidone, THF, -78 °C to room
temperature, 80%; (c) (i) n-Bu2BOTf, Et3N, CH2Cl2, 0 °C; (ii) CH3CHO, -78 to 0 °C, 67%, (92% based on recovered substrate); (d) MEMCl,
DIPEA, CH2Cl2, rt, 93%; (e) (i) LiOH, H2O2, THF-H2O, 0 °C, (ii) Na2SO3, 86%; (f) MeONHMe‚HCl, i-Pr2NEt, DCC, CH2Cl2, 44%; (g)
EtSH, DCC, DMAP, CH2Cl2, rt, 91%; (h) ClMg(CH2)3OMgCl 9, CuI, THF, 77%, (93% based on recovered substrate); (i) PDC, DMF, H2O,
75%; (j) (i) i-BuOCOCl, Et3N, THF, -20 °C, (ii) CH2N2, Et2O, 0 °C to room temperature, 72%.
elaborated in a straightforward manner to produce diazo
ketone precursor 12b. The tandem carbene cyclization-
cycloaddition initiated by a catalytic amount of rhodium
acetate produced two cycloadducts in 63% yield and in a
ratio of 4:1 (Scheme 2). Gratifyingly, the major diaste-
reomer was found to be 14a , in which the methyl
substituent and the benzyloxymethylene group were syn,
as required in the structure of pseudolaric acid. The
relative stereochemistry in 14a was determined by the
observation of an NOE between the methyl and the
benzyloxymethylene protons, which showed that these
groups were on the same side of the cyclopentane ring,
and confirmed by the absence of this effect in isomer 14b.
acetaldehyde produced alcohol 16 as one diastereomer,
which was subsequently protected as the MEM ether 17.
Following the route previously worked out for model
compound 12a , transamination to give Weinreb amide
19 was the next step. Although the conversion of acylox-
azolidinones directly to Weinreb amides is a well-
documented methodology,25 this transformation failed for
the hindered substrate 17. A variety of alkylaluminum
amides reagents based on Me3Al, Me2AlCl, and Et2AlCl
were tried, but the major product isolated was urea 20,
resulting from the attack of the oxazolidone, accompanied
by MEM ether cleavage (Scheme 4). Employing the
unprotected alcohol 16 as substrate also resulted in the
same product in 32% yield.
P r ep a r a tion of th e Ch ir a l P r ecu r sor 4.
With these preliminary results in hand, the synthesis
of the optically pure diazo ketone precursor 4 was
undertaken (Scheme 3). The absolute stereochemistry at
C3 was conferred using Evan’s chiral auxiliary methodol-
ogy.24 Thus, ester 7a was hydrolyzed to give acid 7d ,
which was activated to synthesize the acylated oxazoli-
dinone 15. Aldol reaction via the boron enolate of 15 with
(24) (a) Cowden, C. J .; Paterson, I. Org. React. 1997, 51, 1. (b) Evans,
D. A. Aldrichimica Acta 1982, 15, 23. (c) Evans, D. A.; Takacs, J . M.;
McGee, L. R.; Ennis, M. D.; Mathre, D. J .; Bartroli, J . Pure Appl. Chem.
1981, 53, 1109.
(25) (a) Evans, D. A.; Bender, S. L.; Morris, J . J . Am. Chem. Soc.
1988, 110, 2506. (b) Evans, D. A.; Bender, S. L. Tetrahedron Lett. 1986,
27, 799. (c) Cane, D. E.; Tan, W.; Ott, W. R. . J . Am. Chem. Soc. 1993,
115, 527.
J . Org. Chem, Vol. 68, No. 11, 2003 4197

Chen et al.
SCHEME 5. Der iva tiza tion of 3a a n d 3b to
SCHEME 4. Tr a n sa m in a tion of Acyloxa zolid on es
16 a n d 17
Dik eton es 24a a n d 24b
TABLE 1. Meta l Ca r ben e Cycliza tion -Cycloa d d ition of
Dia zo Keton e 4
with the Dess-Martin periodinane to afford ketones 24a
and 24b (Scheme 5). The signal of H3 in ketone 24b now
appeared at δ 2.60 ppm, and its 2D-NOESY spectrum
clearly showed an NOE between H3 and the benzy-
loxymethylene protons (δ 4.48 ppm). The structure of the
minor compound 3a was similarly determined by the
analysis of its derivative 24a , whose 2-D NOESY spec-
trum showed the absence of a cross-peak between H3 (δ
3.30 ppm) and the benzyloxymethylene protons at δ 4.49
ppm, confirming that the benzyloxymethylene substitu-
ent was in a cis relationship with the methyl ketone.
Therefore, the major isomer possessed the structure as
shown for 3b, while the minor isomer 3a was the desired
diastereomer with the correct absolute stereochemistry
for elaboration into the pseudolaric acids.
Other commercially available rhodium compounds
were also tried as catalysts. Reaction of diazo ketone 4
with the less active dirhodium caprolactam was capri-
cious but generally led to inferior yields of products (Table
1, entry 4). The more reactive dirhodium trifluoroacetate
catalyst gave good yields of products, but the preference
was even greater for the undesired isomer (Table 1, entry
5).
A solvent effect on the yield and the ratio of cycload-
ducts was observed. The decomposition of the diazo
ketone and the subsequent tandem cyclization cycload-
dition reaction proceeded rapidly in dichloromethane.
Benzene was also an acceptable solvent, although with
a more reactive catalyst such as dirhodium trifluoroac-
etate, the addition of the carbene to the aromatic ring
was a major side reaction.27 The use of benzotrifluoride28
as a solvent generally gave similar yields of the cycload-
ducts compared to dichloromethane, but the formation
of the desired isomer 3a was more favored. Thus in the
case of dirhodium trifluoroacetate, the reaction in ben-
zotrifluoride improved to 1:1.2 from a ratio of 1:1.9 in
dichloromethane (entry 6). However, in all these cases,
the desired compound 3a remained as the minor diaste-
reomer.
product
% yield
entry
catalyst
solvent
3a :3b
1
2
3
4
5
6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(CAP)4
Rh2(OCOCF3)4
Rh2(OCOCF3)4
CH2Cl2
PhH
CF3Ph
CH2Cl2
CH2Cl2
CF3Ph
61
66
45
25
61
32
1:1.3
1:1.2
1:1.2
1:1.2
1:1.9
1:1.2
A two-step protocol was then attempted for the syn-
thesis of Weinreb amide 19. Hydrolysis of the acylox-
azolidone 17 using lithium hydroperoxide produced acid
18, which was activated by DCC for amidation. However,
the conversion was extremely inefficient; reaction over
3 days produced amide 19 in only 44% yield. Similarly,
coupling with BOP also resulted in a low yield of amide
19 (Scheme 3).
After some experimentation, a thioester was found to
be a viable alternative electrophilic substrate for chain
extension. Thus acid 18 was converted in high yield to
thioester 21, which was then homologated by the addition
of the cuprate derived from Normant’s Grignard reagent
9 to produce alcohol 22 in good yield.26 Oxidation of the
alcohol to acid 23, followed by activation and treatment
with diazomethane, generated the requisite chiral diazo
ketone 4.
Ta n d em Ca r ben e Cycliza tion -Cycloa d d ition of 4.
Diazo ketone 4 was subjected to treatment with a
variety of rhodium catalysts. The results are summarized
in Table 1. Diazo decomposition with a catalytic amount
of dirhodium acetate produced, in one step, the oxatri-
cyclic adduct 3 in 61% yield as two diastereomers 3a and
3b in a ratio of 1:1.3 (entry 1).
Elucidation of the structures of isomers 3a and 3b was
initially hampered because the key proton signals be-
longing to H3 were superimposed on other upfield peaks
1
Although our preliminary results in the tandem cy-
clization-cycloaddition of substrate 12b gave the desired
diastereomer 14a with the C3 substituent being cis with
respect to the bridgehead substituent, it is not clear why
the analogous reaction of substrate 4 generated the
in the H NMR spectrum. Thus the cycloadducts 3a and
3b were converted to their ketone derivatives 24a and
24b, respectively, whose H3 were expected to absorb at
more downfield chemical shifts. Compounds 3a and 3b
obtained from the tandem cyclization-cycloaddition re-
action were treated with acidic methanol to remove the
MEM group, then the secondary alcohols were oxidized
(27) Padwa, A.; Austin, D. J .; Hornbuckle, S. F. J . Org. Chem. 1996,
61, 63.
(28) (a) Kitagaki, S.; Anada, M.; Kataoka, O.; Matsuno, K.; Umeda,
C.; Watanabe, N.; Hashimoto, S. J . Am. Chem. Soc. 1999, 121, 1417.
(b) Ogawa, A.; Curran, D. P. J . Org. Chem. 1997, 62, 450.
(26) Anderson, R. J .; Henrick, C. A.; Rosenblum L. D. J . Am. Chem.
Soc. 1974, 96, 3654.
4198 J . Org. Chem., Vol. 68, No. 11, 2003

Metal Carbene Approach to the Pseudolaric Acids
tigated first. Catalysts based on chiral carboxamides29
(entries 1-3) resulted in poor yields of the cycloadducts.
The catalysts based on N-arylsulfonylprolinate ligands
Rh2(DOSP)4 led to good yields of the cycloadducts,30 but
the stereochemical results of both the (R)- and (S)-
enantiomeric catalysts remained in favor of the undesired
diastereomer 3b (entries 4-6). Although Hodgson’s cata-
lyst Rh2(R-DDBNP)4 was extremely successful in the
enantioselective intramolecular cyclization-cycloaddition
of a stabilized carbene, the diastereoselectivity of the
reaction with our substrate was low (entry 7).17 Finally,
Hashimoto’s catalyst Rh2(S-BPTV)4, which induced highly
enantioselective carbene cyclization in tandem with
intermolecular cycloadditions, was tried.28a To our relief,
the ratio of cycloadducts was reversed in favor the desired
isomer 3a for the first time (entry 8). Switching the
solvent from dichloromethane to benzotrifluoride further
improved the ratio in favor of 3a to 1.4:1 (entry 9).
Rin g-Op en in g Stu d ies Usin g Mod el Su bstr a te 27.
While further optimization of the diastereoselectivity
of the cyclization-cycloaddition of diazo ketone 4 was
being pursued, reductive ring-opening strategies that
would cleave the oxygen bridge of oxatricyclic compound
3a toward intermediate 2 were also explored. This
transformation was studied in the context of a simpler
and more readily accessible oxatricyclic model compound
27,14b which contains the essential elements of the
oxatricyclic framework found in compound 3.
