Template-directed C-H activation: Development and application to the total synthesis of 7-episordidin

Article abstract of DOI:10.1016/S0957-4166(03)00091-0

The development of a template-directed C-H activation strategy and its application to the diastereoselective synthesis of (±)-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopolites sordidus Germar, is reported. The key step of t

Full text of DOI:10.1016/S0957-4166(03)00091-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 929–940
Template-directed CꢀH activation: development and application
to the total synthesis of 7-episordidin
Duncan J. Wardrop,* Raymond E. Forslund, Chad L. Landrie, Adriana I. Velter, Donald Wink
and Bushan Surve
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607, USA
Received 5 December 2002; accepted 14 January 2003
Abstract—The development of a template-directed CꢀH activation strategy and its application to the diastereoselective synthesis
of ( )-7-episordidin, an aggregation pheromone from the male banana weevil, Cosmopolites sordidus Germar, is reported. The key
step of the synthetic route is a regioselective rhodium(II)-catalyzed diazocarbonyl CꢀH activation reaction that simultaneously
generates three of the four stereocenters present in the natural product. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
tones,9 tetrahydrofurans10 and g-butyrolactones,11 there
are potential pitfalls associated with its application in
situations where multiple oxygen atoms are present in
the insertion precursor. Of primary concern is the likeli-
hood of competitive oxonium ylide formation.12
Over the last two decades, the dirhodium(II)-catalyzed
decomposition of a-diazocarbonyl compounds and
intramolecular CꢀH insertion of the resulting Rh car-
benoids has emerged as
a particularly powerful
methodology for the construction of carbocyclic and
heterocyclic rings.1,2 Extensive efforts by a number of
groups to systematically identify the factors which con-
trol the site-selectivity of intramolecular CꢀH insertion
reactions have revealed that, in the absence of overrid-
ing conformational influences, the formation of five-
membered rings is highly favored. Furthermore, in
competitive situations the relative reactivity of car-
bonꢀhydrogen bonds is in the order tertiary>sec-
ondaryꢀprimary and significantly, there is a strong
preference for insertion into CꢀH bonds alpha to het-
eroatoms such as nitrogen3 and oxygen.4 This CꢀH
activation has been presented as evidence4,5 that inser-
tion proceeds with CꢀH bond polarization and con-
comitant charge development on carbon which is
stabilized by heteroatoms through resonance effects.6
As shown in Fig. 1, insertion into oxygen-activated
CꢀH bonds can be considered to be the synthetic
equivalent of an aldol-type reaction and as such is
potentially very useful.7 While the intramolecular vari-
ant of this transformation has been successfully
exploited in the preparation of 3(2H)-furanones,8 b-lac-
Figure 1. Insertion into oxygen-activated CꢀH bonds as an
aldol surrogate.
It occurred to us that by temporarily restraining an
a-diazo ketone and the oxygen-activated CꢀH bonds of
a 1,3-diol 1 within a conformationally restricted tem-
plate structure, we might be able to achieve CꢀH inser-
tion and suppress side reactions, such as ylide
formation. As outlined in Scheme 1, our strategy to
realize this goal is centered around 2-carboxy-1,3-diox-
anes which display a pronounced preference (ꢁ4 kcal/
mol) for the axially oriented 2-carboxylate group.13 The
a-diazo ketones 2 derived from this ring system are
suitable vehicles with which to explore our insertion
strategy since the C-2 diazoacetyl group is positioned in
a coplanar arrangement with the activated CꢀH bonds
at C-4/6. Thus configured, 2 are poised for transannular
CꢀH insertion to form 2,8-dioxabicyclo[3.2.1]octanones
3 which can be viewed as masked aldol products to be
revealed by cleavage of the furanone ring (3“5).14
Alternatively, 3 is the core structure present in both the
* Corresponding author. Tel.: 1-312-355-1035; fax: 1-312-996-0431;
e-mail: wardropd@uic.edu
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00091-0

930
D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
Although it was now expected that we could access 2
from 7, via the corresponding acid chlorides, all
attempts to prepare the latter compounds using thionyl
chloride (SOCl2) or other chlorinating agents proved
unsuccessful. In all substrates examined, addition of
SOCl2 to 7 resulted in rapid decomposition.22 Reason-
ing that a less activated carboxylate derivative would be
more stable yet retain sufficient reactivity to undergo
the Arndt–Eistert synthesis, the mixed anhydrides were
prepared by treating a solution of 7 with Et3N and
isobutyl chloroformate.23 Addition of an ethereal solu-
tion of diazomethane to the reaction mixture then
provided the a-diazo ketones 2 in good yield.
With a protocol for the diastereoselective preparation
of 2 established, attention now turned to the CꢀH
insertion. Thus, slow addition of 2a to dirhodium(II)
tetraacetate (Rh2(O2CCH3)4) (2 mol%) in CH2Cl2
afforded 2,8-dioxabicyclo[3.2.1]octanone 3a, the
product of transannular CꢀH insertion, in 52% yield
together with a small amount of 4a (4%) (Table 2, entry
1). This bicyclic enol ether proved to be rather unstable
to silica gel chromatography in addition to being
volatile. Cyclization of substrates 2b–e (entries 4–7)
under these conditions provided similar yields of 3,
while 4 was isolated from the reactions of 2c and 2d
only. Diazo decomposition of 2f (entry 8) gave an
Scheme 1. Template-directed CꢀH activation.
zaragozic acid15 and the sordidin family of insect
pheromones.16 For symmetrical substrates 2 (R1=R4)
the possibility of desymmetrization through the use of
chiral catalysts was additionally appealing, since up to
four stereocenters could potentially be generated in a
single transformation. Herein, we report the develop-
ment of this CꢀH activation strategy and its application
to the first diastereoselective total synthesis of the natu-
ral product 7-episordidin.
1
inseparable mixture (19:13, H NMR) of C-4 and C-6
Table 1. Preparation of 2-diazoacetyl-1,3-dioxanes 2
2. Results and discussion
2.1. Preparation of 2,8-dioxabicyclo[3.2.1]octanones
Our investigation began with the preparation of a range
of pyruvic acid acetals 6 following a protocol reported
by Ziegler.17 Thus, treatment of a solution of 1a–d,
(Table 1, entries 1–4) in acetonitrile with BF3·Et2O (2
equiv.) and methyl pyruvate (2 equiv.) gave 6, which
were then saponified to furnish the corresponding car-
boxylic acids 7. Reaction of 2-methyl-2-nitromethyl-
propane-1,3-diol (1g) with methyl pyruvate generated
an 8.6:1 mixture of the C-5 diastereomers 6g and 6h
which were separated by column chromatography on
silica gel (Table 1, entries 7–8).18 The relative configura-
tion of nitro-substituted acetal 6g was determined by
X-ray crystallographic analysis.19 Saponification of
esters 6g and 6h, as before, then gave the corresponding
carboxylic acids. Substrates 7e–f (entries 5–6), on the
other hand were prepared by acid-catalyzed acetaliza-
tion of 1e–f (1.5 equiv.) and pyruvic acid (1.0 equiv.)
followed by saponification of the resulting mixture of
ester products.20 In the case of 1b (entry 2) and 1f
(entry 6) acetalization provided a single diastereomer in
which the C-2 carboxylate group was found to be in the
axial orientation, trans to the equatorial ring sub-
stituents. The assignment of the acetal stereochemistry
in these cases was achieved using 13C NMR spec-
troscopy, examining the C-2 methyl groups which are
known to be sensitive to the relative configuration of
the adjoining acetal.21 The 13C NMR spectra of 7b and
7f showed methyl signals at 26.8 and 26.6 ppm respec-
tively, thereby confirming their equatorial position.
Entry
1
R1
H
R2
R3
R4
H
Methoda
a, b, d
2
Yield
(%)b
1
2
3
4
5
6
7
8
1a
1b Me
Me
H
Et
-(CH2)4-
H
H
Me
NO2
Me
H
Et
2a 61
2b 80
2c
2d 68
2e
2f
Me a, b, d
1c
1d
1e
1f
1g
1g
H
H
H
Me
H
H
H
H
H
H
H
a, b, d
a, b, d
c, d
c, d
a, b, d
a, b, d
60
H
H
NO2
Me
49
64
2g 45
2h
H
6
a Methods: (a) MeCOCO2Me, BF3·Et2O, CH3CN, rt, 16 h; (b)
NaOH, THF, H2O, reflux, 5 h; (c) i. MeCOCO2H, Amberlite
IR-120, PhH, reflux 16 h; (ii) NaOH, H2O, reflux, 2 h; (d) i. Et3N,
CH2Cl2, −20°C; (ii) i-BuOCOCl, −20°C, 5 min; (iii) CH2N2, Et2O,
−20°C to rt, 16 h.
b Overall yield of 2 from 1, after purification by silica gel column
chromatography.

D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
931
Table 2. Preparation of 2,8-diazobicyclo[3.2.1]octanones 3
insertion products. While the known preference for
insertion to occur at tertiary CꢀH bonds should favor
insertion at C-6,2 the alternative insertion process at
C-4, which generates a tertiary rather than a quaternary
center, may encounter less steric hindrance. Of note is
the differing reactivity displayed by diastereomers 2g
and 2h. In the case of 2h, Rh2(O2CCH3)4 promoted
decomposition gave 3h (entry 10), albeit in low yield,
while no trace of 3g could be detected in the crude
reaction mixture of the C-5 epimer, 2g (entry 9). The
inhibitory effect of electron withdrawing groups upon
carbenoid CꢀH insertion has previously been
reported.24 The axial C-4/6 CꢀH bonds of 2g are
antiperiplanar to the C-5 nitro group and should there-
fore be more deactivated towards insertion than those
in 2h which are gauche to the electron withdrawing
group.25
Entry
2
Methoda
Yield (%), 3b
Yield (%), 4b
1
2
3
4
5
6
7
8
2a
2a
2ac
2b
2c
a
b
c
a
a
a
a
a
a
a
52
45
–
43
42
50
44
54d
–
4
5
–
–
12
11
–
–
–
2d
2e
2f
9
10
2ge
2h
In contrast to substrate 2g,26 compound 8 underwent
insertion to provide the expected bicycle 9 in 42% yield
(Scheme 2). In this case, the less electron-withdrawing
axial C-5 carbamate group does not appear to inhibit
insertion at the adjoining CꢀH bonds.
