Total synthesis of (+)-4,5-deoxyneodolabelline

Article abstract of DOI:10.1021/ja0279803

The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxyneodolabelline (1) has been accomplished. The highly efficient approach is characterized by the convergent assembly of dihydropyrans 2ab and cyclopentylsilanes 3ab. Allylic silane

Full text of DOI:10.1021/ja0279803

Published on Web 01/23/2003
Total Synthesis of (+)-4,5-Deoxyneodolabelline
David R. Williams* and Richard W. Heidebrecht, Jr.
Contribution from the Department of Chemistry, Indiana UniVersity,
Bloomington, Indiana 47405
Received August 1, 2002 ; E-mail: williamd@indiana.edu
Abstract: The first total synthesis of the marine dolabellane diterpene (+)-4,5-deoxyneodolabelline (1)
has been accomplished. The highly efficient approach is characterized by the convergent assembly of
dihydropyrans 2ab and cyclopentylsilanes 3ab. Allylic silane 3a was prepared from 2-methyl-2-cyclopen-
tenone via a copper-catalyzed 1,4-addition followed by diastereoselective alkylation of the resulting enolate.
A chemical resolution of racemic cyclopentanone 8 was effected by (S)-CBS-catalyzed borohydride
reduction. Direct hydroxymethylation of the enantioenriched ketone 8 to form allylic alcohol 14 was achieved
by a Stille palladium-catalyzed cross-coupling from the cyclopentenyl triflate 13. Treatment of the
corresponding allylic phosphate 15 with trimethylsilylcopper reagent provided for displacement with allylic
transposition yielding the exocyclic allylsilane 3a with excellent diastereoselectivity. Dihydropyrans 2a and
2b were prepared from optically pure acyclic acetals via ring-closing metathesis. Coupling of 3a and 2a or
2b via the carbon-Ferrier protocol gave trans-2,6-disubstituted dihydropyrans 30 and 35 with complete
stereoselectivity. Vanadium-based pinacol coupling reactions were explored for closure of the medium-
sized carbocycle to yield syn-diol 33. X-ray diffraction studies of the monobenzoate 34 have provided
unambiguous stereochemical assignments. Substantial ring strain accounted for the lack of alkene products
typical of reductive elimination using TiCl3 and zinc-copper couple (McMurry) conditions leading to 37.
Finally, the natural product 1 was obtained via Swern oxidation of the diol 37.
Introduction
The dolabellanes are a family of bicyclic diterpenes which
were originally discovered as metabolites of the sea hare
Dolabella californica.1 Since 1975, more than 140 unique
structures have been reported from many sources.2 Dolabellanes
and neodolabellanes share a characteristic bicyclo[9.3.0]-
tetradecane skeleton (Figure 1). The biogenesis of dolabellanes
is proposed to initiate from a π-cation cyclization of gera-
nylgeranyl pyrophosphate. Neodolabellanes are the products of
subsequent stereospecific migrations of hydrogen and methyl
substituents along the carbon backbone, which accounts for the
stereochemistry at C11 and C12, and the translocation of the
methyl substituent (C15) across the ring fusion in these
metabolites as compared to the parent skeleton.
It was originally believed that these diterpenes were exclu-
sively of marine origin. However, several terrestrial sources have
been discovered.2a,b Earlier studies had proposed that the
widespread occurrence of dolabellanes in the marine ecosystem
was a result of dietary intake, distribution, and further metabo-
lism.3 While this may be true in many cases, it is now recognized
that related structures from different species have opposite
absolute stereochemistry, suggesting phenomena of bioconver-
gence.2
Figure 1.
The dolabellanes have exhibited an impressive range of
biological properties, including significant cytotoxic, antibacte-
rial, and antiviral activity.4 Reports include effective inhibition
of K+-induced contractions in blood aortic strips, while another
notes blockage of Ca2+ channels in isolated smooth muscle
tissue.5 Dolabellanes can also display ichthyotoxic and phyto-
toxic properties,6 and the recent discovery of novel structures
continues to spur interest in the family.7 Moreover, the 3,7-
dolabelladienes serve as direct biogenic precursors of the 5-7-6
tricyclic terpenes of the dolastane class, many of which display
significant antitumor properties.8
(4) (a) Mori, K.; Iguchi, K.; Yamada, N.; Yamada, Y.; Inouye, Y. Chem. Pharm.
Bull. 1988, 36, 2840. (b) Tringali, C.; Piattelli, M.; Nicolosi, G. Tetrahedron
1984, 40, 799.
(5) (a) Su, J.; Zhong, Y.; Shi, K.; Cheng, Q.; Synder, J. K.; Hu, S.; Huang, T.
J. Org. Chem. 1991, 56, 2337. (b) Su, J.; Zong, Y.; Zeng, L.; J. Nat. Prod.
1991, 54, 380.
(6) Van Onckelen, H. A.; Verbeek, R. Phytochemistry 1972, 11, 1677.
(7) For recent isolation papers: (a) Duh, C.-Y.; Chia, M.-C.; Wang, S.-K.;
Chen, H.-J.; El-Gamal, A. A. H.; Dai, C.-H. J. Nat. Prod. 2001, 64, 1028.
(b) Hinkley, S. F.; Mazzola, E. P.; Fettinger, J. C.; Lam, Y.-F.; Jarvis, B.
B. Phytochemistry 2000, 55, 663. (c) Costantino, V.; Fattorusso, E.;
Mangoni, A.; Di Rosa, M.; Ianaro, A.; Aknin, M.; Gaydou, E. M. Eur. J.
Org. Chem. 1999, 1, 227.
(1) Ireland, C.; Faulkner, D. J.; Finer, J.; Clardy, J. J. Am. Chem. Soc. 1976,
98, 4664.
