Stereocontrolled synthesis of the sterically encumbered F ring of lancifodilactone G

Article abstract of DOI:10.1021/ol800419v

(Chemical Equation Presented) A stereochemically linear strategy has been developed to prepare the heavily congested F-ring sector of lancifodilactone G (1) from commercially inexpensive (R)-carvone. Prominent operations in our synthesis include Negishi-type sp²-sp³ cross-coupling and intramolecular free-radical cyclization for the purpose of appending the sidearm links of the D and H rings onto the F platform.

Full text of DOI:10.1021/ol800419v

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2115-2118
Stereocontrolled Synthesis of the
Sterically Encumbered F Ring of
Lancifodilactone G
Kwong Wah Lai and Leo A. Paquette*
EVans Chemical Laboratories, The Ohio State UniVersity, Columbus, Ohio 43210
paquette@chemistry.ohio-state.edu
Received February 22, 2008
ABSTRACT
A stereochemically linear strategy has been developed to prepare the heavily congested F-ring sector of lancifodilactone G (1) from commercially
inexpensive (R)-carvone. Prominent operations in our synthesis include Negishi-type sp2-sp3 cross-coupling and intramolecular free-radical
cyclization for the purpose of appending the sidearm links of the D and H rings onto the F platform.
In the preceding letter,1 a concise synthesis of the ABC
network of lancifodilactone G (1, Figure 1) was disclosed.2
Needless to say, our attention subsequently shifted to the
significant hurdles for chemical synthesis. Also recognized
was a 2-fold anomerically stabilized bis-spiro system3 having
anticipated sensitivity to acidic and/or basic conditions. In
so doing, it became paramount that select pendant side chains
be incorporated onto the F platform as progress was realized.
Herein, a synthesis of the key building block 2 with full
utilization of stereochemically linear tactics is described.4
A retrosynthetic overview of the significant strategic
operations is depicted in Scheme 1. According to our plan,
2 was to arise from cyclic acetal 3 whose stereogenic centers
at C13 and C14 were to be properly established by intramo-
lecular free-radical cyclization5 of bromide 4, a step envi-
sioned to enable controlled introduction of the challenging
quaternary carbon center (C13)6 in this compact system.
Compound 4 was to be derived from aldehyde 5 by way of
conventional procedures. Application of Negishi sp2-sp3
Figure 1. Chemical structure of lancifodilactone G (1).
eastern sector of this intricate target. Inspection of its right-
hand region revealed a highly congested F ring which held
(3) For a review of anomeric effects in natural product synthesis, see:
Aho, J. E.; Pihko, P. M.; Rissa, T. K. Chem. ReV. 2005, 105, 4406.
(4) For an early application of stereochemically linear strategy, see:
Smith, A. B., III; Fukui, M. J. Am. Chem. Soc. 1987, 109, 1269.
(5) (a) Stock, G.; Mook, R.; Biller, S. A., Jr.; Rychnovsky, S. D. J. Am.
Chem. Soc. 1983, 105, 3741. (b) Jasperse, C. P.; Curran, D. P.; Fevig, T. L.
Chem. ReV. 1991, 91, 1237.
(1) For our preliminary results on synthesis of ABC fragment of
lancifodilactone G, see: Paquette, L. A.; Lai, K. W. Org. Lett. 2008, 10,
2111–2114.
(2) For the isolation and biological evaluation of lancifodilactone G,
see: Xiao, W.-L.; Zhu, H.-J.; Shen, Y.-H.; Li, R.-T.; Li, S.-H.; Sun, H.-D.;
Zheng, Y.-T.; Wang, R.-R.; Lu, Y.; Wang, C.; Zheng, Q. T. Org. Lett.
2005, 7, 2145.
(6) The carbon numbering is accorded to the system of the parent natural
product in ref 2.
10.1021/ol800419v CCC: $40.75
Published on Web 05/03/2008
2008 American Chemical Society

