Total syntheses of yingzhaosu A and of its C(14)-epimer including the first evaluation of their antimalarial and cytotoxic activities

Article abstract of DOI:10.1021/jo050074z

(Chemical Equation Presented) The molecular structure of the naturally occurring antimalarial agent yingzhaosu A (1) is characterized by a 2,3-dioxabicyclo[3.3.1]nonane system (3a), an allylic alcohol, a homoallylic alcohol, and five stereogenic centers.

Full text of DOI:10.1021/jo050074z

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer Including
the First Evaluation of Their Antimalarial and Cytotoxic
Activities
Alex M. Szpilman,† Edward E. Korshin,† Haim Rozenberg,‡ and Mario D. Bachi*,†
Department of Organic Chemistry and Department of Structural Biology,
The Weizmann Institute of Science, 76100 Rehovot, Israel
mario.bachi@weizmann.ac.il
Received January 13, 2005
The molecular structure of the naturally occurring antimalarial agent yingzhaosu A (1) is
characterized by a 2,3-dioxabicyclo[3.3.1]nonane system (3a), an allylic alcohol, a homoallylic alcohol,
and five stereogenic centers. Herein we report on the total synthesis of yingzhaosu A (1) in eight
steps and 7.3% overall yield starting from (S)-limonene (12). To maximize efficacy, the bridged
bicyclic endoperoxide molecular core was constructed by a multicomponent free-radical domino
reaction in which five bonds are formed in a single operation. In addition, reaction protocols that
are compatible with the sensitivity of the peroxide function to strong basic and nucleophilic reagents
as well as to reducing agents were employed. An intriguing step involved the selective hydrogenation
of a carbon-carbon double bond in the presence of a peroxide and an aldehyde function to give
aldehyde peroxide 7. The two major synthons (aldehydoperoxide 7 and its complementary five-
carbon atom unit 35) were linked through a Mukaiyama aldol reaction followed by in situ
dehydration under mild buffered basic conditions. The carbonyl group in the resulting peroxidic
enone 39 was stereoselectively reduced with either R-CBS catalyst (42b) to give, after in situ
desilylation, yingzhaosu A (1) or with S-CBS catalyst (42a) its C(14)-epimer 40. The first quantitative
in vitro and in vivo data for the antimalarial activity of yingzhaosu A (1) and its C(14)-epimer 40
are reported. The C(14)-epiyingzhaosu A (40) exhibits potent cytotoxic activity against the KB nasal-
pharyngeal cancer cell line in vitro.
Introduction
abortive attempt to repeat its isolation from the plant,4
it was questioned whether yingzhaosu A is a genuine
constituent of the living plant or an artifact.5 Contem-
poraneously, the study of tetracyclic trioxane artemisinin
(qinghaosu) (2), originating from a different Chinese
traditional herbal remedy,6 and many of its synthetic and
semisynthetic derivatives led to the development of the
Bridged-bicyclic peroxide yingzhaosu A (1) was isolated
from an extract of Artabotrys uncinatus (Annonaceae)
that was used in China as a traditional remedy for
treatment of malaria.1 Following isolation and structure
determination, molecular structure 1 was corroborated
through total synthesis and X-ray diffraction analysis of
the carbonate derivative of the synthetic product.2 Al-
though yingzhaosu A was repeatedly reported to be the
antimalarial constituent of the above-mentioned herbal
medicament, no quantitative assessment of its potency
has ever been reported.3 Furthermore, following an
(3) Qualitative statements concerning the antimalarial activity of
yingzhaosu A (1) are given in ref 2 and in: (a) Liang, X. T. In Advances
in Chinese Medicinal Materials; Chang, H. M., Yeung, H. W., Tso, W.
W., Koo, A., Eds.; World Scientific Publ.: Singapore, 1985; pp 427-
432. (b) Tang, W.; Eisenbrand, G. Chinese Drugs of Plant Origin.
Chemistry, Pharmacology and Use in Traditional and Modern Medi-
cine; Springer-Verlag: Berlin, 1992; pp 165-166.
(4) Zhang, L.; Zhou, W.-S.; Xu, X. X. J. Chem. Soc., Chem. Commun.
1988, 523-524.
(5) (a) Jefford, C. W. In Advances in Drug Research. Vol.29:
Peroxidic Antimalarials; Jefford, C. W., Ed.; Academic Press: 1997;
pp 270-325. (b) Jefford, C. W. Curr. Med. Chem. 2001, 8, 1803-1826.
(6) Lin, M.-Y.; Ni, J.-M.; Fan, J. F.; Tu, Y.-Y.; Wu, Z.-H.; Wu Y.-L.;
Chou, W.-S. Acta Chim. Sin. 1979, 37, 129-141.
† Department of Organic Chemistry.
‡ Department of Structural Biology.
(1) Liang, X. T.; Yu, D. Q.; Wu, W. L.; Deng, H. C. Acta Chim. Sin.
1979, 37, 215-230.
(2) (a) Xu, X. X.; Zhu, J.; Huang, D.-Z.; Zhou, W.-S. Tetrahedron
Lett. 1991, 32, 5785-5788. (b) Zhou, W. S.; Xu, X. X. Acc. Chem. Res.
1994, 27, 211-216.
10.1021/jo050074z CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/24/2005
3618
J. Org. Chem. 2005, 70, 3618-3632

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
first-generation antimalarial peroxide drugs.7 On a par-
allel course a variety of endoperoxides containing the
molecular core of yingzhaosu A (1), namely a 2,3-
dioxabicyclo[3.3.1]nonane system 3, as putative pharma-
cophore were synthesized.8-13 While some of these syn-
thetic peroxides, e.g., 4,9a were found to be highly potent
and nontoxic antimalarial drug candidates,8,9 the enigma
concerning the potential antimalarial value of yingzhaosu
A (1) itself remained. The first total synthesis of ying-
zhaosu A (1) by Xu et al.2a was based on a stimulating
strategy but involved a laborious 15-step sequence that
could not be efficaciously applicable on preparative scale.
Yields in several steps of the synthesis of 1 were not
reported,2a but an estimation of the overall yield leads
to a figure well below 1%. The preparation of an endo-
peroxide key intermediate, used in another synthesis,
was outlined in a recent review.14
methodology allows the efficient eight-step syntheses of
yingzhaosu A (1) and of its C(14)-epimer 40 on a
preparative scale.15 We also present, for the first time,
data about their antimalarial activity as well as prelimi-
nary information about their cytotoxic properties.
Synthesis
Retrosynthetic paths a and b outlined in Scheme 1
were considered at the outset of this work. Path a is based
on the two chiral synthons 6 and 7, which together
contain all the stereogenic centers comprised in the target
molecule 1 and its immediate precursor 5, in the correct
absolute configuration. Retrosynthetic path b is based on
the same aldehyde 7, but its complementary synthon 10,
or its synthetic equivalent 11, are achiral thus forcing
the postponement of the consolidation of one of the five
stereogenic centers to the end of the synthesis. The use
of aldehyde 7 as key intermediate was introduced by Xu
et al.; however, their synthesis of 7 was based on an 11-
step low-yielding process.2a As starting material for
aldehyde 7 we chose â-sulfenyl endoperoxide 8. Com-
pound 8 is readily prepared on a multigram scale from
S-limonene (12) by a methodology recently developed in
our laboratory.10 It was originally used as an intermedi-
ate for the preparation of a class of antimalarial â-sul-
fonyl endoperoxides9 represented here by drug candidate
4.9a As summarized in Scheme 2, the 2,3-dioxabicyclo-
[3.3.1]nonane system (3a) in endoperoxide-hydroperox-
ides 13 and 14 is constructed in a multicomponent
domino free-radical reaction in which five new bonds are
formed in one operation. The resulting hydroperoxy group
is reduced in the same vessel to give the â-sulfenyl
endoperoxide 8 and its diastereomer 15 (50% combined
yield, 8:15 ) 55:45).10a,16 Due to difficulties encountered
on attempted chromatographic separation of 8 and 15,
separation of the diastereomers was postponed to a
subsequent step. Our synthetic plan required a stereo-
selective deoxygenation of the hydroxyl group and con-
version of the phenylsulfenyl group into a tertiary formyl
group via a Pummerer reaction.17 The choice of appropri-
ate reactions throughout this synthesis was curbed by
the susceptibility of the peroxide system to reducing
agents as well as to strong nucleophiles and bases.18,19
Driven by the challenge of constructing this intriguing
molecule and by the desire of supplying yingzhaosu A
(1) on a scale that would allow the evaluation of its
antimalarial activity and other biological properties, we
developed the total synthesis described herein. This
(7) For some recent reviews, see: (a) Posner, G. H.; O’Neill, P. M.
Acc. Chem. Res. 2004, 37, 397-404. (b) O’Neill, P. M.; Posner, G. H.
J. Med. Chem. 2004, 47, 2945-2964. (c) Tang, Y.; Dong, Y.; Venner-
strom J. L. Med. Res. Rev. 2004, 24, 425-448. (d) Jung, M.; Lee, K.;
Kim, H.; Park, M. Curr. Med. Chem. 2004, 11, 1265-1284. (e) Bez,
G.; Kalita, B.; Sarmah, P.; Barua, N. C.; Dutta, D. K. Curr. Org. Chem.
2003, 7, 1231-1255. (f) Robert, A.; Dechy-Cabaret, O.; Cazelles, J.;
Meunier, B. Acc. Chem. Res. 2002, 35, 167-174. (g) Vroman, J. A.;
Alvim-Gaston, M.; Avery, M. A. Curr. Pharm. Des. 1999, 5, 101-138.
(h) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999, 51, 1681-
1745. See also ref 5.
(8) (a) Hoffheinz, W.; Schmid, G.; Stohler, H. Eur. Pat. Appl. 311955,
1989; Chem. Abstr. 1990, 112, 20999. (b) Hofheinz, W.; Burgin, H.;
Gocke, E.; Jaquet, C.; Masciadri, R.; Schmid, G.; Stohler, H.; Urwyler,
H. Trop. Med. Parasitol. 1994, 45, 261-265. (c) Jaquet, C.; Stohler,
H. R.; Chollet, J.; Peters, W. Trop. Med. Parasitol. 1994, 45, 266-271.
(9) (a) Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M.;
Cumming, J. N.; Plyopradith, P.; Xie, S. J.; Shapiro, T. A.; Posner, G.
H. J. Med. Chem. 2003, 46, 2516-2533. (b) Bachi, M. D.; Korshin, E.
E.; Ploypradith, P.; Cumming, J. N.; Xie, S. J.; Shapiro, T. A.; Posner,
G. H. Bioorg. Med. Chem. Lett. 1998, 8, 903-908. (c) Bachi, M. D.;
Posner, G. H.; Korshin, E. E. PCT Int. Appl. WO 99/12900, 1999; Chem.
Abstr. 1999, 130, 237573.
(10) (a) Korshin, E. E.; Hoos, R.; Szpilman, A. M.; Konstantinovski,
L.; Posner, G. H.; Bachi, M. D. Tetrahedron 2002, 58, 2449-2469. (b)
Bachi, M. D.; Korshin, E. E. Synlett 1998, 122-124.
(11) O’Neill, P. M.; Stocks, P. A.; Pugh, M. D.; Araujo, N. C.; Korshin,
E. E.; Bickley, J. F.; Ward, S. A.; Bray, P. G.; Pasini, E.; Davies, J.;
Verissimo, E.; Bachi, M. D. Angew. Chem., Int. Ed. 2004, 43, 4193-
4197.
(12) O’Neill, P. M.; Searle, N. L.; Raynes, K. J.; Maggs, J. L.; Ward,
S. A.; Storr, R. C.; Park, B. K.; Posner, G. H. Tetrahedron Lett. 1998,
39, 6065-6068.
(13) (a) Kim, H.-S.; Begum, K.; Ogura, N.; Wataya, Y.; Tokuyasu,
T.; Masuyama, A.; Nojima, M.; McCullough, K. J. J. Med. Chem. 2002,
45, 4732-4736. (b) Tokuyasu, T.; Masuyama, A.; Nojima, M.; Mc-
Cullough, K. J.; Kim, H.-S.; Wataya, Y. Tetrahedron 2001, 57, 5979-
5989. (c) Tokuyasu, T.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Wataya,
Y. Tetrahedron Lett. 2000, 41, 3145-3148.
(14) Boukouvalas, J.; Haynes, R. K. In Radicals in Organic Syn-
thesis. Vol.2: Applications; Renaud, P.; Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; pp 455-484.
(15) A preliminary brief report on our first-version total synthesis
of yingzhaosu A (1) was included in the proceedings to 17th Interna-
tional Congress of Heterocyclic Chemistry, Vienna, Austria, Aug
1999: Bachi, M. D.; Korshin, E. E.; Hoos, R.; Szpilman, A. M. J.
Heterocycl. Chem. 2000 37, 639-646.
(16) For the safety precautions in working with endoperoxides, see
ref 10a.
(17) For reviews on the Pummerer reaction, see: (a) De Lucchi, O.;
Miotti, U.; Modena, G. Org. React. 1991, 40, 157-405. (b) Moiseenkov,
A. M.; Dragan, V. A.; Veselovski, V. V. Russ. Chem. Rev. 1991, 60,
643-657.
(18) (a) Kornblum, N.; DeLamare, H. E. J. Am. Chem. Soc. 1951,
73, 880-881. (b) Clennan, E. L.; Foote, C. S. In Organic Peroxides;
Ando, W., Ed.; Wiley: Chichester, 1992; pp 255-318. (c) Saito, I.;
Nittala, S. S. In The Chemistry of Peroxides; Patai, S., Ed.; Wiley:
Chichester, 1983; pp 311-374.
J. Org. Chem, Vol. 70, No. 9, 2005 3619

Szpilman et al.
SCHEME 1
SCHEME 210a,a
It resulted in a mixture of all the eight possible stereo-
and regioisomeric sulfoxides 18a-d and 19a-d (Scheme
3). Except for a small sample, which was fractionated for
analytical purposes,21 the synthetic process was contin-
ued with the mixture of all isomeric sulfoxides.
Treatment of sulfoxides 18a-d and 19a-d with tri-
fluoroacetic anhydride and 2,6-lutidine afforded via a
Pummerer rearrangement the thiohemiacetal esters
20a-h (Scheme 4). Standard hydrolysis of thiohemi-
acetals 20 by saturated NaHCO3 solution17 was found to
be slow and inefficient. Acidic hydrolysis22 of the thio-
hemiacetal ester function of 20 on silica, by trans-
acetalization to glyoxalic acid impregnated on silica gel,23
as well as sulfur extrusion by mercury24a-c or copper
salts,24d resulted in the formation of sulfur containing
byproducts and low to moderate yields of crude unsatur-
ated aldehydes 21-24. However, hydrolysis of crude
20a-h at -10 °C, under the mild basic conditions
provided by 1 equiv of morpholine in methanol/dichlo-
romethane,25 afforded a mixture of the four isomeric
aldehydes 21-24 in high yield. Under these conditions
the adverse base-catalyzed destruction of the peroxide
functionality through a Kornblum rearrangement was
prevented.18,19
a Key: (a) AIBN, hν, CH3CN; (b) Ph3P.
Removal of the hydroxyl group in 8 by dehydration
followed by hydrogenation complies with such require-
ments.20
Indeed, dehydration of the mixture of sulfides 8 and
15 afforded a mixture of endocyclic alkene 16 and
exocyclic alkene 17 (each as a mixture of the 4R and 4S
diastereoisomers) in 93% combined yield (Scheme 3).
Since previous attempts to selectively hydrogenate the
olefinic function in â-sulfenyl peroxides similar to 16 and
17 gave poor results,9a this operation was postponed to
a latter stage. To avoid affecting the double bond of 16
and 17, selective m-CPBA oxidation of the sulfide func-
tionality of 16a,b and 17a,b was performed at -40 °C.
The mixture of aldehydes 21-24 was separated by
flash chromatography to afford a fraction containing two
regioisomeric olefinic aldehydes 21 and 22 possessing the
desired 4S chirality and another fraction containing the
two regioisomers 23 and 24 having 4R configuration
(21) See the Experimental Section.
(22) Satchell, D. N. P.; Satchell, R. S. Chem. Soc. Rev. 1990, 19,
55-81.
(23) Muxfeldt, H.; Unterweger, W.-D.; Helmchen, G. Synthesis 1976,
694-696.
