Synthetic and Mechanistic Studies of the Retro-Claisen Rearrangement 4. An Application to the Total Synthesis of (+)-Laurenyne

Article abstract of DOI:10.1021/ol0267174

(Matrix Presented) A novel asymmetric total synthesis of marine natural product (+)-Laurenyne has been achieved. The key elements of the strategy are the sequential metal ion-templated S_N2′ cyclization affording a highly functionalized chiral vinyl cyclobutane and a retro-Claisen rearrangement for the construction of an eight-membered ring ether.

Full text of DOI:10.1021/ol0267174

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3891-3894
Synthetic and Mechanistic Studies of
the Retro-Claisen Rearrangement 4. An
Application to the Total Synthesis of
(+)-Laurenyne
Robert K. Boeckman, Jr.,* Jing Zhang, and Michael R. Reeder
Department of Chemistry, UniVersity of Rochester, Rochester, New York 14627-0216
rkb@rkbmac.chem.rochester.edu
Received August 12, 2002
ABSTRACT
A novel asymmetric total synthesis of marine natural product (+)-Laurenyne has been achieved. The key elements of the strategy are the
sequential metal ion-templated SN2′ cyclization affording a highly functionalized chiral vinyl cyclobutane and a retro-Claisen rearrangement for
the construction of an eight-membered ring ether.
The species of the Laurencia genus of red algae produce a
plethora of structurally novel C15 nonterpenoid metabolites,
a number containing a medium-ring ether.1 In addition to
an oxocene or oxepine ring, structural features common to
many of these materials include halogen substitution and an
enyne side chain. The medium-sized oxocene ring still
imposes a notable challenge, and numerous synthetic ap-
proaches have been documented.2 Being the initial member
of this class isolated,3 a number of total4 and formal
syntheses5 of Laurencin (1) have been recorded (Figure 1).
Several formal and total syntheses of the structurally related
oxepine derivative isolaurepinnacin (2) have also been
reported.6 The structure and absolute configuration of the
related (+)-Laurenyne (3), isolated from Laurencia obtusa,
had been assigned as 2S,7S,8S by X-ray crystallography.7
The only total synthesis of 3 reported thus far, by Overman
and co-workers,8 afforded the enantiomer (-)-3.7 This
synthesis verified the structure and relative stereochemistry
of 3 but required revision of the absolute stereochemistry of
natural (+)-Laurenyne (3) to 2R,7R,8R.
(4) (a) Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029-
2032. (b) Burton, J. W.; Clark, J. S.; Derrer, S.; Stork, T. C.; Bendall, J.
G.; Holmes, A. B. J. Am. Chem. Soc. 1997, 119, 7483-7498. (c) Bratz,
M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc. 1995,
117, 5958-5966. (d) Tsushima, K.; Murai, A. Tetrahedron Lett. 1992, 33,
4345-4348. (e) Masamune, T.; Matsue, H.; Murase, H. Bull. Chem. Soc.
Jpn. 1979, 52, 127-134. (f) Masamune, T.; Murase, H.; Matsue, H.; Murai,
A. Bull. Chem. Soc. Jpn. 1979, 52, 135-141.
(5) (a) Crimmins, M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121,
5653-5660. (b) Mujica, M. T.; Afonso, M. M.; Galindo, A.; Palenzuela, J.
A. J. Org. Chem. 1998, 63, 9728-9738. (c) Mujica, M. T.; Afonso, M.
M.; Galindo, A.; Palenzuela, J. A. Synlett 1996, 983-984.
(6) (a) Suzuki, T.; Matsumura, R.; Oku, K. i.; Taguchi, K.; Hagiwara,
H.; Hoshi, T.; Ando, M. Tetrahedron Lett. 2001, 42, 65-67. (b) Berger,
D.; Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc. 1997, 119, 2446-
2452. (c) Berger, D.; Overman, L. E.; Renhowe, P. A. J. Am. Chem. Soc.
1993, 115, 9305-9306. (d) Davies, M. J.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 1 1991, 9-12. (e) Davies, M. J.; Moody, C. J. Synlett 1990,
95-96. (f) Kotsuki, H.; Ushio, Y.; Kadota, I.; Ochi, M. J. Org. Chem.
1989, 54, 5153-5161.
(1) (a) Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1-48. (b) Faulkner, D.
J. Nat. Prod. Rep. 2001, 18, 1-49. (c) Faulkner, D. J. Nat. Prod. Rep.
2000, 17, 7-55. (d) Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 1-6.
(2) (a) Holmes, A. B.; Stephenson, G. R. Chem. Ind. (London) 2001,
187-189. (b) Elliott, M. C. Contemp. Org. Synth. 1994, 1, 457-474. (c)
Moody, C. J.; Davies, M. J. Stud. Nat. Prod. Chem. 1992, 10, 201-239.
(3) (a) Irie, T.; Susuki, M.; Masumune, T. Tetrahedron Lett. 1965, 1091-
1099. (b) Irie, T.; Suzuki, M.; Masamune, T. Tetrahedron 1968, 24, 4193-
4205.
10.1021/ol0267174 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002

