The Exocyclic Effect: Protecting Group Strategy to Enhance Stereoselectivity in Hydrogen Transfer Reactions of Acyclic Free Radicals

Article abstract of DOI:10.1021/jo971595s

To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing 1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been demonstrated. This strategy is based upon the "exocyclic

Full text of DOI:10.1021/jo971595s

9276
J . Org. Chem. 1997, 62, 9276-9283
Th e Exocyclic Effect: P r otectin g Gr ou p Str a tegy to En h a n ce
Ster eoselectivity in Hyd r ogen Tr a n sfer Rea ction s of Acyclic F r ee
Ra d ica ls
Yvan Guindon,*,†,‡ Anne-Marie Faucher,§ EÄ lyse Bourque,§ Vale´rie Caron,†,§ Grace J ung,†,‡ and
Serge R. Landry†,§
Institut de recherches cliniques de Montre´al (IRCM), Bio-organic Chemistry Laboratory,
110 avenue des Pins Ouest, Montre´al, Que´bec, Canada H2W 1R7, Department of Biochemistry,
Department of Chemistry and Faculty of Pharmacy, Universite´ de Montre´al, C.P. 6128,
succursale Centre-ville, Montre´al, Que´bec, Canada H3C 3J 7, and Bio-Me´ga Research Division/ Boehringer
Ingelheim (Canada) Ltd., 2100 rue Cunard, Laval, Que´bec, Canada H7S 2G5
Received August 27, 1997X
To enhance the diastereoselectivity of the hydrogen transfer reaction of acyclic substrates bearing
1,2- or 1,3-diols, the feasibility of a strategy employing bifunctional protecting groups has been
demonstrated. This strategy is based upon the “exocyclic effect” or the significant improvement of
anti-selectivity exhibited by the reductions of substrates in which the two substituents (R1 and Y)
at the stereogenic center R to the radical center are linked together. A rationale for the excellent
facial discrimination of these exocyclic radicals is offered based on an analysis of transition state
models, which considers both steric and electronic factors.
In tr od u ction
selectivity became clearer, our hope for the general use
of this reaction in synthesis began to fade; good diaste-
reoselectivity appeared be limited to substrates bearing
an aromatic or a sterically demanding R1 group (eq 1).8
As shown by entries 2 and 3 (Table 1), the ratios are
significantly decreased when R1 is smaller, such as an
ethyl or isopropyl group.
The induction of chirality in radical-based processes
involving acyclic substrates has attracted much attention
in the past decade.1-7 Our group has focused particularly
on atom and group transfer reactions of radicals (eq 1)
which are flanked by an ester and by a stereogenic center
bearing an electron-withdrawing group Y (e.g. OMe,
OBzl, or F).8,9 Typical of kinetically controlled reactions,
the hydrogen transfers demonstrate enhanced diastereo-
selectivity at lower reaction temperatures,8 and ratios as
high as 32:1 in favor of the anti products could be
attained at -78 °C (Table 1, entry 1). However, as our
understanding of the structural prerequisites for facial
If this process had proven to be more general, it would
complement the largely syn-selective aldol methodologies
by providing access to anti aldol-like products. A possible
means to broaden the scope of this radical-based meth-
odology came to light from the observation that sub-
strates, in which Y and R1 (eq 1) were linked together,
reduced with significantly greater diastereoselectivity
than their acyclic counterparts. For example, the hy-
drogen transfer reactions of 10 and 13 (entries 5 and 6)
demonstrate enhanced anti-selectivity compared to the
* To whom correspondence should be addressed (IRCM).
† Institut de recherches cliniques de Montre´al.
‡ Universite´ de Montre´al.
§ Bio-Me´ga Research Division/Boehringer Ingelheim (Canada) Ltd.
X Abstract published in Advance ACS Abstracts, December 1, 1997.
(1) (a) Porter, N. A.; Giese, B.; Curran, D. P. Acc. Chem. Res. 1991,
24, 296. (b) Liotta, D. C.; Durkin, K. A.; Soria, J . J . Chemtracts 1992,
5, 197. (c) Miracle, G. S.; Cannizzaro, S. M.; Porter, N. A. Chemtracts
1993, 6, 147. (d) Smadja, W. Synlett 1994, 1. (e) Giese, B.; Damm, W.;
Batra, R. Chemtracts 1994, 7, 355. (f) Curran, D. P.; Porter, N. A.;
Giese, B. Stereochemistry of Radical Reactions - Concepts, Guidelines
and Synthetic Applications; VCH: New York, 1996.
(2) (a) Hart, D. J .; Huang, H.-C. Tetrahedron Lett. 1985, 26, 3749.
(b) Hart, D. J .; Krishnamurthy, R. J . Org. Chem. 1992, 57, 4457. (c)
Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron Lett.
1992, 33, 1863. (d) Curran, D. P.; Ramamoorthy, P. S. Tetrahedron
1993, 49, 4841. (e) Bartlett, P. A.; Adams, J . L. J . Am. Chem. Soc.
1980, 102, 337.
(3) Selected examples involving the use of chiral auxiliaries: (a)
Crich, D.; Davies, J . W. Tetrahedron Lett. 1987, 28, 4205. (b) Porter,
N. A.; Scott, D. M.; Lacher, B.; Giese, B.; Zeitz, H. G.; Lindner, H. J .
J . Am. Chem. Soc. 1989, 111, 8311. (c) Curran, D. P.; Qi, H.; Geib, S.
J .; DeMello, N. C. J . Am. Chem. Soc. 1994, 116, 3131. (d) Porter, N.
A.; Carter, R. L.; Mero, C. L.; Roepel, M. G.; Curran, D. P. Tetrahedron
1996, 52, 4181, and references therein.
(4) For the use of monodentate Lewis acids, see: (a) Renaud, P.;
Moufid, N.; Kuo, L. H.; Curran, D. P. J . Org. Chem. 1994, 59, 3547.
(b) Renaud, P.; Ribezzo, M. J . Am. Chem. Soc. 1991, 113, 7803. (c)
Curran, D. P.; Kuo, L. H. J . Org. Chem. 1994, 59, 3259. (d) Nishida,
M.; Ueyama, E.; Hayashi, H.; Ohtake, Y.; Yamaura, Y.; Yanaginuma,
E.; Yonemitsu, O.; Nishida, A.; Kawahara, N. J . Am. Chem. Soc. 1994,
116, 6455. (e) Renaud, P.; Bourquard, T.; Gerster, M.; Moufid, N.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1601. (f) Nishida, M.; Hayashi,
H.; Yamaura, Y.; Yanaginuma, E.; Yonemitsu, O. Tetrahedron Lett.
1995, 36, 269. (g) Murakata, M.; Tsutsui, H.; Hoshino, O. J . Chem.
Soc., Chem. Commun. 1995, 481. (h) Urabe, H.; Kobayashi, K.; Sato,
F. J . Chem. Soc., Chem. Commun. 1995, 1043. (i) Moufid, N.; Renaud,
P.; Hassler, C.; Giese, B. Helv. Chim. Acta 1995, 78, 1006.
(5) For the use of bidentate Lewis acids, see: (a) Guindon, Y.;
Lavalle´e, J .-F.; Llinas-Brunet, M.; Horner, G.; Rancourt, J . J . Am.