(19) Szpilman, A. M.; Korshin, E. E.; Hoos, R.; Posner, G. H.; Bachi,
M. D. J. Org. Chem. 2001, 66, 6531-6540.
(20) Attempts to convert the tertiary hydroxyl at C(8) into various
thionocarbonates, thionocarbamates or oxalyl thiohydroxamates for
further application of the Barton-McCombie free radical deoxygenation
failed.
(24) (a) Corey, E. J.; Hase, T. Tetrahedron Lett. 1975, 3267-3268.
(b) Degani, I.; Foci, R.; Regondi, V. Synthesis 1981, 51-53. (c)
Soderquist, J. A.; Miranda, J. L. J. Am. Chem. Soc. 1992, 114, 10078.
(d) Cazes, B.; Julia, S. Tetrahedron Lett. 1978, 4065-4068.
(25) Craig, D.; Daniels, K.; Mackenzie, A. R. Tetrahedron Lett. 1990,
31, 6441-6444.
3620 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
SCHEME 3a
a Key: (a) 4.3 equiv of SOCl2, 11 equiv of pyridine, CH2Cl2, 0 °C, 93% yield; (b) 1.1 equiv of m-CPBA, EtOAc, -40 °C, 94% yield.
SCHEME 4a
a Key: (a) 5 equiv of (CF3CO)2O, 10 equiv of 2,6-lutidine, CH2Cl2, -35 °C; (b) 1.1 equiv of morpholine, MeOH/CH2Cl2, -10 to 0 °C; (c)
Separation by flash chromatography. Yields (two steps): 21 + 22; 43% (ratio: 83:17), 23 + 24; 30% (ratio: 83:17).
SCHEME 5a
(Scheme 4). Configuration at C(4) was determined using
empirical rules established for configurational assign-
ment of geminal substituents on the C(4) stereogenic
center of other 2,3-dioxabicyclo[3.3.1]nonane derivatives.10a
It is based on a significant difference in the chemical
1
shifts of the C(11) methyl group in the H NMR spectra
of epimer 21 versus that of 23 and of epimer 22 versus
that of 24, deriving from higher deshielding effects by
the O(2) atom on its syn methyl groups in 23 and 24 as
compared to the anti methyl group in 21 and 22. Thus,
the C(11)H3 signal of 23 is seen at 1.56 while that of its
C(4)-epimer 21 is observed at 1.07. Likewise, the C(11)-
H3 signal of 24 is detected at 1.44 while that of its 4S-
epimer 22 appears at 1.17.
In our first version of the total synthesis of yingzhaosu
A (1),15 the aldehyde functionality of 21 and 22 was
protected as the dimethyl acetal using acid catalyst
Amberlyst-15 in neat trimethyl orthoformate (Scheme
a Key: (a) Amberlyst-15, neat HC(OMe)3, 94% yield; (b) H2, 0.1
5).26 Chemoselective platinum oxide-catalyzed hydroge-
equiv of PtO2, -10 °C, EtOAc, 84% yield; (c) 2.5 equiv of TsOH,
nation of the double bonds in the resulting acetals 25 and
25 equiv of CHOCOOH‚H2O, CH2Cl2, 93% yield; (d) H2, 0.15 equiv
26 occurs at temperatures below -5 °C without affecting
of PtO2, -11 to -12 °C, EtOAc, 90% yield.
the peroxide functionality. Hydrogenation of both exo-
and endo-cyclic double bonds occurs stereoselectively
from the convex face only to provide the desired saturated
(26) Patwardhan, S. A.; Dev, S. Synthesis 1974, 348-349.
acetal 27 as a single diastereoisomer in good yield.
J. Org. Chem, Vol. 70, No. 9, 2005 3621

Szpilman et al.
SCHEME 6a
conditions essentially pure aldehydes 7 and 31 were
obtained in excellent yield by filtering off the insoluble
material.
The finding that the carbon-carbon double bonds of
endoperoxide acetals 25/26 and 28/29 can be chemose-
lectively hydrogenated at temperatures in the range of
-5 to -10 °C led us to explore the direct hydrogenation
of unprotected aldehydes 21 and 22. In this instance, a
systematic study revealed remarkably high temperature
dependence. It was found that at temperatures above -10
°C concomitant hydrogenation of the olefinic double bond
and of the aldehyde functionality took place. Hydrogena-
tion carried out during 3 h at -13 to -14 °C revealed
that while consumption of starting material was incom-
plete, desired aldehyde 7 (50% yield) was accompanied
by a mixture of products devoid of the peroxide function.
Below -14 °C the exocyclic olefinic bond of aldehyde 22
is reduced within a few minutes but the endocyclic double
bond of aldehyde 21 (the major constituent) is not
hydrogenated. Eventually it was found that when hy-
drogenation is carried out at -11 to -12 °C complete
conversion of the starting material is achieved within 50
min to afford aldehyde 7 in 90% yield (Scheme 5). This
hydrogenation provides a unique example of chemo-
selective hydrogenation of a carbon-carbon double bond
in the presence of both aldehyde and peroxide functions.
a Key: (a) Amberlyst-15, neat HC(OMe)3, 93% yield; (b) H2, 0.1
equiv of PtO2, -10 °C, EtOAc, 77% yield; (c) 2.5 equiv of TsOH,
25 equiv of CHOCOOH‚H2O, CH2Cl2, 98% yield.
FIGURE 1. Selected NOE difference values for acetals 27 (25
°C in CDCl3) and 31 (in C6D6).
Likewise, isomeric acetals 28 and 29, deriving from
aldehydes 23 and 24, were hydrogenated to a single
saturated acetal 30 (Scheme 6).
The configuration at the newly formed stereogenic
center at C(8) was determined by 1H NOE difference
experiments (Figure 1). The C(8) hydrogen atoms of 27
and 30 show a remote NOE of 1.9% and 2.4%, respec-
tively, upon irradiation of the corresponding axial C(9)
hydrogen atom, thus confirming the axial confirmation
and the 8R configuration of this stereogenic center. The
signal of the C(10)-methyl protons of 30 shows a 1.8%
enhancement through interaction with the axial C(7)
proton. The NOE data confirmed also the stereochemistry
at C(4) independently assigned as described above. Thus,
for acetal 27 a NOE response of 8.9% was observed
between the C(12) acetal proton and the equatorial C(9)
proton indicating that the configuration at C(4) is S. No
such interaction is observed on in the case of acetal 30,
where the C(12) acetal hydrogen shows a NOE of 3.7%
on the equatorial C(6) hydrogen and a NOE of 3.5% on
the axial C(7) proton.
Having obtained the bicyclic peroxide synthon, the
enantiomerically pure aldehyde 7, in satisfactory overall
yield, we examined the possibility of condensing it with
a chiral side-chain synthon of type 6 (Scheme 1, path a).
Attempts to induce a condensation of aldehyde 7 with
chiral Julia-Kociensky sulfones27 32 and 33 as well as
with Horner-Wittig reagent28 34 under a variety of
reaction conditions failed.29 Failures seem to derive from
a combination of factors: insufficient reactivity of the
sterically encumbered aldehyde function and high sen-
sitivity of the endoperoxide function in 7 to strong bases
(27) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O.
Bull. Soc. Chim. Fr. 1993, 130, 856-878. (b) Baudin, J. B.; Hareau,
G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 336-357. (c)
Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley, A. Synlett 1998,
26-28.
(28) For leading general reviews on the Wittig and the related
Horner-Wadsworth-Emmons phosphorus-based olefinations, see: (a)
Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863-927. (b)
Clayden, J.; Warren, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 241-
270. (c) Vedejs, E.; Peterson, M. J. Adv. Carbanion Chem. 1996, 2,
1-85. (d) Rein, T.; Pedersen, T. Synthesis 2002, 579-594. (e) Molt,
O.; Schrader, T. Synthesis 2002, 2633-2670. (f) Valentine, D. H., Jr.;
Hillhouse, J. H. Synthesis 2003, 317-334.
Deprotection of acetals 27 and 30 to afford the corre-
sponding aldehydes 7 and 31 was performed by TsOH
catalyzed transacetalization with glyoxalic acid (Schemes
5 and 6). This method takes advantage of the low
solubility of TsOH, glyoxalic acid and its corresponding
acetal in dichloromethane. Under these mild reaction
(29) Szpilman, A. M. Ph.D. Thesis, the Weizmann Institute of
Science, Rehovot, 2003.
3622 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
SCHEME 7a
TABLE 1. Mukaiyama Aldol Addition of TMS-enol
Ether 35 to Aldehyde 7 (Step a) with in Situ Dehydration
(Step b) (Scheme 7)
yield (%)
entry
conditions for step b
36 37 38 39
1
2
3
4
5
0.5 M K2CO3, 0 °C, 1 h, then HCl/MeOH 70
18 equiv of pyridine, 0 °C, 10 min
32 equiv of pyridine, -78 to +25 °C, 2 h
23 equiv of pyridine, -40 to 0 °C, 7 h
21 equiv of pyridine, -20 to -30 °C, 11 h
15a 27 27a
22b 20b
20
13
70
a These products were isolated in impure state, and the yields
were determined after conversion into 36 and 9. b These products
were not separated, and the yields are based on the 1H NMR
spectra of the mixture.
prompted us to develop a one-pot procedure for the
synthesis of R,â-unsaturated ketone 9 involving aldol
addition followed by in situ base-induced dehydration.35
Such a process would be driven by the strong titanium-
oxygen affinity and eventually result in the formation of
the double bond through titaniumoxide dichloride extru-
sion. Quenching the reaction mixture with triethylamine
instead of pyridine resulted in an instant decomposition
of all endoperoxidic compounds. Dehydration using py-
ridine at temperatures above -20 °C resulted in the
partial decomposition of the endoperoxidic products and
afforded R,â-unsaturated ketone 39 in low yield (Table
1, entries 3 and 4). No dehydration could be observed at
temperatures below -40 °C. Eventually, the aldol addi-
tion was carried out by stirring aldehyde 7 with enol
ether 35 (5 equiv) and titanium tetrachloride (4 equiv)
for 4 h at -78 °C.36 Once the reaction was completed as
determined by the consumption of aldehyde 7 (TLC), a
large excess of pyridine was added and the resulting
reaction mixture stirred at -20 °C for 11 h (Table 1, entry
5). This procedure afforded R,â-unsaturated ketone 39
in 70% yield along with bis-TMS protected aldol addition
product 37 (13%). Thus, by careful selection of the
reaction temperature, the Lewis acid and the Lewis base
it became possible to perform a multiple steps one-pot
condensation of aldehyde-peroxide 7 with bis-TMS-enol
ether 35 to form the trimethylsilyloxy-enone peroxide 39.
Slight deviation from the described reaction conditions
may result in significant decrease in yield. The TMS
group in 39 can be efficiently removed by HF in aqueous
acetonitrile37 to give hydroxy enone 9 (95%). Also, sily-
lation of hydroxy enone 9 with trimethylsilyl triflate in
the presence of 2,6-lutidine easily affords the TMS-
protected hydroxy enone 39 (97%).
a Key: (a) 3-4 equiv of TiCl4, -78 °C, CH2Cl2, 4 h; (b) see Table
1.
and nucleophiles. At temperatures above -10 °C, both
synthons are quickly destroyed while at lower tempera-
tures no reaction occurs. While the alternative approach
involving nonchiral synthons of type 10 (Scheme 1, path
b) was successfully applied by Xu et al. using arsenium
ylide Ph3As dCHC(O)CMe2OH,2 a model experiment,
performed in our laboratory, using a stabilized phos-
phorus ylide, namely Ph3P dCHC(O)Ph, gave unsatisfac-
tory results.30,31 To avoid limitations that may derive from
the base-sensitivity of endoperoxide aldehyde 7 we chose
to investigate the application of the Lewis acid catalyzed
Mukaiyama aldol reaction15,32,33 for connecting a side-
chain synthon of type 11 (Scheme 1, path b).
It was found that treatment of aldehyde 7 with 3 equiv
of enol ether 3534 and 3 equiv of titanium tetrachloride
at -78 °C, followed by quenching with aqueous potas-
sium carbonate at low temperature, afforded a crude
mixture of three aldol addition products 36-38 (Scheme
7). Acidic hydrolysis of this crude mixture afforded the
single aldol addition product 36 in good yield (Table 1
entry 1). In contrast, quenching an identical reaction
mixture with pyridine followed by aqueous workup
afforded a moderate yield of impure R,â-unsaturated
ketone 39 together with aldol addition products 37 and
38 (Table 1, entry 2). This serendipitous observation
(30) (1R,4R,5R,8R)-8-Acetoxy-4,8-dimethyl-4-formyl-2,3-dioxabicyclo-
[3.3.1]nonane, structurally related to aldehyde 7, underwent slow
olefination with stabilized phosphorus ylide Ph3PdCHCOPh (6 equiv)
to give after 30 days at rt the corresponding (1R,4R,5R,8R)-8-acetoxy-
4,8-dimethyl-4-(3-oxo-3-phenyl-1-propenyl)-2,3-dioxabicyclo-
[3.3.1]nonane (48%) and 5% recovered aldehyde. The experimental
details are described in the Supporting Information. For few additional
examples of Wittig reactions of structurally related bridged bicyclic
endoperoxide aldehydes with semistabilized phosphorus ylides, see refs
8a,b and 11.
(31) It has been noted that olefination of less sterically hindered
secondary aldehydes, having acyclic peroxide moiety, through the
Horner-Emmons reaction with phosphineoxide carbanions is consider-
ably more efficient than using Wittig’s phosphorus ylides. See:
Dussault, P. Synlett 1995, 997-1003.
(32) For reviews on Mukaiyama aldol addition, see: (a) Mukaiyama,
T. Org. React. 1982, 28, 203-301. (b) Cowden, C. J.; Paterson, I. Org.
React. 1997, 51, 1-200. (c) Mahrwald, R. Chem. Rev. 1999, 99, 1095-
1120. (d) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc. Rev. 2004,
33, 65-75.
(33) Titanium tetrachloride mediated bis-aldol addition of artem-
ether (a 1,2,4-trioxane containing a fused cyclic acetal fragment) to
bis-trimethylsilyl enol-ethers has been recently applied for synthesis
of highly active antimalarial and antitumor 1,2,4-trioxane dimers.
See: Posner, G. H.; Ploypradith, P.; Parker, M. H.; O’Dowd, H.; Woo,
S.-H.; Nortrop, J.; Krasavin, M.; Dolan, P.; Kensler, T. W.; Xie, S.;
Shapiro, T. A. J. Med. Chem. 1999, 42, 4275-4280.
Reduction of enone 9 with LiBH4 in ether was reported
to give a mixture of yingzhaosu A (1) and its C(14) epimer
(34) (a) Sakai, T.; Ito, H.; Yamawaki, T.; Takeda, A. Tetrahedron
Lett. 1984, 25, 2987-2988. (b) Limat, D.; Schlosser, M. Tetrahedron
1995, 51, 5799-5806.
(35) (a) According to
a literature search using the SciFinder
database, the only report on a one-pot Mukaiyama reaction directed
toward synthesis of R,â-unsaturated ketones has been found. The
reported procedure consists of the sequential treatment of an initially
formed titanium aldol product with TFAA followed by triethylamine
See: Bouhlel, E.; Ben Hassine, B. Synth. Commun. 1992, 22, 2183-
2186. (b) ZnCl2-catalyzed condensation of some silyl enol-ethers with
dialkylacetals was reported to produce R, â-unsaturated ketones. See:
Makin, S. M.; Kruglikova, R. I.; Tagirov, T. K.; Kharitonova, O. V. Russ.
J. Org. Chem. (Engl. Ed.) 1984, 20, 1075-1078.
(36) Attempts to employ in the aldol addition the TBS-analogue of
TMS-enol ether 35 were unsuccessful.
(37) (a) Boschelli, D.; Takemasa, T.; Nishitani, Y.; Masamune, S.
Tetrahedron Lett. 1985, 26, 5239-2542. (b) Nelson, T. D.; Crouch, R.
D. Synthesis 1996, 1031-1069.
J. Org. Chem, Vol. 70, No. 9, 2005 3623

Szpilman et al.
