Asymmetric synthesis of trans-3,4-dialkyl-γ-butyrolactones via an acyl-claisen and iodolactonization route

Article abstract of DOI:10.1021/ol050578j

(Chemical Equation Presented) A new, efficient, and general asymmetric synthesis of enantiomerically pure trans-3,4-dialkyl-γ-lactones has been developed. The key steps are (1) copper-catalyzed three-component coupling of chiral amine, aldehyde, and alkyne, (2) acyl-Claisen rearrangement, and (3) iodolactonization. The products, chiral γ-lactones, are versatile synthetic intermediates and structural units of natural products and modified nucleosides.

Full text of DOI:10.1021/ol050578j

ORGANIC
LETTERS
2005
Vol. 7, No. 14
2821-2824
Asymmetric Synthesis of
trans-3,4-Dialkyl- -butyrolactones via an
Acyl-Claisen and Iodolactonization
Route
γ
Qun Xu and Eriks Rozners*
Department of Chemistry and Chemical Biology, Northeastern UniVersity,
Boston, Massachusetts 02115
e.rozners@neu.edu
Received March 16, 2005
ABSTRACT
A new, efficient, and general asymmetric synthesis of enantiomerically pure trans-3,4-dialkyl-
γ
-lactones has been developed. The key steps
are (1) copper-catalyzed three-component coupling of chiral amine, aldehyde, and alkyne, (2) acyl-Claisen rearrangement, and (3) iodolactonization.
The products, chiral -lactones, are versatile synthetic intermediates and structural units of natural products and modified nucleosides.
γ
Chiral trans-3,4-dialkyl-γ-butyrolactones are common struc-
tural units of natural products1 and versatile intermediates
in their total syntheses.2,3 Despite the many approaches
available for preparation of γ-lactones, stereoselective syn-
thesis of highly substituted derivatives is still challenging.
Our laboratory4,5 and others3 have used trisubstituted γ-
butyrolactones bearing a 2-hydroxyl function (as exemplified
by 2 in Scheme 1) to prepare C-branched nucleoside
analogues. Similar intermediates have also been used in the
total syntheses of rhizoxin D2b and bafilomycin A1.2c
Scheme 1. Retrosynthetic Analysis of 3′,5′-C-Branched
Nucleosides via the γ-Lactone Intermediate 2
(1) For selected recent examples, see: (a) Avenaciolide: Aggarwal, V.
K.; Davies, P. W.; Schmidt, A. T. Chem. Commun. 2004, 1232-1233. (b)
Nephrosteranic acid: Schleth, F.; Studer, A. Angew. Chem., Int. Ed. 2004,
43, 313-315. (c) Paraconic acids: Barros, M. T.; Maycock, C. D.; Ventura,
M. R. Org. Lett. 2003, 5, 4097-4099. (d) Sesquiterpenes: Nosse, B.; Chhor,
R. B.; Jeong, W. B.; Boehm, C.; Reiser, O. Org. Lett. 2003, 5, 941-944.
(2) For recent examples, see: (a) Hale, K. J.; Dimopoulos, P.; Cheung,
M. L. F.; Frigerio, M.; Steed, J. W.; Levett, P. C. Org. Lett. 2002, 4, 897-
900. (b) White, J. D.; Blakemore, P. R.; Green, N. J.; Hauser, E. B.;
Holoboski, M. A.; Keown, L. E.; Kolz, C. S. N.; Phillips, B. W. J. Org.
Chem. 2002, 67, 7750-7760. (c) Hanessian, S.; Ma, J.; Wang, W. J. Am.
Chem. Soc. 2001, 123, 10200-10206. (d) Peng, Z. H.; Woerpel, K. A.
Org. Lett. 2001, 3, 675-678. (e) Refs 1b-d.
Traditional routes to γ-lactones having multiple hydroxyl
groups (e.g., 2) recognize their similarity with carbohydrates,
which are readily available chiral pool starting materials. The
advantages are that the carbon skeletons and the stereochem-
ical relationships are in many cases already set in the starting
carbohydrates or can be easily adjusted. However, carbohy-
drate routes are frequently lengthy and labor intensive
because the multifunctional and sensitive intermediates
(3) Gumina, G.; Chu, C. K. Org. Lett. 2002, 4, 1147-1149.