Scheme 2
Figure 1.
by selective mesylation of the primary alcohol followed by
silylation of the secondary alcohol (TBSOTf) affording
mesylate 10 in 86% yield. Alkylation of the sodium anion
of diethyl malonate with mesylate 10 in DMF smoothly
provided diester acetal 11 in 93% yield. Finally, unmasking
the aldehyde function in acetal 11 by catalytic reduction
furnished aldehyde 7 in 95% yield.
Here we disclose the first synthesis of the natural enan-
tiomer (+)-Laurenyne (3) using a novel approach that applies
two key methodologies recently developed in our laborato-
ries: (1) a completely diastereoselective metal-templated SN2′
cyclization and (2) a retro-Claisen rearrangement of the
derived homochiral cyclobutane dicarboxaldehyde affording
the eight-membered ring ether.9,10
Condensation of aldehyde 7 and stabilized ylide 8 readily
afforded the enone 12 in 90% yield (Scheme 3). A CBS
Scheme 1
Scheme 3
reduction was then employed to introduce the required
stereogenic center, from which the chirality at C2 in 3 will
ultimately be derived, affording allylic alcohol 13 in 98%
de.13 Activation of the allylic alcohol via acylation with 2,6-
dimethylphenyl chloroformate provided the allylic carbonate
6, the substrate for the SN2′ cyclization, in 85% yield over
two steps.
Our synthetic plan is depicted in Scheme 1. We anticipated
that (+)-Laurenyne (3) could be elaborated from dihy-
drooxocene 4. The allylic silyloxy group was intended to
facilitate the required double-bond migration. Dihydrooxocene
4, in turn, would be derived via a retro-Claisen rearrangement
from vinyl cyclobutane 5. A stereoselective SN2′ cyclization
of allyl carbonate 6 would then produce 5, which is available
from enantiomerically pure aldehyde 7 and the known ylide
811 via a Wittig olefination.
(7) Falshaw, C. P.; King, T. J.; Imre, S.; Islimyeli, S.; Thomson, R. H.
Tetrahedron Lett. 1980, 21, 4951-4954.
(8) Overman, L. E.; Thompson, A. S. J. Am. Chem. Soc. 1988, 110,
2248-2256.
(9) Boeckman, R. K., Jr.; Reeder, M. R. J. Org. Chem. 1997, 62, 6456-
Our synthesis of the aldehyde 7 starts from the readily
available known (-)-(1S)-diol 9 (97% ee) as shown in
Scheme 2.12 A one-pot double protection of 9 was effected
6457.
(10) Boeckman, R. K., Jr.; Shair, M. D.; Vargas, J. R.; Stolz, L. A. J.
Org. Chem. 1993, 58, 1295-1297.
3892
Org. Lett., Vol. 4, No. 22, 2002