27
–
a Methods: (a) A solution of 2 in CH2Cl2 was added via syringe pump
to a solution of Rh2(O2CCH3)4 (2 mol%) in CH2Cl2 (0.023 M), over
20 h; (b) A solution of 2 in CH2Cl2 was added via syringe pump to
a solution of Rh2(cap)4 (2 mol%) in CH2Cl2, at reflux, over 72 h; (c)
A solution of 2a in CH2Cl2 was added via syringe pump to a
solution of Rh2(O2CCF3)4 (2 mol%) in CH2Cl2, over 20 h.
b Yields of 3 and 4 after purification by silica gel chromatography.
c Treatment of 2a with Rh2(O2CCF3)4 generated a complex mixture
of products.
d 3f was isolated as an inseparable (19:13, 1H NMR) mixture of C-4
and C-6 CꢀH insertion products.
e Diazo decomposition of 2g generated a complex mixture of products
which did not contain 3g.
Scheme 2.
decomposition than other a-diazo ketones which may
be due to the electron-withdrawing effect of the acetal
group adjoining the diazo center. On the other hand,
With regard to the formation of 4, Clark and co-work-
ers have recently reported the formation of analogous
products during a study of the rhodium(II)-mediated
decomposition of a-diazo-a%-alkoxy ketones.27 Accord-
ing to Clark’s mechanistic rationale, the rhodium car-
benoid species 10, generated upon diazo decomposition
of 2a, faces two possible fates: (i) concerted CꢀH
insertion to form 3(2H)-furanone 4a or, (ii) oxygen-
assisted hydride transfer28 to the electron-deficient car-
bene center generating oxonium ion-rhodium enolate
species 11.29 Cyclization of 11, or its enol tautomer 12,
could then generate 4a (Scheme 3). Hydride transfers
have recently been reported by Doyle, White and
others27 who note that this process becomes prevalent
when the oxonium ion species 11/12 are stabilized.30
Our substrates seem to fit this pattern since the axial
lone pairs of the ring oxygens are positioned
antiperiplanar to the departing hydrogen atom.
treatment
of
2a
with
dirhodium(II)
tetra-
(trifluoroacetate) (Rh2(O2CCF3)4) resulted in a very
complex reaction mixture which, as indicated by 1H
NMR spectroscopy, did not contain the insertion
product 3a (entry 3). It appears that, in this case,
hydride transfer is the dominant pathway but the enol
ether generated is unstable in the presence of the elec-
trophile catalyst and decomposes during the reaction.
Indeed, exposure of 4a to Rh2(O2CCF3)4 in CH2Cl2 led
to extensive decomposition.
Reasoning that a less electrophilic catalyst might sup-
press hydride transfer and favor insertion, dirhodium-
(II) tetra(caprolactamate) (Rh2(cap)4) was examined as
a catalyst.29b However, decomposition of 2a was pro-
hibitively slow at room temperature and only pro-
ceeded upon heating for 72 h. The yields of 3a and 4a
in this case were similar to those found with
Rh2(O2CCH3)4 (Table 2, entry 2). It appears that bis-a-
alkoxy-a%-diazoketones 2 are more resistant to diazo
Scheme 3.

932
D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
2.2. Total synthesis of ( )-7-episordidin
Having established a protocol to access 2,8-bicy-
clo[3.2.1]octanones, we now proceeded to evaluate this
methodology through its application to natural product
synthesis and specifically to the development of a route
to the insect aggregation pheromone ( )-7-episordidin.16
The banana weevil, Cosmopolites sordidus Germar, is a
widespread and highly destructive pest of banana
trees.31 The impact on crop production is particularly
acute since current methods for controlling this insect
are hampered by its longevity, propensity to reproduce,
and resistance to most classes of insecticides. In 1993,
Budenberg first reported evidence that the male of this
species releases a volatile aggregation pheromone.32 The
major component of this mixture, 1-ethyl-3,5,7-
trimethyl-2,8-dioxabicyclo[3.2.1]octane (13a), was sub-
sequently isolated, identified, and synthesized by Ducrot
and co-workers who assigned it the trivial name sordidin
(Fig. 2).33a More recently, Kitching has shown that, in
addition to 13a, 7-episordidin (13b) is also released by C.
sordidus from Australia,33d while Oehlschlager reported
that all four isomers of sordidin (13a–d) are produced by
weevils collected in Kenya.33b Field trials in Costa Rica31
have shown that traps baited with mixtures of 13 have
a high capture rate and offer a viable method for
controlling the population this pest. Since the natural
abundance of these pheromones is very low (1500 wee-
vils yield ca. 100 mg), synthesis provides the only practi-
cal method for securing quantities of 13. All reported
syntheses of the sordidin family involve formation of the
acetal moiety through acid-catalyzed cyclization of the
corresponding acyclic keto-1,3-diols.33 Under these con-
ditions, however, the C-7 stereocenter readily epimerizes
and mixtures of diastereomers are obtained. To date, no
stereoselective syntheses of 13 have been reported.
Scheme 4.
to achieve this goal using a variety of conditions led only
to the decomposition of diol 14. Accordingly, we opted
to follow a stepwise approach to 15, which we had
previously developed during our synthesis of the diox-
abicyclooctane core of the zaragozic acid family
(Scheme 6).16 Thus, 14 was treated with triethyl ortho-
propionate in the presence of a catalytic amount of
p-TsOH to generate ortho ester 16 which was immedi-
ately treated in situ with trimethylsilyl cyanide and
BF3·Et2O. Upon stirring at room temperature for 16 h,
cyanation proceeded with retention of configuration to
furnish 2-cyano-1,3-dioxane 17 as
a
single
diastereomer.35 Hydrolysis of this nitrile with alkaline
hydrogen peroxide then gave 18 in excellent overall yield
from 14. The relative configuration of 18 was confirmed
by a NOESY experiment, which revealed correlations
between the axial protons at C-4/6 and the amide
protons.
Scheme 5.
Figure 2.
As outlined in Scheme 4, we envisioned 13a arising from
ketone 20, which could, in turn, be accessed through the
metal-catalyzed intramolecular CꢀH insertion of sym-
metric diazoketone 19. In this way, three of the four
stereocenters present in the target molecule would be
established in a single transformation. With regards to
the regioselectivity of this process, we expected that
insertion into the C-1 ethyl side chain would be highly
disfavored over the axial C-4/6 CꢀH bonds of 19 since
these bonds are activated by the adjoining oxygens
atoms.2
Scheme 6. Reagents and conditions: (a) CH3CH2C(OEt)3, p-
TsOH (2 mol%), CH2Cl2, rt, 16 h; (b) Me3SiCN, BF3·Et2O (10
mol%), CH2Cl, rt, 16 h, 99%; (c) NaOH, H2O2, EtOH, reflux,
3 h, 91%; (d) DMF–DMA (3 equiv.), MeOH, 110°C (sealed
tube), 48 h, 97%; (e) NaOH, H2O, THF, reflux, 16 h, 98%; (f)
i. Et3N, i-BuOCOCl, CH2Cl2, −20°C, 5 min, ii. CH2N2, Et2O,
−20°C to rt, 16 h, 96%.
Given the ease with which we had prepared simple
pyruvate acetals in our initial study (Table 1), our
opening efforts to prepare acetal 15 focused on direct
acetalization of methyl 2-oxopropylbutyrate and cis-2,4-
pentanediol 14 (Scheme 5).34 Unfortunately, all attempts

D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
933
In view of the low levels of asymmetric induction
observed during the cyclization of 19, we now opted to
complete our synthesis of 13b with racemic 20. Accord-
ingly, we now attempted to install the remaining stereo-
center at C-7 through a sequence of olefination and
reduction. However, 22, the a,b-unsaturated acetal gen-
erated upon Wittig methylenation of 20, proved to be
highly unstable and we were unable to isolate this
material (Scheme 7).39 Fortunately, addition of methyl-
magnesium iodide to 20 proceeded very efficiently to
provide 23 as a single diastereomer. After considerable
investigation, we found that this tertiary alcohol could
be most effectively deoxygenated to generate 13b using
the method of Dolan and MacMillan.40 Thus, sequen-
tial treatment of 23 with n-BuLi and methyl
chlorooxoacetate gave 24 which, after purification, was
heated with Bu3SnH and AIBN in benzene for 16 h.
The reaction mixture was then concentrated by distilla-
tion (1 atm) and the residue purified by radial chro-
matography (pentane/Et2O, SiO2) to provide
( )-7-episordidin (13b) as the sole reduction product.