TABLE 2. Reduction of r,â-Unsaturated Ketones 9 and 39 under Various Conditions (Scheme 8)
reduction
of ketone
yield
(%)
ratioa
1:40
entry
reaction conditions
1
2
3
4
9
1.5 equiv of NaBH4, 1 equiv of EuCl3, EtOH, 0 °C, 1 h
4.5 equiv of DIBAL-H, THF, -60 °C, 4 h
95
45:55
45:55
55:45
66:33
9
99b
50c,f
97d,f
39
39
2 equiv of R-BINAL-H (41), THF, -55 °C, 6 h
1.1 equiv of S-CBS catalyst (42a), 1.2 equiv of catecholborane,
dichloromethane/toluene, -20 °C, 16 h
1 equiv of S-CBS catalyst (42a), 1.1 equiv of BH3‚THF,
dichloromethane/toluene/THF 3:1:0.1, -40 °C, 17 h
1.2 equiv of S-CBS catalyst (42a), 1.2 equiv of BH3‚THF, THF, -55 °C, 45 h
1.2 equiv of R-CBS catalyst (42b), 1.2 equiv of BH3‚THF, THF, -55 °C, 47 h
5
39
90e,f
16:84
6
7
39
39
70f
71f
11:89
89:11
a The ratio was determined by 1H NMR (400 MHz). b Calculated at 56% conversion. c Calculated at 75% conversion. d Calculated at
51% conversion. e Calculated at 70% conversion. f After desilylation with 2% HF in aqueous methanol or 10% HF in aqueous THF.
(1) and its epimer 40 in a 16:84 ratio (Table 2, entry 5).42
Replacing dichloromethane/toluene with THF and lower-
ing the temperature to -55 °C further increased the
diastereoselectivity (Table 2, entry 6). Below -65 °C
reduction was arrested (<10% conversion after 48 h.).
Finally, reduction of 39 with the enantiomeric R-CBS
catalyst (42b) followed by acidic workup, afforded ying-
zhaosu A (1) as the main product in an 89:11 ratio with
its epimer 40 (Table 2, entry 7).43
SCHEME 8a
a Key: (a) see details in Table 2.
40 in a 40:60 ratio (Scheme 8).2a In an early stage of this
research,15 we examined the suitability of other achiral
reducing agents. It was found that chemoselective 1,2-
reduction using the Luche procedure38 affords yingzhaosu
A (1) and its C(14)-epimer 40 in excellent yield, but this
process is devoid of any significant stereoselectivity
(Scheme 8, Table 2, entry 1). Similar results were
obtained using DIBAL-H39 in THF (Table 2, entry 2). In
view of these results, we investigated the use of chiral
nonracemic reducing agents. Reduction of TMS-protected
enone 39 with the R-enantiomer of Noyroi’s BINAL-H
reagent (41)40 followed by acidic workup did not lead to
better results (Table 2, entry 3). More promising results
were obtained in the reduction of 39 by boranes and the
Corey/Bakshi/Shibata (CBS) catalyst (42).41 Consider-
ations relating to stereoselection and stability of the
peroxide function determined that the reduction should
be carried out at of low temperatures. When 39 was
reduced using an equimolar amount of S-CBS catalyst
(42a) and catecholborane at -20 °C in dichloromethane
followed by TMS deprotection in the same vessel, ying-
zhaosu A (1) and its epimer 40 were obtained in a 2:1
ratio and high yield (Table 2, entry 4). Changing the
hydride donor to the more reactive borane-THF and
lowering the temperature to -40 °C resulted in a reversal
and increase in stereoselection, affording yingzhaosu A
The first samples of yingzhaosu A (1) and its C(14)
epimer 40 were obtained in our laboratory from batches
deriving from the reduction of enone 9 as described in
Table 2, entries 1 and 2, namely containing approxi-
mately equimolar amounts of the two diasteromers.15
Since direct chromatographic separation between these
epimers is problematic, we used a reported bypass
involving the intermediacy of their corresponding carbon-
ates 43 and 44 (Scheme 9).2 Treatment of dihydroxy
compounds 1 and 40 with carbonyldiimidazole,44 rather
than phosgene,2 conveniently affords carbonates 43 and
44 (90% combined yield) which, after chromatographic
separation, are individually deprotected by treatment
2,45
with LiBH4
to give yingzhaosu A (1, 92% yield) and
its C(14)-epimer (40, 94% yield).
The pure samples of 1 and 40, obtained as shown in
Scheme 9, allowed us to study and develop a crystalliza-
tion protocol that provides long cylindrical colorless
crystals of yingzhaosu A (1) [mp 94-94.5 °C; [R]20
)
D
(42) Similar reversals of stereoselectivity have been reported previ-
ously. See: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37,
1987-2012 and references therein.
(43) As described herein, the use of borane-THF as the hydride
donor at temperatures below -20 °C requires equimolar rather than
catalytic amounts of CBS-catalyst (42).42 This disadvantage was
minimized by recovering from the reaction mixture the expensive
amino alcohol (80%), which was used for generating the CBS reagent
(42).
(44) (a) Kutney, J. P.; Ratcliffe, A. H. Synth. Commun. 1975, 5, 47-
52. (b) Armstrong, A. In Encyclopedia of Reagents for Organic
Synthesis. Vol. 2; Paquette, L. A. Ed.; Wiley: Chichester, 1995; pp
1006-1010.
(45) Brown, H. C.; Narasimhan, S.; Choi, Y. M. J. Org. Chem. 1982,
47, 4702-4708.
(38) (a) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454-5459. (b) Gemal, A. L.; Luche, J. L. Tetrahedron Lett. 1981, 22,
4077-4080.
(39) Wilson, K. E.; Sediner, R. T.; Masamune, S. J. Chem. Soc.,
Chem. Commun. 1970, 213-214.
(40) (a) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am.
Chem. Soc. 1984, 106, 6709-6716. (b) Noyori, R.; Tomino, I.; Yamada,
M.; Nishizawa, M. J. Am. Chem. Soc. 1984, 106, 6717-6725.
(41) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926. (b) Corey, E. J.; Bakshi,
R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551-5553.
3624 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
SCHEME 9a
Plasmodium falciparum. It was found that yingzhaosu
A (1) showed moderate activity (IC50 )115 nM) against
the chloroquine-resistant K1 strain, while its C(14)-
epimer 40 was found to exhibit higher activity (IC50
)
56 nM). The activities of both compounds against the
chloroquine-sensitive NF54(3D7) strain were found to be
considerably lower (IC50 of 380 nM and 210 nM, respec-
tively) than that of the positive drug control artemisinin
(2, IC50 )2.5 nM).47
In vivo antimalarial assays indicated ED50 ) 50 mg/
kg for yingzhaosu A (1) and ED50 ) 95 mg/kg for its C(14)-
epimer 40 against chloroquine-resistant P. yoelii ssp. NS,
as compared to ED50 ) 5 mg/kg of sodium artesunate that
was taken as positive drug control. The parallel values
against chloroquine-sensitive P. berghei NY are ED50
)
250 mg/kg for yingzhaosu A (1), ED50 ) 90 mg/kg for its
C(14)-epimer 40, and 4.2 mg/kg for sodium artesunate
control.48
Preliminary in vitro toxicity tests against the KB nasal-
pharyngeal cancer cell lines showed that while cyto-
toxicity of yingzhaosu A (1) is low (ED50 ) 36.6 µg/mL),
its C(14)-epimer 40 exhibit high cytotoxicity (0.57 µg/mL).
Cytotoxicity of podophyllotoxin control against this cell
line is 0.00125 µg/mL.47
a Key: (a) 5 equiv of 1,1-carbonyldimidazole THF, 55 °C; (b) 2
equiv of LiBH4, ether, 0 °C.
Conclusion
Twenty-five years after the discovery of yingzhaosu A
(1), we now provide preparative-scale syntheses of this
intriguing natural product, as well as of its C(14)-epimer
40. Since the chemistry developed was adapted to the
particular properties of peroxides, it can be readily
applied to the synthesis of other analogues of yingzhaosu
A (1) as well as to a variety of additional cyclic peroxides.
The preliminary antimalarial and cytotoxic testing pro-
vided data, which are relevant to the structure activity
relationship studies directed toward the development of
new drugs.
+227.4 (c 1.30, CHCl3) [lit.1,2 mp 95-96 °C; [R]25D ) +226
(CHCl3)]] and small colorless crystals of 40: mp 88-89
°C; [R]20D ) +238. 0 (c 0.896, CHCl3) [lit.2 mp 55-56 °C;
[R]20 ) +234 (CHCl3)]. Single-crystal X-ray analysis of
D
yingzhaosu A (1) confirmed the structure and relative
stereochemistry (see the Supporting Information).46 The
absolute stereochemistry of the chiral centers was de-
termined as 1S,4S,8R,14S by correlation to that of C(5),
namely 5S as in the starting material, (S)-limonene (12).
This is consistent with the previously assigned stereo-
chemistry of yingzhaosu A (1).1,2
Since the stereoselective reductions described above
provided us with products containing either mainly
yingzhaosu A (1) or mainly 40, it became possible to
efficiently separate 1 and 40 by direct fractional recrys-
tallization. Indeed, by this process pure yingzhaosu A (1)
is obtained by recrystallization from tert-butyl methyl
ether/pentane, while its C(14)-epimer 40 is obtained by
recrystallization from ethyl acetate/hexane. Avoiding the
intermediacy of carbonates 43 and 44 saves two synthetic
steps.
These practical and effective total syntheses of ying-
zhaosu A (1) and of its C(14)-epimer 40 require just eight
synthetic operations starting from (S)-limonene (12) and
provide the target compounds on a preparative scale
(7.3% overall yield in each case).
Experimental Section
(1S,4S,5S)-4,8-Dimethyl-4-phenylsulfenylmethyl-2,3-
dioxabicyclo[3.3.1]non-7-ene (16a), (1S,4R,5S)-4,8-Di-
methyl-4-phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]-
non-7-ene (16b), (1S,4S,5S)-4-Methyl-8-methylidene-4-
phenylsulfenylmethyl-2,3-dioxabicyclo[3.3.1]nonane (17a),
and (1S,4R,5S)-4-Methyl-8-methylidene-4-phenylsulfen-
ylmethyl-2,3-dioxabicyclo [3.3.1]nonane (17b). To a solu-
tion of SOCl2 (4.5 equiv; 1.90 g; 16.0 mmol) and pyridine (11
equiv; 3.165 g; 40.0 mmol) in dry dichloromethane (150 mL)
at 0 °C was added a solution of hydroxysulfides 8 and 1510a
(1.10 g; 3.74 mmol, 8:15 ca. 55:45) in dichloromethane (30 mL)
over 1.5 h. The reaction mixture was allowed to warm to room
temperature and stirred for an additional 2 h. At that time,
the mixture was poured into cold 0.1 M HCl (100 mL) and
extracted with 10% ethyl acetate/hexane (2 × 300 mL). The
organic extract was washed with saturated NaHCO3 (2 × 80
mL), dried (Na2SO4 + NaHCO3), and evaporated. The residue
was purified by flash chromatography (5% ethyl acetate/
hexane) to give a mixture of unsaturated sulfides 16a,b and
Biological Evaluation
Yingzhaosu A (1) and its C(14)-epimer 40 were assayed
for in vitro antimalarial activity against two strains of
(47) In vitro antimalarial and cytotoxic activities were determined
by Prof. Simon L. Croft, Department of Infectious and Tropical
Diseases, London School of Hygiene and Tropical Medicine, U.K.
(48) In vivo antimalarial activity was tested on rodents. and ED50
values were obtained by graphic interpolations. The testing was
performed by Mr. Brian L. Robinson, CTAC, Northwick Park Institute
for Medical Research, Harrow, Middlesex, U.K.
(46) Crystallographic data for the structure of yingzhaosu A (1) have
been deposited with the Cambridge Crystallographic Data Center
(CCDC) and allocated the deposition number CCDC 253141. Copies
of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge CB2 1EZ, U.K. (fax: +44-1223-336033 or
e-mail: deposit@ccdc.cam.ca.uk).
J. Org. Chem, Vol. 70, No. 9, 2005 3625

Szpilman et al.
17a,b (955 mg; total yield 92%; 16a:16b:17a:17b ca.
47:39:8:6 according to the integration of the H(1) peaks in 1H
NMR spectrum at 400 MHz): colorless oil; Rf ) 0.29 (5% ethyl
acetate/hexane); 1H NMR (400 MHz, CDCl3) δ 1.20 (d, J ) 0.7
Hz, 16a), 1.29 (d, J ) 0.6 Hz, 17a), 1.57 (d, J ) 0.5 Hz, 17b),
1.58 (d, J ) 0.8 Hz, Me(11), 16b), total 3H; 1.55 (ddd, J )
13.1, 3.0, 2.0 Hz, 16a), 1.63 (dddd, J ) 13.0, 2.9, 2.4, 0.5 Hz,
16b), total ca.1H; 1.79-1.81 (m, ca. 3H, 16a,b); 1.93 (m, 16b),
2.04 (m, 16a), total ca. 1H; 2.15-2.37 (m), 2.48 (dddd, J ) 13.0,
3.6, 3.6, 1.6 Hz, 16b), total 3H; 2.90 (d, J ) 11.8 Hz, 16b),
3.03 (dd, J ) 11.8, 0.8 Hz, 16b), 3.00 (d, J ) 12.0 Hz, 17b)
3.10 (dd, J ) 12.0, 0.5 Hz, 17b), 3.30 (d, J ) 12.2 Hz, 17a),
3.33 (d, J ) 12.7 Hz, 16a), 3.79 (dd, J ) 12.7, 0.7 Hz, 16a),
total 2H; 4.10 (br dd, J ) 3.6, 2.0 Hz, ca. 0.47H, H(1)eq, 16a),
4.13 (br dd, J ) 3.6, 2.4 Hz, ca. 0.39H, H(1)eq, 16b), 4.34 (br
dd, J ) 4.0, 1.4 Hz, ca. 0.08H, H(1)eq, 17a), 4.40 (br dd, J )
4.3, 1.7 Hz, ca. 0.06H, H(1)eq, 17b), total 1H; 4.89 (m, ca. 0.3
H, 17a,b), 5.73 (m, 16b), 5.75 (m, 16a), total ca. 1H; 7.18-
7.46 (m, 5H). The major component 16a was purified by
additional semipreparative reversed-phase HPLC (60% MeCN/
H2O).
29.8 (CH2), 30.3 (CH2), 30.4 (CH), 31.6 (CH), 65.5 (CH2), 65.5
(CH2), 76.8 (CH), 80.8 (CH), 82.2 (C), 113.3 (CH2), 123.7 (CH),
123.8 (CH), 126.0 (CH), 129.4 (CH), 129.5 (CH), 131.3 (CH),
131.4 (CH), 131.8 (C), 144.7 (C), 146.1 (C). (ii) The second
fraction consists of a colorless oil: Rf ) 0.43 (50% ethyl acetate/
hexane) containing four isomers, 18a, 19a, 18d, and 19d
(18:19 ca.94:6; 18a:18d ca.55:45): 1H NMR (400 MHz, CDCl3)
δ 1.39 (br d, J ) 0.7 Hz), 1.88 (br s), 1.90 (br s), total 3H; 1.56
(m), 1.63 (ddd, J ) 13.1, 3.2, 2.1 Hz), 1.75 (ddd, J ) 13.4, 2.4,
2.4 Hz), total ca.1H; 1.77 (m), 1.79 (m), total ca. 3H; 1.99 (m,
ca. 0.5H), 2.20 (m, ca.0.5H); 2.26-2.34 (m, total ca.0.85H);
2.36-2.48 (m, ca. 2H); 2.53-2.59 (m, total ca.0.5H), 2.55 (d, J
) 13.8 Hz, ca. 0.4H), 3.13 (d, J ) 13.9 Hz, ca. 0.5H), total ca.