Scheme 1. Retrosynthetic Analysis of Aldehyde 2
cross-coupling technology7 to append the known iodide 88
to vinyl triflate 7 was expected to provide access to 6; the
latter in turn was thought to be well suited to ring contraction
via a series of steps designed to deliver cyclopentene 5.
actual alkyl donor in this reaction.15 Another factor essential
to success was the utilization of lithium chloride in order to
mediate the cross-coupling under mild conditions.16,17
Our point of departure entailed the stereoselective epoxi-
dation9 of the readily available carvone derivative 9.10 The
use of m-CPBA afforded a 5:1 mixture of epoxides in near
quantitative yield11 (Scheme 2). The major isomer 10 was
subjected to sucrose-controlled NaBH4 reduction12 (dr )
8:1), and the resultant alcohol 11 was protected with
TBDPSCl to give the corresponding silyl ether 12 in
stereochemically homogeneous form after chromatographic
purification. Oxidative cleavage of the epoxide 12 was
achieved using periodic acid as the only workable conditions
uncovered and formed the desired methyl ketone 13 ac-
companied by a significant amount of unwanted aldehyde
14 which originated from facile [1,2] hydride shift.13 The
requisite vinyl triflate 7 was prepared directly from methyl
ketone 13 using Comins’ reagent in combination with LDA
and HMPA.14
Scheme 2. Preparation of Vinyl Triflate 7
With vinyl triflate 7 in hand, the time had arrived to effect
cross-coupling to the organozinc species 15 as illustrated in
Scheme 3.7 Extensive optimization was necessary to realize
a high yield. Especially critical was the premixing of iodide
88 with ZnCl2 prior to addition of three equivalents of t-BuLi.
This finding implicates the tert-butylzinc species 15 as the
(7) (a) Negishi, E.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc.
1980, 102, 3298. (b) Negishi, E. Acc. Chem. Res. 1982, 15, 340. (c) Knochel,
P.; Singer, R. D. Chem. ReV. 1993, 93, 2117.
(8) Heckrodt, T. J.; Mulzer, J. Synthesis 2002, 1857.
(9) Smitt, O.; Ho¨gberg, H.-E. Tetrahedron 2002, 58, 7691.
(10) Gabrie¨ls, S.; Haver, D. V.; Vandewalle, M.; Clercq, P. D.; Verstuyf,
A.; Bouillon, R. Chem. Eur. J. 2001, 7, 520.
(11) The stereochemical outcome was not determined. The major isomer
was separated by column chromatography and was used for the subsequent
reduction reaction.
A further central strategic transformation consisted of
contracting the six-membered ring present in 6 into the five-
membered keto aldehyde 5 by adoption of Schreiber’s two-
directional tactic.18 The three discrete operations involved
the bis-dihydroxylation of diene 6,19 ensuing oxidative
cleavage of tetraol 16 to generate 17, and intramolecular aldol
(12) Denis, C.; Laignel, B.; Plusquellec, D.; Le Marouille, J.-Y.; Botrel,
A. Tetrahedron Lett. 1996, 37, 53.
(13) For periodic acid oxidative cleavage, see: Davisson, V. J.; Neal,
T. R.; Poulter, C. D. J. Am. Chem. Soc. 1993, 115, 1235.
(14) (a) Comins, D. L.; Dehghani, A.; Foti, C. J.; Joseph, S. P. Org.
Synth. 1997, 74, 77. (b) Comins, D. L.; Dehghani, A. Tetrahedron Lett.
1992, 33, 6299.
2116
Org. Lett., Vol. 10, No. 11, 2008