The moderate yield of this final transformation is pri-
marily a reflection of the volatility of 13b, which leads
to significant losses during isolation. A comparison of
the spectral and physical properties of our synthetic
Although the prospect of now converting 18 to the
corresponding methyl ester 15 was somewhat daunting,
Brocchetta and co-workers recently reported the use of
dimethylformamide dimethyl acetal (DMF–DMA) as a
mild reagent for this traditionally difficult transforma-
tion.36 Gratifyingly, upon heating 18 and DMF–DMA
in anhydrous methanol at 110°C in a sealed tube for 48
h, ester 15 was formed in 97% yield. Diazoketone 19
was prepared in 94% overall yield by a sequence of
saponification, mixed-anhydride formation and in situ
treatment with diazomethane. With quantities of 19
available, we now proceeded to evaluate a range of
catalysts for CꢀH activation; the results of this study
are summarized in Table 3. In all cases diazo decompo-
sition of 19 led to the formation of 20, the product of
transannular CꢀH insertion, as well as bicyclic enol
ether 21. As anticipated, products arising from insertion
into the CꢀH bonds of the ethyl chain were not
observed under any conditions. It is clear from Table 3
that Rh2(OAc)4 (entry 1) was the most efficient catalyst
for effecting cyclization while chiral dirhodium(II) tet-
racarboxylates (entries 2–4) and tetracarboxyamides
(entry 5) failed to provide improvement in efficiency or
useful levels of asymmetric induction. Copper salts
(entries 6–8) were also investigated but gave only mod-
est yields of CꢀH insertion. The more electrophilic
copper carbenoids appear to favor the formation of 21
through the hydride abstraction pathway.37
1
material (MS, IR and H and 13C NMR) with those
reported by Mori33e indicated a close match.
Table 3. Intramolecular CꢀH insertion of diazoketone 19a
Entry
Catalystb
Isolated yield (%)c,d
E.e. (%)e,f
20
21
20
21
Scheme 7. Reagents and conditions: (a) Ph3PꢁCH2, THF, rt,
16 h; (b) MeMgI, Et2O, 0°C, 3 h, 98%; (c) n-BuLi, THF,
−78°C, 5 min; (ii) ClCOCO2Me, −78 to 0°C, 2 h, 78%; (d)
Bu3SnH (1.5 equiv.), AIBN (1.5 equiv.), PhH, reflux, 16 h,
50%; (e) p-TsOH, CH2Cl2 (Ref. 33e).
g
1
2
3
4
5
6
7
8
Rh2(OAc)4
58
36
31
17
11
15
19
7
28
10
0
5
8
30
20
17
–
–
38a,b
38c
Rh2(PTPA)4
Rh2(DOSP)4
Rh2(TBSP)4
20
7
10
–
B5
7
–
–
38d
B5
B5
–
–
–
38d
Rh2(MEPY)4
h
Cu(acac)2
h
Cu(tfacac)2
h
3. Summary
Cu(hfacac)2
–
a Unless otherwise noted, reactions were carried as follows: a solution
of 19 (50 mg, 0.24 mmol) in CH2Cl2 was added via syringe pump to
a solution of catalyst (2 mol%) in CH2Cl2 (0.015 M) at reflux, over
20 h.
In summary, we have developed a novel method for the
preparation of 2,8-dioxabicyclo[3.2.1]octanones 3 utiliz-
ing the Rh(II)-mediated CꢀH insertion of 2-diazoacetyl-
1,3-dioxanes 2. Furthermore, we also report the
application of this template-directed insertion strategy
to the first stereoselective synthesis of 7-episordidin
(13b), which is accomplished in nine steps starting from
cis-2,4-pentanediol (2), with an overall yield of 18%.
Since the conversion of ( )-7-episordidin (13b) to sor-
didin (13a) has previously been described by Mori,33e
the work reported herein also represents a formal syn-
thesis of sordidin (13a).
b Rh2(PTPA)4 was prepared according to the method of Taber (see
Ref. 38b). The other catalysts are available commercially.
c Yields after purification by flash chromatography.
d The mass balance consisted of polar, intractable material.
e Enantiomeric excesses were determined by capillary GC analysis
prior to purification using a J&W cyclodex-B column.
f Absolute configuration was not determined.
g Reaction carried out on 8.5 mmol scale.
h 4 mol% catalyst used.

932
D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
4. Experimental
4.1.2.
trans-2-Carboxymethyl-cis-2,4,6-trimethyl-1,3-
dioxane, 6b. (800 mg, 88%): yellow oil; Rf 0.18 (EtOAc/
hexanes, 1:9); IR (film) 2974, 2938, 1745, 1440, 1385,
All reactions were carried out in oven- or flame-dried
glassware under a nitrogen atmosphere, unless other-
wise noted. All solvents were reagent grade. BF3·Et2O
was distilled from calcium hydride, under reduced pres-
sure, and stored under a nitrogen atmosphere. Triethyl-
amine (Et3N), acetonitrile (MeCN) and dichloro-
methane (CH2Cl2) were distilled from calcium hydride
under dry nitrogen. Except as otherwise indicated, all
reactions were magnetically stirred and monitored by
thin-layer chromatography with Merck Kieselgel 60-
1266, 1112, 1052, 978, 817, 695 cm−1; H NMR (400
1
MHz, CDCl3) l 3.81–3.73 (m, 2H), 3.72 (s, 3H), 1.45 (s,
3H), 1.41–1.40 (m, 1H) 1.23–1.20 (m, 1H), 1.15 (d,
J=6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) l 171.8,
98.8, 68.9 (2 C), 52.4, 39.4, 26.7 (2 C), 21.8; high-resolu-
tion mass spectrum (CI) m/z 189.1127 [(M+H)+; calcd
for C9H17O4 189.1127].
4.1.3.
2-Carboxymethyl-5,5-diethyl-2-methyl-1,3-diox-
F
254. Enantiomeric excesses of 20/21 were determined
ane, 6c. (1.06 g, 70%): yellow oil; Rf 0.24 (EtOAc/hex-
anes, 1:3); IR (film) 2966, 2877, 1745, 1460, 1376, 1265,
by capillary GC analysis prior to purification using a
J&W cyclodex-B column. Flash column chromatogra-
phy was carried out according to the method of Still on
Merck silica gel 60 (mesh 230–400). All melting points
were determined in an open capillary on a Thomas
Hoover capillary melting point apparatus and are
uncorrected. Infrared spectra were recorded on an ATI
Mattson genesis series FTIR spectrophotometer. 1H
and 13C NMR spectra were recorded on either a Bruker
Avance 400 (400 MHz 1H, 100 MHz 13C), Bruker
Avance 500 (500 MHz 1H, 125 MHz, 13C), Bruker
1118, 1031, 892, 805, 658 cm−1; H NMR (200 MHz,
1
CDCl3) l 3.83 (s, 3H), 3.68 (d, J=11.7 Hz, 2H), 3.45
(d, J=11.7 Hz, 2H), 1.70 (q, J=7.5 Hz, 2H), 1.51 (s,
3H), 1.04 (q, J=7.5 Hz, 2H), 0.86 (t, J=7.5, 3H), 0.75
(t, J=7.5, 3H); 13C NMR (100 MHz, CDCl3) l 171.3,
98.4, 70.7 (2 C), 52.5, 34.1, 25.8, 24.3, 22.3, 7.6, 6.5;
high-resolution mass spectrum (CI) m/z 217.1445 [(M+
H)+; calcd for C11H21O4 217.1440].
4.1.4.
8-Carboxymethyl-8-methyl-7,9-dioxaspiro[4.5]-
1
AM-400 (400 MHz, H, 100 MHz, 13C) or a Bruker
decane, 6d. (1.14 g, 80%): yellow oil; Rf 0.38 (EtOAc/
hexanes, 1:1); IR (film) 2962, 2807, 2103, 1724, 1647,
1
AM-200 (200 MHz, H, 50 MHz, 13C) spectrometer.
1
Chemical shift values (l) are reported relative to chlo-
1334, 1280, 1192, 1132, 886, 830 cm−1; H NMR (400
roform (1H l 7.27 ppm, 13C l 77.23 ppm) or dimethyl-
MHz, CDCl3) l 3.78 (s, 3H), 3.59–3.49 (m, 4H), 1.84–
1.77 (m, 2H), 1.66–1.58 (m, 2H), 1.55–1.52 (m, 4H),
1.50 (s, 3H); 13C NMR (100 MHz, CDCl3) l 171.4,
98.3, 72.4 (2 C), 52.6, 41.2, 34.5, 32.0, 26.0, 25.4, 24.7;
high-resolution mass spectrum (CI) m/z 232.1538 [(M+
NH4)+; calcd for C11H22NO4 232.1549].
sulfoxide (1H
l l 39.51 ppm).
2.50 ppm, 13C
High-resolution electron impact (EI) mass spectra were
obtained on a Kratos Concept 1H spectrometer at the
University of Illinois Research Resources Center with a
typical ionization voltage of 70 eV. High-resolution
chemical ionization (CI) mass spectra were obtained on
a FINNIGAN MAT 95 at the Mass Spectrometry
Service Laboratory, University of Minnesota.
4.1.5. trans-2-Carboxymethyl-2,5-dimethyl-5-nitro-1,3-
dioxane, 6g. (11.99 g, 74%): white solid: mp 80–81°C; Rf
0.53 (EtOAc/hexanes, 1:1); IR (KBr) 2999, 2949, 1742,
1547, 1449, 1129, 909, 742 cm−1; H NMR (500 MHz,
1
4.1. Representative procedure for the preparation of
pyruvate ester acetals 6
CDCl3) l 4.72 (d, J=11.9 Hz, 2H), 3.86 (m, 5H), 1.51
(s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3) l
170.2, 98.7, 82.6, 67.8 (2 C), 53.3, 25.7, 19.9; high-reso-
lution mass spectrum (CI) m/z 220.0828 [(M+H)+; calcd
for C8H14NO6 220.0821].
4.1.1. 2-Carboxymethyl-2,5,5-trimethyl-1,3-dioxane, 6a.