Chem. Soc. 1991, 113, 9701. (b) Guindon, Y.; Gue´rin, B.; Chabot, C.;
Mackintosh, N.; Ogilvie, W. W. Synlett. 1995, 449. (c) Guindon, Y.;
Gue´rin, B.; Rancourt, J .; Chabot, C.; Mackintosh, N.; Ogilvie, W. W.
Pure Appl. Chem. 1996, 68, 89. (d) Toru, T.; Watanabe, Y.; Tsusaka,
M.; Ueno, Y. J . Am. Chem. Soc. 1993, 115, 10464. (e) Ru¨ck, K.; Kunz,
H. Synthesis 1993, 1018. (f) Nagano, H.; Kuno, Y. J . Chem. Soc., Chem.
Commun. 1994, 987. (g) Yamamoto, Y.; Onuki, S; Yumoto, M.; Asao,
N. J . Am. Chem. Soc. 1994, 116, 421. (h) Gerster, M.; Audergon, L.;
Moufid, N.; Renaud, P. Tetrahedron Lett. 1996, 37, 6335.
(6) For the use of chiral Lewis acids, see: (a) Sibi, M. P.; J asperse,
C. P.; J i, J . G. J . Am. Chem. Soc. 1995, 117, 10779. (b) Wu, J . H.;
Radinov, R.; Porter, N. A. J . Am. Chem. Soc. 1995, 117, 11029. (c) Sibi,
M. P.; J i, J . G. J . Am. Chem. Soc. 1996, 118, 3063. (d) Sibi, M. P.; J i,
J . G. Angew. Chem., Int. Ed. Engl. 1996, 35, 190. (e) Sibi, M. P.; J i, J .
G.; Wu, J . H.; Gurtler, S.; Porter, N. A. J . Am. Chem. Soc. 1996, 118,
9200. (f) Fhal, A. R.; Renaud, P. Tetrahedron Lett. 1997, 38, 2661.
(7) For intramolecular hydrogen bonding, see: (a) Ku¨ndig, E. P.;
Xu, L.-H.; Romanens, P. Tetrahedron Lett. 1995, 36, 4047. (b) Curran,
D. P.; Abraham, A. C.; Liu, H.-T. J . Org. Chem. 1991, 56, 4335. (c)
Hanessian, S.; Yang, H.; Schaum, R. J . Am. Chem. Soc. 1996, 118,
2507.
(8) Guindon, Y.; Yoakim, C.; Lemieux, R.; Boisvert, L.; Delorme, D.;
Lavalle´e, J .-F.; Tetrahedron Lett. 1990, 31, 2845.
S0022-3263(97)01595-8 CCC: $14.00 © 1997 American Chemical Society

The Exocyclic Effect
J . Org. Chem., Vol. 62, No. 26, 1997 9277
Ta ble 1. Effect of Su bstitu en ts on Dia ster eoselectivity of Ra d ica l Red u ction a
reactions of their respective acyclic analogues 4 and 7
(entries 2 and 3), respectively. These intriguing observa-
tions have subsequently led us to examine the role of the
ring in increasing facial selectivity of the radical,10 as well
as to consider various means by which this effect could
be exploited synthetically to access molecules with an
anti-aldol motif.
prepared from a Mukaiyama aldol condensation between
the corresponding dimethyl acetal and 2-bromo-1-meth-
oxy-1-[(trimethylsilyl)oxy]-1-propene in the presence of
TiCl4 (eq 2).
Opportunities to employ this strategy to good advan-
tage are often presented by synthetic targets bearing
functionalities such as 1,2 or 1,3-diols, -amino alcohols,
and -diamines, which can be linked together by bifunc-
tional protecting groups11 prior to radical reduction. To
demonstrate the practicality of this strategy, we subjected
a series of cyclic and acyclic protected 1,3- and 1,2-diols
to hydrogen transfer conditions, the results of which are
reported herein.
Scheme 1 shows the two-step synthesis of cyclic
substrates 22, 25, 28, 31, and 34. Aldol condensation
between the R-phenylseleno ester 39 and the appropriate
aldehyde (40, 41, 42, or 43) gave a mixture of diastere-
omers, which were separated chromatographically. Each
diastereomer was subsequently converted to a cyclic
acetal (22, 25, 28, 31, or 34) under conditions that
permitted in situ deprotection of either the tert-butyldi-
methylsilyl ether (for 40, 41, and 43) or the methoxy-
methyl ether (for 42).
Resu lts a n d Discu ssion
The radical reduction of acyclic protected 1,3- and 1,2-
diols 16 and 19 would serve as controls for the reactions
of their cyclic counterparts. These compounds were

9278 J . Org. Chem., Vol. 62, No. 26, 1997
Guindon et al.
Sch em e 1
Sch em e 2
obtained at reaction temperatures of -30 °C or 23 °C (cf.
entries 9-11; cf. entries 12 and 13). The solvent effect
on the stereochemical outcome is shown by a comparison
between entries 9, 14, and 15: greater selectivity was
observed when the reaction was conducted in THF or
toluene, while there was some erosion in the anti-
selectivity when dichloromethane was employed as sol-
vent.
The relative configuration of reduced products was
1
deduced by correlation of H NMR spectral data. In all
cases, the methyl group R to the ester in the anti
diastereomer resonates slightly upfield to that of the syn
diastereomer, in agreement with previously published
results.13 A more rigorous stereochemical assignment
was performed for the anti and syn reduction products
26 and 27, each of which was subjected to acidic metha-
nolic conditions to afford the respective lactones 37 and
38 (Scheme 2). Lactone 37 which is derived from anti
product 26 is characterized by a smaller H(2)-H(3)
coupling constant (3.5 Hz) than that (7 Hz) of lactone 38
derived from syn product 27.
Mech a n istic Con sid er a tion s. While the results
described here clearly demonstrate the feasibility of a
strategy employing bifunctional cyclic protecting groups
to enhance the selectivity of the radical reduction, a
rationale for the greater facial discrimination offered by
an exocyclic14 radical (the “exocyclic effect”) would be
insightful for the development of other strategies based
on the same phenomenon. Because these radical-medi-
ated processes are under kinetic control, the rationale
for the stereochemical outcome is based on transition
state analysis. To account for the predominant anti-
product, we and others have favored transition state
model A (Scheme 3),15 which is stabilized by a balance
of steric and electronic factors.8 Minimization of 1,3- and
1,2-allylic strain, minimization of intramolecular dipole-
dipole effects, as well as the beneficial hyperconjugative
contribution12 of R1 (depicted in A to D as an ethyl group)
have been cited as possible controlling elements that
stabilize this transition state model.
Hyd r ogen Tr a n sfer Rea ction s. Compounds 16, 19,
22, 25, 28, 31, and 34 were subjected to hydrogen transfer
with tributyltin hydride for 30 min. These reactions were
initiated by the addition of catalytic amounts of Et3B.
As shown by entry 7, the 1,3-diol protected as the acyclic
bis(methyl ether) 16 was predictably reduced with little
selectivity. By contrast, the hydrogen transfer reactions
of the cyclic analogues, such as benzylidene acetal 22 and
isopropylidene acetal 25 proceeded with excellent dias-
tereoselectivity (g32:1; entries 9 and 16) in favor of the
anti product. In these cases, the relative configuration
of the substrate at C-2 had little influence on the
stereochemical outcome since the reaction of epimeric
selenides 22a and 22b (cf. entries 9 and 12; cf. entries
10 and 13) afforded essentially the same product distri-
bution.
