Comparison of solid-phase and solution-phase chiral auxiliaries in the alkylation/iodolactonization sequence to γ-butyrolactones

Article abstract of DOI:10.1021/jo0260692

Five prolinol-based chiral auxilaries have been compared for the stereoselective synthesis of γ-butyrolactones via the sequence of N-acylation, C_α-allylation, and iodolactonization under both solution-phase and solid-phase conditions. Comparisons of stereoselectivity of both the C_α-allylation and iodolactonization processes indicate that incorporation of a non-C₂-symmetric auxiliary as a polymer cross-link gives results superior to those obtained either in solution or with other non-C₂-symmetric auxiliaries and comparable to those observed using a polymer-supported pseudo-C₂-symmetric auxiliary.

Full text of DOI:10.1021/jo0260692

Com p a r ison of Solid -P h a se a n d Solu tion -P h a se Ch ir a l Au xilia r ies
in th e Alk yla tion /Iod ola cton iza tion Sequ en ce to γ-Bu tyr ola cton es
Michael D. Price, Mark J . Kurth, and Neil E. Schore*
Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616
neschore@ucdavis.edu
Received J une 17, 2002
Five prolinol-based chiral auxilaries have been compared for the stereoselective synthesis of
γ-butyrolactones via the sequence of N-acylation, CR-allylation, and iodolactonization under both
solution-phase and solid-phase conditions. Comparisons of stereoselectivity of both the CR-allylation
and iodolactonization processes indicate that incorporation of a non-C2-symmetric auxiliary as a
polymer cross-link gives results superior to those obtained either in solution or with other non-
C2-symmetric auxiliaries and comparable to those observed using a polymer-supported pseudo-C2-
symmetric auxiliary.
SCHEME 1. Syn th esis of Au xilia r ies 4a a n d 4b
In tr od u ction
In recent years, we have explored several approaches
to the transfer of resident stereochemistry in the syn-
thesis of 3,5-disubstituted γ-butyrolactones via an alky-
lation-iodolactonization protocol.1 We have examined
both non-C2-symmetric prolinol-based auxiliaries and
their pseudo-C2-symmetric counterparts, both in solution
and polymer supported.2-4 Non-C2-symmetric auxiliaries
in general provide modest CR-allylation stereoselectivity
and good but incomplete stereocontrol of the subsequent
electrophilic cyclization. Use of a polymer-supported
pseudo-C2-symmetric auxiliary improves the selectivity
of both processes, but its synthesis is laborious. We
describe herein a reexamination of the more readily
accessible prolinol-based auxiliaries, modified by increas-
ing steric bulk. We also describe the use of a novel
strategy in which the auxiliary is incorporated as a cross-
linker for the polymer matrix itself.
by converting N-(t-BOC)-L-proline 1 into its methyl ester
2, followed by addition of excess phenylmagnesium
bromide. Several standard methods for deprotection of
the amine were discarded because ring closure to the
bicyclic oxazolidinone 5 interfered. Hydrolysis with KOH
in methanolic DMSO proved successful, affording 4a in
50% overall yield for the three steps on a large scale. Once
this route was established, it was repeated using (p-
vinylphenyl)magnesium bromide, providing 4b in similar
overall yield (Scheme 1).
Am id e Syn th esis. Addition of propionic acid and DCC
to solutions of DMAP containing 4a and 4b gave rise to
amides 6a and 6b in yields of 71% and 88%, respectively.
There was no interference by O-acylation in either
process (Scheme 2).
Resu lts a n d Discu ssion
Ch ir a l Au xilia r y Syn th esis. We chose to prepare
auxiliaries 4a and 4b for solution- and solid-phase
applications, respectively. We followed Corey’s general
procedure,5 slightly modified, rather than alternatives
utilizing phosgene or phosgene analogues.6,7 We began
(1) For reviews of the halolactonization reactions, see: (a) Dowle,
M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171-197. (b) Bartlett, P.
A. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press:
Orlando, 1983; Vol. 3, pp 411-454. (c) Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321-3408.
In contrast, and as we had earlier found in some
related situations,4 attempts at CR-allylation in the
presence of the unprotected tertiary alcohol functionality
did not succeed. We chose therefore to block the alcohol
(2) Najdi, S.; Reichlin, D.; Kurth, M. J . J . Org. Chem. 1990, 55,
6241-6244.
(3) Moon, H.; Schore, N. E.; Kurth, M. J . J . Org. Chem. 1992, 57,
6088-6089.