BF3·Et2O (21.70 g, 153.8 mmol) was added dropwise to
a stirred solution of 2,2-dimethyl-1,3-propanediol (8.00
g, 76.9 mmol) and methyl pyruvate (15.70 g, 153.8
mmol) in MeCN (200 mL). The mixture was stirred for
16 h then quenched with saturated aqueous NaHCO3
(60 mL) and allowed to stir for an additional 20 min.
The resulting mixture was concentrated under reduced
pressure to one third of its original volume. The con-
centrate was then extracted with CH2Cl2 (4×30 mL)
and the combined organic extracts dried (Na2SO4) and
concentrated. The resulting residue was purified by
flash chromatography on silica gel (EtOAc/hexanes,
1:1) to give 6a (10.40 g, 72%): yellow oil; Rf 0.66
(EtOAc/hexanes, 1:1); IR (film) 2955, 2871, 1744, 1471,
4.1.6.
cis-2-Carboxymethyl-2,5-dimethyl-5-nitro-1,3-
dioxane, 6h. (1.40 g, 9%): white solid: mp 79–80°C; Rf
0.26 (EtOAc/hexanes, 1:1); IR (KBr) 1744, 1539, 1275,
1
1184, 1125, 1075, 909, 742 cm−1; H NMR (500 MHz,
CDCl3) l 4.18 (d, J=11.7 Hz, 2H), 4.09 (d, J=11.7 Hz,
2H), 3.87 (s, 3H), 1.86 (s, 3H), 1.60 (s, 3H); 13C NMR
(125 MHz, CDCl3) l 169.7, 98.9, 79.5, 68.0 (2C), 53.4,
24.9, 22.0; high-resolution mass spectrum (CI) m/z
237.1093 [(M+NH4)+; calcd for C8H16N2O6 237.1087].
4.2. Representative procedure for the preparation of
pyruvate acid acetals 6 (Method A)
1
1369, 1121, 1079, 1015, 882, 807, 668 cm−1; H NMR
4.2.1. 2-Carboxy-2,5,5-trimethyl-1,3-dioxane, 7a.
A
(400 MHz, CDCl3) l 3.79 (s, 3H), 3.46 (s, 4H), 1.49 (s,
3H), 1.16 (s, 3H), 0.68 (s, 3H); 13C NMR (100 MHz,
CDCl3) l 171.1, 98.1, 73.4 (2 C), 52.5, 29.4, 25.8, 22.6,
21.8; high-resolution mass spectrum (CI) m/z 189.1132
[(M+H)+; calcd for C9H17O4 189.1127].
solution of ester 6a (10.40 g, 0.06 mol) and NaOH
(11.60 g, 0.27 mol) in a mixture of THF (100 mL) and
H2O (100 mL) was stirred at rt for 5 h. After cooling to
0°C, the reaction mixture was then acidified to pH 1
with ice cold 6 M aqueous H3PO4 (20 mL) and quickly

D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
935
extracted with EtOAc (5×20 mL). The combined
4.3. Representative procedure for the preparation of
pyruvate acid acetals 6 (Method B)
organic extracts were then dried (Na2SO4), and concen-
trated to provide 7a (8.20 g, 85%): white solid; mp
115–116°C; IR (KBr) 3503, 3957, 2871, 1719, 1198,
1138, 1073, 1011, 748 cm−1; 1H NMR (400 MHz,
CDCl3) l 10.56 (s, 1H), 3.54 (m, 4H), 1.58 (s, 3H), 1.18
(s, 3H), 0.73 (s, 3H); 13C (100 MHz, CDCl3) l 175.9,
98.0, 73.7 (2 C), 29.6, 25.8, 22.7, 22.0; high-resolution
mass spectrum (EI) m/z 129.0916 [(M−CO2H)+; calcd
for C7H13O2 129.0916].
4.3.1. trans-2-Carboxy-cis-2,4-dimethyl-1,3-dioxane, 7f.
A mixture of 1,3-butanediol (10.00 g, 111.1 mmol),
pyruvic acid (6.50 g, 74.1 mmol) and Amberlite IR-120
(plus) resin (1.30 g) in benzene (CAUTION!) (250 mL)
were heated at reflux in a Dean–Stark apparatus for 16
h. After cooling to rt, the reaction mixture was filtered,
concentrated and the resulting residue dissolved in 2 M
aqueous NaOH (40 mL). The reaction mixture was
then heated at reflux for 2 h, cooled to rt, acidified to
pH 1 with ice cold 6 M aqueous H3PO4 (25 mL) and
rapidly extracted with EtOAc (4×20 mL). The com-
bined organic extracts were then dried (Na2SO4), con-
centrated and the resulting residue purified by flash
chromatography on silica gel (EtOAc/hexanes, 3:1) to
provide 7f (8.42 g, 65%): brown solid; mp 75–76°C; Rf
0.50 (EtOAc/hexanes, 3:1); IR (KBr) 3507, 2974, 1741,
4.2.2. trans-2-Carboxy-cis-2,4,6-trimethyl-1,3-dioxane,
7b. (550 mg, 96%): white solid; mp 117–118°C; IR
(KBr) 3058, 2982, 1733, 1320, 1207, 1152, 1098, 976,
1
912, 742 cm−1; H NMR (400 MHz, CDCl3) l 3.95–
3.87 (m, 2H), 1.60 (s, 3H), 1.51 (d, J=13.2 Hz, 1H),
1.33–1.31 (m, 1H), 1.26 (d, 6H); 13C NMR (100 MHz,
CDCl3) l 176.4, 98.7, 69.3 (2 C), 39.35, 26.8, 21.9;
high-resolution mass spectrum (CI) m/z 175.0981 [(M+
H)+; calcd for C8H15O4 175.0970].
1
1206, 1155, 911, 743, 666 cm−1; H NMR (400 MHz,
CDCl3) l 4.00 (m, 1H), 3.95–3.83 (m, 2H), 1.75–1.65
(m, 1H), 1.58 (s, 3H), 1.45 (m, 1H), 1.31 (d, J=6.1 Hz,
3H); 13C (100 MHz, CDCl3) l 176.2, 98.6, 69.5, 63.5,
31.9, 26.7, 22.0; high-resolution mass spectrum (EI) m/z
115.0760 [(M−CO2H)+; calcd for C6H11O2 115.0760].
4.2.3. 2-Carboxy-5,5-diethyl-2-methyl-1,3-dioxane, 7c.
(930 mg, 99%): white solid; mp 122–23°C; IR (KBr)
3476, 2961, 1674, 1470, 1353, 1279, 1141, 1014, 952, 773
1
cm−1; H NMR (400 MHz, CDCl3) l 3.74 (d, J=11.6
Hz, 2H), 3.52 (d, J=11.6 Hz, 2H), 1.71 (q, J=7.5 Hz,
2H), 1.59 (s, 3H), 1.10 (q, J=7.5 Hz, 2H), 0.86 (t,
J=7.5 Hz, 3H), 0.75 (q, J=7.5 Hz, 3H); 13C (100 MHz,
CDCl3) l 176.1, 98.2, 71.0 (2 C), 34.4, 25.7, 24.4, 22.4,
7.7, 6.7; high-resolution mass spectrum (CI) m/z
203.1285 [(M+H)+; calcd for C10H19O4 203.1283].
4.3.2. 2-Carboxy-2-methyl-1,3-dioxane, 7e. (1.87 g,
73%): white solid; mp 94–95°C; Rf 0.65 (EtOAc/hex-
anes, 3:1); IR (KBr) 3501, 2924, 1735, 1208, 1153, 910,
1
742 cm−1; H NMR (400 MHz, CDCl3) l 4.06–4.02 (m,
2H), 3.96–3.89 (m, 2H), 2.15–2.10 (m, 1H), 1.59 (s, 3H),
1.44–1.41 (m, 1H); 13C NMR (100 MHz, CDCl3) 174.8,
98.3, 63.4, 26.1, 24.6; high-resolution mass spectrum
(EI) m/z 101.0602 [(M−CO2H)+; calcd for C6H10O4
101.0602].
4.2.4. 8-Carboxy-8-methyl-7,9-dioxaspiro[4.5]decane, 7d.
(550 mg, 86%): white solid; mp 127–28°C; IR (KBr)
2996, 2880, 1747, 1461, 1265, 1189, 1124, 1034, 879, 807
1
cm−1; H NMR (400 MHz, CDCl3) l 11.31 (bs, 1H),
4.4. Representative procedure for the preparation of a-
diazo ketones 2
3.69 (d, J=11.2 Hz, 2H), 3.62 (d, J=11.2 Hz, 2H), 1.84
(m, 2H), 1.70–1.63 (m, 2H), 1.59 (s, 3H), 1.58–1.54 (m,
2H) 1.16 (m, 2H); 13C (100 MHz, CDCl3) l 175.9, 99.0,
72.3 (2 C), 41.1, 34.3, 31.9, 25.7, 25.3, 24.6; high-resolu-
tion mass spectrum (CI) m/z 218.1402 [(M+NH4)+;
calcd for C10H20NO4 218.1392].