SCHEME 6. Ta n d em Cycliza tion -Cycloa d d ition of
Dia zo Keton e 25
TABLE 2. Ca r ben e Cycliza tion -Cycloa d d ition of Dia zo
Keton e 4 Usin g Ch ir a l Ca ta lysts
product
entry
catalyst
solvent
% yield
3a :3b
1
2
3
4
5
6
7
8
9
Rh2(R-MEPY)4
Rh2(S-MEPY)4
Rh2(S-MEOX)4
Rh2(R-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DOSP)4
Rh2(S-DDBNP)4
Rh2(S-BPTV)4
Rh2(S-BPTV)4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CF3Ph
CH2Cl2
CH2Cl2
CF3Ph
17
13
0
53
62
35
54
67
51
1:1.5
1:1.3
1:1.3
1:1.7
1:1.3
1:1.6
1.3:1
1.4:1
Ring-opening at the oxygen bridge of oxabicyclo[2.2.1]
ketones using single-electron reductants such as lithium
or samarium iodide generated hydroxy ketones as prod-
ucts, and this transformation of oxapolycyclic substrates
has been exploited in several syntheses.16a,31 However,
under the same reaction conditions, the reductive opening
of oxabicyclo[3.2.1] systems with the carbonyl group in
the two-carbon bridge was inefficient and apparently
plagued by side reactions.32 The facility of the ring
opening in the [2.2.1] oxabicyclic series may be attributed
in part to the greater strain in these systems.
In our synthesis, the carbonyl group of the oxatricyclic
compound 3a is situated in the three-carbon bridge. This
should render flexibility to the ketyl anion to adopt an
antiperiplanar position, leading to ring opening. Indeed,
when model compound 27 was treated with samarium
iodide, reduction with concomitant ring opening of the
oxygen bridge occurred to give hydroxy ketone 29 as a
1:6 mixture with its hemiacetal form in 69% yield
(Scheme 7). Alcohol 30, obtained in single diastereomeric
form as a minor product from the reduction, could in
theory be reoxidized to ketone 27 and resubjected to
reduction to improve the overall yield of the ring-opening
reaction.
opposite diastereomer as the major product. In fact, the
increase in the steric demand of the C3 substituent in
compound 4 over 12b was initially expected to further
enhance the factors that led to the predominance of 14a
over 14b. It was surmised that perhaps the MEM ether
at C11 was providing a chelating element that was not
present in substrate 12b and this resulted in an electron-
donating perturbation of the original transition state. If
this were the case, the use of a different protective group
should restore the previously observed stereoselectivity.
To see whether the MEM group was responsible for the
reversal in the diastereoselectivity, a structurally similar
diazo ketone 25, whose hydroxyl group was protected as
a noncoordinating triethylsilyl ether, was synthesized
and subjected to treatment with catalytic rhodium
(Scheme 6). The results of the tandem reaction was
almost 5:1 in favor of the undesired diastereomer (()-
26b. Thus it appears that the change in the diastereo-
selectivity from the case of model compound 12b was
mainly due to an increase in the steric demands of the
substituent at C3 in substrate 4, which led to an
undesirable steric interaction that was alleviated by
cycloaddition in the opposite sense.
Ta n d em Ca r ben e Cycliza tion -Cycloa d d ition of
(29) (a) Doyle, M. P.; Winchester, W. R.; Hoorn, J . A. A.; Lynch, V.;
Simonsen, S. H.; Ghosh, R. J . Am. Chem. Soc. 1993, 115, 9968. (b)
Doyle, M. P.; Dyatkin, A. B.; Protopopova, M. N.; Yang, C. I. Miertschin,
C. S.; Winchester, W. R.; Simonsen, S. H.; Lynch, V.; Ghosh, R. Recl.
Trav. Chim. Pays-Bas 1995, 114, 163.
(30) (a) Davies, H. M. L. Current Org. Chem. 1998, 2, 463. (b) Davies,
H. M. L. Aldrichimica Acta 1997, 30, 107.
(31) (a) De Schrijver, J .; De Clercq, P. J . Tetrahedron Lett. 1993,
34, 4369. Alternative photoreductive methods: (b) Cossy, J .; Ranai-
vosata, J . L.; Bellosta, V.; Ancerewicz, J .; Ferritto, R.; Vogel, P. J . Org.
Chem. 1995, 60, 0, 8351.(c) Cossy, J .; Aclinou, P.; Bellosta, V.; Furet,
N.; Baranne-Lafont, J .; Sparfel, D.; Souchaud, C. Tetrahedron Lett.
1991, 32, 1315.
4 Usin g Ch ir a l Ca ta lysts.
The recent results in highly enantioselective tandem
carbene cyclization-cycloaddition reactions strongly sug-
gest that the rhodium complex remains associated with
the carbonyl ylide during the cycloaddition.17,28a There-
fore, chiral rhodium catalysts were examined to see if
reagent control could be exerted to overcome the sub-
strate bias and direct the formation of the desired isomer
3a . These results are summarized in Table 2. Com-
mercially available chiral rhodium catalysts were inves-
(32) Lautens, M.; Ma, S. Tetrahedron Lett. 1996, 37, 1727.
J . Org. Chem, Vol. 68, No. 11, 2003 4199

Chen et al.
SCHEME 7. Rin g-Op en in g Stu d ies on Keton e 27
Con clu sion
The synthesis of the key chiral intermediate 3a con-
taining three out of the four required stereocenters in
the pseudolaric acids has been achieved in 12 steps from
commercially available 6a in an overall yield of 5.1%. The
absolute stereochemistry at C3 was set by an asymmetric
aldol reaction using Evan’s chiral auxiliary. Chain elon-
gation to obtain diazo ketone 4 was accomplished via
thioester 21. The optically pure tricyclic intermediate 3a
was obtained as the major diastereromer resulting from
the tandem carbene cyclization-cycloaddition cascade
reaction of diazo ketone 4, using Hashimoto’s chiral
rhodium catalyst Rh2(S-BPTV)4. Further investigations
to improve the diastereoselectivity for 3a are being
conducted. Ring opening of the oxatricyclic core has been
achieved in a model substrate 27 and these results will
be applied to the actual intermediate. Elaborations of 3a
toward the completion of the total synthesis of the
pseudolaric acids and their analogues are being actively
pursued in our laboratory.
SCHEME 8. An Alter n a tive Str a tegy for
Oxygen -Br id ge Clea va gea
Exp er im en ta l Section
a
Gen er a l. All anhydrous reactions were performed in oven-
dried glassware under a positive pressure of dry argon. Air-
or moisture-sensitive reagents and anhydrous solvents were
transferred with oven-dried syringes or cannulae using stan-
dard inert atmosphere techniques. All chemicals and solvents
for reactions were used as received, unless otherwise men-
tioned. Tetrahydrofuran (THF) and diethyl ether were distilled
from Na/Ph2CO ketyl under argon. Dichloromethane, benzene,
triethylamine, and diisopropylethylamine were distilled from
calcium hydride. Methanol was distilled from magnesium
methoxide. Dimethylformamide (DMF) and N,N′-dimethylac-
etamide (DMA) were distilled from barium oxide under
reduced pressure. Benzotrifluoride was refluxed and distilled
from phosphorus pentoxide. Flash column chromatography
was performed on E. Merck silica gel 60 (230-400 mesh
ASTM) using EtOAc/n-hexane as eluents.
(2-Br om om eth yla llyloxym eth yl)ben zen e (6b). To (2-
chloromethylallyloxymethyl)benzene 6a 20 (7.20 g, 36.64 mmol)
and Aliquat 336 (0.70 g, 1.73 mmol) was added anhydrous LiBr
(6.38 g, 73.47 mmol). The mixture was heated to 60 °C for 2
h. After cooling, the mixture was filtered on Florisil and
washed with Et2O. The volatiles were removed in vacuo to
afford compound 6b (8.53 g, 97% yield) as a pale yellow oil,
which was used without further purification: Rf 0.75 (15%
Et2O/hexane); IR (film) 2935, 2858, 1612, 1513, 1468, 1252,
1174, 1093, 921, 819 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-
7.28 (m, 5H), 5.37 (s, 1H), 5.29 (s, 1H), 4.55 (s, 2H), 4.17 (s,
2H), 4.07 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 142.4, 138.0,
128.5, 127.7 (2C), 117.3 72.4, 70.3, 33.1; LRMS (EI) m/z 161
(M+ - Br, 23), 91 (100), 81 (56), 79 (61); HRMS (EI) m/z calcd
for C11H13O (M+ - Br) 161.0966, found 161.0965.
Reagents and Conditions: (a) MeMgI, Et2O, 0 °C to room
temperature, 2 h, 92%; (b) SOCl2, DMAP, THF, 0 °C to room
temperature; (c) Na, Et2O reflux 5 h, 71% over two steps.
Since the reductive ring opening was successful in
cleaving the oxygen bridge, efforts were then made to
trap the intermediate enolate 28 formed en route to
ketone 29 to retain the olefinic bond at C7 and C8.
However, attempts to trap enolate 28 using a variety of
reagents, including triflic anhydride, Comins’ reagent,33
TMSCl, or TMSOTf, were all unsuccessful. This might
be attributed to the samarium-oxygen bond being very
strong, and enolate 28 was thus resistant to transmeta-
lation at the oxyanion. Although Motherwell et al. have
reported the trapping of a samarium enolate, the product
yields were consistently low.34 Samarium enolate 28,
however, was reactive as an ambident nucleophile at
carbon. When enolate 28 was treated with iodine, reac-
tion rapidly occurred to regenerate the oxatricyclic
substrate 27, presumably via iodination of the enolate
(Scheme 7). Ring opening using other reducing agents
such as Zn and Zn/TMSCl were uniformly unsuccessful.
Thus an alternative strategy was used for the ring
opening of ketone 27, which also accomplished the
synthesis of the trisubstituted double bond found in
pseudolaric acid A (Scheme 8).35 Treatment of substrate
27 with methyl Grignard reagent generated tertiary
alcohol 31 as a single diastereomer.36 The alcohol was
converted to the volatile chloride 32, which was reduc-
tively cleaved using sodium to yield ring-opened product
33 containing the requisite olefinic bond. Additional
reductive ring-opening methodologies and strategies are
being investigated.
5-Ben zyloxym eth yl-5-h exen oic Acid Eth yl Ester (7a ).