(2) (a) For a review: Rodriguez, A. D.; Gonzalez, E.; Ramirez, C. Tetrahedron
1998, 54, 11683. (b) Asakawa, Y.; Lin, X.; Tori, M.; Kondo, K.
Phytochemistry 1990, 29, 2597.
(3) (a) Sun, H. H.; Fenical, W. Phytochemistry 1979, 18, 340. (b) Ireland, C.;
Faulkner, D. J. J. Org. Chem. 1977, 42, 3157.
9
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J. AM. CHEM. SOC. 2003, 125, 1843-1850
1843

A R T I C L E S
Williams and Heidebrecht
Scheme 1
Scheme 2
Several investigations have focused on strategies for con-
struction of these eleven-membered macrocyclic structures. In
1993, we reported the first synthesis of fully elaborated
dolabellanes via intramolecular Julia reactions of R-sulfonyl
carbanions,9a and in 1995, we described the first synthesis of
R- and â-neodolabellenol.9b An intramolecular alkylation route
was also reported in 1993, leading to a dolabellane progenitor
for biomimetic transannular cyclization resulting in the total
synthesis of (-)-3R,4â-dihydroxyclavulara-1(15),17-diene, an
example of the dolastane family.10 Jenny and Borschberg
demonstrated ring closure via an enolate alkylation to provide
for synthesis of the hydrocarbon (()-δ-araneosene,11 while
Yamada and co-workers have also utilized an intramolecular
alkylation strategy for the synthesis of claenone.12
refluxing ethanol gave the olefin 1 (55%), thereby establishing
the structural and stereochemical relationship of these metabo-
lites.
A convergent plan for total synthesis of 1 is suggested via
bond disconnections at C2/C3 and at C8/C9 to provide precursors
2 and 3. Each component contains approximately one-half of
the structural information and the molecular complexity of the
natural product (1), providing an attractive element of simplicity
for the overall scheme.
Rearrangements leading to both ring expansions and ring
contractions have been effective processes for development of
the eleven-membered carbocycles. Mehta published an early
study of the oxy-Cope ring expansion reaction toward the
dolabellanes.13 Subsequently, Corey and Kania described a
noteworthy enantioselective Claisen rearrangement, as well as
the anionic oxy-Cope reaction for the synthesis of these
diterpenes.14
Recent investigations in our laboratories have pursued strate-
gies for the efficient assembly of cyclic diterpenes which contain
bridging ether linkages. Many marine terpenes incorporate five-
and six-membered ethers as a consequence of transannular
cyclization events. In this regard, 4,5-deoxyneodolabelline (1),
a metabolite of an Australian soft coral, is a typical example
(Scheme 1).15 The parent compound, neodolabelline, was first
identified as the 4,5-epoxide of 1, and structural elucidation was
completed by X-ray diffraction of the C1/C14 dibromide
derivative.16 Deoxygenation of neodolabelline with Zn(Cu) in
Results and Discussion
Our studies initially focused on a convenient pathway for
preparation of the cyclopentenyl silane 3. Using a four-step
procedure, which had been developed and optimized in our
previous efforts,9a the copper-catalyzed conjugate addition of
isopropylmagnesium chloride with 2-methyl-2-cyclopentenone
was accelerated in the presence of trimethylsilyl chloride.17 Piers
and Renaud reported similar findings,18 and the presence of
hexamethylphosphoric triamide as a necessary additive resulted
in high yields of the silyl enol ether 4 (Scheme 2). Treatment
of 4 with methyllithium at -20 °C facilitated regiocontrolled
access to the tetrasubstituted enolate which underwent stereo-
selective alkylation with allyl bromide.
Ozonolysis of 5 followed by immediate reduction of aldehyde
6 with lithium tri-tert-butoxyaluminohydride selectively pro-
vided alcohol 7a and hemiketal 7b as an equilibrating mixture
(2.4:1 ratio in CDCl3 solution). Treatment of this mixture with
tert-butyldimethylsilyl chloride (TBSCl) and imidazole at room
temperature led to nearly quantitative yields of the desired
ketone 8. The attractive sequence was favored because it readily
permitted the dependable preparation of 50-g quantities of 8 in
61% overall yield, although it clearly suffered from a lack of
enantiocontrol. While the latter objective was also feasible
beginning from a chiral pool precursor, the process required
many more steps with lower efficiency.
(8) Dolatriol was the first example: Pettit, G. R.; Ode, R. H.; Herald, C. L.;
Von Dreele, R. B.; Michel, C. J. Am. Chem. Soc. 1976, 98, 4677. Recently,
representatives of this class, known as trichoaurantianolides and guana-
castepenes, have been isolated from fungi, and display the methyl migration
characterizing the neodolabellanes, as well as the 5-7-6 tricyclic skeleton
of the dolastanes. Benevelli, F.; Carugo, O.; Invernizzi, A. G.; Vidari, G.
Tetrahedron Lett. 1995, 36, 3035. Brady, S. F.; Bondi, S. M.; Clardy, J. J.
Am. Chem. Soc. 2001, 123, 9900. For a recent report on the total synthesis
of guanacastepene A: Lin, S.; Dudley, G. B.; Tan, D. S.; Danishefsky, S.
J. Angew. Chem., Int. Ed. 2002, 41, 2188.
(9) (a) Williams, D. R.; Coleman, P. J.; Nevill, C. R.; Robinson, L. A.
Tetrahedron Lett. 1993, 34, 7895. (b) Williams, D. R.; Coleman, P. J.
Tetrahedron Lett. 1995, 36, 35.
(10) Williams, D. R.; Coleman, P. J. Tetrahedron Lett. 1995, 36, 39.
(11) (a) Jenny, L.; Borshberg, H.-J. HelV. Chim. Acta 1995, 78, 715. (b) For a
recent palladium-mediated approach: Hu, T.; Corey, E. J. Org. Lett. 2002,
4, 2441.