Similar results were obtained in the 1,2-diol series.
Compared to the poorly selective hydrogen transfer
reaction of the 1,2-diol protected as bis(methyl ether) 19
(2:1; entry 8), the reaction of the corresponding isopro-
pylidene acetal 28 demonstrated greater facial differen-
tiation, although the anti/syn ratio is modest (9:1; entry
17). It is interesting to note that the diastereoselectivity
could be further enhanced by alkyl substitution at the
γ-carbon (relative to the ester) in this series of cyclic
substrates; subjection of the γ-substituted isopropylidene
acetals 31 and 34 to radical reduction produced exclu-
sively anti products (>100:1; entries 18 and 19). This
effect is consistent with the trends observed for the
hydrogen transfer reaction of other cyclic substrates
studied in our laboratory.12 In the case of acetal 31 in
which the γ-substituent is anti to the radical-bearing
appendage with respect to the ring, the excellent facial
discrimination of the radical is attributed to an electronic
control element (vide infra).
We have proposed two transition state models (B and
C) to account for the formation of the minor syn-product.
(9) Guindon, Y.; Lavalle´e, J .-F.; Boisvert, L.; Chabot, C.; Delorme,
D.; Yoakim, C.; Hall, D.; Lemieux, R.; Simoneau, B. Tetrahedron Lett.
1991, 32, 27.
(10) Guindon, Y.; Yoakim, C.; Gorys, V.; Ogilvie, W. W.; Delorme,
D.; Renaud, J .; Robinson, G.; Lavalle´e, J .-F.; Slassi, A.; J ung, G.;
Rancourt, J .; Durkin, K.; Liotta, D. J . Org. Chem. 1994, 59, 1166.
(11) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley & Sons, Inc.: New York, 1991; pp 118-
142.
Other factors that influence the diastereoselectivity of
the hydrogen transfer reaction include reaction temper-
ature and solvent. In all cases shown in Table 1, the
ratios favoring anti products were higher when the
reduction was performed at -78 °C compared to ratios
(12) Guindon, Y.; Slassi, A.; Rancourt, J .; Bantle, G.; Bencheqroun,
M.; Murtagh, L.; Ghiro, EÄ .; J ung, G. J . Org. Chem. 1995, 60, 288.

The Exocyclic Effect
J . Org. Chem., Vol. 62, No. 26, 1997 9279
Sch em e 3
would arise from attack by the tin reagent on either face
(A or C) of the same radical conformer, and the ratio of
anti- and syn-products would be dictated by the energy
difference between transition states A and C.
In the case of the acyclic radical in which R1 (eq 1) is
an ethyl group, the poor diastereoselectivity (Table 1,
entry 2) suggests little energy difference between A and
C. Furthermore, the facility of top-face attack by the tin
reagent to give syn-product suggests the rotamer depicted
in C (rather than D), in which the methyl group (of the
ethyl chain) is oriented the farthest from the radical
reactive site to provide the least top-face shielding.
This scenario, however, changes considerably when the
ethyl and OMe groups are linked to give the tetrahydro-
furan 10. While the structural changes (loss of two
hydrogens, additional C-C bond) of cycle formation may
seem subtle, they confer a significant enhancement in
selectivity (g8:1) in the hydrogen transfer reaction of 10
(entries 4 and 5). In the reduction of 10, either the
energy barrier to reach the anti transition state is
decreased, or the energy barrier to reach the syn transi-
tion state is increased compared to the reaction of the
acyclic substrate 4. It is not clear how cycle formation
would render the anti pathway more accessible.10 On the
other hand, the enhanced anti preference of the exocyclic
radical could be more easily rationalized by the greater
destabilization of its syn transition state relative to the
acyclic case; that is, the conformational rigidity of the
radical arising from tetrahydrofuran 10 permits greater
steric hindrance by the hydrogen at C-4 (relative to ester
C-1) to top-face approach of the incoming tin reagent in
syn transition state E. In the reduction of acyclic
substrate 4, the rotamerically analogous syn transition
state D that would provide similar steric encumbrance
to top-face attack is destabilized by the steric compression
between the methyl group of the R1 ethyl substituent and
the methyl group residing on the radical-bearing center.
In essence, the steric contribution of R1 is magnified in
exocyclic radicals.
In conjunction with model A, they will be analyzed for
their consistency with observed product distributions.
Indirect support for B as the syn predictive model is
found in the semiempirical calculations performed by
Liotta16 and Giese17 which revealed a similarity between
the second most stable ground state conformer of the
radical and the radical depicted in transition state model
B. Similar to A, B benefits from hyperconjugative
stabilization of the electron-poor, low SOMO radical by
the ethyl group. However, 1,3-allylic strain appears to
be a key destabilizing factor in B; furthermore, intramo-
lecular dipole-dipole interactions are not minimized in
this model as they are in A. The major shortcoming of
the A/B pair as a model to rationalize stereochemical
outcomes is its inability to account for the enhancement
of anti selectivity when bulkier alkyl groups are used in
place of the ethyl group (entries 2 and 3). Since the tin
reagent is approaching the radical from the face opposite
to that shielded by the alkyl group, it is not clear why a
size increase of the alkyl group should affect B (by
diminishing attack by the tin reagent) more than A.
The model that best rationalizes our experimental
observations to date (in conjunction with model A), is
depicted as C. Clearly the contribution of C to the facial
selectivity of the reaction would be influenced by (1) the
spatial orientation of R1 relative to the radical p orbital
(i.e. extent of overlap between the C-R1 bond and the
radical p orbital), and (2) the steric shielding provided
by the alkyl R1 to top-face attack by the tin reagent. On
the basis of the assumption that the radical reaction
proceeds through an early transition state, both models
A and C bear a marked similarity to the ground state
conformer of the radical.15,18 In effect, the two products
This exocyclic effect however is optimal to diminish top-
face attack by the tin reagent only when the C-R1 bond
is orthogonal to the radical π system, permitting overlap
between the σC-R bond and the radical p orbital. The
1
extent of orbital overlap (and therefore orthogonality of
the C-R1 bond to the radical π system) is dependent on
the σ-donating properties of R1 in the stabilization of the
electron-poor, low SOMO radical through hyperconjuga-
tion. We have shown that γ-heteroatom substitutions
(relative to the ester) of cyclic substrates have a deleteri-
ous effect on the anti-selectivity of the hydrogen-transfer
reaction, presumably by weakening the SOMO-(C-R1)
interaction and by producing a slight angular offset of
this alignment.12 The poorer diastereoselectivity (9:1;
entry 17) exhibited in the reduction of acetonide 28, as
opposed to that of tetrahydrofuran 10 (12:1, entry 5), is
attributed to such an offset of alignment (transition state
F ), which would consequently permit more syn product
formation. When the heteroatom substitution is more
remote (e.g. δ-carbon relative to ester) from the radical
center (cf. acetonides 25 and 28), the increased anti
(13) Gouzoules, F. H.; Whitney, R. A. J . Org. Chem. 1986, 51, 2024-
2030.
(14) The term “exocyclic effect” refers to the increased diastereose-
lectivity demonstrated by the reactions of a radical adjacent or exo to
a ring formed by tethering the â-heteroatom (Y) to the R1 substituent
in the radical shown in eq 1. In contrast to such exocyclic radicals,
which undergo hydrogen transfer to give predominantly anti-products,
endocyclic radicals derived from bidentate Lewis acid chelation between
the ester carbonyl and â-heteroatom react with syn-selection.
