A retro-Claisen approach to dolabriferol

Article abstract of DOI:10.1021/ol060347s

The protected precursor 30 to dolabriferol was generated by a DBU-induced, ester-forming, retro-Claisen process. The required linear carbon chain present in 22 was synthesized by a stereoselective lithium aldol reaction. The necessary aldehyde and ketone

Full text of DOI:10.1021/ol060347s

ORGANIC
LETTERS
2006
Vol. 8, No. 9
1827-1830
A Retro-Claisen Approach to
Dolabriferol
Troy Lister and Michael V. Perkins*
School of Chemistry, Physics and Earth Sciences, Flinders UniVersity,
G. P. O. Box 2100, S.A. 5001, Australia
mike.perkins@flinders.edu.au
Received February 9, 2006
ABSTRACT
The protected precursor 30 to dolabriferol was generated by a DBU-induced, ester-forming, retro-Claisen process. The required linear carbon
chain present in 22 was synthesized by a stereoselective lithium aldol reaction. The necessary aldehyde and ketone fragments were synthesized
using stereocontrolled aldol reactions with the ethyl (S)-lactate derived ketone 13.
Dolabriferol (1) was isolated from the ether-soluble acetone
extracts of specimens of Dolabrifera dolabrifera by Ciavatta
and co-workers in 19961 in the first chemical study of an
opisthobranch belonging to the Dolabriferidae family. Found
off the coast of Cuba, D. dolabrifera is readily distinguish-
able from other members of the Aplysia genus by the
presence of small and asymmetrical parapodia, a flattened
body, and a calcified internal shell. The structure of dolab-
riferol (1) was elucidated by extensive NMR studies, and
the complete relative stereochemistry was confirmed by
single crystal X-ray analysis. Without proof of the absolute
stereochemistry, a comparison to the seemingly related
baconipyrones (2-5)2 suggests the absolute configuration
drawn for 1 as a candidate for synthesis. Dolabriferol (1) is
a polypropionate featuring a highly substituted hemiketal
tethered to a â-hydroxy ketone via an unusual ester linkage.
The presence of a noncontiguous carbon backbone assigns
dolabriferol (1) to a group of marine polypropionates that
includes the baconipyrones A-D (2-5)2, siserrone A (6),3
and ester 7 (isolated from S. australis)4 (Figure 1). This
structural motif appears to be the result of rupture of an
intermediate hemiacetal via a retro-Clasien fragmentation.
As such, the natural product status of dolabriferol can be
questioned.2
(1) Ciavatta, M. L.; Gavagnin, M.; Puliti, R.; Cimino, G.; Martinez, E.;
Ortea, J.; Mattia, C. A. Tetrahedron 1996, 52, 12831-12838.
(2) Manker, D. C.; Faulkner, D. J.; Stout, T. J.; Clardy, J. J. Org. Chem.
1989, 54, 5371-5374.
(3) (a) Hochlowski, J. E.; Faulkner, D. J. J. Org. Chem. 1984, 49, 3838-
3840. (b) Sundram, U. N.; Albizati, K. F. Tetrahedron Lett. 1992, 33, 437-
440. (c) Lister, T., Perkins, M. V. Aust. J. Chem. 2004, 57, 787-797.
(4) Brecknell, D. J.; Collett, L. A.; Davies-Coleman, M. T.; Garson, M.
J.; Jones, D. D. Tetrahedron 2000, 56, 2497-2502.
Figure 1. Selected noncontiguous marine polypropionates.
10.1021/ol060347s CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/06/2006