(4) Moon, H.; Schore, N. E.; Kurth, M. J .; Tetrahedron Lett. 1994,
35, 8915-8918.
(6) Mathre, D. J .; J ones, T. K.; Xavier, L. C.; Blacklock, T. J .;
Reamer, R. A.; Mohan, J . J .; J ones, T. T.; Hoogsteen, K.; Baum, M.
W.; Grabowski, E. J . J . J . Org. Chem. 1991, 56, 751-762.
(7) Kaufman, T. S.; Ponze, V. L.; Zinczck, J . OPPI Briefs 1996, 28,
487-490.
(5) (a) Corey, E. J .; Bakshi, R. K.; Shibata, S. J . Am. Chem. Soc.
1987, 109, 5551-5553. (b) Corey, E. J .; Shibata, S.; Bakshi, R. K. J .
Org. Chem. 1988, 53, 2861-2863.
10.1021/jo0260692 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/27/2002
J . Org. Chem. 2002, 67, 7769-7773
7769

Price et al.
SCHEME 3. P r ep a r a tion of P olym er -Su p p or ted
SCHEME 2. P r ep a r a tion of Iod ola cton iza tion
P r ecu r sor s
Iod ola cton iza tion P r ecu r sor
trans disposition of the two substituents in the lactone
ring. The CR-alkylation of chiral amides has been studied
by several groups;8-10 in particular, they report that
stereoselectivity drops and the sense of the enantiose-
lection is reversed upon O-alkylation of the prolinol OH.
Our earlier observations using solution phase 12 (R/S )
81:19 ) 4:1) and pendant-polymer-bound 13 (S/R ) 66:
34 ) 2:1) concurred (Table 1). We additionally found that
the pseudo-C2-symmetric auxiliary 14 gave the best
control over stereoselection in this step (R/S ) 93.5:6.5
) 14:1; reversed because the auxiliary is 2R rather than
2S), higher even than did free prolinol-derived 12.
by methylation prior to C-alkylation. Thus, we ob-
tained amide 7a for direct determination of stereo-
selectivity under solution-phase conditions. Consistent
with spectroscopic observations of other prolinol-derived
amides,2-4,10c the 1H NMR spectra of 6a and 6b indicated
the presence of only a single amide rotamer, presumably
the one in which intramolecular hydrogen bonding is
present between the hydroxy and carbonyl moieties. In
contrast, the NMR of 7a , in which the hydroxy oxygen
has been alkylated, displays two rotamers in a ca. 1:1
ratio.
P olym er P r ep a r a tion . The potential for undesired
involvement of a terminal allyl double bond of an ally-
lated derivative of 6b under radical polymerization
conditions prompted us to delay incorporation of this
moiety until after polymer preparation. We therefore
proceeded with the suspension polymerization of mix-
tures of amide 6b with styrene to furnish polymer 9,
which displayed a broad IR absorption at 3312 cm-1 and
was found to have a loading of 0.33 mequiv/g on the basis
of elemental analysis. The analysis corresponds to ca. 12
wt % or 4 mol % incorporation of the auxiliary in the
polymer. That this polymer was found to be insoluble in
all solvents confirmed that 6b had indeed been incorpo-
rated in a cross-linking role. O-Methylation was achieved
by reaction of the polymer in THF with excesses of both
NaH and MeI under reflux for 2 h. Disappearance of the
O-H absorption in the IR confirmed that conversion to
10 had succeeded. Subsequent CR-allylation was effected
by treatment of 10 in THF with 1 equiv of LDA followed
by a 4-fold excess of allyl iodide to give polymer 11
(Scheme 3).
Iod ola cton iza tion Rea ction s. As described for poly-
mer 11, above, solution-phase CR-allylation of 7a was
carried out to give 8a , which was used immediately in
crude form. Iodolactonizations were carried out by the
addition of iodine in THF to both a THF/H2O solution of
8a and a similar suspension of 11, followed by stirring
at rt for 3d. The expected 3,5-disubstituted γ-butyrolac-
tones 15-18 were isolated as mixtures of stereoisomers
in 42% and 45% yields, respectively, from 7a (via 8a ) and
9 (via 10 and 11).
The solution-phase diaryl amide ether 7a provided
superior enantioselection upon allylation to give 8a (S/R
) 72:28 ) 2.5:1) than did the simpler polymer-bound
(8) Prolinol-based auxiliaries: (a) Sonnet, P. E.; Heath, R. R. J . Org.