(15) This model was first proposed by Hart: (a) Hart, D. J .; Huang,
H.-C. Tetrahedron Lett. 1985, 26, 3749. (b) Hart, D. J .; Krishnamurthy,
R. J . Org. Chem. 1992, 57, 4457. Ab initio calculations have been used
to reveal the collinear arrangement of attacking and leaving radicals
in the transition state of a hydrogen transfer reaction: Dakternieks,
D.; Henry, D. J .; Schiesser, C. H. J . Chem. Soc., Perkin Trans. 2, 1997,
1665.

9280 J . Org. Chem., Vol. 62, No. 26, 1997
Guindon et al.
Ta ble 2. Syn p er ip la n a r ver su s An tip er ip la n a r Atta ck in
th e Ra d ica l Red u ction a
Sch em e 4
ratiob
(anti:syn)
temperature
(°C)
yieldc
(%)
entry
1
2
43:1
20:1
-30
23
62
77
a
All reactions were performed at a substrate concentration of
selectivity (32:1; entry 16) shown in the reaction of 25 is
consistent with a stronger SOMO-(C-R1) interaction
(transition state G).
0.1 M in toluene using 2.0 equiv of Bu3SnH and Et3B for initiation.
Ratios were determined by 1H NMR spectroscopy and/or GC.
b
c Yields of isolated products.
The diastereofacial discrimination attributed to the
extent of the SOMO-(C-R1) interaction can be further-
more controlled by alkyl substitution (γ to the ester) on
the ring. In comparison with the modestly selective
reaction of the unsubstituted acetonide 28, the radical
reduction of the acetonides (entries 18 and 19) substi-
tuted with a γ-methyl group afforded exclusively anti
products (>100:1). By enhancing the hyperconjugative
ability of the C-R1 bond, the methyl substituent anti to
the radical-bearing appendage on the ring in 31 may
confer better top-face shielding through optimal realign-
ment of the C-R1 bond with the radical p orbital as
shown in H. Both hyperconjugative and steric shielding
effects are probably contributing to the excellent selectiv-
ity shown in the reduction of 34, in which the methyl
substituent is syn to the radical-bearing appendage on
the ring.
Approach of the tin reagent syn to the alkyl group may
seem highly improbable chiefly because of steric com-
pression between the incoming tin reagent and alkyl
substituent. Another argument disfavoring this model
could be derived from Houk’s “staggered model” describ-
ing the trajectory and allylic conformation for attack of
radicals on double bonds:19 Syn-attack (with respect to
the R1 alkyl group) would not be favored since rehybrid-
ization of the radical center would afford a transition
state in which the substituents on the radical center and
on the chiral center are eclipsed. While these arguments
may be used more often in the rationalization of major
product formation, syn attack may nevertheless contrib-
ute to a minor reaction pathway, its role becoming more
prevalent in the cases where the orientation of the C-R1
bond deviates from overlap with the radical p orbital.
Does the syn product arise from transition state C?
While this question may be very difficult or impossible
to address, the likelihood of its contribution to the
stereochemical outcome could be evaluated however by
means such as calculation. To ascertain the possibility
of syn attack, we devised a strategy based on the
following line of reasoning: any syn product formation
from the hydrogen transfer reaction of a radical that is
locked in the conformation depicted in a transition state
(eg. C or E) would have to arise from syn attack. To
minimize the steric perturbation introduced by confor-
mational rigidification, we chose as control a substrate
which was already somewhat conformationally limited,
such as the tetrahydrofuran 10 (Scheme 4). A confor-
mational lock could be achieved by linking the methyl
group (C-7) residing on the radical center to the carbon
(C-6) adjacent to the tetrahydrofuran ring oxygen, to
approximate the radical rotamer depicted in E. A study
of a conformationally locked mimic of the radical depicted
in transition state E under hydrogen transfer conditions
thus necessitated the synthesis of 2-bromo-2-exo-car-
bomethoxy-7-oxabicyclo[2.2.1]heptane (44). A mixture of
bicyclic precursors 45 and 46, prepared as described by
Brion,20 was smoothly brominated to afford 44 (eq 3).
Predictably, subjection of the bicyclic bromide 44 to
hydrogen transfer afforded chiefly the endo product (45)
resultant from anti attack (43:1, entry 1, Table 2).21 To
obtain sufficient quantities of the minor product for
characterization, the reaction was conducted at a higher
temperature (20:1, entry 2). The formation of minor
product 46 which can arise only through syn-attack thus
attests to the plausibility of transition state E. Interest-
ingly, the anti-selectivity of the reduction of 44 is 3-fold
higher than that for the tetrahydrofuran case (cf. entry
1, Table 2 and entry 5, Table 1). This observation
suggests that the transition states leading to the syn
product in these two reactions are not identical; indeed,
a slight offset of the C-R1 bond from overlap with the
radical orbital in the tetrahydrofuran case may facilitate
the syn trajectory of the tin reagent to account for the
discrepancy in diastereoselectivities.
Con clu sion s. We have shown that a bifunctional
cyclic protecting group strategy may be employed to
significantly increase the selectivity of free-radical based
processes involving acyclic substrates. Furthermore, this
strategy may be used to best advantage for acyclic
substrates bearing a γ-alkyl substituent (i.e. 1,2-diol, in
which the γ-alcohol is secondary), as well as for acyclic
substrates with 1,3-heteroatom disubstitution. While
benzylidene and isopropylidene ketals have been em-
ployed successfully in this study, other types of cyclic
protecting groups would have to be studied to ascertain
the generality of this approach. Based on the exocyclic
effect, this and other strategies that we are currently
developing should broaden the applicability of radical
processes in organic synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions requiring anhydrous
conditions were conducted under a positive nitrogen atmo-
sphere in oven-dried glassware and by using standard syringe
techniques. The anhydrous solvents were purchased from
Aldrich and were used as received. i-Pr2NH and Et3N were
freshly distilled from CaH2 under N2 atmosphere. n-Butyl-
lithium (1.6 M solution in hexanes) was purchased from
Aldrich and titrated prior to use (diphenylacetic acid end-point

The Exocyclic Effect
J . Org. Chem., Vol. 62, No. 26, 1997 9281
in dry THF). Tributyltin hydride, triethylborane (1 M solution
in hexanes), tert-butyl 2-bromoacetate, and 2,2-dimethoxypro-
pane were also purchased from Aldrich and used as received.
1,1,2-trimethoxyethane and 1,1,3-trimethoxypropane were
purchased from Aldrich and distilled prior to use. Flash
chromatography was performed on Merck silica gel 60 (0.040-
0.063 mm) using nitrogen pressure. Analytical thin-layer
chromatography (TLC) was carried out on precoated (0.25 mm)
Merck silica gel F-254 plates. Melting points were determined
on an electrothermal melting point apparatus and are uncor-
rected.
LDA solution was cooled to -78 °C, the R-selenenyl ester was
added. After the reaction mixture was stirred at -78 °C for 1
h, the appropriate aldehyde was added, and the resultant
solution was stirred at -78 °C until the reaction was complete
(1-3 h; TLC). Subsequently, the cold bath was removed, and
the reaction mixture was quenched with a saturated aqueous
solution of NH4Cl. The mixture was then extracted once with
Et2O and twice with CH2Cl2, dried with MgSO4, filtered, and
concentrated under reduced pressure. Purification of the crude
mixture by flash column chromatography afforded two dia-
stereomers a (least polar) and b (most polar).