1H; 3.08 (br d, J ) 13.8 Hz, ca. 0.4H), 3.13 (br d, J ) 13.8 Hz),
3.66 (dd, J ) 13.9, 0.7 Hz, ca.0.5H), total 1H; 4.15 (m, 0.94H),
4.43 (m, 0.06H), total 1H; 4.90 (br s, ca.0.12H), 5.68 (m,
ca.0.4H), 5.78 (m, ca.0.5H), 7.46-7.56 (m, 3H), 7.61-7.68 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 21.1 (CH3), 21.9 (CH3), 22.1
(CH3), 24.1 (CH3), 26.2 (CH2), 26.5 (CH2), 27.4 (CH2), 27.8
(CH2), 29.2 (CH), 31.5 (CH), 64.8 (CH2), 66.2 (CH2), 76.4 (CH),
77.1 (CH), 80.9 (CH), 81.9 (C), 82.1 (C), 113.1 (CH2), 123.7
(CH), 123.8 (CH), 126.6 (CH), 126.9 (CH), 129.3 (CH), 129.3
(CH), 131.99 (C), 131.01 (CH), 131.06 (CH), 131.09 (C), 144.6
(C), 144.8 (C), 146.3 (C). The most polar fraction consists of a
colorless oil, Rf ) 0.35 (50% ethyl acetate/hexane) containing
the two isomers 18b and 19b (18b:19b ca.91:9). Isomers 18b
and 19b were separated by additional MPLC (40% ethyl
acetate/hexane) to afford isomer 19b (ca.95% purity) as a
colorless waxy solid and isomer 18b as a colorless solid. Isomer
19b: white waxy solid; mp 78-82 °C; 1H NMR (400 MHz,
CDCl3) δ 1.58 (m, 1H, H(9)ax), 1.61 (br s, 3H, Me(11)), 1.72
(dddd, J ) 13.8, 13.8, 6.4, 3.7 Hz, 1H, H(6)ax), 2.04 (dddd, J
) 6.4, 6.4, 3.2, 3.2 Hz, 1H, H(5)eq), 2.18 (m, J ) 13.8 Hz, 1H,
H(6)eq), 2.41 (br dd, J ) 15.2, 6.0 Hz, 1H, H(7)eq), 2.51 (br
ddd, J ) 13.6, 6.4, 3.5 Hz, 1H, H(9)eq), 3.06 (m, 1H, H(7)ax),
3.28 (br d, J ) 14.0 Hz, 1H, H(12)), 3.50 (br d, J ) 14.0 Hz,
H(12′)), 4.37 (br dd, J ) 3.5, 1.5 Hz, 1H, H(1)eq), 4.93 (br dd,
J ) 2.2, 2.2 Hz, 1H, H(10)), 4.96 (m, 1H, H(10′)), 7.52 (m, 1H,
Ar), 7.55 (m, 2H, Ar), 7.69 (m, 2H, Ar); 13C NMR (100 MHz,
CDCl3) δ 22.5 (C(11)H3), 27.0 (C(6)H2), 30.1 (C(9)H2), 30.5
(C(7)H2), 31.7 (C(5)H), 66.2 (C(12)H2), 80.6 (C(1)H), 82.5 (C(4)),
113.6 (dC(10)H2), 123.9 (2 × CH, Ar), 129.3 (2 × CH, Ar), 130.9
(CH, Ar), 146.2 (C(13)), 154.6 (dC(8)). Isomer 18b: white solid;
mp 90-92 °C; 1H NMR (400 MHz, CDCl3) δ 1.51 (br s, 3H,
Me(11)), 1.64 (ddd, J ) 13.3, 3.0, 2.2 Hz, 1H, H(9)ax), 1.79
(ddd, J ) 2.7, 1.6, 1.6 Hz, 3H, Me(10)), 1.99 (m, 1H, H(5)eq),
2.23 (dddq, J ) 19.2, 5.4 Hz, 1.6, 1.6 Hz, 1H, H(6)ax), 2.37-
2.47 (m, 2H, H(6)eq + H(9)eq), 3.30 (d, J ) 14.0 Hz, 1H, H(12)),
3.44 (dd, J ) 14.0, 0.35 Hz, 1H, H(12′)), 4.12 (m, 1H, H(1)eq),
5.78 (m, 1H, H(7)), 7.50 (m, 1H, Ar), 7.53 (m, 2H, Ar), 7.68
(m, 2H, Ar); 13C NMR (100 MHz, CDCl3) δ 21.1 (C(10)H3), 22.7
(C(11)H3) 26.5 (C(9)H2), 27.4 (C(6)H2), 31.0 (C(5)H), 66.1
(C(12)H2), 76.5 (C(1)H), 81.8 (C(4)), 123.8 (2 × CH, Ar), 127.0
(dC(7)H), 129.3 (2 × CH, Ar), 130.8 (CH, Ar), 131.6 (dC(8)),
144.9 (C, Ar).
(1S,4S,5S)-4,8-Dimethyl-4-phenylsulfenylmethyl-2,3-
dioxabicyclo[3.3.1]non-7-ene (16a): white waxy solid; mp
1
61-63 °C; H NMR (400 MHz, CDCl3) δ 1.20 (d, J ) 0.7 Hz,
3H, Me(11)), 1.55 (ddd, J ) 13.1, 3.0, 2.0 Hz, 1H, H(9)ax), 1.80
(ddd, J ) 2.7, 1.6, 1.6 Hz,, 3H, Me(10)), 2.04 (m, 1H, H(5)eq),
2.21 (dddq, J ) 19.0, 5.4, 2.7, 2.7 Hz, 1H, H(6)ax), 2.30 (dddd,
J ) 13.1, 3.6, 3.6, 1.6 Hz, 1H, H(9)eq), 2.33 (dddq, J ) 19.0,
6.4, 1.6, 1.6 Hz, 1H, H(6)eq), 3.34 (d, J ) 12.7 Hz, 1H, H(12)),
3.79 (d, J ) 12.7, 0.7 Hz, 1H, H′(12)), 4.10 (br dd, J ) 3.6, 2.0
Hz, 1H, H(1)eq), 5.76 (m, 1H, H(7)), 7.19 (m, 1H, Ar), 7.29 (m,
2H, Ar), 7.42 (m, 2H, Ar); 13C NMR (100 MHz, CDCl3) δ 21.2
(Me(10)), 22.7 (Me(11)), 26.4 (C(9)H2), 27.6 (C(6)H2), 28.5
(C(5)H), 40.7 (C(12)H2), 76.2 (C(1)H), 83.4 (C(4)), 126.2 (CH,
Ar), 126.8 (C(7)H), 128.9 (2 × CH, Ar), 129.7 (2 × CH, Ar),
131.3 (C(8)), 137.0 (C, Ar); HRMS calcd for C16H21O2S (MH+)
277.1262, found 277.1253,.
(1S,4S,5S)-4,8-Dimethyl-4-phenylsulfinylmethyl-2,3-
dioxabicyclo[3.3.1]non-7-enes (18a,b), (1S,4R,5S)-4,8-Di-
methyl-4-phenylsulfinylmethyl-2,3-dioxabicyclo[3.3.1]-
non-7-enes (18c,d), (1S,4S,5S)-4-Methyl-8-methylene-4-
phenylsulfinylmethyl-2,3-dioxabicyclo[3.3.1]nonanes
(19a,b), and (1S,4R,5S)-4-Methyl-8-methylene-4-phenyl-
sulfinylmethyl-2,3-dioxabicyclo[3.3.1]nonanes (19c,d). To
a solution of sulfides 16a,b and 17a,b (2.95 g; 10.67 mmol) in
ethyl acetate (200 mL) at -50 °C was added a solution of
m-CPBA (ca. 1.06 equiv; 3.25 g of ca. 60% purity, ca. 11.3
mmol) in ethyl acetate (120 mL) over 20 min. The mixture was
stirred at -50 to -30 °C for 1.5 h and then poured into 5%
Na2CO3 (60 mL), extracted with ethyl acetate (4 × 50 mL),
dried (Na2SO4), and evaporated. Flash chromatography (40%
ethyl acetate/hexane) afforded a mixture of eight sulfoxides
18a-d and 19a-d (2.94 g; 94% yield) as a yellowish viscous
oil, which was used directly in the next step without separation
of the isomers. A sample of the mixture of the eight sulfoxides
was separated by MPLC (gradient: 20%-50% ethyl acetate/
hexane) for analytical purposes to give three fractions. (i) The
least polar fraction was a colorless solid containing 18c and
19c (18c:19c ca. 85: 15): mp. 136-139 °C; Rf ) 0.49 (50%
ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3) δ 1.63 (ddd,
J ) 13.4, 3.1, 1.9 Hz), 1.70 (ddd, J ) 13.1, 3.0, 2.2 Hz), total
1H; 1.79 (br dd, J ) 3.8, 2.0, ca. 2.55 H); 1.81 (br d, J ) 0.55
Hz, ca. 0.45H), 1.82 (br d, J ) 0.65 Hz, 2.55H), total 3H; 2.08
(m, ca. 0.15H); 2.16 (m), 2.19 (m), total 1H; 2.27-2.42 (m, total
ca. 2.3H); 2.60 (dddd, J ) 13.2, 3.5, 3.5, 1.2 Hz, ca. 0.85H);
2.67 (m, ca. 0.15H); 2.77 (dd, J ) 13.5, 0.65 Hz), 2.86 (dd, J )
13.4, 0.55 Hz), total 1H; 2.88 (d, J ) 13.5 Hz), 2.97 (d, J )
13.4 Hz), total 1H; 4.17 (br dd, J ) 3.5, 1.9 Hz, 0.85H), 4.44
(br dd, J ) 3.5, 1.5 Hz, 0.15H), total 1H; 4.93 (br s, ca. 0.15H),
4.94 (br s, ca. 0.15H), total ca. 0.3H; 5.73 (m, ca. 0.85H); 7.47-
7.56 (m, 3H), 7.62-7.68 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 21.2 (CH3), 23.2 (CH3), 26.3 (CH2), 27.2 (CH2), 27.9 (CH2),
(1S,4S,5S)-4,8-Dimethyl-2,3-dioxabicyclo[3.3.1]non-7-
ene-4-carbaldehyde (21), (1S,4S,5S)-4-Methyl-8-methyl-
ene-2,3-dioxabicyclo[3.3.1]nonane-4-carbaldehyde (22),
(1S,4R,5S)-4,8-Dimethyl-2,3-dioxabicyclo[3.3.1]non-7-ene-
4-carbaldehyde (23), and (1S,4R,5S)-4-Methyl-8-methyl-
ene-2,3-dioxabicyclo[3.3.1]nonane-4-carbaldehyde (24).
A solution of 18a-d and 19a-d (1.25 g; 4.3 mmol) and 2,6-
lutidine (10 equiv; 5 mL; 43 mmol) in dry dichloromethane
(135 mL) under argon was cooled to -40 °C, and trifluoroacetic
anhydride (5 equiv; 3 mL; 21.4 mmol) was added over 15 min.
The yellow reaction mixture was stirred for 1 h at -40 to -30
°C and 420 mL of cold pentane added. The solution was
washed with 50 mL of saturated NaHCO3, and the solvent was
removed on a rotary evaporator at 0.3-0.5 bar and 40 °C to
give a yellow oil. The oil was dissolved in methanol/dichlo-
romethane (1:10 mixture; 135 mL) and cooled to -10 °C.
Morpholine (1 equiv; 0.4 mL; 4.2 mmol) was added and the
3626 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
reaction mixture stirred at -10 to 0 °C for 2 h. Pentane (350
mL) was added, and the solution was washed with 0.1 M HCl
(100 mL) and saturated NaHCO3 (50 mL). Upon drying (Na2-
SO4), the solvent was removed on a rotary evaporator at 0.3
bar and 40 °C to give an oil consisting of a mixture of
unsaturated aldehydes 21-24. The mixture was fractionated
by three flash chromatograhies (gradient: 0% to 6% ethyl
acetate/hexane) to afford one fraction containing unsaturated
aldehydes 21 and 22 as a colorless oil (335 mg; 43% yield; 21:
22 ca. 83:17 as determined from the integration of the H(1)
and Me(11) peaks) and a fraction containing a mixture of
unsaturated aldehydes 23 and 24 as a white solid (239 mg;
31% yield; 23:24 ca. 83:17 as estimated from the integration
of the Me(11) signals).
Characterization. Mixture of aldehydes 21 and 22 (21:22
ca.83:17): colorless oil; Rf ) 0.30 (6% ethyl acetate/hexane);
1H NMR (400 MHz, CDCl3) δ 1.07 (s, 21, Me(11)), 1.17 (s, 22,
Me(11)), total 3H; 1.59 (ddd, J ) 13.4, 3.0, 2.1, 22, H(9)ax),
1.65 (ddd, J ) 13.1, 3.0, 2.1 Hz, 21, H(9)ax), total 1H; 1.71-
1.82 (m, ca. 0.4H, 22, H(6)eq +H(5)eq); 1.83 (dd, J ) 4.2, 2.2,
ca. 2.5H, 21, Me(10)); 2.05 (dddd, J ) 13.1, 3.5, 3.5, 1.2 Hz,
21, H(9)eq), 2.15 (ddd, J ) 13.4, 6.7, 3.3 Hz, 22, H(9)eq), total
1H; 2.23 (m, ca. 0.8H, 21, H(5)eq), 2.25 (m, ca. 0.8H, 21, H(6)-
eq), 2.30 (dddq, J ) 19.0, 5.3, 2.6, 2.2 Hz, ca. 0.8H, 21, H(6)-
ax), 2.41 (br dd, J ) 14.9, 6.7 Hz, ca.0.2H, 22, H(7)eq), 3.01
(ddddd, J ) 14.9, 14.9, 7.4, 2.5, 2.5 Hz, ca. 0.2H, 22, H(7)ax),
4.14 (m, 0.83H, 21, H(1)eq), 4.38 (m, 0.17H, 22, H(1)eq), 4.96
(dd, J ) 2.5, 2.5 Hz, ca.0.2H, 22, H(10)), 4.99 (m, J ) 2.5, 2.5,
0.5 Hz, ca. 0.2H, 22, H(10′), 5.81, (m, ca. 0.8H, 21, H(7), 9.91
(s, 1H, 21 + 22, H(12), aldehyde); 13C NMR (100 MHz, CDCl3)
δ 18.1 (22, C(11)H3), 18,2 (21, C(11)H3), 21.3 (21, C(10)H3),
25.9 (22, C(9)H2), 26.3 (21, C(9)H2), 27.3 (21, C(5)H), 28.0 (21,
C(6)H2), 28.1 (22, C(5)H), 30.3 (22, C(6)H2), 31.6 (22, C(7)H2),
76.7 (21, C(1)H), 80.7 (22, C(1)H), 88.4 (21, C(4)), 89.0 (22,
C(4)), 114.2 (22,)C(10)H2), 127.3 (21, dC(7)H), 130.9 (21,
dC(8)), 145.6 (22, dC(8)), 205.5 (21, C(12)HdO), 205.6 (22,
C(12)H, aldehyde); IR (neat) v 2931 (m), 2874 (m), 2850 (m),
2836 (m), 2803 (m), 1736 (s), 1450 (m), 1440 (m), 1370 (m),
1108 (m) 1009 (m) cm-1; MS (m/z) 183.10 (MH+, 2), 155.16 (21),
139.09 (100), 127.14 (43); HRMS calced for C10H15O3 [MH+]
183.1021, found 183.1017.
filtrate was dried (Na2SO4 + NaHCO3), the drying material
filtered off, and the solvent removed under reduced pressure.
Flash chromatography (17% ethyl acetate/hexane) afforded an
inseparable mixture of unsaturated acetals 25 and 26 (92 mg;
94%; 25:26 ca. 91:9) as a white solid: mp 67-69 °C; Rf ) 0.32
(17% ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3) δ 1.04
(s, ca.2.75H, 25, Me(11)), 1.14 (s, ca. 0.25H, 26, Me(11)), total
3H; 1.55 (ddd, J ) 12.5, 3.0, 2.0 Hz, 26, H(9)ax), 1.62 (ddd, J
) 13.1, 3.0, 2.1 Hz, 25, H(9)ax), total 1H; 1.80 (ddd, J ) 2.6,
1.5, 1.5 Hz, ca. 2.7H, 25, Me(10)), 2.01 (m, 1H, 25 + 26, H(5)-
eq), 2.18 (dddq, J )19.0, 5.5, 2.6, 2.6 Hz, ca. 0.9H, 25, H(6)-
eq), 2.31 (dddq J ) 19.0, 4.8, 1.6, 1.6, ca. 0.9H, 25, H(6)ax)
2.32-2.38 (m, ca. 0.9H, 25, H(9)eq), 2.39-2.44 (m, 0.1H, 26,
H(7)), 3.05 (m, 0.1H, 26, H(7)); 3.47 (s, 0.3H, 26, OCH3), 3.48
(s, 2.7H, 25, OCH3), 3.66 (s, 0.3H, 26, OCH3), 3.69 (s, 2.7H,
25, OCH3) total 6H; 4.14 (m, ca. 0.9 H, 25, H(1)eq), 4.40 (m,
0.1H, 26, H(1)eq), total 1H; 4.91 (m, ca.0.1H, 26, H(10)), 4.93
(m, ca.0.1H, 26, H(10)), 5.00 (s, ca.0.9H, 25, H(12)), 5.77 (m,
ca. 0.9H, 25, H(7)); 13C NMR (100 MHz, CDCl3) δ 15.2 (26,
C(11)H3), 15.5 (25, C(11)H3), 21.1 (25, C(10)H3), 26.6 (25, C(9)-
H2), 27.4 (26, C(9)H2), 27.5 (25, C(5)H), 27.7 (25, C(6)H2), 28.3
(26, C(5)H), 30.1 (26, C(6)H2), 30.3 (26, C(7)H2), 56.5 (25 +
26, 2 × OCH3), 59.1 (26, OCH3) 59.3 (25, OCH3), 76.3 (25,
C(1)H), 80.4 (26, C(1)H), 85.2 (25, C(4)), 85.9 (26, C(4)), 104.3
(25 + 26, dC(12)H), 112.9 (26, C(10)H2) 127.1 (25, dC(7)H),
131.1 (25, dC(8)), 146.9 (26, dC(8)). Anal. Calcd for C12-
H20O4: C, 63.14; H, 8.83. Found: C, 63.19; H, 8.95.