Chem. 1980, 45, 3137-3139. (b) Evans, D. A.; Takacs, J . M. Tetrahe-
dron Lett. 1980, 21, 4233-4236. (c) Mori, K.; Ito, T.; Tanaka, K.; Honda,
H.; Yamamoto, I. Tetrahedron 1983, 39, 2303-2306. (d) Schultz, A.;
Sundararaman, P.; Macielag, M.; Lavieri, F. P.; Welch, M. Tetrahedron
Lett. 1985, 26, 4575-4578. (e) Evans, D. A.; Dow, R. L.; Shih, T. L.;
Takacs, J . M.; Zahler, R. J . Am. Chem. Soc. 1990, 112, 5290-5313.
(9) 2,5-Disubstituted pyrrolidine (C2-symmetric) auxiliaries: (a)
Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.;
Yamaguchi, M. Tetrahedron Lett. 1984, 25, 857-860. (b) Ito, Y.;
Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1984, 25, 6015-6016.
(c) Enomoto, M.; Ito, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett.
1985, 26, 1343-1344.
(10) Other auxiliaries: (a) Larcheveque, M.; Ignatova, E.; Cuvigny,
T. Tetrahedron Lett. 1978, 3961-3964. (b) Larcheveque, M.; Ignatova,
E.; Cuvigny, T. J . Organomet. Chem. 1979, 177, 5-15. (c) Guoqiang,
L.; Hjalmarsson, M.; Hoegberg, E.; J ernstedt, K.; Norin, T. Acta Chem.
Scand., Ser. B 1984, B38, 795-801. (d) Askin, D.; Wallace, M. A.;
Vacca, J . P.; Reamer, R. A.; Volante, R. P.; Shinkai, I. J . Org. Chem.
1992, 57, 2771-2773. (e) Tamion, R.; Marsais, F.; Ribereau, P.;
Queguiner, G. Tetrahedron: Asymmetry 1993, 4, 2415-2418. (f) Kane-
masa, S.; Ueno, K.; Onimura, K.; Kikukawa, T.; Yamamoto, H.
Tetrahedron 1995, 51, 10453-10462. (g) Myers, A. G.; McKinstry, L.
J . Org. Chem. 1996, 61, 2428-2440.
The stereochemistry of the lactone obtained from this
sequence reflects the stereoselectivity of two independent
processes. The enantioselectivity of the alkylation is
transmitted to the R-carbon of the lactone, while the face
selectivity of the iodolactonization determines the cis or
7770 J . Org. Chem., Vol. 67, No. 22, 2002

Solid-Phase and Solution-Phase Chiral Auxiliaries
TABLE 1. P r od u ct Ra tios fr om Cr-Allyla tion /
Iod ola cton iza tion Rea ction Sequ en ces
energy difference between the pre-trans and pre-cis
transition state structures enough to give rise to this
effect.
Con clu sion s
We have shown that diarylprolinol methyl ethers have
synthetic potential as chiral auxiliaries in the formation
of 3,5-disubstituted γ-butyrolactones. Furthermore, the
cross-linked polymer-supported version of the auxiliary
gave appreciably higher ee values upon CR-allylation than
did its solution-phase counterpart. In contrast to all other
non-C2 symmetric systems we have studied, both diaryl-
based allylated amides underwent iodolactonization with
complete trans selectivity.
benzylic ether 13, but the selectivity using cross-link-
bound 10, giving 11 (S/R ) 89:11 ) 8:1)/ surpassed that
of 12 as well. This latter result is remarkable because
there is no obvious reason based upon the local environ-
ment about CR alone to have expected any significant
difference in behavior in allylation between 7a and 10,
let alone a 3-fold selectivity enhancement. We demon-
strated earlier that bulky functional groups at cross-links
experience a relatively constrained environment with
respect to molecular motion, e.g., freedom of rotation.11
Our results correspond to a ∆G qof ∼0.65 kcal mol-1; it is
impossible to say how much of this is due to conforma-
tional constraints imposed by the cross-link environment
and how much arises from other effects of the microen-
vironment such as modifications in solvation in the
polymer interior. Without a better understanding of the
effects, it can only be considered fortuitous that in this
case selectivity is enhanced. By way of comparison, cross-
link-bound Mn(III)-salen complexes gave comparable or
better chemical yields but considerably poorer enanti-
oselectivity in asymmetric olefin epoxidation than their
solution-phase analogues.12 In those cases, increasing the
spacing between the auxiliary and the polymer chain
improved ee values, implying that the microenvironment
in the vicinity of the polymer chain reduced differentia-
tion between the relevant diastereomeric transition
states. Clearly, more data need to be gathered comparing
pendant- vs cross-link-bound functional behavior before
any sort of generalizations, much less predictions, become
possible.