Scheme 3. Preparation of Bromo Acetal 4
cyclizationselimination under Corey’s conditions.20 This
sequence delivered the targeted keto aldehyde in 48% overall
yield with only a single column chromatographic purification.
Subsequent Pinnick oxidation21 of 5 delivered the corre-
sponding carboxylic acid which was treated with TM-
SCHN222 to afford methyl ester 18. Removal of the TBDPS
protecting group within 18 with TBAF resulted in liberation
of the secondary alcohol 19, the action of NBS and ethyl
vinyl ether on which produced the bromo acetal 20. Chela-
tion-controlled reduction of the ketone carbonyl in 20 with
NaBH4 at -20 °C in MeOH pleasingly gave the secondary
alcohol 21 in 87% yield with 8:1 diastereoselectivity.
Subsequent silylation of the resultant alcohol 21 with
TBDPSOTf and 2,6-lutidine delivered the pivotal precur-
sor 4.
The next task was to set up the two continuous stereogenic
centers at C-13 and C-14 of 4 via an intramolecular free-
radical cyclization (Scheme 4).5 Treatment of bromide 4
under typical radical conditions (n-Bu3SnH and AIBN) made
available the sterically congested system 3 as an inseparable
mixture in good yield. The stereoselectivity encountered in
this step can be rationalized in terms of intermediate 22.
Approach of the radical-bearing side chain to the acceptor
π-bond from the bottom face sets up the quaternary center
at C13 and precedes final delivery of a hydrogen atom from
the more accessible convex face.23
(15) For precedent speculation regarding the formation of mixed tert-
butylalkylzinc species in the Negishi reaction, see: Smith, A. B., III;
Beauchamp, T. J.; LaMarche, M. J.; Kaufman, M. D.; Qiu, Y.; Arimoto,
H.; Jones, D. R.; Kobayashi, K. J. Am. Chem. Soc. 2000, 122, 8654.
(16) For use of LiCl as additive, see: Piers, E.; Friesen, R. W.; Keay,
B. A. Tetrahedron 1991, 47, 4555.
(17) The cross-coupling product 6 was contaminated with the inseparable
deiodination compound derived from 8.
(18) Poss, C. S.; Schreiber, S. L. Acc. Chem. Res. 1994, 27, 9–19.
(19) (a) Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B. Chem.
ReV. 1994, 94, 2483. (b) The use of 1,4-diazabicyclo[2.2.2]octane (DABCO)
was essential to mediate dihydroxylation of the 1,1′-disubstituted olefin in
6; see: Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu,
D.; Zhang, X.-L. J. Org. Chem. 1992, 57, 2768.
(21) Balkrishna, B. S.; Childers, W. E., Jr.; Pinnick, H. W. Tetrahedron
1981, 37, 2091.
(22) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475.
(20) Corey, E. J.; Danheiser, R. L. J. Am. Chem. Soc. 1978, 100, 8031.
Org. Lett., Vol. 10, No. 11, 2008
2117

Scheme 4. Preparation of Aldehyde 2
Formation of dithioketal 23 was achieved using 1,3-
propanedithiol and BF3·OEt2 so as to promote concomitant
deprotection of the PMB functional group and make diol 23
available as a single diastereoisomer in 77% isolated
yield.24,25 The stereochemical assignment to 23 was unam-
biguously corroborated on the basis of extensive COSY and
NOESY NMR experiments.26 The pair of hydroxyl groups
within 23 were simultaneously masked as in 24, with the
ultimate aim of streamlining steps in the eventual end game.
The subsequent dethioacetalization of 24 in the presence of
excess MeI and CaCO3 afforded the target aldehyde in
excellent yield on modest scale.
carvone derivative 9. The present study underscores the
utility of Smith’s stereochemically linear and Schreiber’s
two-directional strategies. The routing involved 19 steps with
an overall yield of 3%. Highlights of the synthesis include
Negishi sp2-sp3 cross-coupling reaction, ring contraction
sequence (6 f 5) and stereoselective intramolecular free
radical cyclization. Pursuit of the union of aldehyde 2 with
the ABC segment of lancifodilactone G is currently in
progress.
Acknowledgment. We thank The Ohio State University
for partial financial support and Robert Dura (The Ohio State
University) for assistance with the NOE and 2D NMR
experiments.
In summary, a synthesis of the sterically congested F ring
component 2 has been successfully realized from the known
(23) The stereo-outcome of this process was elucidated after the
subsequent dithiane removal step.
Supporting Information Available: Experimental pro-
cedures and spectral data for all stable new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Smith, A. B., III; Chen, K.; Robinson, D. J.; Laakso, L. M.; Hale,
K. J. Tetrahedron Lett. 1994, 35, 4271
(25) The minor diastereoisomers were easily separated during column
chromatography
.
.
(26) Diagnostic NOE enhancements between H-14 and H-17, H-14 and
H-22, and H-17 and H-22 were observed.
OL800419V
2118
Org. Lett., Vol. 10, No. 11, 2008