A New Synthetic Approach to Forskolin: Construction of the ABC Ring System from D-Galactose

Article abstract of DOI:10.1021/jo970999h

Intramolecular Diels-Alder reaction of dienyne 14 afforded naphthopyran 18 which underwent 1,4-addition of methyl copper reagent to give the functionalized tricyclic system of forskolin 17. The synthesis of dienyne 14 is based on a stereoselective introduction of carbon side chains at C(1) and C(2) of tri-O-acetyl-D-galactal via C-Ferrier followed by Claisen-Ireland rearrangements.

Full text of DOI:10.1021/jo970999h

J . Org. Chem. 1997, 62, 6985-6990
6985
A New Syn th etic Ap p r oa ch to F or sk olin : Con str u ction of th e ABC
Rin g System fr om D-Ga la ctose
Issam Hanna* and Philippe Wlodyka
Laboratoire de Synthe`se Organique associe´ au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received J une 4, 1997X
Intramolecular Diels-Alder reaction of dienyne 14 afforded naphthopyran 18 which underwent
1,4-addition of methyl copper reagent to give the functionalized tricyclic system of forskolin 17.
The synthesis of dienyne 14 is based on a stereoselective introduction of carbon side chains at C(1)
and C(2) of tri-O-acetyl-D-galactal via C-Ferrier followed by Claisen-Ireland rearrangements.
Sch em e 1
Forskolin, a highly oxygenated labdane diterpene,
exhibits a broad range of physiological activities through
its ability to activate adenylate cyclase. The therapeutic
potential of this natural product combined with its highly
challenging structure has served to stimulate an impor-
tant synthetic activity in a number of laboratories.1,2
In the majority of previous synthetic approaches, an
intramolecular Diels-Alder reaction was selected as the
key step for the construction of an adequately function-
alized AB ring system. In almost all cases, the elabora-
tion of ring C was carried out in the final stages of the
synthesis. In a new synthetic approach, we envisioned
the construction of the ABC ring system of forskolin
starting from the C ring by using a suitably functional-
ized tetrahydropyran subunit. An added feature of our
design lies in the use of the “chiron approach”,3 where
the intermediates could be constructed from optically
active starting materials. The presence of the tetrahy-
dropyran C ring obviously suggested the choice of car-
bohydrate derivatives as chiral building blocks. The
sugar therefore serves as more than a source of chiral-
ity: the ring will form an integral part of the structure
of the target.
tricyclic skeleton of forskolin. The success of such an
approach depends on two crucial requirements: (a) the
regio- and stereocontrolled introduction of substituents
at C(1) and C(2) into the sugar, and (b) the degree to
which trienones such as 1 undergo Diels-Alder cycliza-
tion.
Examination of the structure of 1 reveals the presence
of two vicinal functionalized chains: the dienophile and
the diene moities with (1R) (2R) trans orientation. The
need for carbon branches at C(1) and C(2) with the correct
sense of chirality suggested the use of galactal derivative
2, which is readily available from D-galactose, as the
starting material. We believed that these substituents
could be introduced successively by way of Ferrier and
Claisen-Ireland rearrangements. We describe here the
preparation of trienones 1 by stereoselective addition of
carbon branches at C(1) and C(2) of D-galactal and their
reactivity under Diels-Alder reaction conditions.6
The synthesis (Scheme 2) was initiated by introduction
of the allyl group at C(2) using the carbon-Ferrier
Carbohydrates have been extensively exploited in the
synthesis of carbocyclic natural products.4 In particular,
a whole series of synthetic routes have been described
in which conjugated enal and dienes derived from car-
bohydrates were used in Diels-Alder reactions to obtain
chiral carbocyclic systems as intermediates in the syn-
thesis of natural products.5
Our strategy, outlined in Scheme 1, involves an in-
tramolecular Diels-Alder cyclization of trienone 1 which
should simultaneously assemble the A and B rings of the
X Abstract published in Advance ACS Abstracts, September 15, 1997.
(1) For total syntheses of forskolin see: (a) Ziegler, F. E.; J aynes,
B. H.; Saindane, M. T. J . Am. Chem. Soc. 1987, 109, 8115-8116. (b)
Hashimoto, S.; Sakata, S.; Sonegawa, M.; Ikegami, S. J . Am. Chem.
Soc. 1988, 110, 3670-3672. (c) Corey, E. J .; Da Silva J ardine, P.;
Rohloff, J . C. J . Am. Chem. Soc. 1988, 110, 3672-3673. (c) Delpech,
B.; Calvo, D.; Lett, R. Tetrahedron Lett. 1996, 37, 1015-1018 and
1019-1022. Calvo, D.; Port, M.; Delpech, B.; Lett, R. Tetrahedron Lett.
1996, 37, 1023-1024 .
(2) For an exhaustive review on synthetic routes to forskolin see:
Colombo, M. I.; Zinezuk, J .; Ruveda, E. A. Tetrahedron 1992, 48, 963-
1037. For recent syntheses of the "Ziegler intermediate" see: Leclaire,
M.; Pericaud, F.; Lallemand, J .-Y. J . Chem. Soc., Chem. Commun.
1995, 1333-1334. Anies, C.; Pancrazi, A.; Lallemand, J .-Y.; Prange´,
T. Bull. Soc. Chim. Fr. 1997, 134, 203-222.
(3) (a) Fraser-Reid, B.; Anderson, R. C. Fortsch. Chem. Org. Naturst.
1980, 39. (b) Hanessian, S. Total Synthesis of Natural Products: the
Chiron Approach; Pergamon: Oxford, 1983.
(5) For recent examples see: (a) Lopez, J . C.; Lameignie`re, E.;
Burnouf, C.; Laborde, A. A.; Ghini, A. A.; Olesker, A.; Lukacs, G.
Tetrahedron 1993, 49, 7701-7722. (b) Lopez, J . C.; Gomez, A. M.;
Fraser-Reid, B. J . Chem. Soc., Chem. Commun. 1993, 762-764. (c)
Herscovici, J .; Delatre, S.; Bouma¨ıza, L.; Antonakis, K. J . Org. Chem.
1993, 58, 3928-3937. (d) Giuliano, R. M.; J ordan, A. D., J r.; Gauthier,
A. D.; Hoogsteen, K. J . Org. Chem. 1993, 58, 4979-4988. (e) Tsang,
R. B.; Fraser-Reid, B. J . Org. Chem. 1992, 57, 1065-1067. (f) Bonnert,
B. V.; Davies, M. J .; Howarth, J .; J enkins, P. R.; Lawrence, N. J . J .
Chem. Soc., Perkin Trans. 1 1992, 27-29. (g) Hanessian, S.; Faucher,
A.-M. J . Org. Chem. 1991, 65, 2947-2949.
(4) For a recent review see: Ferrier, R. J .; Middleton, S. Chem. Rev.