4.4.1. 2-Diazoacetyl-2,5,5-trimethyl-1,3-dioxane, 2a. A
solution of acid 7a (500 mg, 2.8 mmol) and Et3N (48
mL, 3.4 mmol) in anhydrous CH2Cl2 (10 mL) was
cooled to −20°C and isobutyl chloroformate (38 mL, 3.0
mmol) was added dropwise via syringe. After stirring
for 5 min, an ethereal solution of diazomethane (CAU-
TION!) (0.1 M, 43 mL, 4.3 mmol) was added via a
flame-polished pipette and the reaction mixture allowed
to warm to rt over 16 h. The mixture was then concen-
trated and the resulting residue purified by flash chro-
matography on silica gel (EtOAc/hexanes, 2:5) to
provide 2a (550 mg, 99%): yellow solid; mp 65–66°C; Rf
0.48 (EtOAc/hexanes, 2:5); IR (KBr) 2952, 2867, 2106,
4.2.5. trans-2-Carboxy-2,5-dimethyl-5-nitro-1,3-dioxane,
7g. (1.85 g, 99%): white solid; mp 148–149°C; IR (KBr)
3007, 1708, 1543, 1451, 1268, 1142, 1075, 1044, 894, 681
1
cm−1; H NMR (400 MHz, CDCl3) l 4.76 (d, J=11.8
Hz, 2H), 3.92 (d, J=11.8 Hz, 2H), 1.58 (s, 3H), 1.39 (s,
3H); 13C NMR (100 MHz, DMSO) l 170.3, 97.9, 83.4,
66.9 (2 C), 25.2, 18.7; high-resolution mass spectrum
(CI) m/z 223.0937 [(M+NH4)+ calcd for C7H15N2O6
223.0930].
1
1645, 1336, 1193, 909, 741 cm−1; H NMR (400 MHz,
CDCl3) l 5.73 (s, 1H), 3.52 (d, J=11.1 Hz, 2H), 3.49
(d, J=11.1 Hz, 2H), 1.45 (s, 3H), 1.18 (s, 3H), 0.72 (s,
3H); 13C NMR (100 MHz, CDCl3) l 194.5, 100.4, 73.2
(2 C), 53.7, 29.7, 25.3, 22.6, 22.0; high-resolution mass
spectrum (CI) m/z 199.1079 [(M+H)+; calcd for
C9H15N2O3 199.1083].
4.2.6.
cis-2-Carboxy-2,5-dimethyl-5-nitro-1,3-dioxane,
7h. (830 mg, 99%): white solid; mp 127–128°C; IR
(KBr) 3073, 1707, 1533, 1260, 1136, 1074, 906, 740, 493
cm−1; H NMR (400 MHz, CDCl3) l 4.29 (d, J=11.8
1
Hz, 2H), 4.11 (d, J=11.8 Hz, 2H), 1.84 (s, 3H), 1.66 (s,
3H); 13C NMR (100 MHz, CDCl3) l 173.0, 98.1, 79.3,
67.5 (2C), 23.8, 21.4; high-resolution mass spectrum
(CI) m/z 223.0941 [(M+NH4)+; calcd for C7H15N2O6
223.0930].
4.4.2. trans-2-Diazoacetyl-cis-2,4,6-trimethyl-1,3-diox-
ane, 2b. (540 mg, 95%) yellow oil; Rf 0.28 (EtOAc/hex-
anes, 3:1); IR (film) 3123, 2973, 2934, 2106, 1646, 1330,

936
D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
1199, 1175, 1109, 972, 911, 743, 693 cm−1; H NMR
(400 MHz, CDCl3) l 5.68 (s, 1H), 3.91–3.77 (m, 2H),
1.52–1.48 (m, 1H), 1.48 (s, 3H), 1.27–1.24 (m, 1H), 1.22
(d, J=6.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) l
195.0, 101.4, 68.7 (2 C), 53.4, 39.5, 26.9 (2 C), 21.9;
high-resolution mass spectrum (CI) m/z 199.1078 [(M+
H)+; calcd for C10H17N2O3 199.1083].
4.4.8.
cis-2-Diazoacetyl-2,5-dimethyl-5-nitro-1,3-diox-
1
ane, 2h. (750 mg, 67%): yellow solid; mp 104–105°C; Rf
0.41 (EtOAc/hexanes, 2:5); IR (KBr) 3120, 2115, 1642,
1
1547, 1346, 1198, 1077, 1043, 832 cm−1; H NMR (400
MHz, CDCl3) l 5.70 (s, 1H), 4.70 (d, J=12.9 Hz, 2H),
3.87 (d, J=12.9 Hz, 2H), 1.44 (s, 3H), 1.35 (s, 3H); 13C
NMR (100 MHz, CDCl3) 192.7, 100.8, 82.5, 67.3 (2 C),
54.3, 25.7, 19.7; high-resolution mass spectrum (CI) m/z
247.1040 [(M+NH4)+; calcd for C8H15N4O5 247.1042].
4.4.3.
2-Diazoacetyl-5,5-diethyl-2-methyl-1,3-dioxane,
2c. (660 mg, 87%): white solid; mp 70–71°C; Rf 0.38
(EtOAc/hexanes, 3:1); IR (KBr) 2965, 2875, 2106, 1647,
1460, 1336, 1196, 1087, 1030, 888, 832, 656; H NMR
4.5. Representative procedure for CꢀH insertion
1
(400 MHz, CDCl3) l 5.72 (s, 1H), 3.60 (d, J=11.3 Hz,
2H), 3.49 (d, J=11.3 Hz, 2H), 1.68 (q, J=7.5 Hz, 2H),
1.44 (s, 3H), 1.06 (q, J=7.5 Hz, 2H), 0.85 (t, J=7.5 Hz,
3H), 0.75 (t, J= 7.5 Hz, 3H); 13C NMR (50 MHz,
CDCl3) l 194.3, 100.3, 70.1 (2 C), 53.2, 34.2, 25.2, 24.1,
22.1, 7.4, 6.3; high-resolution mass spectrum (CI) m/z
227.1391 [(M+H)+; calcd for C11H19N2O3 227.1396].
4.5.1. Substrate 6a (Table 2, entry 1). To a flame-dried
flask, under nitrogen, was added Rh2(OAc)4 (12.0 mg, 2
mol%) and anhydrous CH2Cl2 (48 mL). A solution of
a-diazo ketone 2a (250 mg, 1.28 mmol) in CH2Cl2 (8
mL) was then added to the reaction mixture over 20 h
via syringe pump. The mixture was then filtered, con-
centrated and the resulting residue purified by flash
chromatography on silica gel (EtOAc/hexanes, 1:9) to
give ketone 3a (110 mg, 52%) and enol ether 4a (8 mg,
4%).
4.4.4. 2-Diazoacetyl-8-methyl-7,9-dioxaspiro[4.5]decane,
2d. (670 mg, 99%): white solid; mp 62–63°C; Rf 0.17
(EtOAc/hexanes, 1:9); IR (KBr) 3123, 3084, 2953, 2864,
1
2106, 1647, 1336, 1194, 1032, 893, 831 cm−1; H NMR
4.5.2. ( )-1,4,4-Trimethyl-2,8-dioxabicyclo[3.2.1]octan-7-
one, 3a. Yellow oil; Rf 0.37 (EtOAc/hexanes, 2:5); IR
(film) 2957, 2870, 1787, 1469, 1389, 1176, 1028, 921,
741 cm−1; 1H NMR (400 MHz, CDCl3) l 4.20 (d,
J=7.5 Hz, 1H), 3.62 (d, J=12.1 Hz, 1H), 3.47 (d,
J=12.1 Hz, 1H), 2.60 (dd, J=18.4, 7.5 Hz, 1H), 2.40
(d, J=18.4 Hz, 1H), 1.37 (s, 3H), 1.33 (s, 3H), 0.76 (s,
3H); 13C (100 MHz, CDCl3) l 211.5, 98.0, 80.4, 71.8,
37.6, 33.2, 24.7, 22.0, 18.2; high-resolution mass spec-
trum (CI) m/z 171.1015 [(M+H)+; calcd for C9H15O3
171.1021].
(100 MHz, CDCl3) l 5.73 (s, 1H), 3.61 (d, J=11.0 Hz,
2H), 3.52 (d, J=11.0 Hz, 2H), 1.79 (t, J=6.9 Hz, 2H),
1.68–1.60 (m, 2H), 1.58–1.51 (m, 2H), 1.42 (s, 3H), 1.11
(t, J=6.9 Hz, 2H); 13C NMR (400 MHz, CDCl3) l
194.3, 100.1, 71.6 (2 C), 53.4, 41.0, 33.9, 31.9, 25.3,
25.1, 24.4; high-resolution mass spectrum (CI) m/z
225.1259 [(M+H)+; calcd for C11H17N2O3 225.1239].
4.4.5. 2-Diazoacetyl-2-methyl-1,3-dioxane, 2e. (620 mg,
67%): yellow solid; mp 38–39°C; Rf 0.25 (EtOAc/hex-
anes, 2:5); IR (KBr) 3086, 2968, 2873, 2100, 1635, 1345,
1196, 1145, 976, 869, 821, 656 cm−1; 1H NMR (400
MHz, CDCl3) l 5.73 (s, 1H), 3.97–3.83 (m, 4H), 2.09–
1.98 (m, 2H), 1.42 (s, 3H); 13C (100 MHz, CDCl3) l
194.1, 100.4, 62.6 (2 C), 53.4, 25.8, 24.5; high-resolution
mass spectrum (CI) m/z 171.0769 [(M+H)+; calcd for
C7H11N2O3 171.0770].
4.5.3. ( )-1,4,4-Trimethyl-7-methylene-2,6,8-trioxabicyclo-
[3.2.1]octane, 4a. White solid; readily sublimes; Rf 0.82
(EtOAc/hexanes, 2:5); IR (film) 3049, 2986, 2350, 1437,
1
895, 737, 699 cm−1; H NMR (400 MHz, CDCl3) l 5.16
(s, 1H), 4.45 (d, J=2.9 Hz, 1H), 4.12 (d, J=2.9 Hz,
1H), 3.76 (d, J=11.6 Hz, 1H), 3.43 (d, J=11.6 Hz,
1H), 1.58 (s, 3H), 1.19 (s, 3H), 0.83 (s, 3H); 13C (100
MHz, CDCl3) l 156.9, 107.7, 101.8, 80.2, 71.23, 35.2,
22.6, 21.4, 20.6; high-resolution mass spectrum (CI) m/z
188.1287 [(M+NH4)+; calcd for C9H18NO3 188.1287].