(4) Rozners, E.; Xu, Q. Org. Lett. 2003, 5, 3999-4001.
(5) Rozners, E.; Liu, Y. Org. Lett. 2003, 5, 181-184.
10.1021/ol050578j CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/16/2005

require extensive protecting group manipulations. For ex-
ample, the synthesis of L-oxetanocin by Gumina and Chu
required 10 steps for preparation of an intermediate similar
to 2 in 36% yield starting from L-xylose.3 Asymmetric
syntheses that start from small organic molecules are
potentially shorter and more efficient routes to highly
substituted 2-hydroxy-γ-lactones.4-6
propargylamines via an acyl-Claisen and iodolactonization
route.
Initially, we attempted to access amide 4 via the aza-
Claisen rearrangement10 of allylic amide 6. Synthesis of 6
(Scheme 2) started with the condensation of the known
aldehyde 811 with chiral hydroxylamine 1012 to give the
nitrone 11.13
Recently, we reported4 a total synthesis of 3′,5′-C-branched
uridine 1 (Base ) uracyl, TES ) triethylsilyl, TBDPS )
tert-butyldiphenylsilyl, Tr ) trityl) (Scheme 1), which we
are using as a monomer for preparation of amide-linked RNA
analogues.7 In our synthesis, we prepared γ-butyrolactone 2
from small achiral molecules (7-9) in only six steps and
29% yield using Ireland-Claisen rearrangement of 5 fol-
lowed by iodolactonization of 3 as the key steps (Scheme
1). Although the total synthesis of 2 was shorter than
analogous routes from carbohydrates,4 several problems
remained unsolved. First, the asymmetric propynylation8 of
aldehyde 8 with propargyl ether 9, which we used as the
first step to establish the absolute stereochemistry, gave a
modest yield (50%) and enantioselectivity (ee 92%) with our
substrates. The enantioselectivity was a particular concern
because multiple couplings of azido acids 1 during the
synthesis of amide-linked RNA would create complex
mixtures of diastereomeric oligoamides. Second, the iodola-
ctonization of carboxylic acid 3 was not stereoselective, and
acceptable yields were obtained only after separation and
recycling of the undesired 3,4-cis diastereomer, thus making
the procedure laborious.
Scheme 2. Aza-Claisen Route to trans-3,4-Dialkyl-γ-lactones
Addition of the trityl propargyl ether 9 to nitrone 11 under
conditions developed by Carreira and co-workers8b,14 resulted
in the formation of two diastereomers in a ratio of 88:12.
Interestingly, deprotonation of the alkyne with n-butyllithium
reversed the diastereomeric ratio, but the stereoselectivity
under these conditions was low (Scheme 2). At this point,
we decided to probe the feasibility of the aza-Claisen
rearrangement without determining the absolute stereochem-
istry at the newly established chiral center in 12. If the
planned syntheses were successful, the required absolute
stereochemistry of the final product could be ensured by
choosing the correct enantiomer of 10.
Thus, both diastereomers of 12 were separated by silica
gel column chromatography and separately converted into
(Z)-alkenes 13 using Lindlar reduction. The anti relationship
of the 2-OH and 3-alkyl substituents in 4 required the (Z)-
configuration in 13. The N-OH group was replaced by the
benzyloxy acetyl function in a two-step sequence of N-O
cleavage15 and standard acylation with 7. In contrast to our
On the other hand, iodolactonization of amide 4 (Scheme
1) was expected, on the basis of our previous work,5 to give
respectable stereoselectivity.9 Therefore, we hypothesized that
an aza-Claisen rearrangement of 6 followed by iodolacton-
ization of 4 would constitute a more efficient and general
route to trans-3,4-dialkyl-γ-butyrolactones, including the
desired intermediate 2. Moreover, we envisioned that a chiral
auxiliary (R*) bound to nitrogen in 6 or earlier intermediates
could ensure high stereochemical purity of 1, because the
diastereomeric intermediates could be separated by conven-
tional means. In this communication, we report the experi-
mental realization of this design that resulted in a novel
synthesis of trans-3,4-dialkyl-γ-butyrolactones from chiral
(6) For selected recent examples, see: (a) Evans, D. A.; Wu, J.; Masse,
C. E.; MacMillan, D. W. C. Org. Lett. 2002, 4, 3379-3382. (b) Chen, Y.;
Eltepu, L.; Wentworth, P., Jr. Tetrahedron Lett. 2004, 45, 8285-8288. For
earlier precedents similar to our approach, see: Okamura, H.; Kuroda, S.;
Tomita, K.; Ikegami, S.; Sugimoto, Y.; Sakaguchi, S.; Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1991, 32, 5137-5140. Okamura, H.;
Kuroda, S.; Ikegami, S.; Tomita, K.; Sugimoto, Y.; Sakaguchi, S.; Ito, Y.;
Katsuki, T.; Yamaguchi, M. Tetrahedron 1993, 49, 10531-10554. Konno,
T.; Kitazume, T. Tetrahedron: Asymmetry 1997, 8, 223-230.