1993, 93, 2776-2831. Fraser-Reid, B.; Tsang, R. In Strategy and
Tactics in Organic Synthesis; Lindberg, T., Ed.; Academic Press: New
York, 1989; Vol. 2, pp 123-162.
(6) Portions of this work have been reported in preliminary form:
Hanna, I.; Lallemand, J .-Y.; Wlodyka, P. Tetrahedron Lett. 1994, 35,
6685-6688.
S0022-3263(97)00999-7 CCC: $14.00 © 1997 American Chemical Society

6986 J . Org. Chem., Vol. 62, No. 20, 1997
Hanna and Wlodyka
1
6 as a mixture of methyl epimers (7:1 ratio, H NMR)12
Sch em e 2
in 97% overall yield after flash chromatography.
Chemoselective cleavage of the terminal double bond
in compound 6 was achieved by hydroxylation (cat. OsO4,
NMO)13 followed by diol cleavage with NaIO4 to give 7
in 70% overall yield. After protection of the aldehyde as
a dimethyl acetal (HC(OMe)3, cat. TsOH, CH2Cl2, 95%),
ester 8 was converted into aldehyde 9 by reduction
(excess DIBALH) followed by oxidation of the resulting
alcohol (Dess-Martin’s periodinane14) in 80% yield. At-
tempts to achieve this transformation in 1 one step using
1 equiv of DIBALH led to a mixture of 9 and the primary
alcohol, along with the starting ester.
Elaboration of the diene part at C(2) involved addition
of vinylmagnesium bromide to aldehyde 9 followed by
dehydration of the resulting mixture of stereoisomeric
alcohols. While the Grignard reaction was smoothly
effected in THF at -70°C (89%), the elimination proved
troublesome. Initial attempts using various dehydrating
agents were rather disappointing. The best yields of 10
were obtained with POCl3-Py at 0°C (36%) and with
MsCl-Et3N followed by treatment of the resulting mesy-
late with diisopropylethylamine and DMPU at 185°C15
(40%). Fortunately, we found that treatment of the
corresponding allylic acetate with Pd(PPh3)4 in refluxing
THF16, afforded the conjugated diene 10 as a mixture of
E and Z isomers (2:1 ratio, 1H NMR)) in 80% overall yield.
In order to introduce the dienophile moiety, the formyl
group was first deprotected. Treatment of 10 with
aqueous CF3COOH in THF at room temperature fur-
nished hydroxy aldehyde 11a . The primary alcohol was
then reprotected as its tert-butyldiphenylsilyl ether 11b.
All attempts to hydrolyze selectively the dimethyl acetal
group in the presence of the tert-butyldimethylsilyl ether
under milder conditions (PPTS, PTSA, aqueous oxalic
acid...) led only to the desilylated product, and the formyl
protective group was unaffected.
To test the feasibility of the intramolecular Diels-
Alder (IMDA) reaction, trienone 12 was prepared by
addition of vinylmagnesium chloride to 11b at -78 °C
in THF, giving rise to a mixture of diastereomeric
alcohols (85%). These were readily oxidized with Dess-
Martin’s periodinane reagent14 leading to the Diels-
Alder precursor 12 in 60% overall yield (Scheme 3).
The IMDA reaction of 12 was performed in a sealed
tube at 160 °C as a 6.5 × 10-2 M solution in toluene in
the presence of few crystals of hydroquinone for 20 h. In
contrast to similar carbocyclic systems which gave a
single isomer,18 we found that IMDA reaction of 12
rearrangement.7 Thus, treatment of galactal triacetate8
with allyltrimethylsilane in the presence of BF3-Et2O
at -50°C cleanly afforded 3 as the single R isomer in 97%
yield. Hydrolysis of the acetates with Et3N in aqueous
MeOH followed by protection of the primary hydroxyl
group led to allylic alcohol 4, which upon esterification
furnished 5 in good overall yield. At this stage, the
carbon chain extension with transfer of asymmetry at
C(2) was achieved by Ireland’s enolate-Claisen rear-
rangement.9 To this end, allyl propionate 5 was treated
with LHMDS-THF-DMPU followed by TBDMS(Cl) to
give the ketene silyl acetal10 which was heated in
refluxing toluene.11 The crude rearrangement product
was subjected to desilylation and methylation affording
(11) It is worthy of note that first attempts to effect this rearrange-
ment in refluxing benzene gave mostly the starting ester. For a study
on the stereoelectronic effect on the Claisen rearrangement of carbo-
hydrate glycal ketene acetals see: Curran, D. P.; Suh, Y.-G. Carbohyr.
Res. 1987, 117, 161-191.
(12) The next steps were performed on this mixture, the asymmetry
at this center being destroyed later in the synthesis.
(13) For a review see: Schro¨der, M. Chem. Rev. 1980, 80, 187-213.
(14) (a) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-
4156. (b) Dess, D. B.; Martin, J . C. J . Am. Chem. Soc. 1991, 113, 7277-
7287.
(15) Kitahara, T.; Matsuoka, T.; Kiyota, H.; Warita, Y.; Kurata, H.;
Horiguchi, A.; Mori, K. Synthsis 1994, 692-694.
(16) Trost, B. M.; Verhoeven, T. R.; Fortunak, J . M. Tetrahedron
Lett. 1979, 301-2304. Tsuji, J .; Yamakawa, T.; Kaito, M.; Mandai, T.
Tetrahedron Lett. 1978, 2075-2078. For a proposed mechanism see:
Keinan, E.; Kumar, S.; Dangur, V.; Vaya, J . J . Am. Chem. Soc. 1994,
116, 11151-11152.
(7) (a) Danishefsky, S. J .; Kerwin, J . F., J r. J . Org. Chem. 1982, 47,
3803-3805. (b) Danishefsky, S. J .; DeNinno, S.; Lartey, P. J . Am.
Chem. Soc. 1987, 109, 2082-2089.
(8) Although this starting material is commercially available, its
price is rather exorbitant. We therefore prepared it according to the
published procedure: Kozikowski, A. P.; J aemoon, L. J . Org. Chem.
1990, 55, 863-870.
(9) Ireland, R. E.; Smith, M. G. J . Am. Chem. Soc. 1988, 110, 854-
860 and references cited therein.
(10) Under these conditions, the Z-ketene silyl acetal is the major
product. For a review on regio- and stereoselective formation of enolates
see: Heathcock, C. H. In Modern Synthtic Methods; Scheffold, R. , Ed.;
VCH: Basel, 1992, vol. 6, chapter 1.
(17) For general reviews on the IMDA reactions see: (a) Roush, W.
R. In Comprhensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; vol. 5, pp 513-550. (b) Cigank, E. Org.
React. 1984, 32, 1. (c) Craig, D., Chem. Soc. Rev. 1987, 16, 187.