While dolabriferol (1) has attracted some synthetic inter-
est,5 its total synthesis has yet to be reported. Our6 and
others’5 previous attempts to prepare the ester linkage in
dolabriferol (1) by coupling acid and alcohol equivalents have
not proved successful. We now report the synthesis of the
direct precursor to dolabriferol (1) using a “biomimetic”
retro-Claisen reaction to install this ester linkage.
aldehyde 12 and ketone 11. Noticeably, these sequences
install all but one of the stereocenters present in dolabriferol
(1). Adjustment of the C3 oxidation state and protection of
the formed hydroxyl in 12 was proposed to avoid potential
hemiketalization at various stages of the synthesis.
Scheme 2
Scheme 1
The synthesis of aldehyde 12 is shown in Scheme 2. The
(E)-enol dicyclohexylborinate of known7 ketone (S)-13 was
reacted with an excess of freshly prepared8 R-methyl chiral
aldehyde (R)-14 to give 17 in excellent yield (99%) and
diastereoselectivity (>97% ds). The generated alcohol was
masked as a TBS ether (TBSOTf), and subsequent reductive
removal of the R-benzoate7 using SmI2 gave 18 in high yield
(93%, two steps). At this stage, temporary C3 reduction and
protection was required to avoid cyclization upon liberation
of the primary benzyl ether. To this end, carbonyl reduction
with NaBH4 gave a 4:1 ratio of Felkin isomer 19 and its
C-3 epimer that could be readily separated by flash chro-
matography.
While both epimers could be used in the synthesis, as this
center is ultimately at the carbonyl oxidation state, the major
epimer 19 was taken forward to simplify subsequent spectral
analysis. Protection of alcohol 19 using PMB-trichloroace-
timidate under modified conditions9 gave the p-methoxy-
benzyl ether 20 in good yield (84%). Selective debenzylation
of 20 with Raney nickel10 followed by Dess-Martin oxida-
tion11 furnished aldehyde 12 in 84% overall yield.
Retrosynthetic analysis (Scheme 1) revealed that com-
pound 8, the protected precursor to dolabriferol (1), is formed
by retro-Claisen reaction of hemiketal 9 and deprotection/
oxidation of C3. The pseudosymmetrical acyclic precursor
10 to hemiacetal 9 should be available from an aldol coupling
of ketone 11 with â-silyloxy-δ-alkoxy aldehyde 12 followed
by oxidation. Substrate-directed aldol reactions of the lactate-
derived (S)-2-benzoyloxypentan-3-one ((S)-13) with alde-
hydes 14-16 were proposed for the preparation of both
(7) (a) Paterson, I.; Wallace, D. J.; Vela´zquez, S. M. Tetrahedron Lett.
1994, 35, 9083-9886. (b) Paterson, I.; Wallace, D. J. Tetrahedron Lett.
1994, 35, 9087-9090. (c) Paterson, I.; Wallace, D. J.; Cowden, C. J.
Synthesis 1998, 639-652.
(8) (a) Paterson, I.; Yeung, K.-S.; Watson, C.; Ward, R. A.; Wallace, P.
A. Tetrahedron 1998, 54, 11935-11954. (b) Paterson, I.; Florence, G. J.;
Gerlach, K.; Scott, J. P.; Sereinig, N. J. Am. Chem. Soc. 2001, 123, 9535-
9544.
(5) (a) Dias, L. C.; de Sousa, M. A. Tetrahedron Lett. 2003, 44, 5625-
5628. (b) Chenevert, R.; Courchesne, G.; Caron, D. Tetrahedron: Asym-
metry 2003, 14, 2567-2571.
(6) Our attempts to access an analogue of ester 8 by coupling alcohol
20 with the acid derived from 18 using various protocols proved unsuc-
cessful due to unfavorable steric interactions and facile dehydration of
compound 20. Lister, T. Unpublished results.
(9) Paterson, I.; Lombart, H.; Allerton, C. Org. Lett. 1999, 1, 19-22.
1828
Org. Lett., Vol. 8, No. 9, 2006