Chemical resolution of 8 was accomplished by asymmetric
reduction utilizing the Corey CBS borohydride reaction.19 The
slow addition of cyclopentanone 8 into a warm solution of
oxazaborolidine catalyst and borane dimethyl sulfide complex
at 40 °C was necessary to obtain products with satisfactory
(12) (a) Miyaoka, H.; Isaji, Y.; Kajiwara, Y.; Kunimune, I.; Yamada, Y.
Tetrahedron Lett. 1998, 39, 6503. (b) See also: Kato, N.; Higo, A.; Wu,
X.; Takeshita, H. Heterocycles 1997, 46, 123.
(13) Mehta, G.; Karra, S. R.; Krishnamurthy, N. Tetrahedron Lett. 1994, 35,
2761.
(17) For information regarding TMSCl and organocopper reagents: Nakamura,
E. Me3SiCl-accelerated conjugate addition reactions of organocopper
reagents. In Organocopper Reagents; Taylor, R. J. K., Ed.; Oxford
University Press: New York, 1994; pp 129-140.
(14) (a) Corey, E. J.; Kania, R. S. J. Am. Chem. Soc. 1996, 118, 1229. (b) Corey,
E. J.; Kania, R. S. Tetrahedron Lett. 1998, 39, 741.
(15) Bowden, B. F.; Coll, J. C.; Gulbis, J. M.; Mackay, M. F.; Willis, R. H.
Aust. J. Chem. 1986, 39, 803.
(18) Piers, E.; Renaud, J. J. Org. Chem. 1993, 58, 11.
(16) Kobayashi, M.; Son, B.-W.; Fujiwara, T.; Kyogoku, Y.; Kitagawa, I.
Tetrahedron Lett. 1984, 25, 5543.
(19) For a general review: Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed.
1998, 37, 1986.
9
1844 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Synthesis of (+)-4,5-Deoxyneodolabelline
A R T I C L E S
Scheme 3
Scheme 4
Scheme 5
optical purity.20,21 Equal quantities of two diastereomeric
cyclopentanols 9 and 10 were readily separated by flash silica
gel chromatography. Product formation can be rationalized as
illustrated in Scheme 3 via an internally directed hydride
addition to the activated ketone 8 through diastereomeric
transition states which place the bulky R-position toward the
convex face of the cis-fused CBS scaffold. Thus, facial
selectivity is not influenced by the absolute stereochemistry of
the fully substituted R-carbon of 8. Assignments of relative
stereochemistry for 9 and 10 were confirmed, following the
treatment of the individual alcohols with Jones’ reagent at -10
°C (THF; Celite), yielding the cis-fused lactone 11 and the keto
aldehyde (-)-6, respectively.22
alcohol 14. Transformation of 8 to the corresponding triflate
13 was followed by Stille cross-coupling26 with tri-n-butylstan-
nylmethanol (Scheme 4)27,28 Initial attempts noted that con-
sumption of stannane was much faster than that of the triflate.
Thus, syringe-pump addition of tri-n-butylstannylmethanol to
the reaction mixture, maintained at 70 °C, afforded the allylic
alcohol in 67% yield. Examination of the catalyst load revealed
that 5% (Ph3P)4Pd with 3 equiv of LiCl (based on triflate)
afforded highly reproducible reactions, however, the allylic
alcohol 14 was invariably accompanied by protodesulfonated
cyclopentene. This reduction pathway has been recognized as
the result of butyl group participation from the Pd-insertion
intermediate resulting in â-hydride elimination. The procedure
has been used to reduce triflates to their corresponding alkenes.29
In our case, this complication could reasonably be circumvented
by the use of the analogous trimethylstannyl methanol but was
not explored in favor of the use of the less volatile tri-n-
butylstannane.
Our synthesis plan required the transformation of ketone 8
into an allylic system with the addition of a methylene unit.
Upon TPAP oxidation23 of the optically enriched cyclopentanol
9, two options were explored for one-carbon homologation of
the (+)-cyclopentanone 8 (Scheme 4). Initial formation of the
hydrazone derivative permitted a radical-induced decomposition
leading to the cyclopentenyl iodide 12 with loss of nitrogen in
the presence of 1,1,3,3-tetramethylguanidine (TMG).24 While
the low-temperature halogen-metal exchange of 12 was effec-
tive, the preparative-scale alkylations with gaseous formaldehyde
leading to 14 proceeded with significantly reduced yields.25
A
palladium-catalyzed cross-coupling strategy proved most suc-
cessful for conversion of the ketone 8 to the requisite allylic
(20) (a) For temperature effects on CBS reduction: Stone, G. B. Tetrahedron:
Asymmetry 1994, 5, 465. (b) For a related reduction of an R,R-disubstituted
cyclopentanone: Denmark, S. E.; Schnute, M. E.; Marcin, L. R.; Thora-
rensen, A. J. Org. Chem. 1995, 60, 3205.
(21) (a) The optical purities were determined by Mosher ester analysis: Dale,
J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1969, 34, 2534. (b) Dale,
J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem. 1973, 95, 512. (c) The
esters were prepared using a carbodiimide coupling: Albert, J. S.; Hamilton,
A. D. 1,3-Dicyclohexylcarbodiimide-4-Dimethylaminopyridine. In Ency-
clopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley and Sons: Chichester, England, 1995; Vol. 3, pp 1755-1756.
(22) The lactone 11 was also confirmed via the unambiguous stepwise
elaboration from 9 by acetylation of the secondary alcohol, TBS ether
cleavage, TPAP oxidation, deacetylation with methanolic potassium carbon-
ate, and TPAP oxidation of the resulting lactol. Keto aldehyde (-)-6 was
compared to racemic material from direct oxidative cleavage of (()-5.