3-Iodopropionic acid ethyl ester (ICH2CH2COOEt) was pre-
pared from the corresponding bromide (BrCH2CH2COOEt) by
a Finkelstein reaction.37 3-Iodopropionic acid ethyl ester (9.65
g, 43.86 mmol) and Zn(Cu)38 (3.41 g, 52.46 mmol) in DMA (5.64
mL, 62.04 mmol) and THF (50 mL) were stirred at room
temperature under argon for 2 h and then at 60 °C for 1 h to
form homoenolate 5a . This reaction mixture was filtered and
transferred by cannula to bromide 6b (8.24 g, 34.19 mmol) and
CuCN (0.51 g, 5.70 mmol) in THF (30 mL). After stirring
(33) Comins, D. L.; Dehghani, A.; Foti, C. J .; J oseph, S. P. Org.
Synth. 1996, 74, 165.
(34) Batey, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32,
6211.
(35) Bromidge, S. M.; Sammes, P G.; Street, L. J . J . Chem. Soc.,
Perkin Trans. 1 1985, 1725.
(36) Although the stereochemistry of 31 was not rigorously estab-
lished, it was presumed to be the R-alcohol on the basis of the
characteristic reactivity patterns of oxabicyclic compounds; see: Chiu,
P.; Lautens, M. Top. Curr. Chem. 1997, 190, 1.
(37) Sondheimer, F.; Rosenkranz, G.; Mancera, O.; Djerassi, C. J .
Am. Chem. Soc. 1953, 75, 2601.
(38) Smith, R. D.; Simmons, H. E. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 855.
4200 J . Org. Chem., Vol. 68, No. 11, 2003

Metal Carbene Approach to the Pseudolaric Acids
overnight at room temperature, the mixture was quenched
with saturated NH4Cl. The organic phase was separated,
washed sequentially with saturated NaHCO3 and brine, dried
(MgSO4), and concentrated in vacuo. Flash chromatography
of the residue afforded compound 7a (7.84 g, 88% yield) as a
colorless oil: Rf 0.35 (15% Et2O/hexane); IR (film) 2930, 2856,
1732, 1454, 1373, 1097, 1074, 1029 cm-1; 1H NMR (300 MHz,
CDCl3) δ 7.35-7.27 (m, 5H), 5.08 (s, 1H), 4.95 (s, 1H), 4.49 (s,
2H), 4.12 (q, J ) 7.1 Hz, 2H), 3.96 (s, 2H), 2.31 (t, J ) 7.5 Hz,
2H), 2.13 (t, J ) 7.7 Hz, 2H), 1.80 (m, 2H), 1.25 (t, J ) 7.1 Hz,
3H); 13C NMR (75 MHz, CDCl3) δ 173.6, 145.1, 138.3, 128.4,
127.7, 127.6, 112.4, 73.0, 72.0, 60.3, 33.9, 32.4, 22.8, 14.3;
LRMS (EI) m/z 262 (M+, 5), 231 (11), 171 (19), 156 (41), 91
(100); HRMS (EI) m/z calcd for C16H24O4 262.1569, found
262.1567.
5-Ben zyloxym eth yl-5-h exen oic Acid Meth yl Ester (7b).
Following the procedure for the preparation of compound 7a ,
ester 7b was prepared in a similar manner in 86% yield from
ICH2CH2COOMe (69.5 g, 0.325 mol), Zn(Cu)38 (24.56 g), DMA
(38 mL, 0.464 mol), THF (320 mL), bromide 6b (59.0 g, 0.245
mol), and CuCN (3.65 g, 0.041 mol). 7b: a colorless oil; Rf (20%
EtOAc in hexane) 0.67; IR (CH2Cl2) 3020, 2954, 2862, 1731,
1654, 1454, 1438, 1211, 1072 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.37-7.27 (m, 5H), 5.08 (s, 1H), 4.95 (s, 2H), 4.49 (s, 2H),
3.96 (s, 2H), 3.66 (s, 3H), 2.33 (t, J ) 7.5 Hz, 2H), 2.13 (t, J )
7.7 Hz, 2H), 1.81 (quintet, J ) 7.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 174.0, 145.1, 138.4, 128.4, 127.7, 127.6, 112.4, 73.0,
72.0, 33.6, 32.5, 22.8; LRMS (EI) m/z 157 (M+ - Bn, 18), 142
(40), 125 (15), 107 (16); HRMS (EI) m/z calcd for C8H13O3 (M+-
Bn) 157.0865, found 157.0858.
MeONHMe‚HCl (3.35 g, 34.4 mmol), and Me3Al (17.2 mL, 34.4
mmol). 8b: a colorless oil; Rf 0.16 (20% EtOAc/hexane); IR
(film) 2939, 2898, 1648, 1457, 1389, 1074, 1029, 998 cm-1; 1H
NMR (CDCl3, 300 MHz) δ 7.34-7.25 (m, 5H), 5.06 (s, 1H), 4.95
(s, 1H), 4.48 (s, 2H), 3.95 (s, 2H), 3.64 (s, 3H), 3.16 (s, 3H),
2.88-2.87 (m, 1H), 2.11-1.93 (m, 2H), 1.91-1.82 (m, 1H),
1.59-1.49 (m, 1H), 1.12 (d, J ) 6.9 Hz, 3H); 13C NMR (CDCl3,
75 MHz) δ 177.4, 145.4, 138.2, 128.2, 127.9, 127.5, 127.3, 111.6,
72.8, 71.7, 61.2, 34.6, 31.2, 30.7, 29.5, 17.2; LRMS (EI) m/z
200 (M+ - Bn, 11), 153 (11), 139 (11), 127 (13), 113 (16); HRMS
(EI) m/z calcd for C16H24O4 200.1287, found 200.1287.
8-Ben zyloxym eth yl-1-h ydr oxy-8-n on en -4-on e (10a). The
Grignard reagent ClMg(CH2)3OMgCl 923 (10 mL, ∼0.5 M) was
added to Weinreb amide 8a (0.60 g, 2.17 mmol) in THF (5 mL)
at 0 °C under argon. The reaction mixture was stirred
overnight at room temperature. The reaction was quenched
with saturated NH4Cl (10 mL) and extracted with EtOAc (4
× 10 mL). The combined organics were washed with brine,
dried (MgSO4), and concentrated in vacuo. Flash chromatog-
raphy of the residue afforded compound 10a (0.556 g, 92%
yield) as a colorless oil: Rf 0.20 (40% EtOAc/hexane); IR (film)
3618, 2932, 2860, 1710, 1454, 1097, 1072 cm-1; 1H NMR (300
MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.07 (s, 1H), 4.94 (s, 1H),
4.48 (s, 2H), 3.95 (s, 2H), 3.61 (t, J ) 5.6 Hz, 2H), 2.53 (t, J )
6.9 Hz, 2H), 2.44 (t, J ) 7.4 Hz, 2H), 2.09 (t, J ) 7.4 Hz, 2H),
1.88-1.73 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 211.5, 145.2,
138.3, 127.7, 127.6, 112.4, 72.9, 72.0, 42.2, 39.5, 32.4, 26.4, 21.5;
LRMS (EI) m/z 276 (M+, 3), 259 (7), 191 (17), 168 (28), 127
(100), 91 (36), 89 (23); HRMS (EI) m/z calcd for C17H21O3
273.1491, found 273.1489.
Meth yl 5-Ben zyloxym eth yl-2-m eth yl-5-h exen oa te (7c).
To a solution of ester 7b (8.0 g, 32 mmol) in THF was added
LDA (0.38 L, 0.1 M, 38.4 mmol) dropwise at -78 °C. After
stirring for 30 min, MeI (6.0 mL, 96 mmol) was added. The
reaction mixture was stirred for a further 30 min at -78 °C,
quenched with saturated NH4Cl solution, and extracted with
EtOAc. The combined organics were dried (MgSO4) and
concentrated in vacuo. Flash chromatography of the residue
afforded 7c (7.4 g, 88%) as a pale yellow oil: Rf 0.63 (20%
EtOAc/hexane); IR (film) 2953, 2862, 1729, 1454, 1365, 1168,
1072, 1029 cm-1; 1H NMR (CDCl3, 300 MHz) δ 7.33-7.22 (m,
5H), 5.06 (s, 1H), 4.93 (s, 1H), 4.49 (s, 2H), 3.94 (s, 2H), 3.63
(s, 3H), 2.63-2.39 (m, 1H), 2.10 (t, J ) 7.7 Hz, 2H), 1.90-1.78
(m, 1H), 1.62-1.50 (m, 1H), 1.15 (d, J ) 7 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) δ 176.7, 145.1, 138.2, 128.1, 127.4, 127.3,
111.9, 72.8, 71.7, 51.2, 38.8, 31.4, 30.5, 16.8; LRMS (EI) m/z
262(17), 171 (18), 156 (30), 139 (21), 124 (8); HRMS (EI) m/z
calcd for C16H24O4 262.1569, found 262.1572.
8-Be n zyloxym e t h yl-1-h yd r oxy-5-m e t h yl-8-n on e n -4-
on e (10b). Following the procedure for the preparation of
compound 10a , alcohol 10b was similarly prepared in 96%
yield from ester 8b (3.63 g, 1.25 mmol) and 9 (25 mL, ∼1.1M).
10b : a colorless oil; Rf 0.26 (35% EtOAc/hexane); IR (film)
3610, 2938, 2884, 1708, 1454, 1370, 1102, 1061 cm-1; 1H NMR
(CDCl3, 300 MHz) δ 7.32-7.23 (m, 5H), 5.05 (s, 1H), 4.92 (s,
1H), 4.46 (s, 2H), 3.93 (s, 2H), 3.65 (s, br, 1H), 3.53 (t, J ) 6.2
Hz, 2H), 2.59-2.45 (m, 2H), 2.06-2.0 (m, 2H), 1.97-1.72 (m,
3H), 1.51-1.39 (m, 1H), 1.06 (d, J ) 7 Hz, 3H); 13C NMR
(CDCl3, 300 MHz) δ 214.7, 145.0, 137.8, 128.0, 127.4, 127.2,
111.9, 72.5, 71.5, 61.3, 45.5, 40.4, 37.3, 30.3, 30.2, 26.3, 26.0,
16.2, 16.0, 11.3; LRMS (EI) m/z 272 (M+ - H2O, 5), 181 (10),
153 (13); HRMS (EI) m/z calcd for C16H24O4 (M+ - H2O)
272.1776, found 272.1785.