(7) Rozners, E.; Katkevica, D.; Bizdena, E.; Stro¨mberg, R. J. Am. Chem.
Soc. 2003, 125, 12125-12136.
(8) (a) Frantz, D. E.; Faessler, R.; Carreira, E. M. J. Am. Chem. Soc.
2000, 122, 1806-1807. (b) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.;
Carreira, E. M. Acc. Chem. Res. 2000, 33, 373-381.
(9) For similar precedents, see: Masaki, Y.; Arasaki, H.; Itoh, A.
Tetrahedron Lett. 1999, 40, 4829-4832. Ha, H. J.; Lee, S. Y.; Park, Y. S.
Synth. Commun. 2000, 30, 3645-3650. For recent reviews, see: Ranga-
nathan, S.; Muraleedharan, K. M.; Vaish, N. K.; Jayaraman, N. Tetrahedron
2004, 60, 5273-5308. Robin, S.; Rousseau, G. Tetrahedron 1998, 54,
13681-13736.
(10) For reviews, see: (a) Martin Castro, A. M. Chem. ReV. 2004, 104,
2939-3002. (b) Nubbemeyer, U. Synthesis 2003, 961-1008. (c) Chai, Y.;
Hong, S.; Lindsay, H. A.; McFarland, C.; McIntosh, M. C. Tetrahedron
2002, 58, 2905-2918. (d) Enders, D.; Knopp, M.; Schiffers, R. Tetrahe-
dron: Asymmetry 1996, 7, 1847-1882.
(11) Shiao, M. J.; Yang, C. Y.; Lee, S. H.; Wu, T. C. Synth. Commun.
1988, 18, 359-366.
(12) Wovkulich, P. M.; Uskokovic, M. R. Tetrahedron 1985, 41, 3455-
3462.
(13) Keirs, D.; Moffat, D.; Overton, K.; Tomanek, R. J. Chem. Soc.,
Perkin Trans. 1 1991, 1041-1051.
(14) Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 1999,
121, 11245-11246. Fassler, R.; Frantz, D. E.; Oetiker, J.; Carreira, E. M.
Angew. Chem., Int. Ed. 2002, 41, 3054-3056.
(15) Pulz, R.; Al-Harrasi, A.; Reissig, H.-U. Org. Lett. 2002, 4, 2353-
2355. Keck, G. E.; McHardy, S. F.; Wager, T. T. Tetrahedron Lett. 1995,
36, 7419-7422.
2822
Org. Lett., Vol. 7, No. 14, 2005

previous success with the Ireland-Claisen rearrangement,
no attempts to engage either diastereomer of 6 into the aza-
Claisen rearrangement gave the desired amide 4. The lack
of reactivity cannot be due to a mismatched stereochemical
relationship of the N-R-methylbenzyl auxiliary and the allylic
chiral center because neither diastereomer of 6 rearranged.16
In general, the thermal aza-Claisen rearrangement requires
higher temperatures and more reactive substrates than the
Ireland-Claisen variant.10 Although successful aza-Claisen
rearrangements of (E)-allylic amides similar to 6 have been
reported,16,17 it is conceivable that the (Z)-configuration of
the double bond and the bulky trityl protecting group
prevented the rearrangement of 6.18
15a, and methyl propargyl ether 16a according to procedures
developed by Knochel and co-workers.21 The reaction gave
a separable mixture of diastereomers (95:5) from which the
desired propargylamine 17a was isolated in 86% yield. The
absolute stereochemistry at the newly formed center was
assigned on the basis of the literature precedent.21a Lindlar
reduction quantitatively converted 17a into the required (Z)-
allylamine 18a.