used to generate the enolate of 11 (30 min at -78 °C
followed by 30 min at -50 °C), which smoothly reacted
with aldehyde 12 at -78 °C to give adduct 22 in good yield
(78%) as a separable mixture of just two diastereomers (85%
ds). The stereocenters formed in this coupling are lost in
the subsequent oxidation, but the formation of one major
isomer allows the progression of stereochemically pure
material. The dominant isomer was tentatively assigned as
the 6,7-anti-Felkin-7,8-syn-8,10-anti product 22 (Scheme 4)
based on literature precedent for similar double stereodif-
ferentiating lithium aldol reactions.12 In preliminary experi-
ments, Swern oxidation13 of â-hydroxy ketone 22 gave the
corresponding dione 10, which surprisingly existed exclu-
sively as a single epimer of the â-diketone with no enol form
present. Selective desilylation proceeded smoothly under
either acidic conditions (p-TSOH) or the action of fluoride
ion (HF‚pyr/pyr) giving the deprotected acyclic dione 23,
but this compound did not cyclize to give the hemiacetal 24
required for retro-Claisen reaction.14 Failure of this cycliza-
tion caused us to abandon this fully protected approach.
Scheme 3
Assuming that the cyclization was inhibited by steric
hindrance, we chose to change our strategy and now adjust
the oxidation state of C3 to that required in dolabriferol. To
this end, adduct 22 was treated with DDQ in moist CH2Cl2,
followed by double Swern oxidation13 to give trione 25 in
good yield (79%, two steps). This species proved similarly
stable to epimerization and selective desilylation gave
compound 26. Again, this compound failed to cyclize15 to
the desired hemiacetal 27, indicating that the bulky TBS
protecting groups were the cause of the problem. Removal
of one or both of these TBS groups introduces a variety of
competing cyclization modes but still seemed a viable path
forward.
The synthesis of ketone 11 is shown in Scheme 3. Reaction
of the (E)-enol dicyclohexylborinate of ketone (S)-13 with
2-methyl propanal (16) gave ketone 21 with high selectivity
(99%, >95% ds). Protection (TBS ether), conversion to the
diol with LiBH4, and oxidative cleavage gave aldehyde 15
(91% over 3 steps). In an iterative process, the (E)-enol
dicyclohexylborinate ketone (S)-13 was now reacted with
1.5 equiv of aldehyde 15 giving a single detectable isomer
of adduct 20 in 77% yield. This level of diastereoselectivity
highlights the high π-facial selectivity exhibited by (S)-13
considering its dominance over any facial preference of
aldehyde 15. Protection of the free hydroxyl as a triethylsilyl
ether, followed by benzoate cleavage7 (SmI2) gave ketone
11 in good yield (90%, 2 steps).
The base sensitivity of dione 25 was highlighted during
attempted deprotection with TBAF which lead only to the
formation of enone 28 (Scheme 5). However, controlled
desilylation could be achieved (5 equiv of TAS-F,16 2 h, or
HF‚pyr/pyr, 7 days) with the removal of the C-5 TBS and
C-11 TES ethers. The product from the HF‚pyr/pyr reaction
was identified as the unusual trioxaadamantane 29.17 The
With the key aldol fragments in hand, our attention was
focused on their coupling (Scheme 4). In an optimized
procedure, lithium hexamethyldisilyl azide (LiHMDS) was
Scheme 4
Org. Lett., Vol. 8, No. 9, 2006
1829