Construction of the ABC Ring System of Forskolin
J . Org. Chem., Vol. 62, No. 20, 1997 6987
Sch em e 3
Sch em e 5
Sch em e 4
substructure would slow down the rate of cycloaddition.19
The addition to 11b of (2-methylpropenyl)lithium, gener-
ated from t-BuLi and 1-bromo-2-methylpropene, and
subsequent oxidation with the Dess-Martin reagent
provided trienone 13. Attempts to accomplish the cy-
cloaddition under both thermal and Lewis acid catalyzed
conditions failed to give the desired product 17 (Scheme
5). Thus, when 13 was heated at 180 °C for three days,
the starting material was recovered unchanged. In the
same manner, treatment of 13 with BF3-Et2O in CH2Cl2
was also ineffective, and the starting trienone was again
unaltered. The greater steric demands imparted by the
gem-dimethyl group on the transition state are sufficient
to impede the cyclization.
In order to overcome this difficulty, the construction
of the framework of forskolin was envisaged from tricyclic
ketone 18a , which could be formed via the IMDA reaction
of dienynone 14. 1,4-addition of methyl copper reagent
to 18a should then lead to 17 (Scheme 5). To this end,
addition to 11b of 1-propynyllithium, generated by treat-
ment of 1-bromopropene with 2 equiv of n-butyllithium
at -78 °C,20 gave rise to a mixture of isomeric alcohols
(82%) which were oxidized by Dess-Martin’s reagent
affording dienynone 14 in 68% overall yield.
provided a 3:1 mixture of two cycloadducts 15a and 16a ,
separated by flash chromatography in 62 and 20% yield,
respectively (Scheme 4). The trans-fused stereochemistry
of the major isomer 15a was deduced by a combination
of COSY and NOESY 1H spectra at 400 MHz. In
particular, the NOESY experiment revealed a cis rela-
tionship of the angular methyl group at C(10) with H(8)
(terpenoid numbering). This product may result from a
“down side” facial approach of the dienophile which is
dictated by the geometrical restriction in the IMDA
transition state (Scheme 4). Upon treatment with HF
in acetonitrile, 15a underwent desilylation affording
alcohol 15b having the same AB trans-fused stereochem-
istry as for 15a . This compound remained unchanged
when subjected either to acidic (BF3-Et2O) or basic
(NaOMe, MeOH, rt) isomerization conditions.
The stereochemistry of cis-fused product 16a , the
minor component of the mixture, was deduced from the
corresponding alcohol 16b on the basis of NMR spectral
data. Of special significance was the strong NOE effect
observed between Me(10R) at δ 1.32 ppm and the H(11)
vinylic hydrogen at δ 6.17 ppm and the absence of any
NOE effect between the angular methyl group and H(8â).
Heating a 0.05 M solution of 14 in toluene at 200 °C
for 24 h provided a 4:3 mixture of cycloadducts 18a and
It remained to determine whether trienone 13 could
undergo the IMDA cyclization, bearing in mind that the
presence of the gem-dimethyl group on the dienophile
(19) For recent examples of the IMDA cyclization with
a gem-
dimethyl on the diene see: (a) Bonnert, R. V.; J enkins, P. J . Chem.
Soc., Perkin Trans. 1 1989, 413-418. (b) Rubenstein, S. M.; Williams,
R. M. J . Org. Chem. 1995, 60, 7215-7223. (c) alaima, C. A.; Coburn,
C. A.; Danishefsky, S. J . Tetrahedron Lett. 1994, 35, 6603-6606, and
references therein. (d) Gwaltney, S. L. II; Sakata, S. T.; Shea, K. J .
Tetrahedron Lett. 1995, 36, 7177-7180 and references therein. (e)
Winkler, J . D.; Kim, H. S.; Kim, S. Ando, K.; Houk, K. N. J . Org. Chem.
1997, 62, 2957-2962.
(18) For recent examples of related IMDA cyclization see: Zoller,
T.; Uguen, D.; DeCian, A.; Fischer, J .; Sable´, S. Tetrahedron Lett. 1997,
38, 3409-3412. Shishido, K.; Omodani, T.; Shibuya, M. J . Chem. Soc.,
Perkin Trans. 1 1991, 2285-2287. Shing, T. K. M.; Tang, Y. Tetrahe-
dron 1990, 46, 2187-2194.
(20) Suffert, J .; Toussaint; D. J . Org. Chem. 1995, 60, 3550-3553.

6988 J . Org. Chem., Vol. 62, No. 20, 1997
Hanna and Wlodyka
CCl4. 1H and 13C NMR spectra were recorded at 200 or 400
MHz (1H), and at 100.6 or 50.3 MHz (13C) as solutions in
CDCl3, using residual protic solvent CHCl3 (δH ) 7.27) or
CDCl3 (δC ) 77.1) as internal reference. All reactions were
monitored by TLC carried out on 0.2 mm Merck aluminum
silica gel (60 F254) precoated plates using UV light and 5%
ethanolic phosphomolybdic acid and heat as developing agent.
Flash chromatography was performed on 40-63 µm (400-230
mesh) silica gel 60 with ethyl acetate-petroleum ether (bp 40-
60 °C) (AcOEt-PE) as eluent. Commercially available re-
agents and solvents were purified and dried when necessary
by usual methods.
19a , which were separated by flash chromatography in
71% combined yield. Desilylation of these products with
HF in acetonitrile at room temperature cleanly gave
alcohols 18b and 19b in good yield. It is worthy of note
that initial attempts to accomplish this reaction using
tetrabutylammonium fluoride proved to be troublesome.
Thus, treatment of 18a with TBAF in THF at room
temperature resulted in concomitant cleavage of the silyl
group as well as the migration of the C(1) double bond
leading to conjugated diene 21. Under the same condi-
tions, cycloadduct 19a gave 22a by migration of the C(4)
double bond. In this reaction, the fluoride ion obviously
acted as a desilylating agent as well as a base. In fact,
exposure of both 18a and 19a to DBU in refluxing THF
for 1 h led to conjugated dienes 20 and 23, respectively
in good yield.
The structure of cycloadducts 18a and 19a and their
derivatives was established on the basis of 1H NMR, 13C
NMR, IR, and mass spectra. The syn relationship
between the methyl group at C(10) and (8â) proton in
compoud 18b was deduced from the 2D NOESY spectra
which indicated clearly a cross peak between Me(10â) at
δ 0.89 ppm and H(8â) at δ 3.88. In contrast, examination
of the 2D NOESY spectra of the minor isomer 19b reveals
a strong NOE interaction between the angular methyl
at δ 1.07 and H(9R) at δ 3.78, but not with H(8â), which
clearly indicated the R-configuration for the methyl group
at C(10). The stereochemistry of this carbon was con-
firmed unambiguously by X-ray analysis of the p-bro-
mobenzoate 22b.21
According to the foregoing results, the IMDA cycliza-
tion of 14 presumably proceeded through chairlike tran-
sition state, with slight preference for the endo orienta-
tion. Attempts to improve the selectivity of this reaction
by using Lewis acid catalysts were unsuccessful. No
reaction occurred when 14 was treated with BF3-Et2O,
EtAlCl2, or BCl3 in CH2Cl2 at -78 to -50 °C. At higher
temperatures, the reaction gave rise to a intractable
mixture of products.