Our initial attempts to induce the acyl-Claisen rearrange-
ment of 18a met with limited success. NMR analysis
suggested that the reaction was incomplete and gave complex
mixtures under a variety of conditions.22 Next, we probed a
slightly modified chiral amine 18b that had O-tert-butyldi-
methylsilyl (TBS) and O-methoxymethyl (MOM) groups
instead of methyl ethers. This modification was chosen with
the reasoning that the low reactivity of 18a might arise from
an unfavorable conformation involving coordination of the
Lewis basic methyl ether of the auxiliary with the Lewis
acid promoter. In the event, substitution of methyl by TBS
did improve the outcome of the acyl-Claisen rearrangement.
Propargylamine 17b was prepared using the same three-
component coupling as an 88:12 mixture of diastereomers
from which pure 17b was isolated in 82% yield and
converted into 18b using Lindlar reduction. Exposure of 18b
to MacMillan’s conditions (TiCl4 catalyst, NEt(i-Pr)2, 7)
resulted in 75% conversion and gave the desired unsaturated
amide 20 in 70% yield (based on recovered 18b). Alterna-
tively, the use of Zn(OSO2CF3)2 as a Lewis acid resulted in
complete consumption of 18b and 64% yield of 20. Several
other Lewis acid/base combinations22 were briefly investi-
gated but gave either no reaction (Me3SiOSO2CF3 and
Yb(OSO2CF3)3), incomplete conversion (SnCl4), or complex
mixtures (AlMe3 and Ti(Oi-Pr)4). Although further optimiza-
tion of the chiral auxiliary and rearrangement conditions is
clearly desirable and currently in progress in our laboratory,
the preliminary results allowed us to proceed to the next
iodolactonization step.
We therefore explored alternative synthetic routes using
an acyl-Claisen rearrangement19 of (Z)-allylic amines 18a,b
having smaller protecting groups instead of the trityl group
(Scheme 3). The acyl-Claisen is a charge-accelerated and
Scheme 3. Acyl-Claisen Route to trans-3,4-Dialkyl-γ-lactones
Exposure of 20 to iodine in a THF/water mixture resulted
in a rapid lactonization to give an inseparable 3.5:1 mixture
of the desired trans-21 and the undesired cis-21 isomers
(Scheme 4). This result was in good agreement with the
selectivity previously observed by us for a structurally similar
amide substrate.5 During the iodolactonization step, the chiral
amine was released and recovered in 68% yield. Pure trans
isomer was isolated after the next step, removal of iodine,
which completed the synthesis of the target γ-butyrolactone
22 in five steps and 32% overall yield. This result is an
improvement over the route previously developed in our
laboratory, which required six steps and gave 29% yield of
2.4 It should be noted that besides being shorter, easier to
scale-up, and more efficient, the new route also provides
enantiomerically pure lactones, whereas the previous syn-
thesis yielded products with 92% ee only.
Lewis acid-promoted version of the aza-Claisen rearrange-
ment that belongs to a larger group of zwitterionic [3,3]-
sigmatropic rearrangements known under the names of
ketene or Bellusˇ-Claisen rearrangements.10b,20 Mechanisti-
cally, the acyl-Claisen is believed to proceed through a
charged intermediate 19 and a six-center cyclic transition
state (Scheme 3).
The synthesis of 18a started with a copper-catalyzed
asymmetric three-component coupling of aldehyde 8, amine
(16) Davies, S. G.; Garner, A. C.; Nicholson, R. L.; Osborne, J.; Savory,
E. D.; Smith, A. D. Chem. Commun. 2003, 2134-2135.
(17) Tsunoda, T.; Nishii, T.; Yoshizuka, M.; Yamasaki, C.; Suzuki, T.;
Ito, S. Tetrahedron Lett. 2000, 41, 7667-7671. Tsunoda, T.; Tatsuki, S.;
Shiraishi, Y.; Akasaka, M.; Ito, S. Tetrahedron Lett. 1993, 34, 3297-3000.