The preparation and characterization data of 1-15 have
ter t-Bu tyl (()-5-(ter t-Bu tyld im eth ylsiloxy)-3-h yd r oxy-
2-m eth yl-2-(p h en ylselen en yl)p en ta n oa te (40). Compound
40a was isolated as a colorless oil (50%): Rf 0.45 (hexanes-
EtOAc, 5:1); IR (neat) νmax 3540, 1730 cm-1; MS (EI) m/e 474
(3%, M+), 361 (17%, M+ - CO2tBu), 241 (100%, M+ - 233); 1H
NMR (200 MHz, CDCl3) δ 0.11 (s, 6H), 0.95 (s, 9H), 1.40 (s,
9H), 1.45 (s, 3H), 1.5-1.9 (m, 2H), 3.62 (s, 1H, OH), 3.75-
3.95 (m, 2H), 4.08-4.18 (m, 1H), 7.28-7.5 (m, 3H), 7.68-7.75
(m, 2H); 13C NMR (50 MHz, CDCl3) δ -5.5, 17.1, 18.2, 25.9,
27.7, 34.2, 56.7, 61.8, 71.7, 81.3, 127.0, 128.6, 129.1, 138.1,
172.0; HRMS (EI) calcd for C22H38O4SeSi: 474.1705, found:
474.1693 (-2.5 ppm). Anal. Calcd: C 55.80%, H 8.09%;
found: C 55.44%, H 8.22%.
Compound 40b was isolated as a colorless oil (25%): Rf 0.4
(hexanes-EtOAc, 5:1); IR (neat), νmax 3500, 1740 cm-1; MS (EI)
m/e 474 (0.8%, M+), 361 (33%, M+ - CO2tBu), 241 (100%, M+
- 233). 1H NMR (200 MHz, CDCl3) δ 0.11 (s, 6H), 0.94 (s,
9H), 1.38 (s, 3H), 1.46 (s, 9H), 1.55-1.75 (m, 1H), 2.10-2.25
(m, 1H), 3.24 (d, J ) 5.5 Hz, 1H, OH), 3.8-3.95 (m, 2H), 4.05-
4.17 (m, 1H), 7.25-7.48 (m, 3H), 7.6-7.7 (m, 2H); 13C NMR
(50 MHz, CDCl3) δ -5.4, 18.3, 18.5, 25.9, 27.9, 34.4, 54.9, 61.2,
73.3, 81.7, 126.9, 128.6, 129.1, 138.1, 172.9; HRMS (EI) calcd
for C22H38O4SeSi: 474.1705, found: 474.1721 (+3.3 ppm).
Anal. Calcd: C 55.80%, H 8.09%; found: C 55.57%, H 8.24%.
Ald ol Con d en sa tion of ter t-Bu tyl (()-2-(P h en ylsele-
n en yl)p r op ion a te (39) w ith (()-2-[(2-Meth oxyeth oxy)-
m eth oxy]p r op ion a ld eh yd e. The use of THF as solvent
produced a mixture of the (3S*,4S*) diastereomers (epimeric
at C-2). To also access the desired (3R*,4S*) diastereomers,
toluene was used as a solvent; four diastereomers were
obtained as a 1:1:2:2 mixture in 60% yield. Purification by
dry-packed flash column chromatography (CH2Cl2-acetone,
20:1) afforded the (3R*,4S*) 42a and 42b diastereomers as an
unseparable mixture (minor), and the (3S*,4S*) 42c and 42d
diastereomers as an unseparable mixture (major).
been previously reported.10
Meth yl (()-2-Br om o-3,5-dim eth oxy-2-m eth ylpen tan oate
(16). To a stirred, cold (-78 °C) solution of 1,1,3-trimethoxy-
propane (595 µL, 4.17 mmol) in CH2Cl2 (20 mL) was added
TiCl4 (457 µL, 4.17 mmol). After this solution was stirred for
5 min, 2-bromo-1-methoxy-1-(trimethylsiloxy)-1-propene (2 g,
8.34 mmol) was added dropwise. When the reaction was
complete (20 min; TLC), the reaction mixture was quenched
with saturated aqueous NaHCO3, extracted with CH2Cl2, dried
with MgSO4, filtered, and concentrated under reduced pres-
sure. The crude isolate was purified by flash column chro-
matography (hexanes-EtOAc, 5:1) and afforded the two
diastereomers 16a (least polar, 409 mg, 37%) and 16b (most
polar, 576 mg, 51%).
Compound 16a : white solid, mp 31-2 °C; Rf 0.4 (hexanes-
EtOAc, 5:1); IR (neat) υmax 1740 cm-1; MS (CI, isobutane) m/e
270 (57%, MH+, 81Br), 268 (55%, MH+, 79Br), 238 (100%, M+
- 34, 81Br), 236 (97%, M+ - 34, 79Br); 1H NMR (400 MHz,
CDCl3) δ 1.64-1.70 (m, 1H), 1.80 (s, 3H), 2.27-2.31 (m, 1H),
3.36 (s, 3H), 3.41 (s, 3H), 3.50-3.58 (m, 2H), 3.80 (s, 3H), 4.02
(dd, J ) 9.9, 1.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.7,
30.9, 52.8, 58.3, 60.5, 60.9, 69.3, 81.6, 171.2; HRMS (CI,
isobutane) calcd for C9H18BrO4: 269.0388, found: 269.0399 (+4
ppm). Anal. Calcd for C9H17BrO4: C 40.16%, H 6.37%;
found: C 39.76%, H 6.33%.
Compound 16b: colorless oil; Rf 0.3 (hexanes-EtOAc, 5:1);
IR (neat) νmax 1740 cm-1; MS (EI) m/e 210 (3%, MeOCHC81Br-
(Me)CCO2Me), 208 (3%, MeOCHC79Br(Me)CCO2Me), 103 (100%,
1
M+ - 166); H NMR (400 MHz, CDCl3) δ 1.59-1.76 (m, 2H),
1.82 (s, 3H), 3.32 (s, 3H), 3.43-3.55 (m, 2H), 3.58 (s, 3H), 3.78
(s, 3H), 3.87 (dd, J ) 9.5, 2.9 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 23.0, 32.4, 53.0, 58.3, 61.7, 64.9, 68.9, 82.4, 170.8.
Anal. Calcd for C9H17BrO4: C 40.16%, H 6.37%; found: C
40.15%, H 6.42%.