Having cycloadduct 18a in hand, with the right con-
figuration of the angular methyl group at C(10), we next
introduced the gem-methyl group. Thus, treatment of
18a with MeCu‚BF3 in ether, according to Yamamoto’s
procedure,22 provided 17 in 62% yield. The structure of
this compound was fully assigned on the basis of its
spectroscopic data (See Experimetal Section).
2(R )-(2-P r o p e n y l)-5(R )-p r o p a n o y lo x y -6(R )-[[(t er t -
bu tyldim eth ylsilyl)oxy]m eth yl]-5,6-dih ydr o-2H pyr an (5).
To a stirred solution of 4 (13 g, 45.7 mmol) in CH2Cl2 (110
mL) cooled to 0 °C was added DMAP (75 mg, 0.61 mmol), and
propionic acid (10.3 mL, 139 mmol). Dicyclohexylcarbodiimide
DCC (29.2 mL, 139 mmol) in CH2Cl2 (40 mL) was then added
dropwise, and the resultant mixture was allowed to warm to
room temperature. After stirring at this temperature for 5 h
30 min, the mixture was diluted with CH2Cl2, and filtered
through a pad of Celite. The filtrate was washed with cooled
0.5 N HCl and saturated NaHCO3 and dried (MgSO4). Evapo-
ration of the solvent left a residue which was purified by flash
chromatography (AcOEt/EP 5:95 followed by 1/9) to give 15.23
g (98 %) of 5 as colorless oil. Rf 0.42 (AcOEt/PE 1/9); IR 3079,
1
1736 cm-1; H NMR (200 MHz) δ 6.00-6.08 (m, 1H), 5.70-
5.87 (m, 1H), 5.01-518 (m, 2H), 4.27 (t, J ) 14, 1H), 3.89 (td,
J ) 6.7, 2.3, 1H), 3.67-3.63 (m, 2H), 2.43-2.24 (m, 4H), 1.08
(t, J ) 15.1, 3H), 0.82 (s, 9H), 0.002 (s, 3H), -0.01(s, 3H); 13C
NMR (50.3 MHz) δ 173.8 (C), 134.7 (CH), 134.2 (CH), 122.5
(CH), 117.3 (CH2), 72.6 (CH), 70.6 (CH), 63.5 (CH2), 61.8 (CH),
36.8 (CH2), 27.5 (CH2), 25.7 (3 CH3), 18.1(C), 9.0 (CH3), -5.3 (2
CH3). MS (CI, NH3) m/ z (%): 358(0.5) (M + NH4)+, 341(15),
268(21), 267(100). [R]D -249° (c 3.8, CHCl3). Anal. Calcd for
C18H32O4Si: C, 64.49; H, 9.47. Found C, 64.75; H, 9.41.
Meth yl 3(R)-[[[2(R)-(2-p r op en yl)-6(R)-[[(ter t-bu tyld i-
m eth ylsilyl)oxy] m eth yl]- 2,3-d ih yd r o-6H-p yr a n yl]p r o-
p a n ote (6). Hexamethyldisilazane (HMDS) (5.9 mL, 28.9
mmol) in 75 mL of THF was cooled to -78 °C, and n-BuLi
(9.8 mL of a 2.5 M solution in hexanes, 24.48 mmol) was added
dropwise. After the mixture was stirred for 10 min, TBSCl
(4.36 g, 24.48 mmol) dissolved in 20.5 mL of dimethyl tetrahy-
dro-2(1H)-pyrimidinone (DMPU) was added, and the reaction
solution was stirred for 3 min. Ester 4 (4.68 g, 13.76 mmol)
dissolved in 32 mL of THF was then added dropwise, and the
mixture was allowed to warm to 0 °C. After stirring at this
temperature for 2 h 30 min, the mixture was poured into 270
mL of petroleum ether and washed with 130 mL of ice-water
and cold brine and dried (MgSO4) and the solvent removed
under reduced pressure.
The residue was briefly dried under high vacuum, and 34
mL of toluene was added. After this solution was refluxed for
7 h, the solvent was again removed, and 17 mL of DMPU was
added. Potassium fluoride dihydrate (3.2 g, 41.3 mmol), water
(0.5 mL), and potassium bicarbonate (5.5 g, 55 mmol) were
added. After 5 min of stirring this suspension at room
temperature, methyl iodide (5.5 mL, 68.75 mmol) was added,
and the reaction was stirred overnight at ambiant tempera-
ture. The product was then extracted with ether, and the
organic layer washed with water and brine and dried. The
solvent was removed on a rotary evaporator, and the residue
was flash chromatographed (AcOEt/EP 93/7) to give 4.7 g of 5
(97%) as a colorless oil of 1:7 inseparable mixture of methyl
epimers. Analysis and spectral data of the major isomer: IR
In conclusion, a new route to functionalized tricyclic
framework of forskolin has been developed using an
intramolecular Diels-Alder reaction for simultaneous
construction of A and B rings as the key step. The
synthesis of precursor dienyne 14 is based on stereose-
lective introduction of carbon chains at C(1) and C(2) of
tri-O-acetyl-D-galactal via C-Ferrier followed by Claisen-
Ireland rearrangements. The functionalities present in
this skeleton provide a handle for further transformations
which could lead to forskolin.
Exp er im en ta l Section
3079, 1737 cm-1
.
1H NMR (200 MHz) δ 5.85-5.68 (m, 3H),
5.05 (d, J ) 18.9, 1H), 5.01 (d, J ) 10 Hz, 1H), 4.02 (m, 1H),
3.86 (t, J ) 14, 1H), 3.61 (dd, J ) 10, 5.8, 1H), 3.59 (s, 3H),
3.45 (dd, J ) 10, 6.3, 1H), 2.55 (t, J ) 6.9, 1H), 2.39 (m, 1H),
2.19 (m, 1H), 2.11 (m, 1H), 1.13 (d, J ) 7.2, 3H), 0.84 (s, 9H!,
0.005 (s, 6H); 13C NMR (50.3 MHz) δ 175.6 (C), 135.0 (CH),
128.7 (CH), 122.5 (CH), 116.8 (CH2), 71.8(CH), 69.9 (CH), 65.8
(CH2), 51.3 (CH3), 42.5 (CH), 40.3 (CH), 36.8 (CH2), 25.9 (3
CH3), 18.3 (C), 14.5 (CH3), -5.3 (2 CH3); MS (CI, NH3) m/ z
Melting points were determined on a Reichert hot stage
apparatus. Infrared spectra were recorded as solutions in
(21) The author has deposited atomic coordinates for 22b with the
Cambridge Crystallographic Data Centre. The coordinates can be
obtained from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge, CB2 1EZ, UK.
(22) For reviews see: Yamamoto, Y.; Muruyama, K. J . Am. Chem.