(23) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. J. Chem.
Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V.
Aldrichimica Acta 1990, 23, 13.
Esterification of alcohol 14 was followed by SN2′ displace-
ment of the diethyl phosphate by trimethylsilyl cuprate (Scheme
5).30 Exclusive formation of the exo olefin was observed, and
the allylsilane 3 was formed as a 24:1 ratio of 3a:3b diastere-
omers. We observed a progressive erosion of diastereoselectivity
(26) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033.
(27) For preparation of the stannane: Danheiser, R. L.; Romines, K. R.; Koyama,
H.; Gee, S. K.; Johnson, C. R.; Medich, J. R. Org. Synth. 1993, 71, 133.
(28) (a) For previous results utilizing this unprotected stannane: Kosugi, M.;
Sumiya, Y.; Ohhashi, K.; Sano, H.; Migita, T. Chemistry Lett. 1985, 997.
(b) Yasuda, N.; Yang, C.; Wells, K. M.; Jensen, M. S.; Hughes, D. L.
Tetrahedron Lett. 1999, 40, 427.
(29) Cook, G. K.; Hornback, W. J.; Jordan, C. L.; McDonald, J. H., III; Monroe,
J. E. J. Org. Chem. 1989, 54, 5828.
(30) Smith, J. C.; Henke, S. L.; Mohler, E. M.; Morgan, L.; Rajan, N. I. Synth.
Comm. 1991, 21, 1999.
(24) (a) Barton, D. H. R.; Bashiardes, G.; Fourrey, J. L. Tetrahedron Lett. 1983,
24, 1605. (b) Coleman, P. J. Ph.D. Thesis, Indiana University, August 1994.
(25) Transformation to 14 was also carried out in moderate overall yield by
halogen/lithium exchange of 12 (nBuLi/Et2O/-78 °C), acylation with methyl
chloroformate, and hydride reduction.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1845

A R T I C L E S
Williams and Heidebrecht
Table 1. Stereochemical Assignment of 3a via nOe NMR
Experiments of 16
Scheme 7
entry
irradiation
% nOe
1
2
3
Me3Si
Me3Si
Me3Si
4.4% Ha
1.3% CH2
3.4% Hb
Scheme 6
Finally, ring-closing metathesis using the Grubbs ruthenium
catalyst 20, bearing the 1,3-dimesityl-4,5-dihydroimidazole-2-
ylide ligand, provided the desired 2a as a 1:1 mixture of
anomers.34 The metathesis reaction is a superior strategy for
synthesis of these dihydropyrans.35 In our example, catalyst
loads as low as 2% were utilized to effect cyclization at room
temperature in nearly quantitative yields. By comparison,
experiments using the bis-tricyclohexylphosphine-based ruthe-
nium catalyst36 also provided 2a, although reactions failed to
progress to completion even with high catalyst loads.
A second pathway was developed to incorporate the C-8
methyl substituent. The known aldehyde 2137 was transformed
into the homoallylic alcohol 22 via the chelation-controlled
addition38 of allyltrimethylsilane at -78 °C. As anticipated,
acetal exchange and ring-closing metathesis yielded 2b (95%)
as a mixture (1:1) of ethyl acetals.
Formation of the C2-C3 Bond via Allylation. Fundamental
understanding of our proposed allylation process requires some
digression of the discussion to describe our initial plans for a
convergent synthesis involving the use of a carbon-Ferrier
strategy as precedented, in principle, by the elegant work of
Danishefsky, Fraser-Reid, and others.39,40 To this end, we
prepared the glycals 23 as shown in Scheme 7. Substituted
acetaldehydes 24 were subjected to hetero-Diels-Alder reac-
tions with diene 2541 using boron trifluoride etherate at -78
°C. The racemic γ-pyranones 26 were isolated in approximately
50-60% yields, and a subsequent Luche reduction42 was
followed by acetylation to provide the equatorial acetates 23.
as the scale of the reaction was increased from approximately
100 mg of 15 to the 2-g level. This was attributed to the
prolonged cannulation of the cuprate and local exotherms in
the larger-scale reactions. Fortunately, our subsequent experi-
ments demonstrated that either diastereomer 3a or 3b could be
effectively utilized without stereochemical consequences (vide
infra). The stereochemical selectivity of the allylic displacement
can be rationalized by the preferred pseudoaxial addition of the
silyl reagent with the cyclopentenyl conformer characterized
by pseudoequatorial disposition of the isopropyl group.
Careful silica gel chromatography led to the isolation of pure
samples of 3a for complete characterization. The relative
stereochemistry at C14 of 3a was secured via nOe difference
experiments after silyl ether hydrolysis as shown in Table 1.31
Synthesis of the 5,6-Dihydropyran Component. Syntheses
of homochiral dihydropyrans 2a and 2b were accomplished
using two pathways which differed in the nature of the
substitution at C8 (Scheme 6). The C-8 desmethyl-5,6-dihydro-
pyran 2a was prepared in four steps. Protection of (R)-glycidol
as its methoxymethyl ether 1732 was followed by copper-
catalyzed nucleophilic oxirane opening using vinylmagnesium
bromide. Formation of the mixed acetal 19 was promoted by
acid-catalyzed exchange of ethanol at room temperature under
reduced pressure (55 mmHg).33
(34) (a) Grubbs, R. H.; Miller, S. J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446.
(b) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (c) Scholl, M.;
Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
(35) (a) Rutjes, F. P. J. T.; Kooistra, T. M.; Hiemstra, H.; Schoemaker, H. E.