8-Ben zyloxym eth yl-4-oxo-8-n on en oic Acid (11a ). Alco-
hol 10a (156 mg, 0.565 mmol) in 2.0 mL of DMF and 0.05 mL
of H2O was treated with PDC (1.28 g, 3.40 mmol) at room
temperature for 8 h. Water (20 mL) was added and the mixture
was extracted with EtOAc (5 × 10 mL). The combined organics
were dried (MgSO4) and concentrated in vacuo. Flash chro-
matography of the residue afforded acid 11a (110 mg, 71%
yield) as a pale yellow oil. Rf 0.75 (75% EtOAc/hexane); IR
(film) 3685, 3499, 2936, 1714, 1454, 1399, 1091, 1074, 908
5-Ben zyloxym et h yl-5-h exen oic Acid N,N′-Met h oxy-
m eth yla m id e (8a ). To a suspension of MeONHMe‚HCl (1.50
g, 15.10 mmol) in anhydrous CH2Cl2 (15 mL) was added Me3Al
(7.60 mL, 15.20 mmol, 2 M in toluene) at 0 °C. After 1 h at
room temperature, a solution of ester 7a (1.31 g, 5.0 mmol) in
CH2Cl2 (5 mL) was added at 0 °C. After 12 h, the reaction was
quenched by saturated NH4Cl solution. The mixture was
acidified by 0.5 N HCl to pH 4 and extracted with CH2Cl2 (4
× 15 mL). The combined organics were dried (Na2SO4) and
concentrated in vacuo. Flash chromatography of the residue
afforded Weinreb amide 8a (1.28 g, 92% yield) as a colorless
oil: Rf 0.50 (40% EtOAc/hexane); IR (film) 2937, 2855, 1662,
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.07
(s, 1H), 4.93 (s, 1H), 4.48 (s, 2H), 3.94 (s, 2H), 2.68 (m, 2H),
2,61 (m, 2H), 2.45 (t, J ) 7.3 Hz, 2H), 2.08 (t, J ) 7.3 Hz, 2H),
1.75 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 208.7, 178.3, 145.1,
138.2, 128.4, 127.7, 127.6, 112.5, 72.9, 72.0, 42.0, 36.8, 32.4,
27.7, 21.5; LRMS (EI) m/z 290 (M+, 5), 245 (16), 199 (27), 154
(31), 91 (100); HRMS (EI) m/z calcd for C17H22O4 290.1518,
found 290.1525.
1454, 1385, 1100, 997 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.35-7.27 (m, 5H), 5.08 (s, 1H), 4.97 (s, 1H), 4.49 (s, 2H), 3.97
(s, 2H), 3.66 (s, 3H), 3.17 (s, 3H), 2.44 (t, J ) 7.5 Hz, 2H), 2.15
(t, J ) 7.6 Hz, 2H), 1.84 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 174.4 (br), 145.4, 138.4, 128.4, 127.7, 127.5, 112.1, 73.0, 72.0,
61.2, 32.7, 32.2, 31.4, 22.4; LRMS (EI) m/z 277 (M+, 2), 217
(4), 186 (9), 92 (7), 91 (100); HRMS (EI) C16H23NO3 277.1678,
found 277.1680.
8-Ben zyloxym et h yl-5-m et h yl-4-oxo-8-n on en oic Acid
(11b). Following the procedure for the preparation of com-
pound 11a , acid 11b was similarly prepared in 45% yield from
alcohol 10b (3.18 g, 10.9 mmol) and PDC (65.7 mmol, 24.7 g).
11b: pale yellow oil; Rf 0.12 (20% EtOAc/hexane); IR (film)
3672, 3488, 2929, 1702, 1454, 1073, 1028 cm-1 1H NMR
;
5-Ben zyloxym et h yl-2-m et h yl-5-h exen oic Acid N,N′-
Meth oxym eth yla m id e (8b). Following the procedure for the
preparation of compound 8a , amide 8b was prepared in a
similar manner in 75% yield from ester 7c (3.0 g, 11.5 mmol),
(CDCl3, 300 MHz) δ 10.71 (s, br, 1H), 7.35-7.23 (m, 5H), 5.05
(s, 1H), 4.92 (s, 1H), 4.46 (s, 2H), 3.93 (s, 2H), 2.78-2.75 (m,
2H), 2.72-2.63 (m, 3H), 2.07-1.98 (m, 2H), 1.90-1.87 (m, 1H),
1.86-1.53 (m, 1H), 1.07 (d, J ) 7.1 Hz, 3H); 13C NMR (CDCl3,
J . Org. Chem, Vol. 68, No. 11, 2003 4201

Chen et al.
75 MHz), δ 212.1, 178.0, 144.9, 137.9, 128.1, 127.4, 127.3,
112.1, 72.5, 71.5, 45.3, 35.1, 30.3, 27.4, 16.2; LRMS (EI) m/z
198 (M+ - Bn - CH3, 50), 180 (21), 167 (26), 153 (15), 139 (6);
HRMS (ESI) m/z calcd for C16H24O4Na (M+ + Na) 327.1572,
found 327.1575.
(d, J ) 12.1 Hz, 1H), 4.27 (dd, J ) 8.1, 0.5 Hz, 1H), 3.32 (d, J
) 9.4 Hz, 1H), 3.29 (d, J ) 9.4 Hz, 1H), 2.46 (ddd, J ) 18.0,
11.3, 4.5 Hz, 1H), 2.36 (ddd, J ) 18.1, 9.1, 4.5 Hz, 1H), 2.17
(m, 3H), 2.01 (dd, J ) 12.9, 8.2 Hz, 1H), 1.89 (m, 2H), 1.59
(ddd, J ) 13.1, 7.6, 2.4 Hz, 1H), 1.38 (m, 1H), 0.90 (d, J ) 7.4
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 213.2, 137.8, 128.4,
127.76, 127.74, 94.5, 82.1, 74.5, 73.6, 54.4, 43.5, 42.9, 36.7, 33.9,
30.3, 23.8, 14.3; LRMS (EI) m/z 300 (M+, 33), 257 (10), 209
(18), 191 (24), 164 (66), 151 (83), 147 (100), 133 (42); HRMS
(EI) m/z calcd for C19H24O3 (M+) 300.1725, found 300.1726.
14b: Rf 0.55 (20% EtOAc/hexane); IR (film) 2959, 2870, 1723,
9-Ben zyloxym et h yl-1-d ia zo-9-d ecen e-2,5-d ion e (12a ).
To acid 11a (121 mg, 0.417 mmol) in dry ether (2 mL) and
THF (2 mL) at -20 °C was added Et3N (0.097 mL, 0.698
mmol), followed by isobutyl chloroformate (0.090 mL, 0.694
mmol). The solution was stirred for 30 min and then warmed
to 0 °C. Ethereal diazomethane39 (3 mL, about 1.0 mmol) was
added dropwise. The reaction mixture was allowed to warm
to room temperature, stirred for 3 h, and then reduced to one-
third of its original volume. The residue was diluted with ether
(10 mL); washed with water, saturated aqueous NaHCO3, and
brine; dried (Na2SO4); and concentrated in vacuo. Flash
chromatography of the residue afforded diazo ketone 12a (97
mg, 74% yield) as a yellow oil: Rf 0.40 (67% EtOAc/hexane);
IR (film) 2930, 2896, 2108, 1734, 1717, 1645, 1385, 1099, 1037
1
1456, 1364, 1113 cm-1; H NMR (500 MHz, CDCl3) δ 7.37-
7.27 (m, 5H), 4.47 (s, 2H), 4.29 (d, J ) 8.2 Hz, 1H), 3.30 (d, J
) 9.4 Hz, 1H), 3.25 (d, J ) 9.4 Hz, 1H), 2.48 (ddd, J ) 18.0,
11.3, 4.6 Hz, 1H), 2.37 (ddd, J ) 18.0, 9.2, 4.9 Hz, 1H), 2.19
(ddd, J ) 13.8, 11.3, 4.9 Hz, 1H), 2.10 (dd, J ) 13.0, 1.0 Hz,
1H), 1.99 (dd, J ) 13.0, 8.3 Hz, 1H), 1.71 (m, 3H), 1.59 (m,
3H), 1.05 (d, J ) 6.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
212.9, 137.9, 128.4, 127.72, 127.65, 93.0, 82.0, 74.4, 73.5, 54.7,
43.2, 41.9, 36.8, 33.9, 30.7, 23.2, 12.6; LRMS (EI) m/z 300 (M+,
34), 209 (20), 194 (15), 176 (19), 164 (71); HRMS (EI) m/z calcd
for C19H24O3 (M+) 300.1725, found 300.1728.
1
cm-1; H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.30
(br s, 1H), 5.07 (s, 1H), 4.94 (s, 1H), 4.48 (s, 2H), 3.95 (s, 2H),
2.75 (t, J ) 6.2 Hz, 2H), 2.59 (br s, 2H), 2.47 (t, J ) 7.4 Hz,
2H), 2.09 (t, J ) 7.7 Hz, 2H), 1.76 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 209.1, 193.4, 145.2, 138.3, 128.4, 127.7, 127.6, 112.3,
72.9, 72.0, 54.5, 42.1, 39.6, 33.9, 32.4, 21.5.
(S)-Ben zyl-3-(5-ben zyloxym eth yl-5-h exen oyl)oxa zoli-
d in -2-on e (15). A solution of ester 7a (7.80 g, 29.77 mmol) in
MeOH (60 mL) was stirred vigorously with 10% NaOH (30
mL) at room temperature for 4 h. The methanol was removed
in vacuo, and the residue was acidified with 10% HCl to pH 3
and extracted with EtOAc (3 × 50 mL). The combined organic
layers were dried (MgSO4), filtered, and concentrated in vacuo
to give acid 7d (6.76 g, 97%) as colorless oil, which was pure
and used without further purification. 7d : Rf 0.15 (40% EtOAc
9-Ben zyloxym eth yl-1-d ia zo-6-m eth yl-9-d ecen e-2,5-d i-
on e (12b). Following the procedure for the preparation of
substrate 12a , diazo ketone 12b was similarly prepared in 68%
yield from acid 11b (667 mg, 2.19 mmol), isobutyl chlorofor-
mate (0.284 mL, 2.19 mmol), and diazomethane (13 mL, about
4 mmol). 12b: a yellow oil; Rf ) 0.17 (20% EtOAc/hexane); IR
1
(film) 2938, 2855, 2109, 1711, 1647, 1379, 1113, 1072 cm-1
;
in hexane); H NMR (300 MHz, CDCl3) δ 7.35-7.27 (m, 5H),
1H NMR (300 MHz, CDCl3) δ 7.30-7.19 (m, 5H), 5.22 (br s,
1H), 4.99 (s, 1H), 4.87 (s, 1H), 4.41 (s, 2H), 3.88 (s, 2H), 2.82-
2.67 (m, 2H), 2.56-2.45 (m, 3H), 2.02-1.95 (m, 2H), 1.85-
5.10 (s, 1H), 4.96 (s, 1H), 4.49 (s, 2H), 3.96 (s, 2H), 2.38 (t, J
) 7.4 Hz, 2H), 2.15 (t, J ) 7.5 Hz, 2H), 1.82 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 179.4, 144.8, 138.2, 128.4, 127.7, 127.6,
112.6, 72.9, 72.0, 33.4, 32.3, 22.5; IR (film, cm-1) 3444 (br),
2940, 2867, 1709, 1454, 1274, 1096, 1072, 910; LRMS (EI) m/z
234 (M+, 2), 143 (9), 128 (25), 125 (18), 107 (60), 91 (100);
HRMS (EI) m/z calcd for C14H18O3 234.1256, found 234.1259.