Soc. 1977, 99, 947-1038. Yamamoto, Y.; Ibuka, T. In Organocopper
Reagents; Taylor, R. J . K., Ed.; Oxford University Press: Oxford, 1994;
pp 143-158.
(%): 372(26) (M
C19H34O4Si: C, 64.36; H, 9.66. Found C, 64.44; H, 9.58.
+
NH4)+, 355(100). Anal. Calcd for

Construction of the ABC Ring System of Forskolin
J . Org. Chem., Vol. 62, No. 20, 1997 6989
Meth yl 2(R)-[[[1(R)-(2-oxoeth yl)-5(R)-[[( ter t-bu tyld i-
m eth ylsilyl)oxy]m eth yl]- 1,2-d ih yd r o-5H-p yr a n yl]]p r o-
p a n ote (7). To a stirred solution of the alkene 6 (2 g, 5.634
mmol) in THF (8.4 mL) was added a solution of N-methyl-
morpholine N-oxide (NMO) (798 mg, 6.28 mmol) in water (2.8
mL), followed by 0.04 M solution of osmium tetraoxide in tert-
butyl alcohol (7 mL, 0.28 mmol). After 3 h, a saturated
aqueous solution of sodium dithionite (Na2S2O4) (30 mL) was
added. The mixture was stirred for a further 3 h and then
filtered on a pad of Celite, and the filter cake was washed
thoroughly with CH2Cl2. The solvent was evaporated off under
reduced pressure and the resultant oil dissolved in ethanol
(51 mL). Aqueous saturated NaIO4 (11.3 mL) was then added
to the vigorously stirred solution, followed, after 30 min, by
saturated aqueous Na2SO3 (14 mL), and the mixture was
diluted with water and extracted with CH2Cl2. The combined
organic extracts were washed with water and brine, and dried
(MgSO4). The solvent was removed under reduced pressure
and the residue purified by flash chromatography (AcOEt/EP
1/6, then 1/3) affording 1.4 g (70%) of a 1:7 mixture of epimers
7 as colorless oil. Analysis and spectral data of the major
isomer: IR 1731, 1690 cm-1; 1H NMR (200 MHz) δ 9.8 (s, 1H),
5.89 (dt, J ) 10.6, 1.5, 1H), 5.77 (ddd, J ) 10.6, 4.4, 1.6, 1H),
4.50 (ddd, J ) 8, 5.3, 2.7, 1H), 4.05 (m, 1H), 3.68 (dd, J ) 10.0,
3.0, 1H), 3.67 (s, 3H), 3.51 (dd, J ) 10, 6.0, 1H), 2.76 (ddd, J
) 16.0, 7.9, 3.0, 1H), 2.64 (m, 1H), 2.61 (ddd, J ) 16.0, 5.4,
1.5, 1H), 2.20 (m, 1H), 1.24 (d, J ) 7.2, 3H), 0.89 (s, 9H), 0.05
(s, 6H). 13C NMR (50.3 MHz) δ 200.7 (C), 176.0 (CH), 128.7
(CH), 125.6 (CH), 70.1 (CH), 67.8 (CH), 65.6 (CH2), 51.7 (CH3),
46.6 (CH2), 42.2 (CH), 40.9 (CH), 26.0 (3 CH3), 19.1 (C),
14.0(CH3), -5.4 (2 CH3); MS (CI, NH3) m/ z (%) : 374(100) (M
+ NH4)+, 357(67). Anal. Calcd for C18H32O5Si: C, 60.64; H,
9.03. Found C, 60.75; H, 8.97.
Meth yl 3(R)-[[[2(R)-(2,2-Dim eth oxyeth yl)-6(R)-[[(ter t-
b u t yld im e t h ylsilyl)oxy]m e t h yl]-2,3-d ih yd r o-6H p yr a -
n yl]]p r op a n oa te (8). A mixture of 7 (11.2 g, 31.4 mmol),
trimethyl orthoformate (25.3 mL, 220 mmol), and p-toluene-
sulfonic acid (150 mg, 0.58 mmol) in CH2Cl2 was stirred at
room temperature under nitrogen for 30 h. Solid NaHCO3 (1
g, 11.9 mmol) was added, and the solvent was evaporated off
under reduced pressure. The resultant residue was flash
chromatographed (AcOEt/EP 1/6) to furnish 12.37 g (98%) of
8 as a mixture of epimers. Analysis and spectral data of the
major isomer: IR 1737 cm-1; 1H NMR (200 MHz) δ 5.83 (d, J
) 10.5, 1H), 5.73 (dd, J ) 10.5, 3.7, 1H), 4.55,(dd, J ) 7.6, 3.7,
1H), 4.1 (m, 1H), 3.98 (m, 1H), 3.67 (dd, J ) 9.7, 6, 1H), 3.64
(s, 3H), 3.5 (dd, J ) 9.7, 6.1, 1H), 3.34 (s, 3H), 3.30 (s, 3H),
2.59 (t, J ) 7, 1H), 2.1 (m, 1H), 1.97 (ddd, J ) 14.2, 9.3, 3.7,
1H), 1.72 (ddd, J ) 14.2, 7.4, 4.6, 1H), 1.2 (d, J ) 7.0, 3H),
0.98 (s, 9H), -0.05 (s, 6H); 13C NMR (50.3 MHz) δ 175.4 (C),
128.1 (CH),125.5 (CH), 70.5 (CH), 68.6 (CH), 65.6 (CH2), 53.0
(CH3), 52.4 (CH3), 51.7 (CH3), 42.3 (CH), 41.1 (CH), 35.3 (CH2),
25.7 (3 CH3), 18.2 (C), 14.4 (CH3), -5.5 (2 CH3); MS (CI, NH3)
m/ z (%): 371(86), 356(35), 313(39), 239(100), 167(53), 75(45).
2(R)-(2,2-Dim eth oxyeth yl)-3(R)-(1-m eth yl-2-oxoeth yl)-
6(R)[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-2,3-d ih yd r o-
6H p yr a n (9). To a solution of the ester 8 (15.9 g, 39.5 mmol)
in ether (280 mL) cooled to -78 °C with stirring was added
dropwise a 1.2 M solution of DIBALH in toluene (100 mL, 120
mmol). After being stirred for 20 min at -78 °C, methanol
(10 mL) was added and the dry ice bath was removed. More
ether (500 mL) was added followed by 480 mL of 5% aqueous
sodium potassium tartrate. This biphasic mixture was vigor-
ously stirred for 1 h at room temperature and then separated.