We were pleased to find the total absence of any cis
isomers (17 and 18) in the iodolactonization products
derived from both solution-phase 7a (via 8a ) and cross-
link-bound 10 (via 11). Thus, the bulkier diarylprolinol-
derived auxiliary is comparable with the pseudo-C2-
symmetric system and surpasses the allylated derivatives
of both 12 and 13 in the face selectivity of iodolactoniza-
tion. This result is also somewhat surprising in that the
models that have been used to rationalize the trans
selectivity in the halolactonization of such pentenamides
show no direct interaction between a single bulky N-
substituent and the relevant structural elements in the
cyclization transition state.13 We presume that the added
steric bulk affects the dihedral angle about the carbonyl
C-N partial double bond, thereby influencing the free
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed in oven-
dried glassware under an atmosphere of dry nitrogen or argon.
Chromatography was carried out on a silica gel column using
an ethyl acetate-hexane mixture as the eluent unless specified
otherwise. NMR spectra were recorded on a 300 MHz instru-
ment in CDCl3. FTIR spectra of liquids were recorded neat; of
solids either as KBr pellets or using ATR. Optical purities were
determined using a Shimadzu capillary GC with a 25 m
Chirasil column (â-cyclodextrin on OV-1701).
(S)-P yr r olid in e-1,2-d ica r boxylic Acid 1-ter t-Bu tyl Es-
ter 2-Meth yl Ester [N-(ter t-Bu toxyca r bon yl)-L-p r olin e
Meth yl Ester ] (2).14 A solution of 1-hydroxybenzotriazole
(HOBT, 12.74 g, 0.083mol) and N-(tert-butoxycarbonyl)-L-
proline 1 (17.67 g, 0.082mol) in 176 mL of CH2Cl2 and 20 mL
of MeOH was cooled to 0 °C, and 1,3-dicyclohexylcarbodiimide
(DCC, 18.73 g, 0.091mol) in 44 mL of CH2Cl2 was added via
cannula. The mixture was stirred for 12 h at rt. Dicyclohexy-
lurea was removed by filtration, and the filtrate was washed
with water, saturated NaHCO3, and brine. Drying (Na2SO4),
evaporation of solvent, and flash chromatography furnished
15.39 g (82%) of N-(t-BOC)-L-proline methyl ester 2 as a yellow
oil: IR 1751, 1700, 1162 cm-1; 1H NMR δ 4.2-4.1 (m, 1H), 3.6
(m, 3H), 3.4-3.3 (m, 2H), 2.1-2.0 (m, 1H), 1.8-1.7 (m, 3H),
1.3 (s, 9H); 13C NMR δ 173.3, 173.0, 153.9, 153.2, 79.5, 79.4,
58.8, 58.5, 51.8, 51.7, 46.3, 46.1, 30.7, 29.7, 28.2, 28.1, 24.1,
23.5; [R]21 -57.5 (c ) 0.3, MeOH) [lit.14 [R]589 ) -61.5 (c )
589
0.34, MeOH)].
2-[Hyd r oxy(d ip h en yl)m eth yl]p yr r olid in e-1-ca r boxyl-
ic Acid ter t-Bu tyl Ester (3a ).5,6 To 141 mL of a 1.0 M solution
of PhMgBr in THF (0.141mol) was added a solution of N-(t-
BOC)-L-proline methyl ester 2 (19.26 g, 0.040 mol) in 243 mL
of THF slowly via addition funnel. The solution was stirred
for 4 h at 25°C and then cooled to -78 °C. After slow addition
of 10 mL of water, the solution was slowly warmed to rt with
stirring. Decantation and washing of precipitated salt with
ether gave a solution that was washed with brine, dried (K2-
CO3), and evaporated to an oil that was subjected to flash
chromatography to yield 11.68 g, 82% of 3a as a white
crystalline solid: mp 101-103 °C; IR 3370 (br), 1655 cm-1
;
1H NMR δ 7.5-7.2 (m, 10H), 6.4 (s, 1H), 4.9 (dd, J ) 8.9, 3.7
Hz, 1H), 3.4-3.2 (m, 1H), 3.0-2.9 (m, 1H), 2.2-2.0 (m, 1H),
2.0-1.8 (m, 1H), 1.6-1.4 (m, 10H), 0.8 (s, 1H); 13C NMR δ
146.3, 143.6, 128.1, 127.7, 127.5, 127.2, 127.1, 127.0, 126.9,
126.9, 81.6, 80.6, 65.6, 47.8, 29.8, 28.4, 22.9; [R]23 -154.8 (c
589
) 0.025, MeOH) [lit.5,6 [R]21 -154.3 (c ) 0.261, MeOH)].