Synth. Lett. 1998, 192. (b) Weatherhead, G. S.; Houser, J. H.; Ford, J. G.;
Jamieson, J. Y.; Schrock, R. R.; Hoveyda, A. H. Tetrahedron Lett. 2000,
41, 9553. (c) Nadolski, G. T.; Davidson, B. S. Tetrahedron Lett. 2001, 42,
797. (d) Enev, V. S.; Kaehlig, H.; Mulzer, J. J. Am. Chem. Soc. 2001, 123,
10764.
(36) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18-29.
(37) Aldehyde 21 was synthesized from (S)-ethyl lactate in three steps: Banfi,
L.; Bernardi, A.; Colombo, L.; Gennari, C.; Scolastico, C. J. Org. Chem.
1984, 49, 3784.
(38) (a) Heathcock, C. H.; Kiyooka, S.; Blumenkopf, T. A. J. Org. Chem. 1984,
49, 4214. (b) The antipode of 22a is known: Brabander, J. D.; Vandewalle,
M. Synthesis 1994, 855.
(39) (a) Ferrier, J. R. J. Chem. Soc. 1964, 5443. (b) Ferrier, J. R.; Prasad, N. J.
Chem. Soc. (C) 1969, 570. (c) Hurd, C. D.; Bonner, W. A. J. Am. Chem.
Soc. 1945, 67, 1664. (d) Danishefsky, S.; Kerwin, J. F. J. Org. Chem. 1982,
47, 3805.
(31) For a similar deprotection: Trost, B. M.; Grese, T. A.; Chan, D. M. T. J.
Am. Chem. Soc. 1991, 113, 7350.
(32) Bachki, A.; Foubelo, F.; Yus, M. Tetrahedron: Asymmetry 1995, 6, 1907.
(33) (a) Mulzer, J.; Hanbauer, M. Tetrahedron Lett. 2000, 41, 33. (b) Crimmins,
M. T.; King, B. W. J. Am. Chem. Soc. 1998, 120, 9084.
(40) (a) Danishefsky, S.; Kerwin, J. F. J. Org. Chem. 1982, 47, 3803. (b) Dawe,
R. D.; Fraser-Reid, B. J. Chem. Soc., Chem. Commun. 1981, 1180.
(41) (a) Clive, D. L.; Berstra, R. J. J. Org. Chem. 1991, 56, 4976. (b) Sugasawa,
S.; Yamada, S.; Narahashi, M. J. Pharm. Soc. Jpn. 1951, 71, 1345.
9
1846 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Synthesis of (+)-4,5-Deoxyneodolabelline
A R T I C L E S
Table 2. Diastereoselection in Allylation Reactions
of methoxymethyl (MOM) or â-methoxyethoxymethyl (MEM)
ethers 23a or 23b provided for the most stereoselective
allylations as summarized in Table 2. The thiophenyl example
23c, the tert-butyldiphenyl silyl (TBDPS) ether 23d, and the
electron-deficient benzyl ethers 23f and 23g led to modest
selectivity. However, the use of simple esters, as typified by
the pivaloate 23g and the p-nitrobenzoate 23i, as well as that
of the benzyl ether 23e gave surprisingly inferior results.48
Stronger Lewis acids also generally resulted in a deterioration
of diastereoselectivity.49
entry
ratio of 29a/29b
yield, %
The aforementioned problems of the glycal pathway led to
the development of the olefin metathesis route of Scheme 6 as
a source of electrophilic coupling partners for our allylations.
In the event, reaction of optically active dihydropyran acetal
2a and allylsilane 3a afforded a single diastereoisomer 30. A
survey of Lewis acids demonstrated that BF3‚OEt2 was opti-
mum. Since a slight excess of acetal 2a (1.3:1 ratio of 2a to
3a) proved to be beneficial, unconsumed dihydropyran was
recovered and was observed to be predominantly one diaste-
reomer (>95:5). The same dihydropyran anomer was also
generated by thermodynamic equilibration of the 1:1 mixture
of acetals 2a under mildly acidic conditions with PPTs in ethanol
(22 °C) or with BF3‚OEt2 (CH2Cl2 at -78 °C). This pseudoaxial
R-anomer50 was coupled with silane 3a to provide 30 in the
same yields as were previously observed with the mixture 2a,
thus establishing that both anomers of the starting acetal were
equally reaction-competent via a common oxocarbenium ion
or initial acetal isomerization. Additionally, we briefly examined
the role of the protecting group at C-8. Synthesis of the
analogous tert-butyldimethylsilyl (TBS) ether of 2a was achieved
via the pathway described in Scheme 6. In contrast to our
previous efforts in Table 2, allylations using the corresponding
TBS ether of 2a proceeded to give the bis-TBS ether 30 (R1 )
R2 ) TBS) in 73% yield with 100% stereoselectivity.
23a R ) OMOM
9:1
8.1:1
3.5:1
3.5:1
1.8:1
4.6:1
6.7:1
1.9:1
2.2:1
99
80
91
68
91
97
96
80
54
23b R ) OMEM
23c R ) SC6H5
23d R ) OSitBuPh2
23e R ) OCH2C6H5
23f R ) OCH2C6H4NO2
23g R ) OC7H5-3-Cl-4-N3
23h R ) O2CtBu
23i R ) O2C7H4NO2
The silyl ether 26 (R ) OSitBuPh2) was cleaved (TBAF, THF)
to give the corresponding primary alcohol 26 (R ) OH) which
permitted the incorporation of various acid-labile esters and
ethers not well tolerated under the hetero-Diels-Alder condi-
tions. Among these alternatives, the methoxymethyl (MOM)-
substituted example 23a demonstrated the most promise in our
allylation studies (vide infra). Thus, asymmetric induction was
examined for Diels-Alder cycloadditions of acetaldehyde 24
(R ) OMOM). Use of the 1,1′-bi-2-naphthol (BINOL)-based
titanium catalyst 27 as developed by Keck43 led to a 37% yield
of 26 (R ) OMOM) with 84% ee.44 Similar explorations of
the salen-based chromium catalyst 28 described by Jacobsen45
improved the yield of the hetero-Diels-Alder product 26 (R )
OMOM) (87%), but resulted in a deterioration of optical
purity.46
Unforeseen problems also became apparent in the course of
subsequent studies of the allylation-Ferrier process. Upon
attempted optimization of our glycal reactions with pure
allylsilane 3a (Table 2) using boron trifluoride etherate at -78
°C, we observed that diastereoselectivity was strongly affected
by the nature of the remote protecting group (at C8) in 23.