The aqueous layer was extracted with ether, and the combined
organic layers were dried over MgSO4. The solvent was
removed with a rotary evaporator to give 15.1 g of alcohol
which was used for the next reaction without further purifica-
tion.
the aqueous phase was extracted with ether. The combined
organic layers were washed with brine and dried (MgSO4). The
solvent was removed under reduced pressure, and the result-
ant residue was purified by flash chromatography (AcOEt/EP
1/6, 1/4 and 1/2) to furnish 11.7 g (80% overall) as a colorless
oil. Analysis and spectral data of the major isomer: Rf 0.6
1
(AcOEt/EP 1/4); IR 1727 cm-1; H NMR (200 MHz) δ 9.71 (d,
J ) 5.4, 1H), 5.87-5.78 (m, 2H), 4.53 (dd, J ) 7.9, 3.4, 1H),
4.04 (m, 1H), 3.93 (m, 1H), 3.55 (m, 2H), 3.32 (s, 1H), 3.27 (s,
1H), 2.52 (m, 1H), 2.19 (m, 1H), 1.95 (ddd, J ) 12.7, 9.1, 3.4,
1H), 1.75 (ddd, J ) 12.7, 7.8, 4.6, 1H), 1.20 (d, J ) 7.0, 3H),
1.85 (s, 9H), 0.014 (s, 6H); 13C NMR (50.3 MHz) δ 204.0 (CH),
128.5 (CH), 125.6 (CH), 102.2 (CH), 70.5(CH), 69.6 (CH), 65.6
(CH2), 52.6 (CH3), 49.7 (CH3), 40.1 (CH), 38.7 (CH), 35.5 (CH2),
25.9 (3 CH3), 18.4 (C), 11.3(CH3), -5.3 (2 CH3); Anal. Calcd
for C19H36O5Si: C, 60.95; H, 10.14. Found C, 60.85; H, 10.24.
2(R)-(2,2-Dim et h oxyet h yl)-3(R)-(1-m et h yl-1,3-b u t a d i-
en yl)-6(R)-[[(ter t-bu tyld im eth ylsilyl)oxy]m eth yl]-2,3-d i-
h yd r o-6H-p yr a n (10). To a 1.0 M solution of vinylmagne-
sium bromide in THF (4 mL, 4 mmol) cooled to -78 °C and
stirred under nitrogen was added dropwise the aldehyde 9 (514
mg, 1.38 mmol) in dry THF (6 mL). After 20 min the mixture
was quenched with saturated NaHCO3 and extracted with
ether. After the usual workup, the crude product was flash
chromatographed (AcOEt/EP 1/4) to afford 450 mg (81.5%) of
mixture of alcohols as colorless oil.
To a stirred solution of above alcohols (9.7 g, 24.25 mmol)
in CH2Cl2 (19 mL) and dry pyridine (8 mL) was added at 0 °C
a solution of acetyl chloride (6.9 mL, 97 mmol) in CH2Cl2 (8
mL). The reaction mixture was stirred for 30 min at 0 °C and
then allowed to warm to room temperature, and the excess of
AcCl was hydrolyzed by addition of water. Extraction with
ether and usual workup gave a residue which was purified by
flash chromatography to give 10.3 g (93%) of acetates followed
by 0.48 g of starting alcohols.
The above mixture of acetates (6 g, 13.6 mmol) in THF (35
mL) was heated in the dark with tetrakis(triphenylphosphine)
palladium (1.25 g, 1.08 mmol) at 75 °C for 24 h. After cooling,
water was added and the mixture was extracted with ether.
The organic layer was dried (MgSO4) and the solvent removed
under reduced pressure. The residue was purified by flash
chromatography (AcOEt/EP 1/19) to give 4.68 g (90%) of the
diene 10 as a separable 2/1 mixture of isomers E and Z.
Analysis and spectral data of the major isomer: Rf 0.40
1
(AcOEt/EP 1/19); IR 3080, 1641 cm-1; H NMR (400 MHz) δ
6.57 (dt, J ) 16.8, 10.5, 1H) 5.93 (d, J ) 10.3, 1H), 5.86 (dt, J
) 10.3, 2.5, 1H), 5.70 (dt, J ) 10.4, 2.4, 1H), 5.13 (dd, J )
16.8, 1.7, 1H), 5.05 (dd, J ) 10.4, 1.5, 1H), 4.62 (dd, J ) 8.3,
3.2, 1H), 4.17 (m, 1H), 3.80 (m, 1H), 3.78 (dd, J ) 10, 5.8, 1H),
3.65 (dd, J ) 10, 5.8, 1H), 3.33 (s, 6H), 2.61 (m, 1H), 1.87 (ddd,
J ) 14.2, 8.5, 3.0, 1H), 1.73 (ddd, J ) 14.2, 8.3, 3.2, 1H), 1.72
(s, 3H), 0.91 (s, 9H), 0.08 (s, 6H); 13C NMR (100.6 MHz) δ 138.6
(C), 133.2 (CH), 129.3 (CH), 129.0 (CH), 127.5 (CH), 116.0
(CH2), 102.90 (CH), 72.8 (CH), 69.2 (CH), 65.7 (CH2), 53.3
(CH3), 53.2 (CH3), 50.0 (CH), 37.3 (CH2), 26.1 (3 CH3), 18.5
(C), 14.8 (CH3), -5.1 (2 CH3); MS (CI, NH3) m/ z (%): 400(4)
(M + NH4)+, 383(2), 368(3), 351(100), 336(21), 319(11), 279(5),
219(14).
2(R)-(2-Oxoeth yl)-3(R)-(1-m eth yl-1,3-bu ta d ien yl)-6(R)-
[[(ter t-bu tyld im eth ylsilyl)oxy] m eth yl]-2,3-d ih yd r o-6H-
p yr a n (11a ). To a solution of 10 (1.0 g, 2.97 mmol) in THF
(25 mL) cooled to 0 °C was added dropwise 60% aqueous
trifluoroacetic acid (TFA) (16 mL) and the mixture stirred for
20 h at room temperature. Excess TFA was neutralized by
careful addition of solid NaHCO3, and the reaction mixture
was extracted with ether (10 × 25 mL). The combined organic
layers were washed with brine and dried (MgSO4), and the
solvent was removed. Flash chromatography (AcOEt/EP 1/2
then 1/1) of the resultant residue gave 513 mg (78%) of 11a
as a 1/2 mixture of isomers. Analysis and spectral data of the
To a stirred solution of the above alcohol in CH2Cl2 (280
mL) was added 0.6 mL of water followed by dess Martin
periodinane (DMP) (10.6 g, 25 mmol). After 10 min a second
portion of DMP (10.6 g, 25 mmol) was added, and stirring was
continued for further 20 min. Ether was added, and the
reaction mixture was treated with 1:1 saturated NaHCO3-
Na2S2O3 solution for 15 min. The layers were separated, and
major isomer: Rf 0.35 (AcOEt/EP 1/2); IR 3592, 1727 cm-1
;
1H NMR (400 MHz) δ 9.76 (s, 1H), 6.60 (dt, J ) 16.9, 10.4,
1H), 5.97 (d, J ) 10.6, 1H), 5.78 (m, 1H), 5.71 (m, 1H), 5.19
(d, J ) 16.5, 1H), 5.11 (d, J ) 10.3, 1H), 4.27-4.20 (m, 3H),
3.84 (dd, J ) 12.0, 9.4, 1H), 3.59 (dd, J ) 11.9, 3.0, 1H), 2.77-
2.71 (m, 3H), 1.69 (s, 3H); 13C NMR (100.6 MHz) δ 201.1 (C),

6990 J . Org. Chem., Vol. 62, No. 20, 1997
Hanna and Wlodyka
136.7 (C), 132.5 (CH), 129.8 (2 CH), 126.1 (CH), 117.2 (CH2),
73.9 (CH), 64.6(CH), 62.8 (CH2), 49.4 (CH 47.0 (CH2 14.4 (CH3).