589
(13) Tamaru, Y.; Mizutani, M.; Furukawa, Y.; Kawamura, S.;
Yoshida, Z.; Yanagi, K.; Minobe, M. J . Am. Chem. Soc. 1984, 106,
1079-1085.
(14) Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero, L.;
Sa´nchez-Obrego´n, R.; Walls, F.; Garc´ıa Ruano, J . L. Tetrahedron:
Asymmetry 2000, 11, 3079-3090.
(11) Wilson, M. E.; Wilson, J . A.; Kurth, M. J . Macromolecules 1997,
30, 3340-3348.
(12) (a) De, B. B.; Lohray, B. B.; Sivaram, S.; Dhal, P. K. Tetrahe-
dron: Asymmetry 1995, 6, 2105-2108. (b) Minutolo, F.; Pini, D.; Petri,
A.; Salvadori, P. Tetrahedron: Asymmetry 1996, 7, 2293-2302.
J . Org. Chem, Vol. 67, No. 22, 2002 7771

Price et al.
2-[Hyd r oxy[bis(4-vin ylp h en yl)]m eth yl]p yr r olid in e-1-
ca r boxylic Acid ter t-Bu tyl Ester (3b). Freshly cut Mg
ribbon (3.43 g, 0.141mol) was flame dried under vacuum and
stirred for 24 h. A solution of 4-bromostyrene (24.29 g,
0.133mol) in 243 mL of THF was added. The solution was
refluxed for 30 min, and 1,2-dibromoethane (1.52 g, 8.1 mmol)
was added followed by 30 min of additional refluxing. The
solution was cooled to 0 °C, and N-(t-BOC)-L-proline methyl
ester 2 (9.26 g, 0.040 mol) in 20 mL of THF was added. Workup
and purification as for 3a , above, gave 10.71 g (75%) of 3b as
a white crystalline solid: mp 101-103 °C; IR 3310 (br), 1659,
1169, 839 cm-1; 1H NMR δ 7.3-7.2 (m, 8H), 6.7 (ddd, J )
17.6, 10.9, 2.6 Hz, 2H), 5.8 (dd, J ) 17.6, 5.2 Hz, 2H), 5.3 (d,
J ) 10.6 Hz, 2H), 4.9 (dd, J ) 9.1, 3.6 Hz, 1H), 3.4-3.2 (m,
1H), 3.0-2.8 (m, 1H), 2.2-2.0 (m, 1H), 2.0-1.8 (m, 1H), 1.6-
1.4 (m, 10H), 0.9 (s, 1H); 13C NMR δ 145.8, 143.3, 136.4, 136.3,
136.2, 136.1, 128.3, 127.7, 125.6, 125.1, 113.7, 113.6, 81.5, 80.6,
17.7, 10.9 Hz, 2H), 5.6 (dd, J ) 17.6, 4.9 Hz, 2H), 5.24 (dd, J
) 11.0, 2.8 Hz, 2H), 5.20 (dd, J ) 8.8, 4.4 Hz, 1H), 3.4-3.3
(m, 1H), 3.0-2.9 (m, 1H), 2.3-2.2 (m, 2H), 2.1-2.0 (m, 1H),
2.0-1.9 (m, 1H), 1.6-1.5 (m, 1H), 1.1 (t, J ) 7.4 Hz, 3H), 1.0-
0.9 (m, 1H); 13C NMR δ 176.8, 146.0, 143.3, 136.7, 136.6, 128.6,
128.1, 126.0, 125.4, 114.2, 114.0, 82.1, 66.8, 48.8, 29.8, 28.8,
23.7, 9.7; [R]23
-198.3 (c ) 0.03, MeOH). Anal. Calcd for
589
C
24H27NO2: C, 79.74; H, 7.53. Found: C, 79.64; H, 7.63.