Product ratios of major isomer, 2,6-trans-disubstituted 3,6-
dihydro-2H-pyrans 29a, and the cis-2,6-disubstituted (minor)
29b were determined by the integration of pairs of NMR signals
for the C3 hydrogens, which were not further complicated by
the chirality (at C11 and C12) of the cyclopentene.47 The choice
The influence of stereochemistry in the silanes 3ab was also
examined. A control experiment combining a 1:1 mixture of
allylsilane diastereomers 3ab and the usual mixture of acetal
anomers 2a (1:1 ratio) was performed. This reaction provided
30 as a single diastereomer (at C-3) in yields comparable to
those previously observed from pure 3a. A more detailed
(42) (a) Luche, J. L.; Rodriguez-Hahn, L.; Crabbe, P. Chem. Commun. 1978,
601. (b) Gleason, M. M.; McDonald, R. E. J. Org. Chem. 1997, 62, 6432.
(43) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60, 5998.
(44) Remaining material was identified as the Mukaiyama aldol product i which
was cyclized to 26 with mild acid. Unfortunately, these additional quantities
of 26 exhibited greatly reduced enantiopurity.
(48) Although the carbon-Ferrier reactions would appear to proceed via a
commonly held oxocarbenium species, a clear pattern of reactivity emerged
from our experiments with a series of C8 benzyl ethers. Electron-donating
substituents, such as the p-methoxy benzyl ether (PMB) led to a highly
reactive glycal 23 and poor allylation results, whereas one or more electron-
withdrawing aryl substituents (nitro, chloride, and azido substituents were
examined without optimization) provided for sequentially improved yields
and diastereoselectivity for 29.
(49) The reactivity of the nucleophilic olefin may also be an important factor.
Trials with less reactive allyltrimethylsilane and 23 generally resulted in
higher selectivity. Related studies using silyl ketene acetals report modest
diastereoselectivity. See: Paterson, I.; Smith, J. D.; Ward, R. A. Tetrahedron
1995, 51, 9413.
(45) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem., Int. Ed.
1999, 38, 2398.
(46) These efforts produced 26 in 50-60% ee as determined by subsequent
cleavage of the methoxymethyl ether yielding 26 (R ) OH), and formation
of diastereomers by Mosher esterification analysis.
(47) For many entries of Table 2, the pairs of trans-2,6-pyrans 29a and cis-29b
were separated by flash silica gel chromatography. Confirmation of the
structure assignment was provided by comparison with authentic 30 and
the subsequent X-ray diffraction study of 34.
(50) The stereochemistry of the thermodynamically more stable acetal is assumed
on the basis of comparisons with closely related dihydropyran systems.
See: Deslongchamps, P. Stereoelectronic Effects in Organic Chemistry;
Pergamon Press: New York, 1983; pp 4-21.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1847

A R T I C L E S
Williams and Heidebrecht
Figure 2. Stereocontrolled nucleophilic attack for conformers A and B.
analysis was also performed by running reactions to 50%
completion by a reduction in the quantity of Lewis acid.
Unconsumed silane showed an enrichment of the â-isomer 3b
(recovery ratio 3a:3b was 2.2:1). On the basis of the knowledge
of the starting ratio of 3ab (3.3:1), concentrations [3a] and [3b]
of each allylsilane diastereomer at the initiation (t0) and
termination (t1/2) of the reaction were determined. The ratio of
the rate expressions as shown in eq 1 indicated that the
predominant 3a reacted approximately twice as fast as 3b. The
slight differences in reactivity of our diastereomers 3ab are more
interesting in a mechanistic context. However, the impressive
diastereoconvergence of our reaction pathway dramatically
facilitated a successful synthesis.
Figure 3. Synclinal and anticlinal arrangements as shown from Newman
projections and 3-D representations.
Scheme 8
[3a]t
1/2
ln
kR
kâ
[3a]t0
[3b]t
relative rate of reaction
)
)
) 2 (1)
for 3a/3b
1/2
ln
[3b]t0
Rationalization of the stereochemical outcome of the coupling
process recognizes two conformers of the oxocarbenium inter-
mediate as distinguished by the pseudoequatorial substituent in
A and the pseudoaxial substituent in B (Figure 2). From this
standpoint, it is noteworthy that stereoelectronically controlled
axial attack of the allylsilane 3ab with the more stable conformer
A dominates the reaction coordinate leading to the observed
2,6-trans-dihydropyran 30 via a developing chair transition state.
The similar rates of reactions for 3a and 3b provide additional
mechanistic insights. The addition reactions of allylsilanes and
aldehydes are commonly rationalized by open transition states
as described by synclinal and anticlinal arrangements.51
A
Reductive Coupling for Nine-Membered Ring Formation.
Construction of the neodolabelline ring system required C8-
C9 bond formation beginning with the protected diol 30. The
limited degrees of freedom imposed by the preexisting rings in
30 were viewed as a positive contributor for effective closure
of the nine-membered ring via a reductive coupling strategy.