Scheme 5
TAS-F16 reaction initially produced a mixture of hemiacetal
steps, the conditions commonly used for silyl protecting
group removal on sensitive systems.
products and brief exposure to DBU4c rapidly gave triox-
aadamantane 29. Compound 29 was found to be very acid
sensitive and decomposed to a mixture of dihydropyrones18
upon exposure to CDCl3. After some experimentation it was
discovered that extended exposure of 29 to DBU facilitated
retro-Claisen to give the desired ester 30. Under these
reaction conditions the product 30 slowly underwent â-
elimination of the carboxylate giving enone 31, which
although undesirable, helped to confirm the formation of ester
30.
Disappointingly, none of our attempts at this final TBS
removal gave dolabriferol, with the reactions either returning
starting material, complex mixtures or in the case of TBAF
and TAS-F16 enone 31. The one exception to this was
treatment of 30 with aqueous HF/CH3CN/CH2Cl2 which gave
spiroacetal 32 as the only product. Formation of this product
can only occur by acid-catalyzed Claisen reaction to reform
the linear carbon backbone followed by spirocyclization.19
The TBS cleavage may occur before or after the Claisen
reaction.
It appears that the combination of an overly robust TBS
protecting group coupled with a highly sensitive (acid and
base) substrate prevented the current approach from yielding
synthetic dolabriferol (1). Despite this recalcitrant situation,
our synthesis affords 30 as a single isomer in 35% yield after
11 linear steps from ketone 13. We are hopeful that
replacement of the troublesome TBS ether will ultimately
prove successful.
With a direct precursor to dolabriferol (1) in hand we
began searching for a means to cleave the final silyl ether.
Notably this final TBS ether had already endured, in previous
(10) (a) Mozingo, R. Org. Synth. 1941, 21, 15. (b) Horita, K.; Yoshioka,
T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O. Tetrahedron 1986, 42, 3021-
3028.
(11) (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.
(12) (a) Masamme, S.; Ellingboe, J. W.; Choy, W. J. Am. Chem. Soc.
1982, 104, 5526-5528. (b) McCarthy, P. A.; Kageyama, M. J. Org. Chem.
1987, 52, 4681-4686. (c) Evans, D. A.; Yang, M. G.; Dart, M. J.; Duffy,
J. L. Tetrahedron Lett. 1996, 37, 1957-1960.
Acknowledgment. We thank the Australian Research
Council for funding and Flinders University for its support
and facilities. We are also grateful to Dr. Maria Ciavatta for
providing copies of the original NMR spectra for dolabriferol.
(13) (a) Omura, K.; Swern, D. Tetrahedron 1978, 34, 1651-1660. (b)
Mancuso, A..J.; Swern, D. Synthesis 1981, 165-185.
(14) Attempted acid-catalyzed cyclizations were not successful, and
treatment with TFA resulted in decomposition with apparent formation of
the dihydropyrone corresponding to dehydration of compound 24.
(15) Again, acid-catalyzed cyclizations were not successful, and treatment
with TFA resulted in decomposition with apparent formation of the
dihydropyrone corresponding to dehydration of compound 27.
(16) (a) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler, S. R.; Coffey,
D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436-6437. (b) Scheidt, K.
A.; Bannister, T. D.; Tasaka, A.; Wendt, M. D.; Savall, B. M.; Fegley, G.
J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 6981-6990.
(17) This trioxaadamantane ring system has been observed in a number
of polypropionate natural products. See: (a) Roll, D. M.; Biskupiak, J. E.;
Mayne, C. L.; Ireland, C. M. J. Am. Chem. Soc. 1986, 108, 6680-6682.
(b) Paterson, I.; Perkins, M. V. J. Am. Chem. Soc. 1993, 115, 1608-1610.
(c) Blanchfield, J. T.; Brecknell, D. J.; Brereton, I. M.; Garson, M. J.; Jones,
D. D. Aust. J. Chem. 1994, 47, 2255-2269.
Supporting Information Available: Experimental pro-
cedures and data for compounds 17-23, 25, 26, and 29-32
and NMR spectra for compounds 10-12, 22, 25, 29, 30,
and 32. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL060347S
(19) The energy levels of various cyclization and retro-Claisen products
of the unprotected linear precursor to dolabriferol have been reported in:
Socorro, I. M.; Taylor, K.; Goodman, J. M. Org. Lett. 2005, 7, 3541-
3544. The energy (at RHF/3-21G/water) of compound 32, -1183.94750
+ -75.60402 (for water) ) -1259.55077 hartrees, is comparable to that
of dolabriferol, (1) -1259.54938 hartrees (calculated by Goodman at RHF/
3-21G/water, personal communication).
(18) Dihydropyrones resulting from the dehydration of two hemiacetals
(formed from cyclisation of the C5 hydroxyl onto the C9 carbonyl and
from cyclisation of the C11 hydroxyl onto the C7 carbonyl) appeared to be
formed.
1830
Org. Lett., Vol. 8, No. 9, 2006