2(R)-(2-Oxoeth yl)-3(R)-(1-m eth yl-1,3-bu ta d ien yl)-6(R)-
[[(ter t-b u t yld ip h en ylsilyl)oxy]m et h yl]-2,3-d ih yd r o-6H -
p yr a n (11b). To a solution of 11a (1.27 g, 5.7 mmol) in 300
µL of CH2Cl2 at 0 °C was added triethylamine (2.75 mL),
(dimethylamino)pyridine (DMAP) (48 mg, 0.39 mmol), followed
by tert-butyldiphenylsilyl chloride (TBDPSCl) (1.638 mL, 6.3
mmol). The reaction mixture was stirred at room temperature
for 36 h and then hydrolyzed with water (5mL) and extracted
with ether. The combined organic layers were washed with
brine and dried, and the solvent was removed under reduced
pressure. Flash chromatography (AcOEt/EP 1/19) of the
resultant residue furnished 2.58 g (98%) of aldehyde 11b as a
2/1 (order of elution) separable mixture of isomers. Analysis
and spectral data of the major isomer: Rf 0.4 (two elutions
3.74 (d, J ) 6 2, 2H, H-14), 2.80 (dd, J ) 13.9, 5.1, 1H), 2.79
(dd, J ) 22.0, 1H), 2.67 (dd, J ) 23.0, 4.0, 1H), 2.49 (dd, J )
13.9, 12.1, 1H), 2.39 (ddd, J ) 9.5, 4.4, 2.7, 1H), 1.88 (s, 3H,Me-
4), 1.06(s, 9H), 0.83(s, 3H, Me-10); 13C NMR (100.6 MHz) δ
204.2 (C), 137.3 (C), 136.2 (C), 135.6 (4 CH), 133.4 (C), 130.7
(CH), 129.8 (2 CH), 128.9 (CH),127.7 (4 CH), 126.2 (CH), 121.7
(CH), 74.5 (CH), 67.9 (CH), 65.7 (CH2), 49.3 (CH2), 47.0 (CH),
37.8 (C), 33.7 (CH2), 26.8 (3 CH3), 22.8 (CH3), 20.3 (CH3),
19.2(C); MS (CI, NH3) m/ z (%) 516(75) (M + NH4)+, 499(77),
421(43), 311(21), 225(8), 133(100), 102(70), 85(60); [R]D -22°
(c 5.8, CHCl3).
19a : colorless oil; Rf ) 0.4 (AcOEt/EP 1/9); IR 1693 cm-1
;
1H NMR (400 MHz) δ 7.7-7.65 (m, 4H), 7.44-7.35,(m, 6H),
6.08 (d, J ) 10.5, 1H, H-11), 5.98 (dt, J ) 10.5, 3.0, 1H, H-1),
5.93 (dd, J ) 9.6, 3.0, 1H, H-12), 5.75 (ddd, J ) 9.5, 5.0, 2.0,
1H, H-2), 4.36 (m, 1H, H-13), 3.74 (d, J ) 5.6, 2H, H-14), 3.63
(td, J ) 10.5, 6.0, 1H, H-8), 2.77 (d, J ) 18.0, 1H), 2.67 (d, J
) 20, 1H), 2.63 (dd 18.0, 10.5, 1H), 2.31 (dd, J ) 10.0, 6.0,
1H), 2.08 (dd, J ) 10.5, 2.0 1H), 1.89 (s, 3H, Me-4), 1.09 (s,
3H, Me-10) 1.04(s, 9H); 13C NMR (100.6 MHz) δ 202.9 (C);
137.9 (C); 135.6 (4 CH); 133.4 (C); 131.8 (CH); 129.6 (2 C); 127.6
(CH); 125.9 (CH); 125.0 (CH); 73.4 (CH); 65.7 (CH); 65.2 (CH2);
47.4 (CH2); 46.8 (CH); 41.5 (C); 34.2 (CH2); 28.0 (CH3); 26.8 (3
CH3); 20.0 (CH3); 19.2 (C); MS (CI, NH3) m/ z (%): 516(6) (M
+ NH4)+, 499(8), 421(38), 287(7), 225(7), 133(100), 102(5); [R]D
-107° (c 6.2, CHCl3).
1
AcOEt/EP 1/19); IR 3072, 1729 cm-1; H NMR (400 MHz) δ
9.76 (t, J ) 2.2, 1H), 7.74-7.69 (m, 4H), 7.46-7.37 (m, 6H),
6.58 (dt, J ) 16.6, 10.5, 1H), 5.98-5.90 (m, 2H), 5.76 (dt, J )
10.5, 2.0, 2.0, 1H), 5.18 (d, J ) 16.6, 1H), 5.1 (d, J ) 10.5,
1H), 4.31-4.21 (m, 2H), 3.82 (d, J ) 2, 1H), 3.79 (s, 1H), 2.73
(m, 1H), 2.55 (m, 2H), 1.70 (s, 3H), 1.10 (s, 9H); 13C NMR (100.6
MHz) δ 201.1 (C), 137.1 (C), 135.6 (4 CH), 132.5 (2 C), 129.7
(2 CH), 128.9 (2 CH), 127.7 (4 CH), 116.8 (CH2), 73 (CH), 68.5
(CH), 65.8 (CH2), 49.4 (CH), 47.3 (CH2), 26.8 (3 CH3), 19.2 (C),
14.6 (CH3); MS (CI, NH3) m/ z (%): 478(100) (M + NH4)+,
461(4), 383(76), 351(11), 305(14), 196(8), 187(21), 133(5),
78(23).
1-[6(R)-[[(ter t-bu tyld ip h en ylsilyl)oxy]m eth yl]-3,6-d i-
h yd r o-3(R)-(1-m et h yl-1,3-b u t a d ien yl)-2H -p yr a n -3-yl]-3-
p en tyn -2-on e (14). To a stirred solution of Z/ E 1-bromopro-
pene (160 µL, 1.85 mmol) in dry THF (1.5 mL) under nitrogen
at -78 °C was added dropwise 1.6 M solution of n-BuLi in
hexane (1.5 mL, 2.4 mmol). The resultant milky mixture was
stirred at -78 °C for 2 h before a solution of 11b (0.46 g, 1
mmol) in THF (2 mL) was slowly added. The reaction mixture
was stirred for an additional 1 h at -78 °C and then allowed
to warm to 0 °C. A saturated aqueous solution of NH4Cl was
added, and the product was extracted with ether. The organic
layer was washed with brine and dried over MgSO4 and the
solvent removed under reduced pressure. Flash chromatog-
raphy of the residue (AcOEt/PE 5/95 and 10/90) gave 443 mg
(88%) of mixture of alcohols as colorless oil.