To acid 7d (10.38 g, 44.36 mmol) and Et3N (6.78 mL, 48.87
mmol) in THF (100 mL) was added pivaloyl chloride (6.08 mL,
48.87 mmol) slowly at -78 °C under argon. The thick white
paste was allowed to stir at 0 °C for 1 h. A solution of (S)-4-
benzyl-2-oxazolidinone40 (7.80 g, 44.07 mmol), DMAP (0.70 g,
5.738 mmol), and Et3N (6.12 mL) in THF (100 mL) was added
to the mixed anhydride at -78 °C over 5 min. The mixture
was stirred for 5 days at room temperature. The volatiles were
removed in vacuo, and the resultant white paste was redis-
solved in CH2Cl2 (200 mL) and 1 M NaOH (100 mL). The
aqueous phase was separated, the organic phase was washed
with brine and dried (Na2SO4), and volatiles were removed in
vacuo. The residue was purified by flash chromatography to
give compound 15 (13.90 g, 80% yield) as a colorless oil. The
basic aqueous phase was acidified and extracted to recover acid
7d (1.40 g, 18% yield). 15: Rf ) 0.75 (50% EtOAc in hexane);
IR (film) 2922, 2852, 1782, 1702, 1455, 1386, 1352, 1212, 1110,
1078 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (m, 10H),
5.10 (s, 1H), 4.99 (s, 1H), 4.66 (m, 1H), 4.50 (s, 2H), 4.16 (m,
2H), 3.99 (s, 2H), 3.29 (dd, J ) 13.3, 3.2 Hz, 1H), 2.96 (m, 2H),
2.75 (dd, J ) 13.3, 9.6 Hz, 1H), 2.20 (t, J ) 7.6 Hz, 2H), 1.89
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 173.1, 153.5, 145.2, 138.4,
135.4, 129.5, 129.0, 128.4, 127.7, 127.6, 127.4, 112.4, 73.0, 72.0,
66.2, 55.2, 37.9, 35.1, 32.4, 22.1; LRMS (EI) m/z 393 (M+, 2),
302 (33), 287 (94), 232 (64), 219 (29), 178 (77), 91 (100); HRMS
1.74 (m, 1H), 1.48-1.33 (m, 1H), 1.03 (d, J ) 7.0 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 212.7, 193.5,145.3, 138.3, 128.3,
127.6, 127.5, 112.2, 72.9, 71.9, 53.4, 45.7, 385.3, 33.9, 30.6, 16.4;
LRMS (EI) m/z 300 (M+ - N2, 27), 209 (91), 194 (23), 181 (23),
165 (22), 149 (30), 137 (20); HRMS (EI) m/z calcd for C19H24O3
(M+ - N2) 300.1725, found 300.1719.
(1R *,5S *,7R *)-5-B e n zy lo x y m e t h y l-11-o x a t r ic y c lo -
[5.3.1.01,5]u n d eca n -8-on e (13). Diazo ketone 12a (72 mg,
0.229 mmol) in dry benzene (5 mL) was treated with Rh2(OAc)4
(1 mg, 0.00226 mmol) and stirred for 6 h at room temperature.
The reaction mixture was filtered and concentrated in vacuo.
Chromatography of the residue afforded cycloadduct 13 (40
mg, 61% yield) as a colorless oil: Rf ) 0.72 (33% EtOAc/
hexane); IR (film) 2955, 2867, 1725, 1444, 1420, 1236 1085,
1
1042 cm-1; H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m, 5H),
4.49 (s, 2H), 4.31 (dd, J ) 6.0, 3.5 Hz, 1H), 3.30 (q-AB, 2H),
2.53-1.59 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 212.1, 137.9,
128.4, 127.7, 127.6, 92.9, 82.2, 74.0, 73.5, 53.9, 42.4, 39.1, 37.5,
33.7, 26.1, 22.6; LRMS (EI) m/z 286 (M+, 8), 195 (17), 150 (25),
137 (13), 123 (10), 119 (12), 95 (19), 91 (100), 79 (12); HRMS
(EI) m/ z calcd for C18H22O3 286.1569, found 286.1565.
(1S*,2R*,5S*,7R*)-5-Ben zyloxym eth yl-2-m eth yl-11-oxa -
tr icyclo[5.3.1.01,5]u n d eca n -8-on e (14a ) a n d (1R*,2R*,5R*,-
7S*)-5-Ben zyloxym eth yl-2-m eth yl-11-oxatr icyclo[5.3.1.01,5]-
u n d eca n -8-on e (14b). Diazo ketone 12b (28.7 mg, 0.0874
mmol) in dry CH2Cl2 (1.0 mL) was treated with Rh2(OAc)4 (0.5
mg, 0.0011 mmol) for 2 h at 0 °C. The reaction mixture was
filtered and concentrated in vacuo. Chromatography of the
residue afforded cycloadduct 14a (13.1 mg, 50% yield) as a
colorless oil and cycloadduct 14b (3.4 mg, 13% yield) as a
colorless oil. 14a : Rf ) 0.48 (20% EtOAc/hexane); IR (film)
2956, 2919, 2871, 1721, 1462, 1105 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.37-7.27 (m, 5H), 4.49 (d, J ) 12.1 Hz, 1H), 4.46
(EI) m/z calcd for C24H27NO4 393.1940, found 393.1943; [R]20
) +20.6° (c 0.63, CHCl3).
D
(1′R,2′S,4S)-4-Ben zyl-3-[5-b en zyloxym et h yl-2′-(1′-h y-
d r oxyeth yl)-5-h exen oyl]oxa zolid in -2-on e (16). To a solu-
tion of acylated oxazolidinone 15 (1.362 g, 3.466 mmol) in
anhydrous CH2Cl2 (10 mL) at 0 °C was added dibutylboron
(39) (a) De Boer, Th. J .; Backer, H. J . Organic Syntheses; Wiley:
New York, 1963; Collect. Vol. IV; p 250. (b) Hudlicky, M. J . Org. Chem.
1980, 45, 5377.
(40) Gage, J . R.; Evans, D. A. Org. Synth. 1990, 68, 77.
4202 J . Org. Chem., Vol. 68, No. 11, 2003

Metal Carbene Approach to the Pseudolaric Acids
triflate (4.16 mL, 4.16 mmol), followed by Et3N (0.69 mL, 4.973
mmol) dropwise, keeping the internal temperature below 3 °C.
The mixture was cooled to -78 °C and acetaldehyde (0.22 mL,
3.936 mmol) was added slowly. The solution was stirred at
-78 °C for 20 min and then at 0 °C for 1 h. The reaction
mixture was quenched by the addition of 12 mL of 2:1
methanol-30% aqueous hydrogen peroxide at such a rate as
to keep the internal temperature below 10 °C. After the
solution was stirred for 1 h, the volatiles were removed, and
the resulting slurry was extracted with diethyl ether (3 × 20
mL). The combined organic extracts were washed with satu-
rated aqueous NaHCO3 and brine, dried (MgSO4), and con-
centrated in vacuo. The residue was purified by flash chro-
matography to give recovered substrate 15 (0.367 g, 27% yield)
and aldol adduct 16 (1.018 g, 67% yield) as a pale yellow oil.
16: Rf ) 0.40 (50% EtOAc in hexane); IR (film) 3442, 2923,
2852, 1780, 1705, 1444, 1385, 1352, 1211, 1079 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.35-7.19 (m, 10H), 5.07 (s, 1H), 4.98 (s,
1H), 4.70 (m, 1H), 4.47 (s, 2H), 4.12 (m, 4H), 3.98 (s, 2H), 3.35
(dd, J ) 13.2, 3.1 Hz, 1H), 2.62 (dd, J ) 13.2, 10.1 Hz, 1H),
2.52 (br s, 1H), 2.20-2.01 (m, 3H), 1.80 (m, 1H), 1.24 (d, J )
6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 175.0, 153.9, 145.2,
138.2, 135.3, 129.4, 129.0, 128.4, 127.7, 127.6, 127.4, 112.7,
72.9, 72.0, 68.9, 66.1, 55.7, 48.4, 38.0, 31.0, 25.5, 19.5; LRMS
(EI) m/z 393 [M+] (4), 302 [M - Bn]+ (28), 287 (84), 232 (71),
219 (36), 178 (100); HRMS (EI) m/z calcd for C24H27NO4
1), 291 (8), 247 (19), 232 (36), 170 (23), 141 (39), 91 (100), 89
(45); HRMS (EI) m/z calcd for C20H30O6 366.2042, found
366.2044; [R]20 ) +29.8° (c 1.72, CHCl3).
D
(1′R,2S)-5-Ben zyloxym et h yl-2-[1′-(2-m et h oxyet h oxy-
m eth oxy)eth yl]-5-h exen oic Acid S-Eth yl Ester (21). To a
solution of acid 18 (0.770 g, 2.104 mmol) in anhydrous CH2-
Cl2 (5 mL) was added DMAP (0.016 g, 0.130 mmol), ethanethiol
(0.31 mL, 4.145 mmol), and DCC (0.530 g, 2.573 mmol) at 0
°C. The reaction mixture was stirred for 3 h at room temper-
ature. Precipitated DCU was filtered off, and the filtrate was
concentrated. The residue was taken up in CH2Cl2 and washed
twice with 0.5 N HCl and then with saturated NaHCO3 and
brine. The solution was dried (MgSO4) and concentrated in
vacuo. The residue was purified by flash chromatography to
afford thioester 21 (0.790 g, 91% yield) as a colorless oil. 21:
Rf) 0.82 (33% EtOAc in hexane); IR (film) 2973, 2930, 2882,
1
1682, 1454, 1458, 1248, 1078, 1036, 906, 820 cm-1; H NMR
(300 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.08 (s, 1H), 4.96 (s,
1H), 4.77 (d, J ) 7.2 Hz, 1H), 4.71 (d, J ) 7.2 Hz, 1H), 4.48 (s,
2H), 3.95 (s, 2H), 3.88 (m, 1H), 3.70 (m, 2H), 3.54 (m, 2H),
3.38 (s, 3H), 2.88 (q, J ) 7.4 Hz, 2H), 2.70 (m, 1H), 2.10 (m,
2H), 1.86 (m, 2H), 1.82 (m, 3H), 1.24 (t, J ) 7.4 Hz, 3H), 1.20
(d, J ) 6.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 201.0, 145.2,
138.4, 128.3, 127.7, 127.5, 112.3, 94.2, 74.3, 73.0, 71.9, 71.7,
67.1, 59.7, 59.0, 30.7, 27.0, 23.4, 18.2, 14.7; LRMS (EI) m/z
321 (M+ - MEM, 5), 273 (15), 215 (24), 153 (22), 91 (100), 89
393.1940, found 393.1939; [R]20 ) +23.1° (c 0.36, CHCl3).