(1S,4S,5S,8R)-4-Dimethoxymethyl-4,8-dimethyl-
2,3-dioxabicyclo[3.3.1]nonane (27). A mixture of unsatur-
ated acetals 25 and 26 (118 mg, 0.517 mmol; 25:26 ca. 10:1)
was dissolved in ethyl acetate (20 mL). Platinum(IV) oxide (0.1
equiv; 12 mg) was added and the reaction mixture cooled to
-20 °C. A hydrogen atmosphere was introduced by flushing
the system three times, and a hydrogen pressure of 1 atm was
maintained throughout the reaction. The temperature was
allowed to rise, and the reaction mixture was stirred at -8 to
-12 °C until hydrogen consumption ceased (1 h). The reaction
mixture was then cooled to -78 °C, the hydrogen was removed
in vacuo, and the system was flushed several times with air.
The reaction mixture was filtered through a plug of cotton and
concentrated at 0.2 bar and 40 °C. The resulting oil was
purified by flash chromatography (7.5% ethyl acetate/hexane)
to give acetal 27 as a colorless oil (96 mg; 81%): Rf ) 0.29
Mixture of aldehydes 23 and 24 (23:24 ca.83:17): white
1
solid; mp 49-50 °C; Rf ) 0.14 (6% ethyl acetate/hexane); H
(7.5% ethyl acetate/hexane); [R]20 ) 198.0 (c 0.210, CHCl3);
NMR (400 MHz, CDCl3) δ 1.44 (s, 0.51H, 24, Me(11)) 1.56 (s,
2.49H, 23, Me(11)), total 3H; 1.65 (m, 24, H(9)ax), 1.67 (br ddd,
J ) 13.1, 2.9, 2.1 Hz, 23, H(9)ax) total 1H; 1.71-1.83 (m, ca.
0.2H, 24, H(6)), 1.84 (dd, J ) 4.2, 2.2, ca. 2.8 H, 23, Me(10);
1.87-1.95 (m, ca.0.4H, 24, H(6) + H(5)eq), 2.08 (m, J ) 1.6,
1.4 Hz, ca.0.8H, 23, H(6)eq), 2.10 (m, ca.0.8H, 23, H(5)eq), 2.26
(dddq, J ) 19.3, 8.3, 2.9, 2.9 Hz, ca.0.8H, 23, H(6)ax); 2.32 (m,
ca. 0.2H, 24, H(9)eq), 2.47 (dddd, J ) 13.1, 3.6, 3.6, 1.6 Hz,
ca.0.8H, 23, H(9)eq), total 1H; 2.53 (ddddd, J ) 13.3, 4.0, 3.4,
3.4, 0.6 Hz, ca.0.2H, 24, H(7)eq), 2.73 (br m, ca.0.2H, 24, H(7)-
ax), 4.19 (m, 0.83H, 23, H(1)eq), 4.61 (m, J ) 4.5, 0.5 Hz, 0.17H,
24, H(1)eq), total 1H; 4.92 (m, ca.0.4H, 24, 2 × H(10), 5.74 (m,
ca.0.8H, 23, H(7), 9.46 (s, 1H, 23 + 24, H(12), aldehyde); 13C
NMR (100 MHz, CDCl3) δ 18.6 (23, C(10)H3), 21.3 (23, C(11)-
H3), 25.7 (23, C(9)H2), 28.5 (23, C(6)H2), 29.8 (23, C(5)H), 77.0
(23, C(1)H), 88.1 (23, C(4)), 112.7 (24, dC(10)H2), 126.8 (23,
dC(7)H), 130.0 (23, dC(8)), 202.1 (23, C(12)H, aldehyde); IR
(neat) ν 2962 (w), 2922 (m), 2833 (w), 2815 (w), 1734 (s), 1446
(s), 1377 (m), 1363 (w), 1101 (m) 1088 (m) cm-1. Anal. Calcd
for C10H14O3: C, 65.92; H, 7.74. Found: C, 65.63; H, 7.98.
D
1H NMR (400 MHz, CDCl3) δ 1.09 (s, 3H, Me(11)), 1.10 (d, J
) 6.8 Hz, 3H, Me(10)), 1.47 (ddd, J ) 13.2, 3.0, 1.6 Hz, 1H,
H(9)ax), 1.55-1.67 (m, 2H, H(6)eq + H(7)), 1.76-1.87 (m, 1H,
H(8)ax), 1.90 (ddd, J ) 6.3, 3.1, 3.1 Hz, 1H, H(5)eq), 1.95-
2.05 (m, 2H, H(6)ax + H(7′)), 2.32 (dddd, J ) 13.1, 6.6, 4.2,
4.2 Hz, 1H, H(9)eq), 3.47 (s, 3H, OMe), 3.67 (s, 3H, OMe), 3.88
(m, 1H, H(1)eq), 4.97 (s, 1H, H(12)); 13C NMR (100 MHz,
CDCl3) δ 14.8 (C(10)H3), 18.5 (C(11)H3), 27.2 (CH2), 27.9
(C(8)H), 29.5 (CH2), 29.7 (CH2), 35.6 (C(5)H), 56.6 (OCH3), 59.2
(OCH3), 79.3 (C(1)H), 85.1 (C(4)), 104.4 (C(12)H, acetal); IR
(neat) ν 3000 (w), 2874 (m), 2955 (s), 2950 (m), 2844 (w), 2827
(w), 1468 (w), 1455 (m), 1379 (w), 1368 (w), 1191 (m), 1187
(m), 1110 (m), 1082 (m), 1074 (s) cm-1; MS (m/z) 231.15 (MH+,
0.3), 199.12 (M - CH3OH, 28) 139.10 (19), 95.08 (27), 83.94
(48), 75.04 (CH+(OCH3)2, 100); HRMS calcd for C12H22O4 [MH+]
231.1749, found 231.1820.
Synthesis of (1S,4S,5S,8R)-4,8-Dimethyl-2,3-dioxabi-
cyclo[3.3.1]nonane-4-carbaldehyde (7) by Deacetaliza-
tion of 27. To a solution of acetal 27 (48 mg; 0.208 mmol) in
dichloromethane (5 mL) were added toluenesulfonic acid (2.5
equiv; 100 mg; 0.53 mmol) and glyoxalic acid monohydrate (25
equiv; 0.480 g; 5.2 mmol). The resulting heterogeneous mixture
was stirred for 18 h. The solution was decanted into another
flask and the solid residue washed with 3 × 2 mL dichlo-
romethane. The resulting solution was filtered through a short
plug of silica gel with 40 mL of dichloromethane. The solvent
was removed under reduced pressure (40 °C, 0.2 bar) to afford
the desired aldehyde 7 as a white solid (35.5 mg; 93%): mp
(1S,4S,5S)-4-Dimethoxymethyl-4,8-dimethyl-2,3-
dioxabicyclo[3.3.1]non-7-ene (25) and (1S,4S,5S)-4-Di-
methoxymethyl-4-methyl-8-methylene-2,3-dioxabi-
cyclo[3.3.1]nonane (26). A mixture of unsaturated aldehydes
21 and 22 (78 mg; 0.428 mmol, 21:22 ca. 92:8) was dissolved
in trimethylorthoformate (2.0 mL), Amberlyst-15 (200 mg) was
added, and the resulting mixture was stirred for 24 h at room
temperature. The reaction mixture was filtered through Celite
and the Celite washed with 30 mL of dichloromethane. The
J. Org. Chem, Vol. 70, No. 9, 2005 3627

Szpilman et al.
77-78 °C; Rf ) 0.46 (10% ethyl acetate/hexane); [R]20D ) 284.1
(c 0.92, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.11 (s, 3H, Me-
(11)), 1.12 (d, J ) 6.6 Hz, 3H, Me(10)), 1.51 (ddd, J ) 13.1,
3.0, 1.8 Hz, 1H, H(9)ax), 1.66-1.76 (m, 2H, H(6) + H(7)), 1.87
(m, 1H, H(8)ax), 1.91-2.00 (m, 2H, H(6′) + H(7′)), 2.04 (dddd,
J ) 13.1, 3.8, 3.8, 2.4 Hz, 1H, H(9)eq), 2.11 (dddd, J ≈ 3.8,
3.0, 3.0, 3.0 Hz, 1H, H(5)eq), 3.87 (m, 1H, H(1)eq), 9.89 (s, 1H,
H(12)); 13C NMR (100 MHz, CDCl3) δ 17.8 (C(10)H3), 18.5
(C(11)H3), 25.7 (CH2), 27.9 (C(5)H), 29.5 (CH2), 31.2 (CH2), 35.1
(C(8)H), 79.7 (C(1)H), 88.3 (C(4)), 206.1 (C(12)HdO); IR (KBr)
ν 2962 (s), 2949 (s), 2927 (s), 2872 (m), 2808 (m), 1740 (s), 1455
(m), 1382 (m), 1362 (w), 1349 (w), 1333 (w), 1126 (m), 1103
(m), 1048 (w), 1001 (m) cm-1. Anal. Calcd for C10H16O3: C,
65.19; H, 8.75. Found: C, 65.14; H, 8.85.
Synthesis of (1S,4S,5S,8R)-4,8-Dimethyl-2,3-dioxabi-
cyclo[3.3.1]nonane-4-carbaldehyde (7) by Direct Hydro-
genation of Unsaturated Aldehydes 21 and 22. A mixture
of unsaturated aldehydes 21 and 22 (40 mg, 0.22 mmol; 21:22
ca. 83:17) was dissolved in ethyl acetate (20 mL). Platinum-
(IV) oxide (0.15 equiv; 8 mg) was added and the reaction
mixture cooled to -20 °C. A hydrogen atmosphere was
introduced by flushing the system three times, and a hydrogen
pressure of 1 atm was maintained throughout the reaction.
The temperature was allowed to rise to -8 °C and kept at this
temperature for 1 min until the color of the catalyst had
changed from brown to black. The reaction was then cooled to
-11 °C and stirred in the temperature interval -11 to -12
°C for 50 min by which time hydrogen consumption ceased.
The reaction was then cooled to -78 °C, the hydrogen
atmosphere removed in vacuo, and the system flushed several
times with air. The reaction mixture was filtered through a
plug of cotton, and the solvent removed under reduced pres-
sure (0.2 bar, 40 °C). The resulting oil was purified by flash
chromatography (15% ether/pentane) to give aldehyde 7 as a
white solid (36 mg; 90% yield). Analytical data as above.
unsaturated acetals 28 and 29 (135 mg; 0.591 mmol; 28:29
ca. 83:17) afforded acetal 30 (104 mg; 77% yield) as white
solid: mp 38-40 °C; Rf ) 0.29 (15% ether/hexane); [R]20
)
D
145.5 (c 1.0, CHCl3); 1H NMR (400 MHz, C6D6) δ 1.01 (ddd, J
) 13.0, 3.2, 1.6 Hz, 1H, H(9)ax), 1.16 (d, J ) 6.8 Hz, 3H, Me-
(10)), 1.40 (dddd, J ) 13.9, 13.9, 6.4, 3.4, 1H, H(6)ax), 1.46
(dqdd, J ) 13.6, 6.8, 6.4, 3.0 Hz, 1H, H(8)ax), 1.57 (ddd, J )
13.1, 6.4, 6.4 Hz, 1H, H(7)eq), 1.69 (s, 3H, Me(11)), 1.71 (dddd,
J ) 3.2, 3.2, 3.2, 3.2 Hz, 1H, H(5)eq), 1.94 (m, 1H, H(6)eq),
2.13 (dddd, J ) 13.9, 13.6, 13.3, 6.0 Hz, 1H,H(7)ax), 2.21 (dddd,
J ) 12.3, 4.3, 4.3, 3.3 Hz, 1H, H(9)eq), 3.13 (s, 3H, OMe), 3.31
(s, 3H, OMe), 3.59 (m, 1H, H(1)eq), 4.08 (s, 1H, H(12)); 13C
NMR (100 MHz, C6D6) δ 16.1 (C(11)H3), 19.0 (C(10)H3), 26.9
(C(6)H2), 30.1 (C(9)H2), 30.81 (C(5)H), 30.84 (C(7)H2), 35.9
(C(8)H), 56.5 (OCH3), 58.6 (OCH3), 79.2 (C(1)H), 86.6 (C(4)),
106.7 (C(12)H, acetal); IR (KBr) ν 3006 (w), 2989 (w), 2950
(s), 2962 (s), 2947 (s), 2918 (m), 2870 (m), 2830 (w), 1467 (m),
1446(m), 1385 (w), 1366 (m), 1348 (w), 1326 (w), 1318 (w), 1207
(w), 1188 (w), 1172 (w), 1153 (w), 1126 (m), 1101 (m), 1085
(s), 1049 (w) cm-1; MS (m/z) 230.15 (M+, 1.3), 199.12 (M-CH3-
OH, 28) 149.02 (18), 95.08 (11), 83.95 (85), 75.04 (CH(OCH3)2,
100); HRMS calcd for C12H22O4 [M+] 230.1518, found 230.1530.
(1S,4R,5S,8R)-4,8-Dimethyl-2,3-dioxabicyclo[3.3.1]-
nonane-4-carbaldehyde (31). Aldehyde 31 was prepared by
deacetalization of acetal 30 according to the procedure for
deacetalization of acetal 27 described above. Thus, deacetal-
ization of 62 mg (0.269 mmol) of acetal 30 afforded aldehyde
31 (49 mg; 98% yield) as a colorless oil: Rf ) 0.30 (6% ethyl
acetate/hexane); [R]20D ) 172.1 (c 0.98, CHCl3); 1H NMR (400
MHz, CDCl3) δ 1.10 (d, J ) 6.5 Hz, 3H, Me(10)), 1.46 (s, 3H,
Me(11)), 1.52 (ddd, J ) 13.2, 3.1, 1.5 Hz, 1H, H(9)ax), 1.56-
1.69 (m, 2H), 1.74-1.88 (m, 3H), 1.97 (dddd, J ) 3.4, 3.3, 3.2,
3.0 Hz, 1H, H(5)eq), 2.43 (dddd, J ) 13.0, 4.5, 3.4, 2.4 Hz, 1H,
H(9)eq), 3.84 (m, 1H, H(1)eq), 9.68 (s, 1H, H(12)); 13C NMR
(100 MHz, CDCl3) δ 18.6 (C(11)H3), 19.1 (C(10)H3), 26.7 (CH2),
28.8 (CH2), 29.3 (CH2), 31.8 (C(5)H), 35.5 (C(8)H), 79.4 (C(1)H),
87.8 (C(4)), 202.6 (C(12)HdO); IR (neat) ν 2956 (s), 2928 (s),
2869 (s), 2809 (m), 2708 (m), 1732 (s), 1456 (m), 1376 (m), 1131
(m), 1097 (m), 1042 (m) cm-1; MS (m/z) 169.09 (26), 167.06
(12), 152.99 (57), 137.05 (100), 135.05 (33), 108.95(88); HRMS
calcd for C10H17O3 [MH+] 185.1178, found 185.1185.