Meth yl (()-2-Br om o-3,4-d im eth oxy-2-m eth ylbu tyr a te
(19). Compounds 19a (least polar, 243 mg, 15%) and 19b
(most polar, 305 mg, 19%) were prepared using 1,1,2-tri-
methoxyethane (808 µL, 6.271 mmol) by following the proce-
dure described above for 16.
ter t-Bu tyl (()-(3R*,4S*)-4-[(2-m eth oxyeth oxy)m eth oxy]-
3-h ydr oxy-2-m eth yl-2-(ph en ylselen en yl)pen tan oates (42a
and 42b): colorless oil; Rf 0.42 (CH2Cl2-acetone, 20:1); IR
(neat) νmax 3520, 1715, 1575 cm-1; MS (CI, isobutane) m/e 449
(6%, MH+), 393 (27%, MH+ - isobutylene), 373 (28%, M+
-
ter t-Bu tyl (()-2-(p h en ylselen en yl)p r op ion a te (39). To
a solution of diphenyl diselenide (7.53 g, 24.11 mmol) in MeOH
(127 mL) was added in small portions NaBH4 (1.84 g, 48.65
mmol). After the resultant solution was stirred at rt for 10
min, tert-butyl (()-2-bromopropionate (9.0 g, 43.05 mmol) was
added. When the reaction was complete (2 h; TLC), the
reaction mixture was quenched with a saturated aqueous
solution of NaHCO3 (100 mL), extracted with CH2Cl2, dried
with MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by flash column chromatography (hexanes-
EtOAc, 1:0 to 10:1) afforded 39 (11.5 g, 93%) as a pale yellow
oil: Rf 0.6 (hexanes-EtOAc, 9:1); IR (neat) νmax 1725, 1580
cm-1; MS (EI) m/e 286 (75%, M+), 230 (100%, M+ - isobuty-
lene), 185 (97%, M+ - 128), 157 (85%, PhSeH); 1H NMR (200
MHz, CDCl3) δ 1.35 (s, 9H), 1.5 (d, J ) 7.3 Hz, 3H), 3.7 (q, J
) 7.3 Hz, 1H), 7.21-7.68 (m, 5H); 13C NMR (50 MHz, CDCl3)
δ 17.6, 27.8, 38.6, 81.0, 128.1, 128.5, 128.9, 135.3, 172.7; HRMS
(EI) calcd for C13H18O2Se: 286.0472, found: 286.0469 (-0.8
ppm).
OCH2CH2OCH3), 317 (100%, M+ - 131); H NMR (400 MHz,
CDCl3, mixture of diastereomers; major italic) δ 1.22 (d, J )
6.4 Hz, 3H), 1.31 (s, 3H), 1.32 (d, J ) 7.3 Hz, 3H), 1.36 (s,
3H), 1.47 (s, 9H), 3.19 (d, 1H), 3.36 (s, 3H), 3.38 (s, 3H), 3.51
(t, J ) 4.7 Hz, 1H), 3.55 (t, J ) 4.5 Hz, 1H), 3.65-3.78 (m),
3.91 (qd, J ) 6.7, 3.5 Hz, 1H), 3.95 (d, J ) 10.5 Hz, 1H), 4.11
(qd, J ) 6.0, 1.5 Hz, 1H), 4.63 (d, J ) 7.3 Hz, 1H), 4.75-4.83
(m), 7.26-7.4 (m), 7.58-7.68 (m); 13C NMR (100 MHz, CDCl3)
δ 17.1, 20.4, 27.8, 53.2, 58.9, 67.6, 71.7, 71.9, 80.2, 81.9, 93.6,
126.9, 128.7, 129.1, 138.2, 172.8. Anal. Calcd for C20H32O6-
Se: C 53.69%, H 7.21%; found: C 53.54%, H 7.39%.
1
ter t-Bu tyl (()-(3S*,4S*)-4-[(2-m eth oxyeth oxy)m eth oxy]-
3-h ydr oxy-2-m eth yl-2-(ph en ylselen en yl)pen tan oates (42c
and 42d ): colorless oil; Rf 0.35 (CH2Cl2-acetone, 20:1); IR
(neat) 3520, 1715, 1575 cm-1; MS (CI, isobutane) m/e 449 (5%,
MH+), 431 (7%, MH+ - H2O), 373 (50%, M+ - OCH2CH2-
OCH3), 317 (100%, M+ - 131); 1H NMR (400 MHz, CDCl3,
mixture of diastereomers, major italic) δ 1.27 (d, J ) 6.4 Hz,
3H) 1.32 (s, 9H), 1.33 (s, 3H), 1.34 (d, J ) 6.0 Hz, 3H), 1.39 (s,
3H), 1.43 (s, 9H), 2.98 (d, J ) 2.2 Hz, 1H), 3.36 (s, 3H), 3.38
(s, 3H), 3.50 (t, J ) 4.5 Hz, 1H), 3.54 (t, J ) 4.8 Hz, 1H), 3.62-
3.75 (m), 3.91 (quint, J ) 5.7 Hz, 1H), 4.58 (d, J ) 7.3 Hz,
1H), 4.71 (d, J ) 7.3 Hz, 1H), 4.74 (d, J ) 7.0 Hz, 1H), 4.78 (d,
J ) 7.0 Hz, 1H), 7.16-7.40 (m), 7.60-7.64 (m); 13C NMR (100
Gen er a l P r oced u r e for th e Ald ol Con d en sa tion of th e
r-Selen en yl Ester s w ith th e Cor r esp on d in g Ald eh yd es.
To a cold (0 °C), stirred solution of i-Pr2NH (1.2 equiv) in THF
(anhydrous, 0.2 M solution) under a N2 atmosphere was added
a hexane solution of n-butyllithium (1.1 equiv), and the
resultant mixture was stirred for 30 min. When the resultant

9282 J . Org. Chem., Vol. 62, No. 26, 1997
Guindon et al.
MHz, CDCl3) δ 16.0, 16.7, 17.1, 18.4, 27.7, 27.9, 58.0, 59.0,
66.6, 71.7, 74.5, 75.4, 80.7, 94.0, 94.22, 127.1, 128.7, 128.9,
129.3, 137.8, 138.4, 171.1. Anal. Calcd for C20H32O6Se: C
53.69%, H 7.21%; found: C 53.53%, H 7.35%.
Calcd (mixture of diastereomers 25a and 25b): C 57.14%, H
7.07%; found: C 56.92%, H 7.20%.
ter t-Bu tyl (()-[2RS,2(4R*,5S*)]-2-(2,2-Dim eth yl-5-m eth yl-
1,3-d ioxola n -4-yl)-2-(p h en ylselen en yl)p r op ion a te (31). To
a stirred solution of the diastereomeric mixture of alcohols 42a
and 42b (317 mg, 0.709 mmol) in 2,2-dimethoxypropane (7 mL)
and MeOH (2.3 mL) were successively added MgBr2‚Et2O (183
mg, 0.709 mmol) and p-toluenesulfonic acid monohydrate (141
mg, 0.709 mmol). When acetal formation was complete (3 h;
TLC), the reaction mixture was diluted with CH2Cl2, washed
with a saturated aqueous solution of NaHCO3, dried with
MgSO4, filtered, and concentrated under reduced pressure. The
crude acetals were then purified by flash column chromatog-
raphy (hexanes-EtOAc, 3:1) and afforded an unseparable
diastereomeric mixture of the desired products 31 as a colorless
oil (208 mg, 73%): Rf 0.64 (hexanes-EtOAc, 3:1); IR (neat)
νmax 1720, 1575 cm-1; MS (CI, isobutane) m/e 400 (4%, MH+),
287 (27%, M+ - 113), 285 (13%, CH3(PhSe)CHCO2tBu), 230
Gen er a l P r oced u r e for th e in Situ Dep r otection of th e
ter t-Bu tyld im eth ylsilyl Eth er s 40 (a a n d b) a n d F or m a -
tion of th e Ben zylid en e Aceta ls 22 (a a n d b). To a 0.1 M
solution of the alcohol 40a or 40b in MeOH was added
p-toluenesulfonic acid monohydrate (0.3 equiv). The depro-
tection was monitored by TLC (10 min), and when the reaction
was complete, benzaldehyde dimethylacetal (1/10 v/v) was
added. After the resultant mixture was stirred for 20 min,
the solvent was evaporated under reduced pressure and
replaced with an equal volume of CH2Cl2. When the reaction
was completed (5 min; TLC), the reaction mixture was diluted
with more CH2Cl2, washed with a saturated aqueous solution
of NaHCO3, dried with MgSO4, filtered, and concentrated
under reduced pressure. The crude benzylidene acetals were
then purified by flash column chromatography (hexanes-
EtOAc, 20:1).