4.4.6. trans-2-Diazoacetyl-cis-2,4-dimethyl-1,3-dioxane,
2f. (690 mg, 99%): yellow solid; mp 33–34°C; Rf 0.31
(EtOAc/hexanes, 2:5); IR (KBr) 3124, 2972, 2106, 1652,
1
1335, 1198, 1045, 966, 913, 740, 681 cm−1; H NMR
(400 MHz, CDCl3) l 5.70 (s, 1H), 3.96–3.79 (m, 3H),
1.71–1.60 (m, 2H), 1.42 (s, 3H), 1.23 (d, J=6.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) l 194.8, 101.1, 68.8,
62.9, 53.5, 32.0, 26.8, 22.0; high-resolution mass spec-
trum (CI) m/z 185.0924 [(M+H)+; calcd for C8H13N2O3
185.0926].
4.5.4. ( )-(1a,3a,5ab)-1,3,5-Trimethyl-2,8-dioxabicyclo-
[3.2.1]octan-7-one, 3b. (51 mg, 43%): colorless oil; Rf
0.05 (EtOAc/hexanes, 1:9); IR (film) 2972, 1762, 1445,
1375, 1170, 908, 741 cm−1; 1H NMR (400 MHz, CDCl3)
l 3.97–3.93 (m, 1H), 2.35 (s, 2H), 1.68 (d, J=11.2 Hz,
1H), 1.59 (dd, J=11.2, 3.8 Hz, 1H), 1.48 (s, 3H), 1.39
(s, 3H), 1.24 (d, J=6.0 Hz, 3H); 13C (100 MHz,
DMSO) l 212.5, 99.7, 77.2, 67.1, 45.1, 42.1, 25.6, 21.8,
18.5; high-resolution mass spectrum (CI) m/z 171.1019
[(M+H)+; calcd for C9H15O3 171.1021].
4.4.7. trans-2-Diazoacetyl-2,5-dimethyl-5-nitro-1,3-diox-
ane, 2g. (340 mg, 62%): white solid; mp 64–65°C; Rf
0.59 (EtOAc/hexanes 2:5); IR (KBr) 3124, 2993, 2118,
1
1646, 1548, 1345, 1247, 1073, 887, 744 cm−1; H NMR
(400 MHz, CDCl3) l 5.72 (s, 1H), 4.31 (d, J=12.5 Hz,
2H), 4.01 (d, J=12.5 Hz, 2H), 1.72 (s, 3H), 1.52 (s,
3H); 13C NMR (100 MHz, CDCl3) l 191.2, 100.3, 80.8,
66.9 (2C), 54.1, 22.0, 21.2; high-resolution mass spec-
trum (CI) m/z 247.1042 [(M+NH4)+; calcd for
C8H15N4O5 247.1042].
4.5.5. ( )-4,4-Diethyl-1-methyl-2,8-dioxabicyclo[3.2.1]-
octan-7-one, 3c. (71 mg, 42%): colorless oil; Rf 0.27
(EtOAc/hexanes, 1:9); IR (film) 2968, 2877, 1767, 1463,
1
1384, 1089, 863, 802, 711 cm−1; H NMR (400 MHz,
CDCl3) l 4.41 (d, J=7.5 Hz, 1H), 3.62 (d, J=12.3 Hz,
1H), 3.50 (d, J=12.3 Hz, 1H), 2.61 (dd, J=18.2, 7.5

D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
937
Hz, 1H), 2.61 (d, J=7.5 Hz, 1H), 2.45 (d, J=18.2 Hz,
1H), 1.94 (q, J=7.6 Hz, 2H), 1.35 (s, 3H), 1.09 (q,
J=7.6 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H), 0.77 (t, J=7.6
Hz, 3H); 13C (100 MHz, CDCl3) l 211.6, 128.3, 98.0,
69.4, 37.5, 37.1, 23.3, 22.8, 18.0, 7.5, 6.4; high-resolu-
tion mass spectrum (CI) m/z 199.1333 [(M+H)+; calcd
for C11H19O3 199.1334].
NMR) of C-4 and C-6 CꢀH insertion products (110 mg,
54%): colorless oil: Rf 0.20 (EtOAc/hexanes, 1:9); IR
(film) 2936, 2344, 1754, 1445, 1376, 1173, 1102, 665
cm−1; 1H NMR (400 MHz, CDCl3) l 4.81–4.78 (m,
1H), 4.05–3.88 (m, 3H), 2.72 (dd, J=17.9, 7.5 Hz, 1H),
2.36–2.26 (m, 3H), 2.17–2.15 (m, 1H), 2.04–2.00 (m,
1H), 1.59–1.56 (m, 2H), 1.55 (s, 3H), 1.45 (s, 6H), 1.35
(d, J=6.1 Hz, 3H); 13C (100 MHz, CDCl3) l 211.9,
211.4, 100.6, 98.5, 71.7, 66.7, 61.8, 45.8, 40.26, 37.1,
35.2, 26.5, 22.3, 18.8; high-resolution mass spectrum
(CI) m/z 157.0875 [(M+H)+; calcd for C8H13O3
157.0865].
4.5.6. ( )-4,4-Diethyl-1-methyl-7-methylene-2,6,8-trioxa-
bicyclo[3.2.1]octane, 4c. (20 mg, 12%) colorless oil; Rf
0.51 (EtOAc/hexanes, 1:9); IR (film) 2966, 2876, 1689,
1
1390, 1336, 1201, 1125, 958, 911, 855, 743 cm−1; H
NMR (400 MHz, CDCl3) l 5.35 (s, 1H), 4.44 (d, J=2.4
Hz, 1H), 4.11 (d, J=2.4 Hz, 1H), 3.62 (d, J=11.5 Hz,
1H) 3.58 (d, J=11.5 Hz, 1H), 1.74 (q, J=7.6 Hz, 2H),
1.55 (s, 3H), 1.34 (q, J=7.6 Hz, 2H), 0.88 (t, J=7.6 Hz,
3H), 0.80 (t, J=7.6 Hz, 3H); 13C (100 MHz, CDCl3) l
157.1, 105.8, 101.9, 80.0, 69.5, 40.0, 29.9, 22.8, 20.6, 7.8,
6.6; high-resolution mass spectrum (CI) m/z 199.1334
[(M+H)+; calcd for C11H19O3 199.1334].
4.5.11. ( )-(1a,3a,5a)-1,4-Dimethyl-4-nitro-2,8-dioxabi-
cyclo[3.2.1]octan-7-one, 2g. (21 mg, 27%): colorless oil;
Rf 0.42; (EtOAc/hexanes, 1:1); IR (film) 2934, 1767,
1
1536, 1387, 1178, 1082, 859, 804, 481 cm−1; H NMR
(400 MHz, CDCl3) l 4.97 (d, J=7.6 Hz, 1H), 4.20 (d,
J=12.8 Hz, 1H), 4.10 (d, J=12.8 Hz, 1H), 2.85 (dd,
J=19.0, 7.6 Hz, 1H), 2.28 (d, J=19.0 Hz, 1H), 2.03 (s,
3H), 1.42 (s, 3H); 13C (100 MHz, CDCl3) l 207.4, 98.8,
81.1, 76.0, 66.0, 38.2, 23.7, 17.5; high-resolution mass
spectrum (CI) m/z 219.0971 [(M+NH4)+; calcd for
C8H15N2O5 219.0981].
4.5.7.
( )-1-Methyl-2,8-dioxaspiro[4.5]bicyclo[3.2.1]-
octan-7-one, 3d. (90 mg, 50%): white solid; mp 65–66°C;
Rf 0.30 (EtOAc/hexanes, 2:5); IR (KBr) 2952, 2864,
1
1765, 1448, 1179, 1102, 864 cm−1; H NMR (400 MHz,
CDCl3) l 4.30 (d, J=7.4 Hz, 1H), 3.65 (d, J=13.2 Hz,
1H), 3.57 (d, J=13.2 Hz, 1H), 2.66 (dd, J=18.2, 7.4
Hz, 1H), 2.29 (d, J=18.2 Hz, 1H), 2.16–2.06 (m, 1H),
1.89–1.87 (m, 1H), 1.78–1.74 (m, 1H), 1.66–1.56 (m,
3H), 1.40 (s, 3H), 1.38–1.25 (m, 1H), 1.08–1.03 (m, 1H);
13C (100 MHz, CDCl3) l 211.6, 98.2, 80.1, 70.67, 45.0,
38.9, 36.5, 32.5, 25.6, 25.1, 18.2; high-resolution mass
spectrum (CI) m/z 197.1162 [(M+H)+; calcd for
C11H17O3 197.1178].