(36); HRMS (EI) m/z calcd for
C
22H34O5S (M+ - MEM)
D
321.1534, found 321.1528; [R]20 ) +36.7° (c 1.32, CHCl3).
(1′R,2′S,4S)-4-Ben zyl-3-{5-b en zyloxym et h yl-2′-[1′-(2-
m eth oxyeth oxy)eth yl]-5-h exen oyl}oxa zolid in -2-on e (17).
A solution of compound 16 (2.07 g, 4.74 mmol) in CH2Cl2 (10
mL) was treated with i-Pr2NEt (1.75 mL, 10.07 mmol) and
MEMCl (1.10 mL, 9.64 mmol) at room temperature. After
stirring for 4 h, water (10 mL) was added and the resultant
mixture was extracted with ether (3 × 30 mL). The combined
organics were dried (Na2SO4) and concentrated in vacuo. The
residue was purified by flash chromatography to afford
compound 17 (2.31 g, 93% yield) as a colorless oil. 17: Rf )
0.48 (50% EtOAc in hexane); IR (film) 2928, 2887, 1779, 1701,
1454, 1385, 1198, 1108, 1042 cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.35-7.19 (m, 10H), 5.07 (s, 1H), 4.98 (s, 1H), 4.69 (s, 2H),
4.67 (m, 1H), 4.48 (s, 2H), 4.14 (m, 3H), 4.02 (t, J ) 5.9 Hz
1H), 3.97 (s, 2H), 3.67 (m, 2H), 3.54 (m, 2H), 3.36 (s, 3H), 3.35
(dd, J ) 13.2, 3.1 Hz, 1H), 2.64 (dd, J ) 13.2, 10.2 Hz, 1H),
D
(1′R,5S)-8-Ben zyloxym et h yl-1-h yd r oxy-5-[1′-(2-m et h -
oxyet h oxym et h oxy)et h yl]-8-n on en -4-on e (22). Grignard
reagent 9 (10 mL, 5 mmol) was added into thioester 21 (0.680
g, 1.659 mmol), Me2S (1.20 mL), and CuI (1.43 g, 7.5 mmol)
suspended in THF (10 mL) at 0 °C. The resultant mixture was
stirred at room temperature overnight and quenched with
saturated NH4Cl. The organic layer was separated and the
aqueous layer was extracted with EtOAc (3 × 20 mL). The
combined organics were washed with brine, dried (MgSO4),
and concentrated in vacuo. The residue was purified by flash
chromatography to give alcohol 22 (0.52 g, 77% yield), as a
colorless oil, and unreacted thioester 21 (116 mg, 17%). 22: Rf
) 0.25 (67% EtOAc in hexane); IR (film) 3480 (br), 1708, 1454,
1375, 1245, 1097, 1042 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.37-7.25 (m, 5H), 5.06 (s, 1H), 4.93 (s, 1H), 4.76 (d, J ) 7.1
Hz, 1H), 4.71 (d, J ) 7.1 Hz, 1H), 4.47 (s, 2H), 3.93 (s, 2H),
3.90 (m, 1H), 3.69 (m, 2H), 3.56 (m, 4H), 3.39 (s, 3H), 2.78 (m,
2H), 2.52 (dt, J ) 18.3, 6.6 Hz, 1H), 2.26 (br s, 1H), 2.00 (m,
2H), 1.82 (m, 3H), 1.62 (m, 1H), 1.11 (d, J ) 6.3 Hz, 3H); 13C
NMR (75 MHz, CDCl3) δ 212.9, 145.3, 138.2, 128.4, 127.7,
127.6, 112.5, 93.9, 74.1, 72.9, 72.0, 71.7, 67.2, 61.9, 59.0, 56.7,
41.5, 31.1, 26.0, 25.9, 17.3; LRMS (EI) m/z 302 (M+ - MEM -
OH, 4), 375 (2), 301 (4), 284 (18), 257 (15), 195 (37), 193 (70),
174 (40), 91 (100), 89 (64); HRMS (EI) m/z calcd for C19H26O3
(M+ - MEM - OH) 302.1882, found 302.1880; [R]D ) +17.5°
(c 0.76, CHCl3).
2.17-2.02 (m, 3H), 1.75 (m, 1H), 1.22 (d, J ) 6.3 Hz, 3H); 13
C
NMR (75 MHz, CDCl3) δ 173.9, 153.3, 145.3, 138.3, 135.5,
129.4, 128.9, 128.4, 127.7, 127.6, 127.4, 112.4, 93.9, 73.6, 72.9,
72.0, 71.8, 67.1, 65.9, 59.0, 55.9, 47.1, 37.9, 31.0, 25.9, 17.3;
LRMS (EI) m/z 525 (M+, 1), 450 (5), 358 (15), 330 (100), 304
(17), 178 (29), 91 (53), 89 (35); HRMS (EI) m/z calcd for C30H39
-
NO7 525.2727, found 525.2726; [R]20D ) +18.3° (c 0.81, CHCl3).
(1′R,2S)-5-Ben zyloxym et h yl-2-[1′-(2-m et h oxyet h oxy-
m eth oxy)eth yl]-5-h exen oic Acid (18). To a solution of
oxazolidone 17 (2.0055 g, 3.82 mmol) in 25 mL of 4:1 THF-
distilled water was added 0.91 mL of 50% aqueous H2O2 at 0
°C, followed by LiOH‚H2O (273.5 mg, 6.51 mmol) in distilled
water (18 mL). After stirring for 3 h, sodium sulfite (1.204 g,
9.55 mmol) in 16 mL of distilled water was added. The bulk
of the THF was removed in vacuo and the residue (pH 12-
13) was extracted with CH2Cl2 (3 × 30 mL). The aqueous layer
was cooled in an ice bath and acidified to pH 4. The resultant
cloudy solution was extracted with EtOAc (3 × 30 mL). The
combined organics were dried (MgSO4) and concentrated in
vacuo to afford the desired acid 18 (1.1604 g, 83% yield) as a
pale yellow oil. 18: Rf ) 0.21 (50% EtOAc in hexane); IR (film)
(1′R,5S)-8-Ben zyloxym et h yl-5-[1′-(2-m et h oxyet h oxy-
m eth oxy)eth yl]4-oxo-8-n on en oic Acid (23). Following the
procedure for the preparation of acid 11a , acid 23 was similarly
prepared in 75% yield from alcohol 22 (88 mg, 0.216 mmol)
and PDC (0.49 g, 1.293 mmol). 23: a colorless oil; Rf ) 0.18
(75% EtOAc in hexane); IR (film) 3502, 2930, 1712, 1456, 1384,
1112, 1040 cm-1; 1H NMR (300 MHz, CDCl3) δ 9.77 (br s, 1H),
7.37-7.25 (m, 5H), 5.06 (s, 1H), 4.93 (s, 1H), 4.76 (d, J ) 7.1
Hz, 1H), 4.71 (d, J ) 7.1 Hz, 1H), 4.47 (s, 2H), 3.93 (s, 2H),
3.88 (m, 1H), 3.68 (m, 2H), 3.54 (m, 2H), 3.38 (s, 3H), 2.88 (m,
1H), 2.72 (m, 2H), 2.57 (m, 2H), 2.02 (m, 2H), 1.90 (m, 1H),
1.62 (m, 1H), 1.11 (d, J ) 6.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 210.3, 177.9, 145.2, 138.2, 128.3, 127.7, 127.5, 112.4,
93.9, 74.0, 72.8, 71.9, 71.7, 67.1, 59.0, 56.4, 39.3, 31.0, 27.5,
25.9, 17.1; LRMS (EI) m/z 333 (M+ - MEM, 6), 391 (5), 347
(9), 242 (28), 197 (31), 91 (100); HRMS (EI) m/z calcd for
3475 (br), 2975, 2932, 2867,1712, 1455, 1383, 1107, 1039 cm-1
;
1H NMR (300 MHz, CDCl3) δ 7.34-7.27 (m, 5H), 5.08 (s, 1H),
4.97 (s, 1H), 4.78 (d, J ) 7.2 Hz, 1H), 4.73 (d, J ) 7.2 Hz, 1H),
4.49 (s, 2H), 3.98 (m, 1H), 3.96 (s, 2H), 3.70 (m, 2H), 3.54 (m,
2H), 3.38 (s, 3H), 2.58 (m, 1H), 2.15 (m, 2H), 1.82 (m, 2H),
1.24 (d, J ) 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.7,
145.0, 138.2, 128.4, 127.7, 127.6, 112.6, 94.1, 73.9, 72.9, 71.9
71.7, 67.1, 59.0, 50.8, 31.1, 25.9, 17.6; LRMS (EI) m/z 366 (M+,
C
19H25O5 (M+ - MEM) 333.1702, found 333.1699; [R]20
)
D
+24.1° (c 0.69, CHCl3).
J . Org. Chem, Vol. 68, No. 11, 2003 4203

Chen et al.
(1′R,6S)-9-Ben zyloxym eth yl-1-d ia zo-6-[1′-(2-m eth oxy-
eth oxym eth oxy)eth yl]-9-d ecen e-2,5-d ion e (4). Following
the procedure for the preparation of diazo ketone 12a , diazo
ketone 4 was prepared in a similar fashion in 72% yield from
acid 23 (120 mg, 0.294 mmol), Et3N (0.061 mL, 0.439 mmol),
isobutyl chloroformate (0.057 mL, 0.440 mmol), and ethereal
diazomethane (3 mL, about 1.0 mmol). 4: a yellow oil; Rf )
0.23 (40% EtOAc in hexane); IR (film) 2929, 2896, 2108, 1711,
trated in vacuo. The residue was purified by flash chromatog-
raphy to afford a mixture of alcohols (25 mg, 80%) as a colorless
oil.