1
(22%, M+ - 170), 115 (100%, M+ - 285); H NMR (200 MHz,
CDCl3, 2 diastereomers, major italic) δ 1.27 (d, J ) 6.0 Hz,
3H), 1.37 (s, 9H), 1.38 (s, 3H), 1.39 (s, 3H), 1.40 (s, 9H), 1.43
(s, 3H), 1.44 (s, 6H), 1.46 (s, 3H), 1.52 (d, J ) 6.0 Hz, 3H),
4.01 (d, J ) 7.6 Hz, 1H), 4.05 (qd, J ) 6.0, 7.3 Hz, 1H), 4.19
(qd, J ) 5.7, 7.3 Hz, 1H), 4.22 (d, J ) 7.3 Hz, 1H), 7.26-7.32
(m, 3H), 7.35-7.40 (m, 3H), 7.60-7.63 (m, 2H), 7.68-7.71 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 18.2, 18.3, 19.8, 21.5, 26.9,
27.4, 27.5, 27.8, 50.5, 73.2, 73.9, 81.3, 81.6, 84.0, 84.8, 107.9,
108.2, 126.5, 127.1, 128.5, 128.7, 129.2, 137.9, 138.2, 170.9,
171.0. Anal. Calcd for C19H28O4Se: C 57.14%, H 7.07%;
found: C 56.84%, H 7.16%.
ter t-Bu tyl (()-2(2R*,4R*)-2-[2-P h en yl-1,3-d ioxa n -4-yl]-
2-(p h en ylselen en yl)p r op ion a te (22). Compound 22a , pre-
pared from 40a , was isolated as a colorless oil (88%); Rf 0.35
(hexanes-EtOAc, 9:1); IR (neat) νmax 1710, 1580 cm-1; MS (EI)
m/e 448 (39%, M+), 241 (13%, M+ - 207), 163 (100%, M+
-
1
CH3(PhSe)CHCO2tBu); H NMR (200 MHz, CDCl3) δ 1.40 (s,
9H), 1.56 (s, 3H), 1.94 (qd, J ) 12, 5 Hz, 1H), 3.88 (qd, J ) 12,
2.6 Hz, 1H), 4.03 (dd, J ) 11, 1.8 Hz, 1H), 4.24 (dd, J ) 11,
4.4 Hz, 1H), 5.42 (s, 1H), 7.2-7.7 (m, 10H); 13C NMR (50 MHz,
CDCl3) δ 17.8, 26.1, 27.8, 53.6, 66.6, 78.5, 81.4, 101.3, 126.0,
127.1, 128.2, 128.5, 128.7, 129.2, 138.4, 138.5, 171.0; HRMS
(EI) calcd for C23H28O4Se: 448.1153, found: 448.1148 (-1.0
ppm). Anal. Calcd: C 61.74%, H 6.31%; found: C 61.80%, H
6.29%.
(()-exo-2-Br om o-2-ca r bom eth oxy-7-oxa bicyclo[2.2.1]-
h ep ta n e (44). To a solution of a 1:2 mixture20 of 45 and 46
(2.19 g, 14.0 mmol) in CCl4 (50 mL) was added N-bromosuc-
cinimide (12.5 g, 72.2 mml), and the resultant solution was
then refluxed for 17 h. After the reaction mixture was allowed
to cool to room temperature, it was filtered through Celite,
and the filtrate was concentrated under vacuum. 1H NMR
analysis of the crude reaction isolate indicated a 2.5:1 mixture
of 46 and the desired bromide 44, respectively. Flash column
chromatography (CH2Cl2) afforded 46 Rf 0.75 (CH2Cl2-
acetone, 10:1) and 44 as a white solid (817 mg, 52% based on
recovered starting material): Rf 0.95 (CH2Cl2-acetone, 10:1);
IR (neat) νmax 1730 cm-1; MS (CI, isobutane) m/e 236 (9%,
Gen er a l P r oced u r e for th e in Situ Dep r otection of th e
ter t-Bu tyld im eth ylsilyl Eth er s 40, 41, a n d 43, a n d F or -
m a tion of th e Isop r op ylid en e Aceta ls 25, 28, a n d 34. To
a 0.1 M solution of the alcohol a or b of 40, 41, or 43 in MeOH
was added p-toluenesulfonic acid monohydrate. The depro-
tection was monitored by TLC (10 min) and when it was
complete, 2,2-dimethoxypropane (1/1 v/v) was added. After the
resultant mixture was stirred for 20 min, the solvents were
evaporated under reduced pressure and replaced with 2,2-
dimethoxypropane. When acetal formation was complete (5
min; TLC), the reaction mixture was diluted with CH2Cl2,
washed with a saturated aqueous solution of NaHCO3, dried
with MgSO4, filtered, and concentrated under reduced pres-
sure. The crude acetals were then purified by flash column
chromatography (hexanes-EtOAc, 20:1).
ter t-Bu tyl (()-2-(2,2-Dim eth yl-1,3-d ioxa n -4-yl)-2-(p h en -
ylselen en yl)p r op ion a te (25). Compound 25a , prepared
from 40a , was isolated as a colorless oil (86%); Rf 0.3 (hex-
anes-EtOAc, 9:1); IR (neat) νmax 1710, 1580 cm-1; MS (EI) m/e
400 (29%, M+), 385 (10%, M+ - 15), 286 (16%, M+ - 114), 115
(100%, M+ - CH3(PhSe)CHCO2tBu); 1H NMR (200 MHz,
CDCl3) δ 1.35 (s, 9H), 1.40 (s, 3H), 1.42 (s, 3H), 1.48 (s, 3H),
1.75 (qd, J ) 12, 5 Hz, 1H), 3.81 (ddd, J ) 12, 6, 2 Hz, 1H),
3.92 (td, J ) 12, 3 Hz, 1H), 4.28 (dd, J ) 11, 3 Hz, 1H), 7.22-
7.41 (m, 3H), 7.62-7.68 (m, 2H); 13C NMR (50 MHz, CDCl3) δ
17.9, 19.1, 26.1, 27.7, 29.7, 54.2, 59.6, 71.8, 81.3, 98.9, 127.4,
128.4, 128.9, 138.1, 171.1; HRMS calcd for C19H28O4Se:
400.1153; found: 400.1157 (+1.1 ppm). Anal. Calcd (mixture
of diastereomers 25a and 25b): C 57.14%, H 7.07%; found: C
56.92%, 7.20%.