Mukaiyama Aldol Addition of Enol Ether 35 to Alde-
hyde 7. Aldehyde 7 (16 mg; 0.087 mmol) and enol ether 35 (3
equiv; 64 mg; 0.26 mmol) were dissolved in dry dichlo-
romethane (0.5 mL) under argon and cooled to -78 °C. A 1.2
M solution of TiCl4 in dichloromethane (3 equiv; 0.2 mL; 0.26
mmol) was added dropwise over 15 min to give a deep red
solution. The reaction mixture was stirred at -78 °C for 4 h
and quenched by addition of 0.5 M K2CO3 (1 mL) and an
additional 2 mL of dichloromethane. After 10 min, the tem-
perature was increased to 0 °C and the reaction mixture was
stirred at this temperature for 1 h. Water (5 mL) was added,
and the mixture was extracted with 33% ethyl acetate/hexane
(2 × 25 mL). The combined extracts were dried (Na2SO4), and
the solvent was removed under reduced pressure. TLC analysis
of the crude residue revealed the presence of three endoper-
oxidic products. To the crude residue was added a 0.2 M
solution of HCl in methanol (3 mL). The reaction mixture was
stirred for 2 h. and then neutralized by addition of NaHCO3
(pH ) 8). The solvent was removed under reduced pressure.
The residue was dried azeotropically with toluene and purified
by flash chromatography (gradient: 10% to 30% ethyl acetate/
hexane) to afford 1-[(1S,2R,5S,6R)-2,6-dimethyl-3,4-dioxabicyclo-
[3.3.1]non-2-yl]-1,4-dihydroxy-4-methyl-3-pentanone (36) as an
oil (17.5 mg; 70% yield): Rf ) 0.18 (30% ethyl acetate/hexane);
1H NMR (400 MHz, CDCl3, major isomer) δ 1.08 (s, 3H, Me-
(11)), 1.09 (d, J ) 6.6 Hz, 3H, Me(10)), 1.41 (s, 3H, Me(16)),
1.42 (s, 3H, Me(16′)), 1.47 (ddd, J ) 13.4, 2.9, 1.7 Hz, 1H, H(9)-
ax), 1.63-1.73 (m, 2H, H(6) + H(7)), 1.84 (m, 1H, H(8)ax),
1.89-2.06 (m, 2H, H(6) + H(7)), 2.11 (dddd, J ) 3.7, 3.7, 3.2,
2.9, 1H, H(5)eq), 2.51 (dddd, J ) 13.4, 6.8, 3.7, 3.7 Hz, 1H,
H(9)eq), 2.56 (dd, J ) 17.8, 10.2 Hz, 1H, H(13)), 2.98 (d, J )
Synthesis of (1S,4R,5S)-4-Dimethoxymethyl-4,8-di-
methyl-2,3-dioxabicyclo[3.3.1]non-7-ene
(28)
and
(1S,4R,5S)-4-Dimethoxymethyl-4-methyl-8-methylene-
2,3-dioxabicyclo[3.3.1]nonane (29). Acetals 28 and 29 were
prepared according to the procedure for the preparation of
acetals 25 and 26 described above. Thus, the acetalization of
210 mg (1.15 mmol) of a mixture of unsaturated aldehydes 23
and 24 (23:24 83:17) afforded an inseparable mixture of acetals
28 and 29 (251 mg; 96% yield; ratio 91:9) as a colorless oil: Rf
) 0.29 (15% ether/hexane); 1H NMR (400 MHz, CDCl3) δ 1.41
(s, 0.3H, Me(11), 29), 1.45 (s, 2.7H, Me(11), 28), total 3H; 1.50
(ddd, J ) 13.2, 3.3, 1.7 Hz, 0.1H, 29), 1.56 (ddd, J ) 13.0, 3.2,
2.1 Hz, 0.9H, H(9)ax 28), total 1H; 1.80 (ddd, J ) 2.6, 1.5, 1.5
Hz, ca. 2.7H, Me(10) 28), 1.79-1.83 (m. 1H, H(5)eq, 28 + 29);
2.01 (m, ca. 0.1H, 29), 2.14 (dddq, J ) 19.0, 5.5, 2.6, 2.6 Hz,
ca. 0.9H, H(6) 28), total 1H; 2.22 (dddq, J ) 19.0, 4.8, 1.7, 1.7
Hz, 1H, H(6) 28 + 29), 2.45 (dddd, J ) 13.0, 3.6, 3.6, 1.5 Hz,
0.9H, H(9)eq 28); 3.44 (s, 2.7H, OCH3, 28), 3.46 (s, 0.3H, 29),
3.48 (s, 2.7H, OCH3, 28), 3.53 (s, 0.3H, 29), total 6H; 4.04 (s,
0.9H, H(12), 28), 4.23 (s, 0.1H, 29), total 1H; 4.09 (m, ca. 0.9
H, H(1) 28), 4.42 (br d, J ) 3.7 Hz, 0.1H, 29), total 1H; 4.93
(m, 0.2H, dCH2 29), 5.74 (m, 0.9H, dC(7)H 28); 13C NMR (100
MHz, CDCl3) δ 15.4 (28, C(11)H3), 15.6 (29, C(11)H3), 21.3 (28,
C(10)H3), 26.7 (29, C(9)H2), 26.9 (28, C(9)H2), 27.4 (28, C(6)-
H2), 29.5 (28, C(5)H), 30.2 (29, CH2), 30.9 (29, CH2), 31.0 (29,
C(5)H), 56.3 (29, OCH3), 56.4 (28, OCH3), 58.8 (28, OCH3) 59.0
(29, OCH3), 76.7 (28, C(1)H), 80.7 (29, C(1)H), 86.0 (28, C(4)),
87.1 (29, C(4)), 106.5 (29, OC(12)HO), 106.6 (28, OC(12)HO),
112.5 (29, dC(10)H2), 126.8 (28, dC(7)H), 131.3 (28, dC(8)),
146.8 (29, dC(8)); IR (neat) ν 2991 (w), 2958 (s), 2934 (s), 2914
(m), 2881 (w), 2835 (m), 1466 (w), 1451 (m), 1382 (w), 1368
(m), 1348 (w), 1324 (w), 1208 (m), 1185 (w), 1170 (w), 1160
(w), 1111 (s), 1082 (s), 1025 (w), 1013 (m), 982 (m) cm-1
.
(1S,4R,5S,8R)-4-Dimethoxymethyl-4,8-dimethyl-
2,3-dioxabicyclo[3.3.1]nonane (30). Acetal 30 was prepared
according to the procedure for the preparation of acetal 27
described above. Thus, the hydrogenation of a mixture of
3628 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
3.3 Hz, 1H, OH), 3.10 (dd, J ) 17.8, 1.6 Hz, 1H, H(13′)), 3.62
(s, 1H, OH), 3.82 (m, 1H, H(1)eq), 4.91 (ddd, J ) 10.2, 3.3, 1.6
Hz; 1H, H(12)); 13C NMR (100 MHz, CDCl3) δ 15.9 (C(11)H3),
18.6 (C(10)H3), 26.5(C(5)H), 26.6 (C(16)H3), 27.03 (C(16′)H3),
27.09 (C(6)H2), 29.2 (C(9)H2), 29.7 (C(7)H2), 35.6 (C(8)H), 36.6
(C(13)H2), 67.0 (C(12)H), 79.4 (C(1)H), 83.4 (C(4)), 217.0
(C(14)dO); MS (m/z) 287.18 (MH+, 12), 269.17 (15), 157.11 (23),
139.11 (100), 113.06 (67), 95.04 (81); HRMS calcd for C15H27O5
[MH+] 287.1858, found 287.1840.
(4 equiv; 0.5 mL; 1.36 mmol) was added dropwise over 15 min
to give a deep red solution. The reaction mixture was stirred
at -78 °C for 4 h, at which time a solution of pyridine (21
equiv; 0.5 mL; 7 mmol) in dichloromethane (1.6 mL) was
added. The resulting solution was heated to -20 °C over 40
min and stirred between -30 and -20 °C for an additional 11
h. The reaction mixture was poured into saturated NaHCO3
(45 mL). The resulting heterogeneous mixture was extracted
with dichloromethane/ether/hexane (1:1:1; 7 × 40 mL). The
combined organic extracts were dried (Na2SO4) and concen-
trated at reduced pressure. Flash chromatography (gradient:
6% to 13% to 30% ethyl acetate/hexane) afforded 19.3 mg (13%
yield) of bis-TMS aldol product (37) as a clear oil and
R,â-unsaturated ketone 39 (81 mg; 70% yield) as a white solid.
Mukaiyama Aldol Addition of Enol Ether 35 to Alde-
hyde 7 and Treatment with Pyridine at 0 °C. Mukaiyama
aldol addition of enol ether 35 (4 equiv; 187 mg; 0.76 mmol)
to aldehyde 7 (35 mg; 0.190 mmol) was carried out as described
above, but after the reaction mixture was stirred for 4 h at
-78 °C, a solution of pyridine (18 equiv; 0.4 mL; 5.6 mmol) in
dichloromethane (1 mL) was added. The resulting mixture was
stirred at -78 °C for 10 min and then at 0 °C for 10 min. The
reaction mixture was poured into a solution of 2.5% NaHCO3
(30 mL) with dichloromethane (2 × 3 mL) to afford an
heterogeneous mixture. Dichloromethane (5 mL), ether (20
mL), and hexane (20 mL) were added. The phases were
separated, and the water phase was extracted with ether (20
mL). The combined organic extracts were filtered through
Celite and dried (MgSO4), and the solvent was removed under
reduced pressure. Three flash chromatographies (first, gradi-
ent 0% to 5% to 10% ethyl acetate/hexane; second, 4% ethyl
acetate/hexane; third, 3% ethyl acetate/hexane) afforded im-
pure 37 (36 mg) and impure 39 (29 mg) and pure aldol addition
product 38 (18.5 mg; 27% yield) as a colorless oil. The yield of
39 was confirmed by conversion into R,â-unsaturated ketone
9 (13.5 mg; 27% yield from aldehyde 7) as described below.
The yield of 37 was determined by conversion into aldol
addition product 36 (8 mg; 15% yield from aldehyde 7) by
reaction with HCl in methanol as described above.
1-[(1S,2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo[3.3.1]-
non-2-yl]-4-methyl-1,4-bis(trimethylsilyloxy)-3-pen-
tanone (37): colorless oil; Rf ) 0.82 (10% ethyl acetate/
hexane); [R]20 ) 23.4 (c 1.0, CHCl3); 1H NMR (250 MHz,
D
CDCl3) δ 0.09 (s, 9H, 3 × CH3Si), 0.16 (s, 9H, 3 × CH3Si), 1.05
(s, 3H, Me(11)), 1.07 (d, J ) 6.6 Hz, 3H, Me(10)), 1.32 (s, 3H,
Me(16)), 1.35 (s, 3H, Me(16′)), 1.44 (ddd, J ) 13.1, 2.8, 1.7 Hz,
1H, H(9)ax), 1.55-2.06 (m, 6H), 2.56 (dddd, J ) 13.0, 6.5, 4.1,
3.7 Hz, 1H, H(9)eq), 2.86 (dd, J ) 18.9, 8.4 Hz, 1H, H(13)),
3.02 (dd, J ) 18.9, 2.1 Hz, 1H, H(13′)), 3.80 (m, 1H, H(1)eq),
5.05 (dd, J ) 8.4, 2.1 Hz; 1H, H(12)); 13C NMR (62.5 MHz,
CDCl3) δ 0.8 (3 × CH3Si), 2.4 (3 × CH3Si), 16.3 (C(11)H3), 18.6
(C(10)H3), 27.1 (C(5)H + C(16)H3), 27.2 (CH2), 27.3 (C(16′)-
H3), 29.2 (CH2), 29.7 (CH2), 35.6 (C(8)H), 38.7 (C(13)H2), 67.4
(C(12)H), 78.9 (C(1)H), 80.1 (C(15)), 84.2 (C(4)), 214.3
(C(14)dO); IR (neat) ν 2945 (s), 2930 (s), 2866 (m), 1721 (s),
1456 (m), 1375 (m), 1254 (s) 1108 (s), 1045 (s); MS (m/z) 431.26
(MH+, 5), 341.22 (21), 325.19 (33), 185.10 (19), 156.97(15),
139.05 (22), 131.09 (100), 95.07 (13); HRMS calcd for C21H43O5-
Si2 [MH+] 431.2649, found 431.2641.
Mukaiyama Aldol Addition of Enol Ether 35 to Alde-
hyde 7 and Treatment with Pyridine at 21 °C. Mukaiyama
aldol addition of enol ether 35 (4 equiv; 171 mg; 0.695 mmol)
to aldehyde 7 (32 mg; 0.174 mmol) was carried out as described
above, but after the addition of pyridine (32 equiv; 0.4 mL;
5.6 mmol) the reaction was allow to warm to room temperature
over 1 h. The reaction mixture was stirred at room tempera-
ture for 1 h and then poured into a 2.5% solution of NaHCO3
(30 mL). The resulting heterogeneous mixture was extracted
with dichloromethane/ether/hexane (1:1:1; 4 × 25 mL). The
combined organic extracts were dried (MgSO4), filtered through
Celite, and concentrated at reduced pressure to afford an oil
(24.7 mg) containing R,â-unsaturated ketone 39 corresponding
to 20% yield and aldol addition product 38 corresponding to
1-[(1S,2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo[3.3.1]-
non-2-yl]-1-hydroxy-4-trimethylsilyloxy-4-methyl-3-pen-
tanone (38): colorless oil; Rf ) 0.15 (10% ethyl acetate/
1
hexane); H NMR (400 MHz, CDCl3, major isomer) δ 0.16 (s,
9H, 3 × CH3Si), 1.05 (s, 3H, Me(11)), 1.08 (d, J ) 6.8 Hz, 3H,
Me(10)), 1.35 (s, 3H, Me(16)), 1.36 (s, 3H, Me(16′)), 1.44 (ddd,
J ) 13.3, 2.9, 1.7 Hz, 1H, H(9)ax), 1.67 (m, 2H, H(6) + H(7)),
1.82 (m, 1H, H(8)ax), 1.89-2.06 (m, 2H, H(6′) + H(7′)), 2.11
(m, 1H, H(5)eq), 2.56 (dddd, J ) 13.3, 6.6, 4.1, 3.9 Hz, 1H,
H(9)eq), 2.69 (dd, J ) 18.2, 10.5 Hz, 1H, H(13)), 3.08 (d, J )
3.5 Hz, 1H, OH), 3.14 (dd, J ) 18.2, 1.6 Hz, 1H, H(13′)), 3.80
(m, 1H, H(1)eq), 4.84 (ddd, J ) 10.4, 3.5, 1.6 Hz, 1H, H(12));
13C NMR (100 MHz, CDCl3) δ 2.3 (3 × CH3Si), 15.9 (C(11)H3),
18.6 (C(10)H3), 27.0 (C(5)H), 27.1 (C(6)H2), 27.2 (C(16)H3), 27.3
(C(16′)H3), 29.3 (C(9)H2), 29.7 (C(7)H2), 35.8 (C(8)H), 37.2
(C(13)H2), 66.9 (C(12)H), 79.3 (C(1)H), 80.3 (C(15)), 83.5 (C(4)),
217.7 (C(14)dO, ketone); MS (m/z) 359.22 (MH+, 8), 341.22
(21), 325.19 (20), 156.97(15), 139.05 (22), 131.09 (100), 95.07
(13); HRMS calcd for C18H34O5Si [MH+] 359.2254, found
359.2230.
1
22% yield as determined from the H NMR spectra.
Mukaiyama Aldol Addition of Enol Ether 35 to Alde-
hyde 7 and Treatment with Pyridine at -40 to 0 °C.
Mukaiyama aldol addition of enol ether 35 (4 equiv; 238 mg;
0.966 mmol) to aldehyde 7 (44.5 mg; 0.242 mmol) was carried
out as described above, but after the addition of pyridine (23
equiv; 0.4 mL; 5.6 mmol) the reaction was stirred at -78 °C
for 1.5 h (no reaction observed by TLC), at -40 to -20 °C for
2 h. (no reaction observed by TLC), at -20 to -10 °C for 2.5
h, and at 0 °C for 2 h and kept at this temperature for 1 h.