To the alcohols (25 mg, 0.076 mmol) in dry CH2Cl2 (1 mL)
was added the Dess-Martin reagent41 (50 mg, 0.12 mmol) at
room temperature. After stirring for 6 h, saturated Na2S2O3
solution was added dropwise until the reaction mixture cleared
up. Saturated NaHCO3 was added and the solution was
extracted with EtOAc (3 × 5 mL). The combined organics were
dried (Na2SO4) and concentrated in vacuo. The residue was
purified by flash chromatography to afford a mixture of 24a
and 24b (24a :24b ) 1.25:1, 23 mg, 93%) as a colorless oil.
1644, 1380, 1100, 1039 cm-1 1H NMR (300 MHz, CDCl3) δ
;
7.37-7.27 (m, 5H), 5.28 (br s, 1H), 5.07 (s, 1H), 4.94 (s, 1H),
4.76 (d, J ) 7.1 Hz, 1H), 4.71 (d, J ) 7.1 Hz, 1H), 4.48 (s, 2H),
3.94 (s, 2H), 3.88 (m, 1H), 3.68 (m, 2H), 3.54 (m, 2H), 3.38 (s,
3H), 2.95 (dt, J ) 18.9, 6.4 Hz, 1H), 2.78 (m, 2H), 2.55 (br m,
2H), 2.01 (m, 2H), 1.86 (m, 1H), 1.60 (m, 1H), 1.11 (d, J ) 6.3
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 210.9, 193.4, 145.3,
138.4, 128.4, 127.7, 127.6, 112.4, 94.0, 74.1, 72.9, 72.0, 71.7,
67.2, 59.1, 56.5, 54.5 (br), 39.4 (br), 33.9 (br), 31.1, 26.1, 17.2;
LRMS (EI) m/z 418 (M+ - N2, 18), 342 (66), 312 (22), 299 (30),
285 (32), 251 (28), 233 (17); HRMS (EI) m/z calcd for C24H34O6
Careful separation of the mixture of 24a and 24b by column
chromatography gave pure samples of 24a and 24b for
analytical purposes. 24a : Rf ) 0.65 (40% EtOAc in hexane);
IR (CH2Cl2) 2958, 2938, 2869, 1726, 1709, 1455, 1364, 1104,
1088, 1028 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m,
5H), 4.52 (d, J ) 12.1 Hz, 1H), 4.46 (d, J ) 12.1 Hz, 1H), 4.30
(d, J ) 7.4 Hz, 1H), 3.62 (d, J ) 9.2 Hz, 1H), 3.44 (d, J ) 9.2
Hz, 1H), 3.33 (dd, J ) 8.3, 2.2 Hz, 1H), 2.38 (m, 3H), 2.25 (m,
1H), 2.21 (s, 3H), 2.15 (q, J ) 6.9 Hz, 1H), 2.03 (dd, J ) 8.8,
6.9 Hz, 1H), 1.98 (dd, J ) 12.8, 8.3 Hz, 1H), 1.83 (ddd, J )
6.6, 3.7, 2.5 Hz, 1H), 1.72 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 211.7, 209.5, 137.9, 128.4, 127.8, 127.6, 93.3, 82.4, 73.4, 72.5,
61.5, 54.9, 42.0, 37.9, 33.8, 31.2, 27.2, 24.6; LRMS (EI) m/z
328 (M+, 19), 237 (26), 194 (100), 179 (53), 149 (67); HRMS
(M+ - N2) 418.2355, found 418.2361; [R]20 ) +19.9° (c 5.85,
D
CHCl3).
(1S,1′R,2S,5S,7R)-5-Ben zyloxym eth yl-2-[1′-(2-m eth oxy-
et h oxym et h oxy)et h yl]-11-oxa t r icyclo[5.3.1.01,5]-8-u n d e-
ca n on e (3a ) a n d (1R,1′R,2S,5R,7S)-5-Ben zyloxym eth yl-
2 - [ 1 ′ - ( 2 - m e t h o x y e t h o x y m e t h o x y ) e t h y l ] - 1 1 -
oxa tr icyclo[5.3.1.01,5]-8-u n d eca n on e (3b). A solution of
diazo ketone 4 (10.1 mg, 0.0226 mmol) in dry benzotrifluoride
(1.0 mL) was treated with Rh2(S-BPTV)4 (0.3 mg, 2.26 × 10-4
mmol) at 0 °C for 2.5 h. The reaction mixture was filtered and
concentrated in vacuo. The residue was purified by flash
chromatography to give product 3 (5.7 mg, 51% yield, 3a :3b
) 1.4:1).
(EI) m/z calcd for C20H24O4 328.1675, found 328.1672; [R]20
)
D
-22.9° (c 0.18, CHCl3). 24b: Rf ) 0.65 (40% EtOAc in hexane);
IR (CH2Cl2) 2960, 2929, 2865, 1726, 1695, 1455, 1358, 1104,
1076, 1030 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.38-7.27 (m,
5H), 4.48 (s, 2H), 4.37 (dd, J ) 5.3, 4.2 Hz, 1H), 3.33 (d, J )
9.5 Hz, 1H), 3.27 (d, J ) 9.5 Hz, 1H), 2.60 (dd, J ) 11.8, 6.4
Hz, 1H), 2.47-2.29 (m, 4H), 2.25 (s, 3H), 2.042 (d, J ) 5.5 Hz,
1H), 2.039 (d, J ) 4.0 Hz, 1H), 1.90 (m, 3H), 1.72 (m, 1H); 13
C
HPLC separation of the mixture of 3a and 3b gave analyti-
cally pure samples of 3a and 3b. 3a : a colorless oil; Rf ) 0.48
(40% EtOAc in hexane); IR (CH2Cl2) 2935, 2874, 1728, 1456,
NMR (75 MHz, CDCl3) δ 211.4, 209.2, 137.5, 128.5, 127.9,
127.6, 92.7, 82.7, 73.6, 73.5, 60.1, 55.3, 42.0, 36.6, 33.6, 30.3,
26.3, 23.9; LRMS (EI) m/z 328 (M+, 23), 237 (33), 194 (100),
179 (45), 149 (60); HRMS (EI) m/z calcd for C20H24O4 328.1675,
1
1362, 1103, 1035 cm-1; H NMR (300 MHz, CDCl3) δ 7.37-
7.27 (m, 5H), 4.60 (d, J ) 7.0 Hz, 1H), 4.57 (d, J ) 7.1 Hz,
1H), 4.50 (s, 2H), 4.32 (br d, J ) 6.6 Hz, 1H), 3.87 (dq, J )
6.3, 2.2 Hz, 1H), 3.62 (m, 1H), 3.53 (q, J ) 4.1 Hz, 1H), 3.50
(s, 2H), 3.48 (d, J ) 9.2 Hz, 1H), 3.46 (d, J ) 9.2 Hz, 1H), 3.38
(s, 3H), 2.61 (dt, J ) 17.7, 8.9 Hz, 1H), 2.36 (m, 1H), 2.22 (m,
1H), 2.18 (m, 2H), 2.12 (m, 1H), 2.01 (m, 1H), 1.91 (m, 3H),
1.66 (m, 1H), 1.19 (d, J ) 6.3 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 209.6, 138.2, 128,4, 127.7, 127.7, 94.7, 94.2, 82.4, 73.5,
73.1, 71.8, 71.4, 67.5, 59.1, 56.2, 53.8, 40.6, 37.7, 33.1, 25.9,
24.3, 19.3; LRMS (EI) m/z 418 (M+, 2), 342 (16), 329 (11) 299
(15), 221 (36),111 (49), 89 (100); HRMS (EI) m/z calcd for
found 328.1670; [R]20 ) +13.6° (c 0.13, CHCl3).
D
(1S*,2R*,5S*,7R*)-5-Ben zyloxym et h yl-2-(1-m et h yl-1-
tr ieth ylsiloxyeth yl)-11-oxa tr icyclo[5.3.1.01,5]u n d eca n -8-
on e (26a ) a n d (1R*,2R*,5R*,7S*)-5-Ben zyloxym et h yl-2-
(1-m eth yl-1-tr ieth ylsiloxyeth yl)-11-oxa tr icyclo[5.3.1.01,5]-
u n d eca n -8-on e (26b). A solution of diazo ketone 25 (20.7 mg,
0.0425 mmol) in dry CH2Cl2 (1 mL) was treated with Rh2(OAc)4
(0.18 mg, 4.25 × 10-4 mmol) for 3.5 h at 0 °C. Workup and
chromatography afforded a mixture of cycloadducts 26a and
26b (11.5 mg, 59%, 26a :26b ) 1:4.9). 26a : a colorless oil; Rf
) 0.61 (20% EtOAc in hexane); IR (film) 2959, 2877, 1726,
C
24H34O6 418.2355, found 418.2360; [R]20 ) -26.3° (c 0.11,
D
1456, 1366, 1105, 1012 cm-1 1H NMR (500 MHz, CDCl3) δ
;
CHCl3). 3b: a colorless oil; Rf ) 0.43 (40% EtOAc in hexane);
IR (CH2Cl2) 2934, 2874, 1728, 1455, 1364, 1103, 1037 cm-1;1H
NMR (600 MHz, CDCl3) δ 7.36-7.25 (m, 5H), 4.76 (q-AB, 2H),
4.48 (s, 2H), 4.31 (t, J ) 4.8 Hz, 1H), 4.05-4.04 (m, 1H), 3.78-
3.75 (m, 1H), 3.73-3.69 (m, 1H), 3.54 (t, J ) 4.7 Hz, 2H), 3.38
(s, 2H), 3.30 (q-AB, 2H), 2.47-2.35 (m, 3H), 2.01 (d, J ) 4.8
Hz, 2H), 1.91-1.84 (m, 1H), 1.83-1.74 (m, 4H), 1.63-1.60 (m,
2H), 1.29 (d, J ) 6.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
212.1, 137.8, 128.4, 127.8, 127.6, 94.2, 92.4, 82.4, 77.5, 74.2,
73.5, 72.1, 71.9, 67.0, 59.1, 56.2, 52.6, 42.1, 36.4, 33.7, 24.9,
24.7, 20.6; LRMS (EI) m/z 418 (M+, 2), 342 (20), 329 (9) 299
(12), 221 (45), 111 (44), 89 (100); HRMS (EI) m/z calcd for
7.36-7.29 (m, 5H), 4.52 (q-AB, 2H), 4.35 (br d, J ) 8.4 Hz,
1H), 3.47 (d, J ) 9.1 Hz, 1H), 3.39 (d, J ) 9.2 Hz, 1H), 2.91-
2.84 (m, 1H), 2.50-2.43 (m, 1H), 2.38-2.33 (m, 1H), 2.24 (dd,
J ) 7.8 Hz, 11.0 Hz, 1H), 2.17-2.12 (m, 1H), 2.05-1.96 (m,
2H), 1.93-1.88 (m, 1H), 1.73-1.65 (m, 1H), 1.61-1.55 (m, 1H),
1.34 (s, 3H), 1.18 (s, 3H), 0.94 (t, J ) 8.0 Hz, 9H), 0.56 (q, J )
8.0 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ 210.0, 139.1, 128.5,
127.8, 127.7, 95.1, 83.4, 75.0, 73.6, 71.9, 60.5, 57.3, 40.4, 36.4,
33.3, 31.6, 29.9, 29.3, 26.2, 7.2, 6.9; LRMS (EI) m/z 427 (M+
-
C2H5, 93), 411 (12), 305 (44), 291 (15), 235 (40), 217 (36); HRMS
(EI) m/z calcd for C25H37O4 Si (M+ - C2H5) 429.2461, found
429.2462. 26b: a colorless oil; Rf ) 0.68 (20% EtOAc in
hexane); IR (film) 2957, 2876, 1724, 1456, 1365, 1130, 1103,
C
24H34O6 418.2355, found 418.2360; [R]20 ) +16.3° (c 0.11,
D
1
1028 cm-1; H NMR (500 MHz, CDCl3) δ 7.35-7.27 (m, 5H),
CHCl3).