4.5.12. ( )-(4-Benzyloxymethyl-1-methyl-7-oxo-2,8-dioxa-
bicyclo[3.2.1]oct-4-yl)-carbamic acid benzyl ester, 8. (365
mg, 43%); colorless oil; Rf 0.65 (EtOAc/hexanes, 1:1);
IR (film) 3352, 3030, 2936, 2874, 1767, 1716, 1526,
1
1453, 1384, 1250, 1180, 1073, 1028, 739, 697 cm−1; H
NMR (500 MHz, CDCl3) l 7.28–7.14 (m, 10H), 5.50 (s,
1H), 5.13 (d, J=12.2 Hz, 1H), 5.10 (d, J=12.2 Hz,
1H), 4.82 (d, J=7.6 Hz, 1H), 4.51 (d, J=12.0 Hz, 1H),
4.42 (d, J=12.0 Hz, 1H), 4.14 (d, J=12.9 Hz, 1H), 3.79
(d, J=10.1 Hz, 1H), 3.56 (d, J=12.9 Hz, 1H), 3.56 (d,
J=10.1 Hz, 1H), 2.69 (dd, J=7.6, 18.7 Hz, 1H), 2.60
(d, J=18.7 Hz, 1H), 1.38 (s, 3H); 13C (125 MHz,
CDCl3) l 209.7, 155.4, 137.6, 136.4, [(128.8, 128.7,
128.4, 128.3, 127.9, (10 C)], 98.6, 75.4, 73.8, 68.0, 66.9,
65.2, 55.5, 37.7, 18.1; high-resolution mass spectrum
(CI) m/z 412.17594 [(M+H)+; calcd for C23H26O6N,
412.17601].
4.5.8. ( )-4-Spiro[4.5]-1-methyl-7-methylene-2,6,8-trioxa-
bicyclo[3.2.1]octane, 4d. (20 mg, 11%): colorless oil; Rf
0.66 (EtOAc/hexanes, 2:5); IR (film) 2955, 2866, 1688,
1453, 1369, 1333, 1198, 1122, 1022, 959, 910, 742 cm−1;
1H NMR (400 MHz, CDCl3) l 5.25 (s, 1H), 4.56 (d,
J=4.2 Hz, 1H), 4.13 (d, J=4.2 Hz, 1H), 3.79 (d,
J=11.2 Hz, 1H), 3.51 (d, J=11.2 Hz, 1H), 1.72–1.63
(m, 1H), 1.61–1.58 (m, 2H), 1.52 (s, 3H), 1.49–1.48 (m,
2H), 1.28–1.26 (m, 1H), 1.06–0.90 (m, 1H), 0.89–0.86
(m, 1H); 13C (100 MHz, CDCl3) l 157.2, 107.4, 101.7,
80.2, 70.6, 46.5, 34.0, 32.1, 25.6, 25.2, 20.6; high-resolu-
tion mass spectrum (CI) m/z 197.1165 [(M+H)+; calcd
for C11H17O3 197.1178].
4.6. Total synthesis of 7-episordidin, 13b
4.6.1. trans-2-Cyano-2-ethyl-cis-4,6-dimethyl-1,3-diox-
ane, 17. To a stirred solution of meso-2,4-propanediol
14 (650 mg, 6.25 mmol) and p-TsOH (25 mg, 0.13
mmol) in CH2Cl2 (40 mL) at rt was added triethyl
orthopropionate (1.83 mL, 9.38 mmol) and the reaction
stirred for 3 h. Trimethylsilyl cyanide (3.10 g, 31.25
mmol) (CAUTION!) and BF3·Et2O (159 mL, 1.27
mmol) were then sequentially added and the resulting
mixture stirred for an additional 16 h at rt. The reac-
tion was then quenched with powdered anhydrous
K2CO3 (1.5 g), stirred for 20 min then filtered through
a pad of Celite. The filtrate was then concentrated
under reduced pressure to provide 17 (1.04 g, 99%).
Analysis of this material by 1H NMR spectroscopy
indicated that it was of sufficient purity to allow direct
submission to hydrolysis: yellow oil; IR (film) 3071,
4.5.9. ( )-1-Methyl-2,8-dioxabicyclo[3.2.1]octan-7-one,
2e. (70 mg, 44%): clear oil; Rf 0.33 (EtOAc/hexanes,
2:5); IR (film) 2977, 2939, 1760, 1383, 1181, 1092, 919,
1
842, 740 cm−1; H NMR (400 MHz, CDCl3) l 4.79 (m,
1H), 4.00–3.93 (m, 2H), 2.71 (dd, J=18.3, 7.8, Hz, 1H),
2.51–2.47 (m, 1H), 2.27 (d, J=18.3 Hz, 1H), 1.43 (m,
1H), 1.29 (s, 3H); 13C (100 MHz, CDCl3) l 211.2, 98.4,
71.7, 60.9, 39.7, 29.3, 18.7; high-resolution mass spec-
trum (CI) m/z 143.0715 [(M+H)+; calcd for C7H11O3
143.0708].
4.5.10. ( )-(1a,5ab)-1,5-Dimethyl-2,8-dioxabicyclo[3.2.1]-
octan - 7 - one/(1a,3ab) - 1,3 - dimethyl - 2,8 - dioxabicyclo-
[3.2.1]octan-7-one, 2f. Inseparable mixture (1:1, 1H
1
2930, 2872, 2260, 1449, 1360, 1209, 1098, 922 cm−1; H

938
D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
1
NMR (400 MHz) l 4.15–4.12 (m, 2H), 1.90 (q, J=7.4
Hz, 2H), 1.60–1.57 (m, 1H), 1.28–1.26 (m, 1H), 1.22 (d,
J=8.7 Hz, 6H), 1.07 (t, J=7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) l 116.1, 97.5, 70.2 (2 C), 39.1, 33.4, 21.0
(2 C), 7.2; high-resolution mass spectrum (CI) m/z
170.1182 [(M+H)+; calcd for C9H16NO2 170.1181].
1012, 717 cm−1; H NMR (400 MHz, CDCl3) l 10.07
(s, 1H), 3.94–3.86 (m, 2H), 1.86 (q, J=7.5 Hz, 2H),
1.53–1.49 (m, 1H), 1.28–1.26 (m, 1H), 1.25 (d, J=8.4
Hz, 6H), 0.98 (t, J=7.5 Hz, 3H); 13C (100 MHz,
CDCl3) l 176.6, 100.8, 69.1 (2 C), 39.6, 32.7, 21.8 (2 C),
7.0; high-resolution mass spectrum (CI) m/z 206.1394
[(M+NH4)+ calcd for C9H20NO4 206.1392].
4.6.2.
trans-2-Carboxyamide-2-ethyl-cis-4,6-dimethyl-
1,3-dioxane, 18. A mixture of 17 (450 mg, 2.66 mmol),
NaOH (1.06 g, 26.50 mmol) and aqueous H2O2 (30%,
812 mL, 26.50 mmol) in ethanol (35 mL) was heated at
reflux for 3 h. The reaction mixture was then concen-
trated under reduced pressure to leave a yellow paste
which was taken up in H2O (10 mL), acidified to pH 1
with 5 M aqueous HCl then quickly extracted with
CH2Cl2 (4×20 mL). The organic extracts were com-
bined, dried (Na2SO4) and concentrated under reduced
pressure to leave a white powder which was recrystal-
lized from hexane to provide 18 (454 mg, 91%): color-
less crystals; mp 118–119°C; Rf 0.32 (EtOAc/hexanes,
9:1); IR (KBr) 3324, 2972, 2934, 1682, 1385, 1200,
4.6.5. trans-2-Diazoacetyl-2-ethyl-cis-2,4-dimethyl-1,3-
dioxane, 19. A solution of the carboxylic acid prepared
in Section 4.6.4 (150 mg, 0.79 mmol) and Et3N (132 mL,
0.95 mmol) in anhydrous CH2Cl2 (10 mL) was cooled
to −20°C and isobutyl chloroformate (112 mL, 0.83
mmol) then added dropwise via syringe. After stirring
for 5 min, an ethereal solution of diazomethane (0.1 M,
12 mL, 1.20 mmol) (CAUTION!) was added via a
flame-polished pipette and the reaction mixture allowed
to warm to rt over 16 h. The mixture was then concen-
trated under reduced pressure (CAUTION!) and the
resulting residue purified by flash chromatography on
silica gel (EtOAc/hexanes, 1:9) to provide 19 (168 mg,
99%): yellow oil; Rf 0.56 (EtOAc/hexanes, 1:4); IR
(film) 2975, 2937, 2132, 1899, 1340, 1277, 1114, 1007
cm−1; 1H NMR (400 MHz, CDCl3) l 5.65 (s, 1H),
3.95–3.83 (m, 2H), 1.76 (q, J=7.5 Hz, 2H), 1.49–1.47
(m, 1H), 1.28–1.26 (m, 1H), 1.26 (d, J=8.4 Hz, 6H),
0.98 (t, J=7.5 Hz, 3H); 13C (100 MHz, CDCl3) l 194.3,
101.4, 68.3 (2 C), 54.3, 39.6, 33.0, 21.9 (2 C), 7.0;
high-resolution mass spectrum (CI) m/z 213.1239 [(M+
H)+; calcd for C10H17N2O3 213.1239].
1
1171, 1112, 1001, 910, 742, 646 cm−1; H NMR (400
MHz, CDCl3) l 6.18 (br s, 1H), 5.57 (br s, 1H),
3.93–3.86 (m, 2H), 1.77 (q, J=7.5 Hz, 2H), 1.52–1.49
(m, 1H), 1.29–1.26 (m, 1H), 1.24 (d, J=8.6 Hz, 6H),
0.98 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3)
l 173.3, 101.2, 68.7 (2 C), 39.7, 33.6, 21.9 (2 C), 7.2;
high-resolution mass spectrum (CI) m/z 188.1285 [(M+
H)+; calcd for C9H18NO3 188.1287].