The reaction mixture was poured into saturated NaHCO3 (30
mL). The resulting heterogeneous mixture was extracted with
dichloromethane/ether/hexane (1:1:1; 8 × 25 mL) and dichlo-
romethane (8 × 15 mL). The combined organic extracts were
dried (Na2SO4), and the solvent was removed under reduced
pressure. Flash chromatography (gradient 6% to 30% ethyl
acetate/hexane) afforded R,â-unsaturated ketone 39 (16 mg;
20% yield) as a white solid.
(E)-1-[(1S,2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo[3.3.1]-
non-2-yl]-4-methyl-4-trimethylsilyloxy-1-penten-3-one (39):
white solid; mp 45-47 °C; Rf ) 0.46 (10% ethyl acetate/
hexane); [R]20 )114.3 (c 1.09, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 0.12 (s, 9H, 3 × CH3Si), 1.12 (d, J ) 6.7 Hz, 3H,
Me(10)), 1.23 (s, 3H, Me(11)), 1.37 (s, 3H, Me(16)), 1.38 (s, 3H,
Me(16′)), 1.48 (ddd, J ) 12.8, 3.3, 1.9 Hz, 1H, H(9)ax), 1.62-
1.73 (m, 2H, H(6) + H(7)), 1.76 (dddd, J ) 2.9, 2.9, 2.5, 2.5
Hz, 1H, H(5)eq), 1.82 (m, 1H, H(8)ax), 1.98-2.08 (m, 2H, H(6′)
+ H(7′)), 2.19 (dddd, J ) 12.8, 5.9, 3.8 3.2 Hz, 1H, H(9)eq),
3.79 (m, 1H, H(1)eq), 7.02 and 7.05 (AB quartet, J ) 16.0 Hz,
2H, H(12) + H(13)); 13C NMR (100 MHz, CDCl3) δ 2.3 (3 ×
CH3Si), 18.6 (C(10)H3), 23.5 (C(11)H3), 26.3 (CH2), 26.9 (C(16)-
H3), 27.1 (C(16′)H3), 29.4 (CH2), 30.5 (CH2), 32.0 (C(5)H), 35.4
(C(8)H), 79.1 (C(15)), 79.3 (C(1)H), 83.8 (C(4)), 123.4
(dC(13)H), 150.7 (dC(12)H), 202.9 (C(14)dO); IR (KBr) ν 2995
(w), 2974 (w), 2974 (m), 2955 (s), 2894 (m), 2870 (m), 1693 (s),
1627 (s), 1450 (m), 1374 (m), 1252 (s) 1044 (s) cm-1; MS (m/z)
One-Pot Procedure for Mukaiyama Aldol Addition of
Enol Ether 35 to Aldehyde 7 and Subsequent Dehydra-
tion in Situ with Pyridine at -20 °C. Aldehyde 7 (63 mg;
0.34 mmol) and enol ether 35 (5 equiv; 420 mg; 1.7 mmol) were
dissolved in dry dichloromethane (1.5 mL) under argon and
cooled to -78 °C. A 2.7 M solution of TiCl4 in dichloromethane
J. Org. Chem, Vol. 70, No. 9, 2005 3629

Szpilman et al.
341.22 (MH+, 36), 325.19 (33), 185.10 (19), 131.09 (100); HRMS
calcd for C18H33O4Si [MH+] 341.2148, found 341.2159.
were dried (Na2SO4) and concentrated under reduced pressure.
Flash chromatography (50% ethyl acetate/hexane) afforded
recovered R,â-unsaturated ketone 9 (10.5 mg; 44% yield) and
a viscous oil containing a 45:55 mixture of yingzhaosu A (1)
and its C(14)-epimer 40 (13 mg; 99% yield based on recovered
ketone 9) as judged from the H(12) signals in the 1H NMR
spectrum. For analytical data, see below.
(E)-1-[(1S,2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo[3.3.1]-
non-2-yl]-4-hydroxy-4-methyl-1-penten-3-one (9). To a
solution of R,â-unsaturated ketone 39 (30.5 mg; 0.089 mmol)
in acetonitrile at 0 °C was added 1 mL of 2% HF in acetonitrile
and the reaction mixture stirred for 25 min. The solution was
poured into saturated NaHCO3 (30 mL) and extracted with
dichloromethane (6 × 15 mL). The organic extract was dried
(Na2SO4) and concentrated under reduced pressure. Flash
chromatography (20% ethyl acetate/hexane) afforded the title
compound 9 (22.9 mg; 95% yield) as a clear oil: Rf ) 0.25 (20%
ethyl acetate/hexane); 1H NMR (400 MHz, CDCl3) δ 1.11 (d, J
) 6.8 Hz, 3H, Me(10)), 1.24 (s, 3H, Me(11)), 1.40 (s, 3H, Me-
(16)), 1.42 (s, 3H, Me(16′)), 1.50 (ddd, J ) 12.9, 3.2, 2.0 Hz,
1H, H(9)ax), 1.63-1.73 (m, 2H, H(6) + H(7)), 1.75 (m, 1H, H(5)-
eq) 1.83 (m, 1H, H(8)ax), 1.97-2.09 (m, 2H, H(6′) + H(7′)), 2.19
(dddd, J ) 12.9, 6.1, 3.1, 3.1 Hz, 1H, H(9)eq), 3.82 (m, 1H,
H(1)eq), 3.97 (s, 1 OH), 6.83 (d, J ) 15.5 Hz, 1H, H(13)), 7.08
(d, J ) 15.5 Hz, 1H, H(12)); 13C NMR (100 MHz, CDCl3) δ
18.6 (C(10)H3), 23.5 (C(11)H3), 26.20 (C(6)H2), 26.20 (C(16)-
H3), 26.24 (C(16′)H3), 29.4 (C(7)H2), 30.6 (C(9)H2), 31.9 (C(5)H),
35.4 (C(8)H), 75.5 (C(15)), 79.6 (C(1)H), 83.9 (C(4)), 122.0
(dC(13)H), 152.4 (dC(12)H), 202.9 (C(14)dO); IR (neat) ν 3476
(br s), 2953 (s), 2930 (s), 2867 (s), 1691 (s), 1628 (s), 1453 (m),
1368 (m), 1283(s), 1066 (s) cm-1; MS (m/z) 269.18 (MH+, 14),
168.98 (23), 139.10 (47), 110.98 (39), 98.04 (87), 95.09 (100);
HRMS calcd for C15H25O4 [MH+] 269.1753, found 269.1780.
Silylation of r,â-Unsaturated Ketone 9 To Afford r,â-
Unsaturated Ketone 39. To a solution of R,â-unsaturated
ketone 9 (33.5 mg; 0.125 mmol) in dichloromethane (2 mL)
was added 2,6-lutidine (2 equiv; 0.03 mL; 0.25 mmol), and the
solution was cooled to -30 °C. Trimethylsilyl triflate (1.5 equiv;
0.034 mL; 0.187 mmol) was added dropwise over 5 min. The
reaction mixture was allowed to heat up to 0 °C over 30 min
and stirred at this temperature for 3 h. The reaction mixture
was poured into water (20 mL) and extracted with dichlo-
romethane (90 mL + 2 ×10 mL). The combined organic
extracts were dried (Na2SO4), and the solvent was removed
under reduced pressure. Flash chromatography (10% ethyl
acetate/hexane) afforded R,â-unsaturated ketone 39 (41 mg;
97% yield) as a white solid. Analytical data as described above.
Reduction of r,â-Unsaturated Ketone 9 by Sodium
Borohydride/Europium(III) Chloride. R,â-Unsaturated
ketone 9 (29 mg; 0.109 mmol) and europium(III) chloride (1
equiv; 28 mg; 0.109 mmol) were dissolved in dry ethanol (3
mL), and the solution was cooled to 0 °C. NaBH4 (1.5 equiv; 7
mg; 0.18 mmol) was added in three portions and the reaction
mixture stirred for 30 min. HCl (0.1 M, 10 mL) was added,
and stirring was continued for 5 min. The solution was
extracted with dichloromethane (6 × 15 mL). The combined
organic extracts were washed with saturated NaHCO3 (35
mL), dried (Na2SO4), and concentrated under reduced pres-
sure. Flash chromatography (50% ethyl acetate/hexane) af-
forded a viscous oil containing a 45:55 mixture of yingzhaosu
A (1) and its C(14)-epimer 40 (28 mg; 95% combined yield) as
judged from the H(12) signals in the 1H NMR spectrum, Rf )
0.13 (30% ethyl acetate/hexane). For analytical data, see below.
Reduction of r,â-Unsaturated Ketone 9 by DIBAL-H.
Ketone 9 (22.9 mg; 0.0853 mmol) was dissolved in dry THF (2
mL) and the solution cooled to -78 °C. A 0.26 mM solution of
DIBAL-H in THF (1.5 equiv; 0.5 mL; 0.129 mmol) was added.
The reaction mixture was stirred for 1.5 h, and then an
additional portion of 0.26 mM DIBAL-H solution (1.5 equiv;
0.5 mL; 0.129 mmol) was added. After the mixture was stirred
for 2 h, a third portion (1.5 equiv; 0.5 mL; 0.129 mmol) was
added. The reaction mixture was stirred for 1 h at -78 °C and
2.5 h at -50 °C and then quenched by the addition of 0.1 mL
of acetic acid. The resulting mixture was poured into saturated
NaHCO3 (35 mL) resulting in a heterogeneous mixture. The
heterogeneous mixture was extracted with dichloromethane/
hexane/ether (1:1:1; 4 × 35 mL). The combined organic extracts
Reduction of r,â-Unsaturated Ketone 39 by R-BINAL-
H. A solution of R-BINAL-H 41 (2 equiv; 0.2 mmol) in THF
(1.5 mL) was freshly prepared according to Noyori’s proce-
dure41 and cooled to -78 °C. A solution of R,â-unsaturated
ketone 39 (34 mg; 0.10 mmol) in THF (1 mL) was added by
cannula. The reaction mixture was stirred for 3 h at -78 °C
(no reaction could be observed by TLC) and 7 h at -50 to -60
°C. The reaction mixture was poured into cold saturated
NaHCO3 (30 mL) resulting in a heterogeneous mixture. The
heterogeneous mixture was extracted with dichloromethane
(7 × 25 mL). The combined organic extracts were dried (Na2-
SO4) and concentrated under reduced pressure. Flash chro-
matography (50% ethyl acetate/hexane) afforded R,â-unsat-
urated ketone 39 (8.4 mg; 25% yield) and a brownish viscous
oil containing crude TMS-protected yingzhaosu A (1) and
C(14)-epimer 40. The brown oil was treated with a 2% HF/
ethanol (3 mL) for 15 min. The resulting solution was poured
into saturated NaHCO3 (40 mL) and extracted with dichloro-
methane (6 × 25 mL). The combined organic extracts were
dried (Na2SO4) and concentrated under reduced pressure.
Flash chromatography (50% ethyl acetate/hexane) afforded a
colorless oil (10.2 mg; 50% yield based on recovered R,â-
unsaturated ketone 9, 2 steps) containing yingzhaosu A (1)
and its C(14)-epimer 40 in a 55:45 ratio (as judged from the
1
H(12) signals in the H NMR spectrum).
Reduction of r,â-Unsaturated Ketone 39 by S-CBS
Catalyst 42a/Catecholborane. A solution of freshly pre-
pared49 S-CBS catalyst 42a (1.0 equiv; 0.1 mmol) in toluene/
dichloromethane (1:1; 1 mL) was cannulated into a vial fitted
with a sidearm and a flo-stopcock under argon. A solution of
0.264 M catecholborane solution in dichloromethane (1.3 equiv;
0.5 mL; 0.13 mmol) was added via a syringe. The resulting
solution was aged for 30 min and then cooled to -78 °C. Ketone
39 (34 mg; 0.1 mmol) was dissolved in dry dichloromethane
(1.5 mL) and cannulated into the reaction vessel. The vessel
was closed and kept at -20 °C for 16 h. At this time the vessel
was cooled to -78 °C. The reaction was quenched by the
addition of methanol (0.3 mL). A 40% solution of HF in water
(0.1 mL) was added, the cooling bath removed, and the reaction
stirred at room temperature for 1 h. The reaction mixture was
poured into a 0.04 M solution of HCl (45 mL) and extracted
with dichloromethane (6 × 20 mL). The combined organic
extracts were dried (Na2SO4) and the solvent removed under
reduced pressure. Flash chromatography (gradient 20% to 30%
to 50% ethyl acetate/hexane) afforded R,â-unsaturated ketone
9 (13.3 mg; 49% yield) as a colorless oil and a mixture of
yingzhaosu A (1) and its C(14)-epimer 40 (13.2 mg; 97% yield
based on recovered R,â-unsaturated ketone 9; 1:40 ca. 66:33
as judged from the H(12) signals in the 1H NMR spectrum) as
a colorless oil.
Reduction of r,â-Unsaturated Ketone 39 by S-CBS
Catalyst 42a/Borane in Dichloromethane. A solution of
freshly prepared49 S-CBS catalyst 42a (1.0 equiv; 0.1 mmol)
in toluene/dichloromethane (1:1; 1 mL) was cannulated into a
vial fitted with a sidearm and a flo-stopcock under argon. A
solution of 1 M borane-THF solution (1.1 equiv; 0.11 mL; 0.11
mmol) was added via a syringe. The resulting solution was
aged for 30 min and then cooled to -78 °C. Ketone 39 (34 mg;
0.1 mmol) was dissolved in dry dichloromethane (0.5) and
cannulated into the reaction vessel with additional dichloro-
methane (0.5 mL). The vessel closed, and then was heated to
(49) Xavier, L. C.; Mohan, J. J.; Mathre, D. J.; Thompson, A. S.;
Carroll, J. D.; Corley, E. G.; Desmond, R. Organic Syntheses; Wiley:
New York, 1998; Collect. Vol. IX, pp 679-688.
3630 J. Org. Chem., Vol. 70, No. 9, 2005

Total Syntheses of Yingzhaosu A and of Its C(14)-Epimer
-40 °C and kept at this temperature for 16 h. The reaction
was quenched by the addition of methanol (0.5 mL). A 40%
solution of HF in water (0.15 mL) was added and the reaction
heated to room temperature. The reaction mixture was stirred
at room temperature for 1 h and then poured into a 0.04 M
solution of HCl (45 mL). The phases were separated, and the
water phase was extracted with dichloromethane (6 × 20 mL).
The combined organic extracts were dried (Na2SO4) and the
solvent removed under reduced pressure. Flash chromatog-
raphy (gradient 20% to 30% to 50% ethyl acetate/hexane)
afforded R,â-unsaturated ketone 9 (8.1 mg; 30% yield) and a
mixture of yingzhaosu A (1) and its C(14)-epimer 40 (17.1 mg;
90% yield based on recovered R,â-unsaturated ketone 9; 1:40
ca. 16:84 as judged from the H(12) signals in the 1H NMR
spectrum) as a colorless oil that solidified on standing.
resulting solution extracted with 25% ethyl acetate/hexane (7
× 15 mL). The combined extract was dried (Na2SO4) and
concentrated at reduced pressure. Flash chromatography (20%
ethyl acetate/hexane) afforded a colorless oil (39.5 mg; 90%)
containing a mixture of the diastereomeric carbonates 43 and
44 (ca. 45:55). The carbonates were separated by semiprepara-
tive direct-phase HPLC (15% ethyl acetate/hexane).