Aside from issues of stereochemistry, a caveat of this approach
was the potential for reductive elimination that would open the
dihydropyran ring. As shown in Scheme 8, sequential depro-
tections of 30 gave diol 31 by removal of the MOM52 and silyl
ethers, respectively. Swern oxidation53 led to the labile dialde-
hyde 32, and reductive coupling using [V2Cl3(THF)6]2[ZnCl6]54
gave the diol 33 as the major component of a 9:1 mixture of
diastereomers (66% for two steps). Preferential production of
cis-diols is attributed to vanadium chelation in this pinacol
dominant feature of these transition states is the anti orientation
of the carbon-silicon bond with the newly forming carbon-
carbon bond. This factor provides for electron donation stabiliz-
ing the transition state. Further considerations of the diastere-
omeric relationship of 3a and 3b suggest that the major isomer
3a proceeds via the synclinal arrangement, whereas 3b reacts
similarly via the anticlinal situation (Figure 3). Steric interactions
are significant factors controlling the relative ease of these
reactions, and these effects are minimized, to an equal extent,
with respect to the adjacent quaternary carbon of the silane
diastereomers, as illustrated below. On the other hand, the
consistent application of either the synclinal or anticlinal model
to both diastereomers would lead to problematic concerns
stemming from steric interactions with substituents of the
quaternary carbon, and certainly portend differences in the
effectiveness and rates of these allylations.
(52) (a) Guidon, Y.; Morton, H. E.; Yoakim, C. Tetrahedron Lett. 1983, 24,
3969. (b) Guidon, Y.; Yoakim, C.; Morton, H. E. J. Org. Chem. 1984, 49,
3912.
(51) Calculations indicate similar opportunities for synclinal and anticlinal
transition states: Paddon-Row: M. N.; Rondan, N. G.; Houk, K. N. J.
Am. Chem. Soc. 1982, 104, 7162. Some examples include: Denmark, S.
E.; Weber, E. J. HelV. Chim. Acta 1983, 66, 1655. Danishefsky, S. J.;
DeNinno, S.; Lartey, P. J. Am. Chem. Soc. 1987, 109, 2082. Masse, C. E.;
Panek, J. S. Chem. ReV. 1995, 95, 1293. Fleming, I.; Dunogues, J.; Smithers,
R. Org. React. 1989, 37, 57.
(53) Mancuso, A. J.; Huang, S.-H.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(54) (a) Generated by reduction of VCl3(THF)3 with zinc dust: Freudenberger,
J. H.; Konradi, A. W.; Pedersen, S. F. J. Am. Chem. Soc. 1989, 111, 8014.
(b) Kammermeier, B.; Beck, G.; Jacobi, D.; Jendralla, H. Angew. Chem.,
Int. Ed. Engl. 1994, 33, 685. (c) This complex has been characterized by
X-ray crystallography: Cotton, A. F.; Duraj, S. A.; Roth, W. J. Inorg. Chem.
1985, 24, 913.
9
1848 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003

Synthesis of (+)-4,5-Deoxyneodolabelline
A R T I C L E S
Scheme 9
Scheme 10
Scheme 11
reaction.55 In our case, the stereochemistry of the major cis-
diol was conclusively demonstrated by single-crystal X-ray
analysis upon conversion of 33 to the monobenzoate 34.56
At this juncture, completion of the synthesis required the
production of a tertiary alcohol at C8 by the installation of a
methyl group corresponding to C17. Inspection of a model based
on the rigid, tricyclic 33 asserted that attack of a methyl
carbanion at a C8 ketone would most likely approach from the
â-face, providing material epimeric to the natural product. Issues
of stereochemistry and the overall inefficiency of sequential
oxidations at C8 and C9 of 33 prompted the early incorporation
of the C17 methyl group in the dihydropyran component 2b.57
Encouraged by the stereoselectivity of the vanadium-reductive
ring closure, we explored the use of the analogous C8 methyl
ketone. The allylation reaction with the ethyl acetals 2b
proceeded with complete diastereoselectivity as previously
described to give the trans-dihydropyran 35 in 87% yield
(Scheme 9). Deprotection of both C8 and C9 protecting units in
35 was effectively executed in good yield upon treatment with
sulfuric acid in methanol, and the Swern oxidation gave a single
keto aldehyde 36. Since base-induced epimerization (at C7) was
clearly feasible, an X-ray diffraction study of the low-melting
36 was undertaken, confirming the stereochemistry of the trans-
2,6-disubstituted dihydropyran.
may be attributed to the high degree of ring strain introduced
by further reductive eliminations. While yields were uniformly
excellent, the ratio of diastereomeric products varied with subtle
changes. These experiences significantly contrast with the
problematic and often low-yielding formation of diols via the
McMurry cyclization as exemplified in the synthesis of taxol.59
Our careful monitoring of concentration, rate of addition of 36,
and solvent purification reproducibly provided 85% yields of
37a, 37b, 37c, and 37d in a ratio of 8:2:1:1, respectively.
Since the separation of diol isomers was impractical, trial
oxidations of the mixture demonstrated that activated DMSO
reagents (oxalyl chloride, DMSO;53 TFAA, DMSO;60 and SO3‚
pyridine61) promoted formation of two separable ketones without
C-C bond cleavage. Mild oxidations with TPAP, Dess-Martin,
and TEMPO reagents resulted in glycol cleavage to 36. The
Swern oxidation was accompanied by methylthiomethyl ether
formation,62,63 as well as some decomposition with prolonged
reaction times. To avoid this problem, oxidations were quenched
at an estimated point of 70-80% completion, and the readily
separated diol mixture was resubmitted. The recombination of
ketone products, followed by flash silica gel chromatography,
led to synthetic 1 in 65% yield and a small amount of the C8
epimer (Scheme 11). All comparisons of spectra, and optical
Unfortunately, treatment under the conditions previously
described for the vanadyl-promoted coupling led to the recovery
of 36 and only traces of diol product. Successful reductive ring
closure was accomplished in excellent yield with TiCl3/Zn(Cu)
in DME, providing diol 37 as a mixture of four diastereomers
(Scheme 10).58 Olefinic products generally derived from the
McMurry conditions are not observed in our case, a fact which
(59) (a) Nicolaou, K. C.; Yang, Z.; Liu, J.-J.; Nantermet, P. G.; Claiborne, C.