1-[2-[Meth oxy(d ip h en yl)m eth yl]p yr r olid in -1-yl]-1-p r o-
p a n on e (7a ). A solution of 0.72 g of 6a (2.33 mmol) in 10 mL
of THF was added via syringe to 0.12 g of NaH (5.0 mmol),
followed by addition of 0.65 g (4.58 mmol) of MeI. The mixture
was heated to reflux for 5 h, cooled, and taken up in 20 mL of
Et2O. The solution was washed with saturated aq Na2S2O3,
saturated NaHCO3, and brine and evaporated, and the residue
was subjected to flash chromatography to yield 0.60 g of 7a
(80%) as a white crystalline solid: mp 80-81 °C; IR 1638, 1074
65.6, 47.9, 29.7, 28.4, 23.1; [R]23 -166.9 (c ) 0.025 MeOH).
589
1
cm-1; H NMR δ 7.5-7.2 (m, 10H), 5.52 (dd, J ) 8.4, 2.3 Hz,
Anal. Calcd for C26H31NO3: C, 77.01; H, 7.70; N, 3.45. Found:
C, 76.83; H, 7.74; N, 3.39.
0.5H), 5.00 (d, J ) 7.7 Hz, 0.5H), 3.7-3.6 (m, 0.5H), 3.3.-3.2
(m, 0.5H), 2.99 (s, 1.5H), 2.88 (s, 1.5H), 2.7-2.2 (m, 2H), 2.1-
1.9 (m, 3H), 1.5-1.4 (m, 1H), 1.1 (t, J ) 7.3 Hz, 3H) 1.0-0.9
(m, 1H); 13C NMR 175.4, 174.1, 142.6, 140.8, 138.2, 137.4,
130.14, 130.07, 130.0, 129.6, 128.3, 128.2, 128.0, 127.9, 127.8,
127.4, 87.9, 86.3, 65.8, 59.5, 52.8, 52.0, 48.2, 46.8, 29.2, 28.6,
Dip h en yl[(S)-p yr r olid in -2-yl]m eth a n ol (4a ).6 A solution
of 6.33 g of 3a (17.9 mmol), 10.04 g of KOH (0.179mol), 17 mL
of MeOH, and 84 mL of DMSO was heated at 65 °C for 4 h.
Water (100 mL) was added, the solution was extracted with 5
× 30 mL of hexane, and the extracts were dried (K2CO3).
Evaporation and flash chromatography yielded 3.32 g (73%)
of 4a as a white solid: mp 79-80°C from hexane (lit.6 mp 79-
79.5 °C); IR 3600-3300(br), 3057 cm-1; 1H NMR δ 7.7-7.5 (m,
4H), 7.4-7.1 (m, 6H), 4.7 (s, 1H), 4.3 (t, J ) 7.4 Hz, 1H), 3.1-
2.9 (m, 2H),1.9-1.5 (m, 5H); 13C NMR δ 148.2, 145.4, 128.2,
128.0, 126.5, 126.4, 125.9, 125.6, 77.1, 64.4, 46.7, 26.3, 25.5;
[R]26 -66.5 (c ) 0.03, MeOH) [lit.6 [R]24 -58.8 (c ) 3.0,
27.9, 27.6, 23.8, 22.3, 10.5, 9.9; [R]22
-20.43 (c ) 0.03,
589
MeOH). Anal. Calcd for C21H25NO2: C, 77.99; H, 7.79. Found:
C, 77.79; H, 7.89.
Dih yd r o-5-iod om eth yl-3-m eth yl-2(3H)-fu r a n on e (Solu -
tion P h a se) (15 a n d 16).2 A solution of 0.31 g of 7a (0.95
mmol) in 15 mL of THF was cooled to -78 °C and treated with
0.53 mL of 2.0 M LDA in THF. The mixture was allowed to
warm to -20°C for 1 h and then cooled to -78 °C, and 0.21 g
of allyl iodide (1.22 mmol) was added. After being stirred at
-78 °C for 2 h, the mixture was warmed to rt and quenched
with 1% aq HCl. Extraction (Et2O), drying (Na2SO4), and
concentration gave 0.32 g of crude 8a as an oil that was taken
up directly in 3 mL of THF and 3 mL of water. This mixture
was cooled to 0 °C, treated in the dark with 0.71 g of I2 (2.8
mmol) in 2 mL of THF, and maintained at 0 °C in the dark
for 3 d, after which time 15 mL of saturated aq Na2S2O3 and
30 mL of Et2O were added. The aqueous layer was separated
and washed with Et2O. The combined organic layers were
washed with 1% aq HCl and brine, dried (Na2SO4), filtered,
and concentrated. The residue was purified by flash chroma-
tography to give 0.10 g (42% yield) of trans-dihydro-5-iodom-
ethyl-3-methyl-2(3H)-furanone as a 72:28 mixture of enanti-
omers 16 and 15 (44.2% ee). None of the cis isomer was
589
589
MeOH)].