(5S)-5-{(E)-2-[(2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo-
[3.3.1]non-2-yl]-1-ethenyl}-4,4-dimethyl-1,3-dioxolan-2-
one (43): viscous oil; Rf ) 0.37 (25% ethyl acetate/hexane); tR
1
)20.99 min. (15% ethyl acetate/hexane); H NMR (400 MHz,
CDCl3) δ 1.10 (d, J ) 6.8 Hz, 3H, Me(10)), 1.21 (s, 3H, Me-
(11)), 1.34 (br s, 3H, Me(16)), 1.48 (ddd, J ) 12.8, 3.0, 1.9 Hz,
1H, H(9)ax), 1.52 (br s, 3H, Me(16′)), 1.62-1.74 (m, 3H, H(5)-
eq + H(6) + H(7)), 1.76-1.86 (m, 1H, H(8)ax), 1.97-2.08 (m,
2H, H(6′) + H(7′)), 2.21 (dddd, J ) 12.8, 3.8, 2.8, 2.5 Hz, 1H,
H(9)eq), 3.80 (m, 1H, H(1)eq), 4.77 (dd, J ) 7.0, 1.2 Hz, 1H,
H(14)), 5.82 (dd, J ) 15.8, 7.0 Hz, 1H, H(13)), 6.06 (dd, J )
15.8, 1.2 Hz, 1H, H(12)); 13C NMR (100 MHz, CDCl3) δ 18.6
(C(10)H3), 22.3 (C(16)H3), 24.1 (C(16′)H3), 25.9 (C(11)H3), 26.4
(C(6)H2), 29.4 (C(7)H2), 30.4 (C(9)H2), 32.2 (C(5)H), 35.5
(C(8)H), 79.5 (C(1)H), 83.3 (C(4)), 84.5 (C(15)), 85.4 (C(14)H),
121.5 (dC(13)H), 140.2 (dC(12)H), 153.9 (O2CdO); IR(KBr) ν
2983 (m), 2961 (m), 2951 (m), 2928 (m) 2904 (w), 2867 (m),
2860 (w), 1787 (s), 1450 (m), 1395 (m), 1379 (m) 1368 (w), 1352
(m), 1334 (w), 1236 (s), 1268 (m), 1122(m), 1104 (m), 1093 (m),
1049 (m), 1024 (s), 973 (m); MS (m/z) 297.19 (MH+, 8), 280.98
(50), 268.98 (35), 250.98 (23), 242.99 (28), 230.99 (35), 220.00
(28), 218.98 (44), 201.16 (30), 185.08 (78), 180.98 (43), 168.99
(100), 141.10 (32), 130.99 (89), 126.03 (28), 123.08 (65), 118.99
(94), 113.09 (64), 109.06 (38), 95.09 (88); HRMS calcd for
C15H25O4 [MH+] 297.1702, found 297.1688.
Reduction of r,â-Unsaturated Ketone 39 by R-CBS
Catalyst 42b/Borane in THF. A solution of freshly pre-
pared49 R-CBS catalyst 42b (1.2 equiv; 65.2 mg; 0.240 mmol)
in THF (3 mL) was cannulated into a vial fitted with a sidearm
and a flo-stopcock under argon. A 1 M solution of borane-
THF complex (1.2 equiv; 0.24 mL; 0.24 mmol) was added via
a syringe. The resulting solution was aged for 30 min and then
cooled to -78 °C. Ketone 39 (68 mg; 0.200 mmol) was dissolved
in dry THF (3 mL) and cannulated into the reaction vessel.
The vessel was closed and kept at - 55 °C for 28 h. At this
time the vessel was cooled to -78 °C. The reaction was
quenched by the addition of 1 mL of methanol and poured into
45 mL of phosphate buffer (pH ) 8). The mixture was stirred
for 30 min at room temperature and then extracted with 50%
dichloromethane/hexane (6 × 20 mL). The extracts were
combined, and the solvent was removed under reduced pres-
sure. A 2% solution of HF in ethanol was added to the residue
and the resulting reaction mixture stirred for 15 min. The
solution was poured into saturated NaHCO3 (40 mL) and
extracted with dichloromethane (6 × 25 mL). The organic
combined extracts were dried (Na2SO4) and concentrated under
reduced pressure. Flash chromatography (50% ethyl acetate/
hexane) afforded 38 mg (71% yield) of a viscous oil that
solidified on standing. This mixture contained a 89:11 mixture
of yingzhaosu A (1) and its C(14)-epimer 40 as judged from
(5R)-5-{(E)-2-[(2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo-
[3.3.1]non-2-yl]-1-ethenyl}-4,4-dimethyl-1,3-dioxolan-2-
one (44): white solid; Rf ) 0.40 (25% ethyl acetate/hexane);
tR )19.08 min. (15% ethyl acetate/hexane); 1H NMR (400 MHz,
CDCl3) δ 1.10 (d, J ) 6.8 Hz, 3H, Me(10)), 1.20 (s, 3H, Me-
(11)), 1.36 (br s, 3H, Me(16)), 1.48 (ddd, J ) 12.8, 3.0, 1.9 Hz,
1H, H(9)ax), 1.53 (br s, 3H, Me(16′)), 1.62-1.74 (m, 3H, H(5)-
eq + H(6) + H(7)), 1.76-1.86 (m, 1H, H(8)ax), 1.97-2.08 (m,
2H, H(6′) + H(7′)), 2.21 (dddd, J ) 12.8, 3.7, 2.9, 2.5 Hz, 1H,
H(9)eq), 3.80 (m, 1H, H(1)eq), 4.76 (dd, J ) 6.2, 1.2 Hz, 1H,
H(14)), 5.83 (dd, J ) 15.8, 6.2 Hz, 1H, H(13)), 6.01 (dd, J )
15.8, 1.2 Hz, 1H, H(12)); 13C NMR (100 MHz, CDCl3) δ 18.6
(C(10)H3), 22.5 (C(11)H3), 24.1 (C(16)H3), 25.9 (C(16′)H3), 26.4
(CH2), 29.4 (CH2), 30.3 (CH2), 32.1 (C(5)H), 35.5 (C(8)H), 79.5
(C(1)H), 83.4 (C(4)), 84.5 (C(15)), 85.3 (C(14)H), 121.3
(dC(13)H), 140.5 (dC(12)H), 153.2 (O2CdO); IR(KBr) ν 2991
(w), 2977 (w), 2959 (m), 2924 (m) 2866 (m), 2856 (m), 1791
(s), 1455 (m), 1447 (w), 1391 (w) 1381 (m), 1332 (w), 1279 (m),
1238 (m), 1100(m), 1025 (m); MS (m/z) 297.18 (MH+, 19),
185.08 (88), 141.12 (28), 126.03 (50), 123.08 (59), 113.10 (57),
109.06 (36), 99.08 (32), 95.09 (100) 81.97 (52), 68.82 (50);
HRMS calcd for C15H25O4 [MH+] 297.1702, found 297.1750.
Synthesis of Yingzhaosu A (1) from Carbonate 43. To
a solution of carbonate 43 (14.1 mg; 0.048 mmol) in dry ether
(1 mL) under argon at 0 °C was added 0.5 mL of a 0.095 M
solution of LiBH4 in ether (1 equiv; 0.048 mmol). The reaction
mixture was stirred at 0 °C for 1 h, after which time an
additional portion of 0.5 mL of the 0.095 M LiBH4 solution
was added. The reaction mixture was stirred for an additional
1 h at 0 °C, at which time 0.1 M HCl (10 mL) was added and
the mixture stirred for 10 min. An additional 10 mL of water
was added and the resulting solution extracted with dichloro-
methane (8 × 15 mL). The combined extract was washed with
saturated NaHCO3 (15 mL), dried (Na2SO4), and concentrated
under reduced pressure. Flash chromatography (50% ethyl
acetate/hexane) gave yingzhaosu A (1) as an oil (11.8 mg; 92%)
which solidified on standing.
1
the H(12) signals in the H NMR spectrum. The two diaste-
reoisomers were separated by several recrystallizations from
25% tert-butyl methyl ether/pentane. Recovery of Diphen-
ylpyrrolidin-2-ylmethanol. The two water phases men-
tioned above were combined (total 80 mL) and basified by the
addition of solid sodium hydroxide (ca. 4.0 g, pH ) 13) and
extracted with toluene (3 × 100 mL). The combined organic
extracts were dried (Na2SO4) and the solvent removed under
reduced pressure to afford diphenylpyrrolidin-2-ylmethanol
(47.5 mg) as an oil that was crystallized from hexane.
Reduction of r,â-Unsaturated Ketone 39 by S-CBS
Catalyst 42a/Borane in THF. The reaction was carried out
according to the procedure described above for reduction of
R,â-unsaturated ketone 39 with the R-CBS catalyst 42b.
Reduction of 38 mg (0.112 mmol) of R,â-unsaturated ketone
39 afforded 21.8 mg (72% yield) of a mixture of 40 and
yingzhaosu A (1) as an oil that solidified on standing. This
mixture contained a 11:89 mixture of yingzhaosu A (1) and
its C(14)-epimer 40 as judged from the H(12) signals in the
1H NMR spectrum. The two diastereoisomers were separated
by fractional recrystallization from 10% ethyl acetate/hexane.
(5S)-5-{(E)-2-[(2S,5S,6R)-2,6-Dimethyl-3,4-dioxabicyclo-
[3.3.1]non-2-yl]-1-ethenyl}-4,4-dimethyl-1,3-dioxolan-2-
one (43) and (5R)-5-{(E)-2-[(2S,5S,6R)-2,6-Dimethyl-3,4-
dioxabicyclo[3.3.1]non-2-yl]-1-ethenyl}-4,4-dimethyl-1,3-
dioxolan-2-one (44). A mixture of yingzhaosu A (1) and its
C(14)-epimer 40 (40 mg; 0.148 mmol; 1:40 ca. 45:55) was
dissolved in dry THF (2 mL). N,N′-Carbonyldiimidazole (120
mg; 0.740 mmol; 5 equiv) was added, and the reaction mixture
was heated and stirred at 50-60 °C for 2 h. Water (15 mL)
was added and the reaction mixture stirred at room temper-
ature for 2h. An additional 7 mL of water was added and the
Synthesis of C(14)-Epiyingzhaosu A (40) from Carbon-
ate 44. Reduction of carbonate 44 (17.1 mg; 0.058 mmol) was
J. Org. Chem, Vol. 70, No. 9, 2005 3631

Szpilman et al.
carried out as described above to afford C(14)-epiyingzhaosu
A (40) as an oil (14.7 mg; 94%) that solidified upon standing.
Yingzhaosu A (1): long, colorless cylindrical crystals; mp
94-94.5 °C (tert-butyl methyl ether/pentane; lit.2a mp 95-96
acetate/hexane); [R]20D ) 238.0 (c 0.896 CHCl3) [lit.2a [R]25
)
D
1
234.0 (CHCl3)]; H NMR (400 MHz, CDCl3) δ 1.11 (d, J ) 6.8
Hz, 3H, Me(10)), 1.17 (br s, 3H, Me(16)), 1.21 (s, 3H, Me(16′)),
1.25 (br s, 3H, (Me(11)), 1.45 (ddd, J ) 12.8, 3.1, 1.9 Hz, 1H,
H(9)ax), 1.61-1.72 (m, 3H, H(5)eq + H(6) + H(7)), 1.75-1.85
(m, 1H, H(8)ax), 1.97-2.08 (m, 2H, H(6′) + H(7′)), 2.12 (br s,
1H, OH), 2.30 (dddd, J ) 12.8, 3.5, 2.9, 2.6 Hz, 1H, H(9)eq),
2.32 (br d, J ) 3.4 Hz, 1H, OH), 3.80 (m, 1H, H(1)eq), 3.97
(ddd, J ) 6.7, 3.4, 1.1 Hz, 1H, H(14)), 5.81 (dd, J ) 16.0, 6.7
°C); Rf ) 0.13 (30% ethyl acetate/hexane); [R]20 ) 227.4 (c
D
1.30, CHCl3) [lit.2a [R]25D ) 224.0 (CHCl3)]; 1H NMR (400 MHz,
CDCl3) δ 1.11 (d, J ) 6.8 Hz, 3H, Me(10)), 1.17 (br s, 3H, Me-
(16)), 1.20 (s, 3H, Me(16′)), 1.25 (br s, 3H, Me(11)), 1.45 (ddd,
J ) 12.8, 3.2, 1.9 Hz, 1H, H(9)ax), 1.62-1.73 (m, 3H, H(5)eq
+ H(6) + H(7)), 1.76-1.84 (m, 1H, H(8)ax), 1.98-2.07 (m, 2H,
H(6′) + H(7′)), 2.12 (br s, 1H, OH), 2.23 (br d, J ) 3.8 Hz, 1H,
OH), 2.30 (dddd, J ) 12.8, 3.8, 2.9, 2.6 Hz, 1H, H(9)eq), 3.81
(m, 1H, H(1)eq), 3.97 (ddd, J ) 7.0, 3.8, 1.0 Hz, H(14)), 5.82
(dd, J ) 16.0, 7.0 Hz, 1H, H(13)), 5.97 (dd, J )16.0, J ) 1.0
Hz, 1H, H(12)); 13C NMR (100 MHz, CDCl3) δ 18.6 (C(10)H3),
23.7 (C(16)H3), 24.3 (C(16′)H3), 26.3 (C(11)H3), 26.5 (C(6)H2),
29.5 (C(7)H2), 30.3 (C(9)H2), 32.1 (C(5)H), 35.5 (C(8)H), 73.0
(C(15)), 79.4 (C(1)H + C(14)H), 83.4 (C(4)), 127.8 (dC(13)H),
138.4 (dC(12)H); IR (KBr) ν 3510 (m), 3356 (br s), 2975 (m),
2963 (m) 2935 (m), 2858 (m), 1457 (m), 1453 (w), 1374 (m),
1343 (w), 1169 (w), 1149 (w), 1090 (m) 985 (m) cm-1; MS: (m/
z) 253.18 (MH+ - H2O, 4), 230.99 (15), 219.15 (10), 219.0 (21),
212.14 (12), 195.15 (13), 177.13 (23), 168.99 (23), 141.09 (100),
139. 11 (25), 130.99 (42), 118.99 (48), 111.09 (38), 109.07 (42);
HRMS calcd for C15H25O3 [MH+ - H2O] 253.1804, found
253.1796;
Hz, 1H, H(13)), 5.99 (dd, J ) 16.0, J ) 1.1 Hz, 1H, H(12)); 13
C
NMR (100 MHz, CDCl3) δ 18.6 (C(10)H3), 23.8 (C(16)H3), 24.3
(C(16′)H3), 26.4 (C(11)H3), 26.5 (C(6)H2), 29.5 (C(7)H2), 30.3
(C(9)H2), 32.3 (C(5)H), 35.5 (C(8)H), 73.0 (C(15)), 79.2 (C(14)H),
79.3 (C(1)H), 83.4 (C(4)), 127.8 (dC(13)H), 138.1 (dC(12)H);
IR (KBr) ν 3548 (m), 3347 (br s), 2950 (m), 2941 (m) 2924 (m),
2867 (m), 1461 (m), 1446 (w), 1384 (m), 1367 (w), 1206 (w),
1152 (w), 1104 (w), 1052 (w), 1034 (w), 1001 (w) 973 (w) cm-1
;
-
MS (m/z) 271.19 (MH+, 5), 253.18 (MH+, 41), 235.15 (MH+
H2O, 19), 219.15 (28) 212.14 (48), 195.13 (27), 177.13 (38),
141.09 (84), 139.09 (100), 135.11 (28), 125.11 (44); HRMS calcd
for C15H27O4 [MH+] 271.1909, found 271.1892.
Acknowledgment. We gratefully acknowledge the
financial support by Keren Lewin, the Weizmann In-
stitute of Science. We also thank the Israel Ministry of
Absorption for a fellowship to E.E.K. and Dr. Leonid
Konstantinovski (WIS) for his help and advice in the
NOE NMR studies.
Crystal Data. X-ray crystallographic data was collected on
a Nonius KappaCCD diffractometer at Mo KR (λ ) 0.71073
Å); C15H26O4, colorless, prism, 0.1 × 0.1 × 0.1 mm3, ortho-
rhombic, P2(1)2(1)2(1) (No. 19), a ) 6.0030(12) Å, b ) 9.981-
(2) Å, c ) 26.437(5) Å, from 20 degrees of data, T ) 293(2) K,
V ) 1584.0(5) Å3, Z ) 4, Fw ) 270.36, Dc ) 1.134 Mg‚m-3, µ
) 0.080 mm-1. Structure solved by direct methods and refined
by full-matrix least-squares refinement based on F2 with
SHELXL-97. The final cycle of refinement based on F2 gave
an R-factor R ) 0.042 for data with I > 2σ(I) and R ) 0.046
on all 1166 reflections with a goodness of fit of 1.041. Idealized
hydrogen atoms were placed and refined in the riding mode.
C(14)-Epiyingzhaosu A (40): white solid; mp 88-89 °C
(ethyl acetate/hexane; lit.2a mp 55-56 °C); Rf ) 0.13 (30% ethyl
Supporting Information Available: Copies of NMR
spectra for all new compounds and X-ray structure data for
yingzhaosu A (1). Additional procedures for model experiments
as well as for the synthesis and characterization of compounds
32-34. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO050074Z
3632 J. Org. Chem., Vol. 70, No. 9, 2005