Ad d ition of Meth yl Cop p er Rea gen t to r,â-Un sa tu r -
a ted Keton e 18a . Com p ou n d 17. To a stirred suspension
of CuI (150 mg, 0.79 mmol) in dry ether (0.5 mL) under nitrgen
cooled to -40 °C was added dropwise a 1.6 M solution of MeLi
in ether (450 µL, 0.72 mmol). After being stirred for 15 min
at -40 to -30 °C, the mixture was cooled to -78 °C, BF3-
Et2O (100 µL) was added followed by a solution of 18a (50 mg,
0.10 mmol) in ether (0.5 mL). The reaction mixture was
allowed to warm to -30 °C during 1.5 h, recooled to -70 °C,
and then quenched with water with vigorous stirring. The
dry ice-acetone bath was removed, and the temperature was
allowed to rise to ambient temperature. The mixture was
filtered through Celite with suction, and the filter cake was
rinsed with ether. The filtrate was tranferred to a separatory
funnel, and the layers were separated. The aqueous layer was
extracted with ether, and the combined organic extracts were
washed with brine, dried over MgSO4 and the solvent was
removed using a rotary evaporator. The resultant oily residue
was purified by flash chromatography (AcOEt/PE 5/95) to
Treatment of this product with Dess-Martin periodinane
(600 mg) in CH2Cl2 (5 mL) for 45 min at room temperature as
indicated above afforded after flash chromatography (AcOEt/
PE 5/95) 60 mg of the minor isomer, 52 mg of the mixture of
isomers, and 231 mg of the major isomer (78% combined yield).
afford 32 mg (62%) of 17 as colorless oil. IR 1721 cm-1 1H
;
NMR (400 MHz) δ 0.83 (s, 3Η), 1.06 (s, 9Η), 1.09 (s, 3Η), 1.15
(s, 3Η), 1.76 (dd, J ) 17.5, 5.5, 1H), 1.94 (br d, J ) 17.5, 1H),
2.29 (br d, j ) 9, 1H), 2.53 (t, J ) 12, 1H), 2.54 (s, 1H, H-5),
2.64 (dd (J ) 12, 5.5, 1H), 3.73 (d, J ) 5, 2H), 3.79-3.85 (m,
1H, H-8), 4.35-4.37 (m, 1H, H-13), 5.60-5.64 (m, 1H, H-2),
5;88-5.93 (m, 2H, H-1 and H-12), 6.15 (br d, J ) 10, 1H, H-11),
7;38-7.44 (m, 6H), 7.67-7.70 (m, 4H); 13C NMR (50.3 MHz) δ
17.8 (CΗ3), 19;3 (C), 23.4 (CΗ3), 26.9 (3CΗ3), 30.5 (CΗ3), 38.8
(C), 39.4 (C), 42.7 (CΗ2), 50.0 (CΗ), 64.3 (CH), 66.0 (CΗ2), 70.7
(CΗ), 75.1 (CH), 124.9 (CH), 126.7 (CH), 127.8 (4CH), 129.0
(CH), 129.9 (2CH), 133.5 (2C), 135.7 (4CH), 207.7(C); [R]D -75°
(c 6.2, CHCl3). [R]D -75° (c 6.2, CHCl3). Anal. Calcd for
C33H42O3Si: C, 77.04; H, 8.17. Found C, 77.12; H, 8.22.
Analysis and spectral data of the major isomer: IR 1677 cm-1
;
1H NMR (400 MHz) δ 7.74-7.68 (m, 4H), 7.45-7.38 (m, 6H),
6.56 (dt, J ) 17, 10.5, 1H), 6.02 (dt, J ) 10.3, 2.3, 1H), 5.94 (d,
J ) 10.8, 1H), 5.74 (dt, J ) 10.3, 2.0, 1H), 5.15 (dd, J ) 16.7,
1.5, 1H), 5.08 (d, J ) 10.5, 1H), 4.3-4.25(m, 2H), 3.82 (dd, J )
10.1, 5.6, 1H), 3.74 (dd, J ) 10.1, 6.9, 1H), 2.7-2.66 (m, 3H),
1.83 (s, 3H), 1.7 (s, 3H), 1.07 (s, 9H); 13C NMR (100.6 MHz) δ
185.0 (C), 137.6 (C), 135.6 (4 CH), 132.7 (CH), 129.7 (2 C and
CH), 129.1 (CH), 128.1 (CH), 127.7 (4 CH), 116.6 (CH2), 94.4
(C), 80.4 (C), 72.5 (CH), 69.4 (CH), 65.7 (CH2), 49.3 (CH and
CH2), 26.8 (3 CH3), 19.2 (C), 14.4 (CH3), 3.9 (CH3); MS (CI,
NH3) m/ z (%): 516(100) (M + NH4)+, 499(11), 421(25), 316(10),
274(16), 256(10), 196(25), 190(23), 134(30), 118(49), 78(43); [R]D
-86° (c 3.7, CHCl3). Anal. Calcd for C32H38O3Si: C, 77.06; H,
7.68. Found C, 77.11; H, 7.77.
Ack n ow led gm en t. We gratefully thank Professor
Thierry Prange´ (Universite´ de Paris Nord) for the X-ray
structure determination of compound 22b, and Ms.
Mireille Bertranne-Delahaye for the 2D NOESY NMR
experiments.
In tr a m olecu la r Diels-Ald er Rea ction of 14. Na p h -
th op yr a n on es 18a a n d 19a . A solution of 14 (155 mg, 0.31
mmol) and few crystals of hydroquinone in degassed toluene
under Ar (6 mL) were heated in a sealed Pyrex tube for 24 h
at 200 °C. After cooling, the toluene was evaporated under
reduced pressure and the residue flash chromatographed
(AcOEt/PE 5/95) to give 64 mg (41%) of 18a followed by 46
mg of 19a (30%).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures including synthesis and characterization of compounds
12, 15, 18b, 19b, 20-23, NMR spectra of 14 and 17, 2D
NOESY spectra of 18b and 19b, and the X-ray crystal data
for compound 22b (11 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
18a : colorless oil; Rf ) 0.5 (AcOEt/EP 1/9); IR 1696 cm-1
;
1H NMR (400 MHz) δ 7.70-7.68 (m, 4H), 7.45-7.39 (m, 6H),
6.11 (d, J ) 10.5, 1H, H-11), 5.93 (dt, J ) 9.6, 1.8, 1H, H-1),
5.92 (dt, J ) 10.5, 2.8, 1H, H-12), 5.70 (dt, J ) 10.1, 3.3, 1H,
H-2), 4.35 (m, 1H, H-13), 3.90 (ddd, J ) 12.1, 9.6, 5.1, 1H, H-8),
J O970999H