Tsunoda, T.; Sakai, M.; Sasaki, O.; Sako, Y.; Hondo, Y.; Ito, S. Tetrahedron
Lett. 1992, 33, 1651-1654.
(18) Tsunoda, T.; Sasaki, O.; Ito, S. Tetrahedron Lett. 1990, 31, 727-
730.
(21) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P. Angew.
Chem., Int. Ed. 2003, 42, 5763-5766. (b) Koradin, C.; Polborn, K.; Knochel,
P. Angew. Chem., Int. Ed. 2002, 41, 2535-2538.
(22) The following Lewis acid/base combinations were tested: (a) TiCl4
and NEt(i-Pr)2, ref 19a; (b) Yb(OSO2CF3)3 and NEt(i-Pr)2, ref 19a; (c)
AlMe3 and K2CO3. Diederich, M.; Nubbermeyer, U. Angew. Chem., Int.
Ed. Engl. 1995, 34, 1026-1028.
(19) (a) Yoon, T. P.; Dong, V. M.; MacMillan, D. W. C. J. Am. Chem.
Soc. 1999, 121, 9726-9727. (b) Yoon, T. P.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2001, 123, 2911-2912.
(20) For a recent review, see: Gonda, J. Angew. Chem., Int. Ed. 2004,
43, 3516-3524.
Org. Lett., Vol. 7, No. 14, 2005
2823

(S)- and (R)-15b are readily available, our synthesis has the
advantage over routes that start from carbohydrates that both
enantiomers of 23, and eventually 1, can be prepared. Further
optimization of the chiral auxiliary is expected to increase
the efficiency of not only the three-component coupling but
also the rearrangement and the iodolactonization steps, for
both of which the use of similar amine auxiliaries has been
reported.24 Our synthesis may represent a general route to
trans-3,4-dialkyl-γ-lactones because it is conceivable that
other substituents at C-2, C-3, and C-4 can be introduced
by the choice of appropriate small-molecule starting materi-
als, e.g., acyl chloride 7, alkyne 16, and aldehyde 8,
respectively. Stereoselective synthesis of highly substituted
γ-butyrolactones will be useful for construction of many
natural products and synthetic intermediates, including the
highly modified C-branched nucleosides that are targets of
our laboratory.1-5
Scheme 4. Iodolactonization and Final Steps
To confirm the structure of 22, the MOM group was
selectively cleaved using TMSBr (prepared in situ). The 1H
and 13C NMR spectra of the resulting alcohol 23 matched
very well the spectra of racemic 23, which was previously
prepared by detritylation of 2.4 For the initial methodological
studies reported herein, we chose (S)-15b, which was made
from the relatively cheaper natural (S)-proline.23 Our present
choice would lead to modified nucleosides enantiomeric to
natural RNA. This is by no means a problem because (R)-
proline is also commercially available. In fact, modified
nucleic acids enantiomeric to natural DNA and RNA may
have unique applications in biotechnology and medicine.
In conclusion, we have developed a new and efficient
asymmetric synthesis of chiral, enantiomerically pure trans-
3,4-dialkyl-γ-lactones. To our knowledge, this is the first
application of the three-component coupling21 and acyl-
Claisen19 sequence in a total synthesis context. Because both
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society (37599-AC1), for support of this research. We thank
James Glick, John Williams, and Prof. Paul Vouros for mass
spectroscopy experiments.
Supporting Information Available: Experimental pro-
cedures, spectral data, and copies of 1H and 13C NMR data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL050578J
(24) Vedejs, E.; Gingras, M. J. Am. Chem. Soc. 1994, 116, 579-588.
Moon, H.; Eisenberg, S. W. E.; Wilson, M. E.; Schore, N. E.; Kurth, M. J.
J. Org. Chem. 1994, 59, 6504-6505. Najdi, S.; Reichlin, D.; Kurth, M. J.
J. Org. Chem. 1990, 55, 6241-6244.
(23) Marik, J.; Bennettova, B.; Tykva, R.; Budesinsky, M.; Hlavacek, J.
J. Peptide Res. 2001, 57, 410-408. Vedejs, E.; Lee, N. J. Am. Chem. Soc.
1995, 117, 891-900.
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