Bis(4-vin ylp h en yl)[(S)-p yr r olid in -2-yl]m eth a n ol (4b).
In a similar manner, 1.07 g of 3b (3.02 mmol), 1.69 g of KOH
(0.030 mol) in 5.0 mL of MeOH, and 14.2 mL of DMSO were
reacted to yield 0.59 g (64%) of 4b as a white solid: mp 85-
1
86 °C; IR 3352 (br), 3084, 1630 cm-1; H NMR δ 7.5-7.4 (m,
4H), 7.4-7.3 (m, 4H), 6.7 (dd, J ) 17.4, 10.9 Hz, 2H), 5.7 (d,
J ) 17.6 Hz, 2H), 5.2 (d, J ) 10.9 Hz, 2H), 4.3 (t, J ) 7.7 Hz,
1H), 3.1-2.8 (m, 2H), 1.8-1.5 (m, 4H); 13C NMR δ 147.6, 144.8,
136.4, 136.2, 135.7, 135.6, 126.0, 125.9, 125.8, 125.5, 113.5,
113.3, 77.0, 64.3, 46.8, 26.3, 25.6; [R]23
-55.6 (c ) 0.03
589
MeOH). Anal. Calcd for C21H23NO: C, 82.59; H, 7.59. Found:
C, 82.48; H, 7.61.
1-[2-[Hyd r oxy(d ip h en yl)m eth yl]p yr r olid in -1-yl]-1-p r o-
p a n on e (6a ). A mixture of 2.00 g of 4a (7.89 mmol) and 0.044
g of DMAP (0.395 mmol) was dissolved in 17.1 mL of CH2Cl2
and cooled to 0 °C. A solution of 1.79 g of DCC (8.68 mmol) in
4.3 mL of CH2Cl2 was added by cannula, followed by 2.34 g of
propionic acid (31.6 mmol). The flask was allowed to slowly
warm to rt and stirred for 12 h. After removal of dicyclohexy-
lurea by filtration, the filtrate was washed with saturated
NaHCO3 and brine. Additional precipitated urea was removed
and the solution dried (Na2SO4). Flash chromatography fur-
nished 1.73 g (71%) of 6a as a white solid: mp 85-86 °C; IR
3248 (br), 1613 cm-1; 1H NMR δ 7.4-7.2 (m, 10H), 7.1(s, 1H),
5.2 (dd, J ) 8.9, 4.5 Hz, 1H), 3.4-3.3 (m, 1H), 2.9-2.8 (m,
1H), 2.3-2.2 (m, 2H), 2.1-1.9 (m, 2H), 1.6-1.5 (m, 1H), 1.1
(t, J ) 7.6 Hz, 3H), 1.0-0.8 (m, 1H); 13C NMR δ 176.5, 146.3,
143.5, 128.2, 128.0, 127.8, 127.4, 127.22, 127.19, 82.1, 66.7,
1
detected: IR (neat) 1770 cm-1; H NMR δ 4.61 (m, 1H), 3.36
(m, 1H), 3.26 (m, 1H), 2.79 (m, 1H), 2.32 (m, 1H), 2.11 (m,
1H), 1.30 (d, J ) 7 Hz, 3H); 13C NMR δ 178.7, 76.3, 35.2, 33.9,
15.9, 7.1.
P olym er -Su p p or ted P r op ion yl Am id e-Alcoh ol (9).
Into a 45/50 500 mL two-necked indented (Morton-style) flask
equipped with a propeller-shaped mechanical stirrer was
placed 188 mL of water and 13 g of gum Arabic, and a stir
rate of 475 rpm was established. A mixture of 9.44 g (90.59
mmol) of styrene, 0.107 g (0.442 mmol) of benzoyl peroxide,
13.4 mL of chlorobenzene, and 0.67 g (1.85 mmol) of monomer
6b was prepared and added to the stirred aqueous mixture.