4.6.3. trans-2-Carboxymethyl-2-ethyl-cis-4,6-dimethyl-
1,3-dioxane, 15. A solution of amide 18 (250 mg, 1.33
mmol) and DMF–DMA (811 mL, 6.68 mmol) in anhy-
drous MeOH (5 mL) was placed in a pressure tube. The
reaction mixture was then subjected to three cycles of
freeze-thawing under nitrogen, sealed and heated at
110°C for 48 h during which time the reaction turned
dark brown. After cooling to 0°C, the pressure tube
was cautiously opened and the reaction mixture con-
centrated under reduced pressure. The resulting residue
was purified by flash chromatography on silica gel
(EtOAc/hexanes, 1:4) to furnish 15 (260 mg, 96%):
yellow oil; Rf 0.66 (EtOAc/hexanes, 1:4); IR (film) 2974,
4.6.6. (1a,3a,5a,b)-1-Ethyl-3,5-dimethyl-2,8-dioxa-bicy-
clo[3.2.1]octan-7-one (20) and (1a,3a,5a,b)-1-ethyl-3,5-
dimethyl-7-methylene-2,6,8-trioxa-bicyclo[3.2.1]octane,
21. A solution of 19 (1.85 g, 8.74 mmol) in anhydrous
CH2Cl2 (30 mL) was added, via syringe pump, to a
solution of Rh2(OAc)4 (77 mg, 2 mol%) in CH2Cl2 (570
mL) over 60 h. The reaction was filtered through Celite
and concentrated under reduced pressure. The resulting
residue was then purified by flash chromatography on
silica gel (EtOAc/hexanes, 1:9) to give furanone 20 (938
mg, 58%) and enol ether 21 (450 mg, 28%). Data for 20:
colorless oil; Rf 0.46 (EtOAc/hexanes, 2:5); IR (film)
2976, 2936, 1764, 1380, 1274, 1179, 1132, 943, 793
cm−1; 1H NMR (400 MHz, CDCl3) l 3.98–3.29 (m,
1H), 2.32 (d, J=8.1 Hz, 1H), 2.26 (d, J=12.8 Hz, 1H),
1.79–1.72 (m, 2H), 1.66–1.62 (m, 1H), 1.59 (dd, J=9.5,
3.9 Hz, 1H), 1.48 (s, 3H), 1.25 (d, J=6.1 Hz, 3H), 0.98
(t, J=7.5 Hz, 3H); 13C (100 MHz, CDCl3) l 221.7,
102.5, 77.0, 67.6, 47.2, 43.3, 26.4, 25.5, 22.2, 7.1; high-
resolution mass spectrum (CI) m/z 185.1170 [(M+H)+;
calcd for C10H17O3 185.1178]. Data for 21: colorless oil;
Rf 0.84 (EtOAc/hexanes, 2:5); IR (film) 2978, 2936,
1685, 1392, 1208, 1158, 1075, 1033, 974, 915, 821, 746
1
1742, 1384, 1104, 1011, 816, 695 cm−1; H NMR (400
MHz, CDCl3) l 3.84–3.78 (m, 2H), 3.76 (s, 3H), 1.72
(q, J=7.5 Hz, 2H), 1.48–1.42 (m, 1H), 1.28–1.26 (m,
1H), 1.22 (d, J=8.4 Hz, 6H), 0.95 (t, J=7.5 Hz, 3H);
13C NMR (100 MHz, CDCl3) l 171.6, 101.1, 68.7 (2 C),
52.3, 39.7, 32.8, 21.8 (2 C), 7.0; high-resolution mass
spectrum (CI) m/z 203.1283 [(M+H)+; calcd for
C10H19O4 203.1290].
4.6.4. trans-2-Carboxy-2-ethyl-cis-4,6-dimethyl-1,3-diox-
ane. A solution of ester 15 (100 mg, 0.50 mmol) and
NaOH (100 mg, 2.50 mmol) in THF (15 mL) and H2O
(15 mL) was heated at reflux for 16 h. The reaction
mixture was then concentrated, cooled to 0°C, acidified
to pH 1 with ice cold 5 M aqueous HCl (5 mL) and
then rapidly extracted with EtOAc (4×15 mL). The
combined extracts were then dried (Na2SO4) and con-
centrated under reduced pressure to provide the title
compound (92 mg, 99%): white solid; mp 79–80°C; IR
(KBr) 3521 3279, 2981, 1729, 1377, 1319, 1200, 1102,
1
cm−1; H NMR (400 MHz, CDCl3) l 4.85 (d, J=2.4
Hz, 1H), 4.70–4.64 (m, 1H), 4.49 (d, J=2.4 Hz, 1H),
2.48–2.33 (m, 1H), 2.31–2.25 (m, 2H), 2.13–2.10 (m,
1H), 2.02 (s, 3H), 1.74 (d, J=6.1 Hz, 3H), 1.36 (t,
J=7.5 Hz, 3H); 13C (100 MHz, CDCl3) l 157.9, 107.5,
105.4, 79.2, 67.0, 42.3, 27.3, 23.3, 21.3, 7.7; high-resolu-
tion mass spectrum (CI) m/z 185.1173 [(M+H)+; calcd
for C10H17O3 185.1178].

D. J. Wardrop et al. / Tetrahedron: Asymmetry 14 (2003) 929–940
939
4.6.7. (1a,3a,5a,b,7b)1-Ethyl-3,5,7-trimethyl-2,8-dioxa-
bicyclo[3.2.1]octan-7-ol, 23. To a solution of MeMgI (1
M in Et2O, 430 ml, 4.3 mmol) in THF (8 mL), at 0°C,
was added a solution of 20 (150 mg, 0.815 mmol) in
THF (2 mL). The reaction mixture was stirred for 3 h
at 0°C then poured into saturated aqueous NH4Cl (5
mL). The mixture was then extracted with pentane (5×5
mL) and the combined extracts dried (Na2SO4) and
concentrated under reduced pressure to provide 23 (160
(d, J=6.1 Hz, 3H), 1.09 (d, J=7.2 Hz, 3H), 0.93 (t,
J=7.5 Hz, 3H); 13C (125 MHz, CDCl3) l 107.6 (C1),
78.7 (C5), 65.6 (C3), 44.6 (C6), 42.4 (C4), 40.6 (C7),
29.1 (C8), 26.5 (C11), 22.2 (C10), 12.7 (C12), 7.9 (C9);
GCMS (EI, 70 eV) 51, 57, 67, 83, 95, 100, 113, 142,
169, 184; high-resolution mass spectrum (CI) m/z
185.1545 [(M+H)+; calcd for C11H21O2 185.1542].
1
mg, 99%) which H NMR spectroscopy indicated was
Acknowledgements
of sufficient purity to be used in the following proce-
dure: white powdery solid; Rf 0.30 (EtOAc/hexanes,
1:3); mp 79–80°C; IR (KBr) 3453, 2971, 2933, 1454,
This work was supported by the National Institutes of
Health (GM59157-01) and the University of Illinois at
Chicago. A.I.V. thanks the Fulbright Commission for
generous support in the form of a scholarship. We are
indebted to Professor Mike Doyle of the University of
1
1376, 1263, 1155, 1045, 948, 827 cm−1; H NMR (400
MHz, CDCl3) l 4.31–4.25 (m, 1H), 2.49 (bs, 1H), 2.04
(d, J=13.3 Hz, 1H), 1.82 (d, J=13.3 Hz, 1H), 1.68–
1.58 (m, 2H), 1.47 (apar.d, J=7.5 Hz, 2H), 1.33 (s, 3H),
1.29 (s, 3H), 1.25 (d, J=6.0 Hz, 3H), 1.01 (t, J=7.5 Hz,
3H); 13C (100 MHz, CDCl3) l 106.5, 80.4, 77.7, 66.6,
51.1, 43.7, 28.2, 26.7, 26.3, 22.2, 7.5; high-resolution
mass spectrum (CI) m/z 201.1488 [(M+H)+; calcd for
C11H21O3 201.1491].
Arizona for generously providing
a
sample of
Rh2(cap)4. We also thank the National Science Foun-
dation (NSF-DUE-98-562167) for partial support of
R.E.F.
4.6.8. (1a,3a,5a,b,7b)1-Ethyl-3,5,7-trimethyl-7-methyl-
oxylate-2,8-dioxa-bicyclo[3.2.1]octane, 24. To a solution
of 23 (9.0 mg, 0.045 mmol) in Et2O (5 mL) was cooled
to −78°C and n-BuLi (1.71 M in hexanes, 30 mL, 0.050
mmol) was dropwise via a syringe. After stirring for 10
min, methyl chlorooxoacetate (6.2 mL, 0.068 mmol) was
added. The reaction was stirred for 1 h at −78°C and
then for 2 h at rt before being poured into aqueous
saturated NaHCO3 (10 mL). This mixture was then
extracted with CH2Cl2 (3×10 mL) and the extracts dried
(Na2SO4) and concentrated under reduced pressure.
The resulting residue was then purified by flash chro-
matography on silica gel (EtOAc/hexanes, 1:3) to
provide 24 (10 mg, 78%): white crystalline solid; Rf 0.33
(EtOAc/hexanes, 1:3); mp 58–60°C; IR (film) 2971,
2938, 1767, 1745, 1446, 1377, 1327, 1204, 1166, 964, 789
cm−1; 1H NMR (400 MHz, CDCl3) l 4.15–4.09 (m,
1H), 3.89 (s, 3H), 2.43 (d, J=14.3 Hz, 1H), 2.10 (d,
J=14.3 Hz, 1H), 1.83–1.74 (m, 1H), 1.72–1.63 (m, 1H),
1.61 (s, 3H), 1.46–1.44 (m, 2H), 1.31 (s, 3H), 1.21 (d,
J=6.0 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H); 13C (100 MHz,
CDCl3) l 159.0, 157.6, 106.3, 90.3, 78.0, 66.1, 53.7,
48.6, 43.8, 27.2, 26.9, 24.5, 22.3, 7.9; high-resolution
mass spectrum (CI) m/z 287.1496 [(M+H)+; calcd for
C14H23O6 287.1495].
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