The key syn-SN2′ cyclization, which assembles the re-
quired homochiral cyclobutane ring, was then effected by
treatment of 2,6-dimethylphenyl carbonate 6 with NaH in
toluene at reflux, which efficiently produced the highly
functionalized vinyl cyclobutane 14 as a single diastereomer
in 85% yield (Scheme 4).
Scheme 4
Figure 2.
the carbonate minimizing charge separation in the nonpolar
medium.9,14 Such a counterion-templated transition state
accounts for the observed stereoselectivity (syn-SN2′), the
apparent rate acceleration, and the dependence on substrate
by enforcing proximity of the two reacting partners. Such a
circumstance is not possible for cyclic carbonate 15 due to
geometric constraints. The failure of the sodium salt of 6 to
cyclize in the presence of 18-C-6 and the failure of Li and
K anions derived from 6 to undergo cyclization to 14 to any
significant extent provide further evidence for the role of
the counterion.
With the vinyl cyclobutane diester 14 in hand, we now
addressed the key retro-Claisen rearrangement to construct
the oxocene ring. Diester 14 was reduced with LAH under
standard conditions affording diol 17 in 93% yield. Upon
Dess-Martin periodinane (DMP) oxidation and subsequent
thermal equilibration at 45 °C, the desired dihydrooxocene
4 was obtained in 92% yield.9,15 Interestingly, in this case,
dialdehyde 18 could be isolated under carefully controlled
conditions. This is the first observation of a dialdehyde
intermediate of type 18 in the cyclobutane series.9,10 Oxocene
aldehyde 4 was stable at -10 °C for at least a month with
no evidence of rearrangement back to the dialdehyde 18.
The efficiency and high stereospecificity of this cyclization
are critically dependent on several (not readily apparent)
variables that shed light on the mechanism of this cyclization.
For example, the related cyclic carbonate 15 failed to undergo
cyclization under any conditions examined, even after
extensive experimentation, affording only the diol precursor
16 resulting from hydrolysis (eq 1). Indeed, deacylation is
To eliminate complexities arising from the fluxional
character of intermediates such as 4, the disubstituted olefin
in 4 was selectively reduced using (Ph3P)3RhCl to give
aldehyde 19 in 91% yield (Scheme 5).16 Catalytic decarbo-
nylation of 19, which was inert to (Ph3P)3RhCl, proceeded
+
smoothly using the more reactive cationic Rh(dppp)2 Cl-
complex in xylenes affording vinyl ether 20 in 90% yield.17
Epoxidation of 20 with dimethyldioxirane (DMDO) cleanly
(13) (a) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986-
2012. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987,
109, 5551-5553. (c) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C. P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926.
(14) (a) Williams, R. M.; Glinka, T.; Kwast, E. J. Am. Chem. Soc. 1988,
110, 5927-5929. (b) Martel, J.; Blade-Font, A.; Marie, C.; Vivat, M.;
Toromanoff, E.; Buendia, J. Bull. Soc. Chim. Fr. 1978, 131-139. (c) Martel,
J.; Toromanoff, E.; Mathieu, J.; Nomine, G. Tetrahedron Lett. 1972, 1491-
1496.
(15) (a) Boeckman, R. K., Jr.; Shao, P.; Mullins, J. J. Org. Synth. 2000,
77, 141-152. (b) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155-
4156.
(16) (a) Stolz, L. A., Ph.D. Dissertation, University of Rochester,
Rochester, NY, 1992. (b) Osborn, J. A.; Jardine, F. H.; Young, J. F.;
Wilkinson, G. J. Chem. Soc. A 1966, 1711-1732.
(17) (a) Doughty, D. H.; Pignolet, L. H. J. Am. Chem. Soc. 1978, 100,
7083-7085. (b) Meyer, M. D.; Kruse, L. I. J. Org. Chem. 1984, 49, 3195-
3199.
the competing side reaction in the conversion of 6 to 14. In
the case of 6, deacylation could be suppressed by conducting
the cyclization at 110 °C rather than 45-50 °C. This dramatic
dependence on the activating group is strongly suggestive
that the conversion proceeds through a highly organized
transition-state involving the counterion as a template for
the SN2′ cyclization. In this transition state (Figure 2), the
sodium counterion simultaneously coordinates to one of the
enolate oxygen atoms and the carbonyl oxygen atom from
(11) Oguri, H.; Hishiyama, S.; Oishi, T.; Hirama, M. Synlett 1995, 1252-
1254.
(12) Oi, R.; Sharpless, K. B. Org. Synth. 1996, 73, 1-12.
Org. Lett., Vol. 4, No. 22, 2002
3893