The reaction vessel was heated to 85 °C while maintaining
the 475 rpm stir rate. After 2 h, the stir rate was lowered to
215 rpm, and 0.178 g of Al2O3 (1.75 mmol) was added to inhibit
droplet coalescence. The temperature and stir rate were
maintained at 85 °C and 215 rpm, respectively, for an
additional 24 h. The newly formed resin was collected by
filtration and washed in turn with water, THF, CH2Cl2, MeOH,
CH2Cl2, MeOH, CH2Cl2, and MeOH. The beads were dried
under vacuum overnight to give 8.23 g, 81.4% yield, of resin
9. Elemental analysis indicated the presence of 0.33 mequiv
of auxiliary/gram of polymer (Anal. Calcd: N, 0.46. Found: N,
48.6, 29.7, 28.7, 23.4, 9.5; [R]23
-196.9 (c ) 0.03, MeOH).
589
Anal. Calcd for C20H23NO2: C, 77.64; H, 7.49. Found: C, 77.56;
H, 7.54.
1-[2-[H yd r oxy[b is(4-vin ylp h en yl)]m et h yl]p yr r olid in -
1-yl]-1-p r op a n on e (6b). In a similar way, 2.41 g of 4b (7.89
mmol) and 0.044 g of DMAP (0.40 mmol) in 17.1 mL of CH2-
Cl2 was treated with 1.79 g of DCC (8.68 mmol) in 4.3 mL of
CH2Cl2 and then 2.34 g of propionic acid. After similar workup,
flash chromatography furnished 2.51 g (88%) of 6b as a white
solid: mp 85-86 °C; IR 3240 (br), 1614, 990, 909, 840 cm-1
;
1H NMR δ 7.4 (s, 4H), 7.3 (s, 4H), 7.1 (s, 1H), 6.7 (dd, J )
7772 J . Org. Chem., Vol. 67, No. 22, 2002
0.45, 0.46): IR 3312, 1740 cm-1
.

Solid-Phase and Solution-Phase Chiral Auxiliaries
P olym er -Su p p or ted P r op ion yl Am id e-Meth oxy Eth er
(10). A mixture of 0.12 g of NaH (5.0 mmol) and 5.06 g of 9
(1.67 mequiv) was treated with 20 mL of THF and the mixture
heated to reflux for 2 h, at which time 1.18 g of MeI (8.3 mmol)
was added and reflux continued for 8 h. Resin 10 was isolated
by filtration and washed with water, THF, CH2Cl2, MeOH,
CH2Cl2, MeOH, CH2Cl2, and MeOH. The beads were dried
under vacuum overnight. IR showed the absence of any
THF was added via syringe. The mixture was agitated at 0
°C for 3 d at which time 15 mL of saturated aq Na2S2O3 and
30 mL of THF were added. The resin was isolated by filtration
and washed with THF, H2O, THF, H2O, and THF. The filtrate
was diluted with brine and extracted with Et2O. The aqueous
layer was extracted once more with Et2O, and the combined
organic layers were washed with 1% HCl and brine, dried (Na2-
SO4), filtered, and concentrated. The oily residue was purified
by flash chromatography to give 0.11 g (45% yield) of trans-
dihydro-5-iodomethyl-3-methyl-2(3H)-furanone as an 89:11
mixture of enantiomers 16 and 15 (78.4% ee).
absorption in the region of 3300 cm-1
.
Dih yd r o-5-iod om eth yl-3-m eth yl-2(3H)-fu r a n on e (Solid
P h a se) (15 a n d 16).2 A mixture of 3.11 g of 10 (assumed 0.33
mequiv/g) and 12 mL of THF was cooled to -78 °C, and 0.61
mL of 2.0 M LDA in THF was added. The mixture was allowed
to warm to -20 °C for 1 h and then recooled to -78 °C, at
which point 0.2 g of allyl iodide (1.22 mmol) was added. After
being agitated at -78 °C for 4 h, the mixture was warmed to
rt and quenched with 1% aq HCl. Resin 11 was isolated by
filtration and washed with H2O, THF, CH2Cl2, MeOH, CH2-
Cl2, MeOH, CH2Cl2, and MeOH. To this resin was added 25
mL of THF and 20 mL of H2O. The mixture was cooled to 0°C,
and in the absence of light 0.77 g of I2 (3.06 mmol) in 5 mL of
Ack n ow led gm en t. We thank the National Science
Foundation (CHE-0078191) for research support. Fund-
ing sources for the NMR instrumentation at UC Davis
include the NSF CRIF program (CHE-9808183), the UC
Davis Office of Research, and Office of the Dean,
Division of Mathematics and Physical Sciences.
J O0260692
J . Org. Chem, Vol. 67, No. 22, 2002 7773