F.; Renaud, J.; Guy, R. K.; Shibayama, K. J. Am. Chem. Soc. 1995, 117,
645. (b) For other McMurry coupling reactions of diketones and keto
aldehydes: McMurry, J. E.; Dushin, R. G. J. Am. Chem. Soc. 1990, 112,
6942. (c) Mukaiyama, T.; Shiina, I.; Iwadare, H.; Saitoh, M.; Nishimura,
T.; Ohkawa, N.; Sakoh, H.; Nishimura, K.; Tani, Y.; Hasegawa, M.;
Yamada, K.; Saitoh, K. Chem. Eur. J. 1999, 5, 121.
(55) (a) Additional examples of selectivity: Konradi, A. W.; Pedersen, S. F. J.
Org. Chem. 1992, 57, 28. (b) Banfi, L.; Guanti, G.; Basso, A. Eur. J. Org.
Chem. 2000, 939.
(56) Benzoate 34 is probably formed by acylation of the less hindered C8 alcohol
and internal acyl transfer. The X-ray data also confirmed the absolute
stereochemistry of 9 arising from the CBS reduction.
(57) Our inability to produce the C8/C9 diketone is most likely due to ring strain.
(58) (a) McMurry, J. E.; Lectka, T.; Rico, J. G. J. Org. Chem. 1989, 54, 3748.
(b) For recent reviews: Ephritikhine, M. J. Chem. Soc., Chem. Commun.
1998, 2549. (c) Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl.
1996, 35, 2442. (d) Lectka, T. The McMurry Reaction. In ActiVe Metals.
Preparation, Characterization, Applications; Fu¨rstner, A., Ed.; VCH
Publishers: New York, 1995; pp 85-131.
(60) Omura, K.; Sharma, A. K.; Swern, D. J. Org. Chem. 1976, 41, 957.
(61) (a) Parikh, J. R.; Doering, W. von E. J. Am. Chem. Soc. 1967, 89, 5505.
(b) Tidwell, T. T. Dimethyl Sulfoxide-Sulfur Trioxide/Pyridine. In Ency-
clopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; John
Wiley and Sons: Chichester, England, 1995; Vol. 3, pp 2156-2157.
(62) (a) Moffatt, J. G.; Pfitzer, K. E. J. Am. Chem. Soc. 1965, 87, 5670. (b)
Johnson, C. E.; Phillips, W. G. J. Am. Chem. Soc. 1969, 91, 682. (c) Corey,
E. J.; Kim, C. U. J. Am. Chem. Soc. 1972, 94, 7586. (d) Hendrickson, J.
B.; Schwartzman, S. M. Tetrahedron Lett. 1975, 4, 273.
(63) Williams, D. R.; Klingler, F. D.; Dabral, V. Tetrahedron Lett. 1988, 29,
3415.
9
J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003 1849

A R T I C L E S
Williams and Heidebrecht
rotations, with data obtained for authentic material confirmed
the major ketone to be synthetic (+)-4,5-deoxyneodolabelline.64
One postscript to this study describes efforts which were
undertaken to confirm the stereochemical identities of diols
37a-d. Information gathered from the X-ray study of 34, and
molecular modeling of the ketone 1, reveals a rigid ring system
in which the C9 carbonyl clearly presents an endo (R)- and exo
(â)-face. Thus, sterically demanding hydride reagents permit
the stereoselective reduction of 1. As expected, reduction of
synthetic 1 with less selective sodium borohydride (EtOH, 0
°C) gave the mix of epimeric diols 37a and 37c in a 1:3 ratio,
identifying the cis-diol 37a as the minor reduction diastereomer.
This parallels observations reported by Kobayashi for the sodium
borohydride reduction of neodolabelline.16 Pinacol product 37b
is not observed upon hydride reductions. However, similarities
of proton NMR coupling of the C9 hydrogen of 37b with the
adjacent diastereotopic methylene were recognized from the
previous characterization of 33. Overall, these studies supported
a consistent rationale for the assignments of Scheme 10, leading
to formation of the natural product.
synthesis of neodolabellenol, our work presents the first
successful strategies for the construction of diterpenes of the
neodolabelline class. The synthesis pathway is particularly
notable for the high level of atom efficiency and remarkable
stereoconvergence.
Acknowledgment. We gratefully acknowledge the National
Institutes of Health (GM-42897) for generous support of our
work.
Note Added after ASAP: In the version published on the
Web 1/23/2003, eq 1 and Table 2 contained errors. The final
Web version published 2/3/2003 and the print version are
correct.
Supporting Information Available: Experimental procedures
and product characterizations for all new compounds of the
synthesis route from Schemes 2-6 and compounds 30 through
37, general procedures for the hetero Diels-Alder reaction and
Luche reduction of Scheme 7 and characterizations of 23a-i
and 26, complete characterizations of synthetic 1 and epi-1 with
1H NMR and 13C NMR spectra, X-ray crystallographic data
for 34 and 36 (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
In conclusion, the total synthesis of (+)-4,5-deoxyneodola-
belline (1) has been achieved in 16 steps along the longest linear
pathway with an overall yield of 4.5%. Together with a previous
(64) We thank Professor Bruce F. Bowden, James Cook University, School of
Pharmacy and Molecular Sciences, Queensland 4811, Australia, for
providing spectra and COSY NMR data for naturally occurring 1.
JA0279803
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1850 J. AM. CHEM. SOC. VOL. 125, NO. 7, 2003