Scheme 5
Scheme 6
generated a single R-epoxide diastereomer,18 which was
directly opened with the lithium enolate of acetaldehyde N,N-
dimethylhydrazone providing the hemiacetal 21 in 76%
overall yield after a mildly oxidative acid hydrolysis.19 The
trans enyne side chain was then introduced via Wittig
olefination to provide 22 in 78% yield (>15:1 E/Z selectiv-
ity). The free hydroxyl group in 21 may be the source of
the unusually high E/Z selectivity.20 NOE studies confirmed
the relative stereochemistry of alcohol 22 (Scheme 5).
Conversion of alcohol 22 to (+)-Laurenyne (3) was
initiated by DMP oxidation of 22 to ketone 23 (Scheme 6).
Assembly of the trans propenyl side chain was accomplished
by sequential treatment of 23 with DDQ, DMP oxidation,
and Takai olefination21 of the resulting aldehyde affording
ketone 24 in 70% yield (three steps). Cleavage of the TBS
ether in 24 with 48% HF in CH3CN followed by in situ
mesylation of the resulting alcohol followed by elimination
with concomitant deconjugation of the resulting alcohol
provided ketone 25, incorporating the key ∆4,5 double-bond,
in 82% yield (overall).22
case), using (2R)-n-butyloxazaborolidine, giving the desired
C7 R-alcohol 26 in 80% yield along with 16% of the C7
epimer. Unexpectedly, conversion of the C7 R-alcohol 26 to
the C7 â-chloride was not trivial. Standard reaction conditions
for this conversion (CCl4/(nC8H17)3P/PhCH3/70 °C) afforded
20% of the desired â-chloride together with 80% of the diene
from elimination.4c However, upon addition of 1 equiv of
BnEt3NCl (TEBAC), (+)-Laurenyne (3) was obtained as a
white solid in 60% overall yield (after removal of the TMS
group with K2CO3 in CH3OH), accompanied by 30% of the
diene and 4% of the a epimeric chloride (unoptimized).
25
Synthetic (+)-3 [mp 78-79 °C, [R]D + 17.9 (CHCl3, c
0.145)] was identical in all respects (mp, 1H NMR, 13C NMR,
IR, [R]D25) to natural (+)-37 and synthetic (-)-3 (except for
the sign of the optical rotation).8
Acknowledgment. We thank the NIH (GM-30345) for
generous financial support of this project and Professor Larry
Overman for providing NMR data for synthetic (-)-3.
Installation of the C7 chlorine was initiated by CBS
reduction of ketone 25 under reagent control (mismatched
Supporting Information Available: Experimental pro-
cedures and spectral data for key compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(18) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377. (b) Adam, W.; Hadjiarapoglou, L. Chem. Ber. 1990, 123, 2077-
2079.
(19) (a) Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 11-14. (b)
Corey, E. J.; Enders, D. Tetrahedron Lett. 1976, 3-6.
(20) Evans, P. A.; Murthy, V. S.; Roseman, J. D.; Rheingold, A. L.
Angew. Chem., Int. Ed. 1999, 38, 3175-3177.
(21) Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108,
7408-7410.
OL0267174
(22) Jeyaraj, D. A.; Kapoor, K. K.; Yadav, V. K.; Gauniyal, H. M.;
Parvez, M. J. Org. Chem. 1998, 63, 287-294.
3894
Org. Lett., Vol. 4, No. 22, 2002