4.50 (s, 2H), 4.29 (dd, J ) 7.4, 2.3 Hz, 1H), 3.36 (d, J ) 9.3
Hz, 1H), 3.30 (d, J ) 9.3 Hz, 1H), 3.10-3.04 (m, 1H), 2.40-
2.36 (m, 2H), 2.01-1.91 (m, 3H), 1.82-1.64 (m, 4H), 1.56-
1.51 (m, 1H) 1.36 (s, 3H), 1.25 (s, 3H), 0.94 (t, J ) 7.9 Hz,
9H), 0.59 (q, J ) 8.1 Hz, 6H); 13C NMR (125 MHz, CDCl3) δ
(1S,2R,5S,7R)-2-Acetyl-5-ben zyloxym eth yl-11-oxa tr icy-
clo[5.3.1.01,5]-8-u n d eca n on e (24a ) a n d (1R,2R,5R,7S)-2-
Acetyl-5-ben zyloxym eth yl-11-oxa tr icyclo[5.3.1.01,5]-8-u n -
d eca n on e (24b). A mixture of 3a and 3b (3a :3b ) 1:1.25, 40
mg, 0.096 mmol) and TsOH (37 mg, 0.20 mmol) in MeOH (3
mL) was heated to reflux for 1 h. MeOH was removed in vacuo.
The residue was taken up in 5 mL of EtOAc, washed with
saturated NaHCO3 and brine, dried (Na2SO4), and concen-
(41) Boeckman J r., R. K.; Shao, P.; Mullins, J . J . Org. Synth. 1999,
77, 141.
4204 J . Org. Chem., Vol. 68, No. 11, 2003

Metal Carbene Approach to the Pseudolaric Acids
212.1, 138.0, 128.4, 127.7, 127.6, 93.3, 82.3, 76.4, 74.3, 73.5,
57.3, 56.3, 42.1, 36.4, 33.7, 32.1, 27.3, 26.2, 25.7, 7.2, 6.9; LRMS
(EI) m/z 429 (M+- C2H5, 51), 265 (93), 218 (8), 205 (20), 191
(34), 173 (49); HRMS (EI) m/z calcd for C25H37O4Si (M+ - C2H5)
429.2461, found 429.2460.
26.3, 25.8; LRMS (EI) m/z 182 (M+, 17), 139 (47), 138 (100),
111 (48), 95 (46); HRMS (EI) m/z calcd for C11H18O2 182.1307,
found 182.1305.
(3aR*,8aS*)-6-Meth yl-2,3,4,5,8,8a-h exah ydr o-1H-azu len -
3a -ol (33). To a solution of alcohol 31 (90 mg, 0.495 mmol) in
DMPU (0.54 mL) was added SOCl2 (0.090 mL, 0.617 mmol)
at 0 °C under Ar. The reaction mixture was stirred overnight
then quenched with water (2 mL). The resulting mixture was
extracted with ether (3 × 5 mL). The combined organics were
washed with water, dried over MgSO4, and removed of solvent
carefully under reduced pressure (0 °C bath, 50 mmHg) to give
the volatile chloride 32, which was taken up in 2.0 mL of Et2O
and used in the next step without further purification.
Sodium (50 mg, 2.174 mmol) was added to the ethereal
solution of chloride 32 under argon. The reaction mixture was
stirred under reflux for 5 h. The reaction was quenched
carefully by the addition of ethanol (0.20 mL) and then water
(2 mL). The resulting mixture was extracted with ether (3 ×
5 mL), and the combined organics were washed with saturated
NH4Cl and brine, dried over MgSO4, and evaporated in vacuo.
The residue was purified by flash chromatography to give
alcohol 33 (64 mg, 71% yield from 31) as a colorless oil: Rf
0.50 (33% Et2O in hexane); IR (film) 3410 (br), 2947, 2871,
1451, 1336, 1089, 950 cm-1; 1H NMR (300 MHz, CDCl3) δ 5.54
(m, 1H), 2.48 (br t, J ) 14.0 Hz, 1H), 2.06 (m, 1H), 1.94-1.35
(m, 12H), 1.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 139.6,
124.6, 81.2, 47.2, 41.9, 37.1, 30.4, 27.5, 27.2, 26.2, 19.6; LRMS
(EI) m/z 166 (M+, 13), 149 (23), 148 (100), 133 (75), 119 (74),
105 (79), 91 (60); HRMS (EI) m/z calcd for C11H18O 166.1358,
found 166.1363.
Red u ctive Clea va ge of Com p ou n d 27. To a solution of
ketone 2714 (110 mg, 0.663 mmol) in THF (2 mL) was added
SmI2 (0.1 M in THF, 14.6 mL, 1.460 mmol) at 0 °C under Ar.
The reaction mixture was allowed to warm to room temper-
ature and stirred overnight. The reaction was quenched with
pH ) 7 phosphate buffer (2 mL). The organic layer was
separated and the aqueous layer was extracted with ether (3
× 5 mL). The combined organic phases were washed with
brine, dried over MgSO4, and evaporated in vacuo. The residue
was purified by flash chromatography to give compounds 29
[76 mg, 69% yield, 29a (keto form):29b (hemiacetal) ) 0.14:
0.86] and 30 (16 mg, 14% yield), both as colorless oils. 29: Rf
0.40 (33% EtOAc/hexane); IR (film) 3347 (br), 2959, 2877, 1721,
1454, 1236, 1090, 1040, 938 cm-1; 1H NMR (300 MHz, CDCl3)
δ 3.58 (s, 0.86 × 1H), 2.94 (dt, J ) 14.1, 3.8 Hz, 0.14 × 1H),
2.50 (m, 0.14 × 2H), 2.32 (m, 0.14 × H) 2.16-1.48 (m, 0.86 ×
15H + 0.14 × 12H); 13C NMR (75 MHz, CDCl3) 29a : δ 214.8,
79.9, 50.6, 43.5, 41.7, 38.2, 34.8, 30.7, 21.9, 19.7. 29b: δ 103.8,
90.5, 50.6, 34.9, 34.4, 32.6, 30.9, 27.9, 21.6, 21.2; LRMS (EI)
m/z 168 (M+, 11), 151 (100), 123 (35), 95 (29); HRMS (EI) m/z
calcd for C10H16O2 168.1150, found 168.1146. 30: Rf ) 0.25
(33% EtOAc/hexane); IR (film) 3400 (br), 2944, 2869, 1464,
1
1456, 1351, 1149, 1128, 1066, 1010, 913 cm-1; H NMR (300
MHz, CDCl3) δ 4.26 (dd, J ) 6.4, 4.5 Hz, 1H), 3.82 (m, 1H),
2.33-2.22 (m, 2H), 1.97-1.81 (m, 5H), 1.66-1.35 (m, 8H); 13
C
NMR (75 MHz, CDCl3) δ 92.5, 80.4, 68.1, 45.7, 36.2, 34.8, 34.0,
32.8, 28.0, 26.0; LRMS (EI) m/z 168 (M+, 16), 124 (100), 97
(43); HRMS (EI) m/z calcd for C18H22O3 168.1150, found
168.1153. The J ax-ax ) 6.4 Hz of the downfield signal at 4.26
ppm implies an axial proton, and thus, the hydroxyl group in
30 is R.
Ack n ow led gm en t. The work described in this paper
was supported by a grant from the Research Grants
Council of Hong Kong Special Administrative Region,
China (Project No. HKU 7081/01P), The University of
Hong Kong Hung Hing Ying Physical Sciences Research
Fund, and the Areas of Excellence Scheme established
under the University Grants Committee of the Hong
Kong Special Administrative Region, China (Project No.
AoE/P-10/01). B.C. thanks the University of Hong Kong
for an exchange scholarship. R.Y.Y.K. thanks the Uni-
versity of Hong Kong for a Swire Fellowship. We thank
Dr. Yunhong Zheng for technical assistance.
8-Meth yl-11-oxa tr icyclo[5.3.1.01,5]u n d eca n -8-ol (31). To
a solution of ketone 27 (83 mg, 0.50 mmol) in Et2O (2 mL)
was added MeMgI at 0 °C under argon. The reaction mixture
was stirred for 2 h at room temperature and then quenched
using saturated NH4Cl (2 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with ether (3 × 5
mL). The combined organics were washed with brine, dried
over MgSO4, and evaporated in vacuo. The residue was
purified by flash chromatography to give alcohol 31 (84 mg,
92% yield, one diastereoisomer) as a colorless oil: Rf 0.35 (33%
EtOAc in hexane); IR (film, cm-1) 3391 (br), 2943, 2869, 1694,
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for compounds 19, 20, and 25;
1H and 13C NMR spectra for compounds 3a ,b, 4, 7, 8, 10-18,
21-26, 29-31, 33. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
1454, 1334, 1265, 1167, 1093, 1039, 1009, 948; H NMR (300
MHz, CDCl3) δ 3.91 (d, J ) 7.1 Hz, 1H), 2.39 (m, 1H), 2.25 (m,
1H), 1.91-1.40 (m, 12H), 1.38 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 93.0, 84.8, 69.7, 45.1, 36.2, 35.1, 34.7, 33.6, 32.4, 29.7,
J O026399M
J . Org. Chem, Vol. 68, No. 11, 2003 4205