Compound 25b, prepared from 40b, was isolated as a white
solid (71%); mp 82-3 °C; Rf 0.4 (hexanes-EtOAc, 9:1); IR
(neat) νmax 1710, 1570 cm-1; MS (EI) m/e 400 (32%, M+), 385
(19%, M+ - 15), 286 (28%, M+ - 114), 115 (100%, M+ - CH3-
(PhSe)CHCO2tBu); 1H NMR (200 MHz, CDCl3) δ 1.31 (s, 3H),
1.36 (s, 9H), 1.37 (s, 3H), 1.40 (s, 3H), 1.75 (qd, J ) 12, 5.4
Hz, 1H), 1.89 (qd, J ) 2.5, 13 Hz, 1H), 3.92 (ddd, J ) 12, 5.4,
2 Hz, 1H), 3.98 (td, J ) 12, 3 Hz, 1H), 4.38 (dd, J ) 12, 2.5
Hz, 1H), 7.26-7.41 (m, 3H), 7.58-7.62 (m, 2H); 13C NMR (50
MHz, CDCl3) δ 16.9, 19.1, 25.8, 27.8, 29.7, 52.9, 60.3, 72.2,
80.7, 98.8, 126.6, 128.7, 129.2, 138.0, 171.7; HRMS calcd for
C19H28O4Se: 400.1153, found: 400.1157 (+1.1 ppm). Anal.
1
MH+), 208 (81%), 206 (82%), 95 (100%); H NMR (400 MHz,
CDCl3) δ 1.37-1.49 (m, 2H), 1.70-1.85 (m, 2H), 2.51 (ddd, J
) 1.7, 6.2, 14.6 Hz, 1H), 2.68 (d, J ) 14.6 Hz, 1H), 3.81 (s,
3H), 4.72 (t, J ) 4.5 Hz, 1H), 4.73 (d, J ) 5.7 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 25.9, 28.6, 46.2, 53.2, 62.8, 78.0,
84.1, 169.9; HRMS calcd for C8H11BrO3: 233.9891; found:
233.9888 (-1.8 ppm). Anal. Calcd for C8H11BrO3: C 40.87%,
H 4.72%; found: C 40.91%, H 4.76%.
Gen er a l P r oced u r e for Ra d ica l Red u ction . A 0.1 M
solution of substrate in solvent was brought to the desired
temperature. Bu3SnH (1.2 equiv for 16, 19, 22, 25, 28, 31,
and 34; or 2.0 equiv for 1, 4, 7, 10, and 13) and Et3B (1 M
solution in hexane, 0.1-0.2 equiv) were then successively
added. When the reduction was completed (TLC), the reaction
mixture was concentrated under reduced pressure, and the
crude isolate was partitioned between hexane and MeCN. The
two phases were concentrated. The crude oil obtained from
1
the hexane phase was analyzed by H NMR to verify that no
product other than Bu3SnX was in the hexane layer. The
ratios were determined by 1H NMR or GC on the crude mixture
obtained from the MeCN layer. This crude mixture was then
purified by flash chromatography to afford the reduced prod-
uct(s) with isolated yields ranging from 49 to 90%.
(16) Durkin, K.; Liotta, D.; Rancourt, J .; Lavalle´e, J .-F.; Boisvert,
L.; Guindon, Y. J . Am. Chem. Soc. 1992, 114, 4912.
(17) Giese, B.; Damm, W.; Wetterich, F.; Zeitz, H.-G. Tetrahedron
Lett. 1992, 33, 1863.
(18) The ground state conformer of the radical is supported by
calculations and ESR studies: Giese, B.; Damm, W.; Wetterich, F.;
Zeitz, H.-G.; Rancourt, J .; Guindon, Y. Tetrahedron Lett. 1993, 34,
5885.
(19) Paddon-Row, M. N.; Rondan, N. G.; Houk, K. N. J . Am. Chem.
Soc. 1982, 104, 7162.
(20) Brion, F. Tetrahedron Lett. 1982, 23, 5299.

The Exocyclic Effect
J . Org. Chem., Vol. 62, No. 26, 1997 9283
Meth yl (()-3,5-Dim eth oxy-2-m eth ylp en ta n oa tes (17
a n d 18). Compounds 17 and 18 were isolated prior to
purification as a 1.5:1 mixture (ratio determined by 1H
NMR): colorless oil; Rf 0.3 (hexanes-EtOAc, 5:1); IR (neat),
νmax 1735 cm-1; MS (CI, isobutane) m/e 191 (59%, MH+), 159
(100%, MH+ - MeOH), 127 (100%, MH+ - 2MeOH); 1H NMR
(400 MHz, CDCl3, 1.5:1 mixture of diastereomers, major anti
product italic) δ 1.09 (d, J ) 7 Hz, 3H), 1.15 (d, J ) 7 Hz, 3H),
1.60-1.82 (m, 2H), 2.61 (qd, J ) 7.0, 5.1 Hz, 1H), 2.72 (quint,
J ) 7 Hz, 1H), 3.30 (s, 3H), 3.31 (s, 3H), 3.32, (s, 3H), 3.34 (s,
3H), 3.40-3.50 (m, 2H), 3.52-3.62 (m, 1H), 3.67 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 11.71, 11.91, 30.75, 32.14, 42.96,
43.18, 51.54, 57.84, 58.17, 58.44, 58.50, 68.79, 69.09, 79.19,
79.37, 175.13.
ter t-Bu tyl (()-(2R*,4R*)-2-(2-P h en yl-1,3-d ioxa n -4-yl)-
p r op ion a tes (23 a n d 24). Compounds 23 (anti) and 24 (syn)
were isolated prior to purification as a mixture, the ratio of
which was determined by GC.22
t-Bu tyl (()-2-(2,2-Dim eth yl-1,3-dioxan -4-yl)pr opion ates
(26 a n d 27). Compounds 26 (anti) and 27 (syn) were isolated
prior to purification as a mixture, the ratio (32:1) of which was
determined by GC.22
(m, 1H), 2.24 (dddd, J ) 14.6, 10.1, 5.5, 4.6 Hz, 1H), 2.64 (qd,
J ) 7.13, 3.65 Hz, 1H), 4.22-4.29 (m, 1H), 4.30 (td, J ) 5.7,
11.5 Hz, 1H), 4.58 (ddd, J ) 11.5, 8.2, 5.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 11.9, 31.0, 41.3, 65.0, 67.2, 173.9.
(()-(2S*,3R*)-3-Hyd r oxy-2-m eth yl-δ-va ler ola cton e (38).
A methanolic solution containing acetal 27 (255 mg, 0.872
mmol) and p-toluenesulfonic acid monohydrate (52 mg, 0.262
mmol) was stirred at rt for 12 h. The reaction mixture was
concentrated under reduced pressure, and the product was
purified by flash chromatography (CH2Cl2-acetone, 5:1) which
afforded 38 (71 mg, 62%) as a colorless oil: Rf 0.3 (CH2Cl2-
acetone, 10:1); IR (neat) νmax 3400, 1720 cm-1; MS (CI,
isobutane) m/e 131 (100%, MH+); 1H NMR (200 MHz, CDCl3)
δ 1.35 (d, J ) 7.0 Hz, 3H), 1.92 (tdd, J ) 6.4, 16.4, 4.2 Hz,
1H), 2.13-2.29 (m, 1H), 2.55 (quint, J ) 7.3 Hz, 1H), 3.23 (d,
J ) 4.4 Hz, 1H, exch. D2O), 3.78-3.92 (m, J ) 7.0 Hz, 1H, q
after exch D2O), 4.26 (ddd, J ) 13.3, 6.6, 4.6 Hz, 1H), 4.50
(ddd, J ) 12.2, 8.2, 4.2 Hz, 1H); 13C NMR (100 MHz, CDCl3)
δ 14.0, 31.0, 44.0, 65.0, 69.2, 174.5. Anal. Calcd for C6H10O3:
C 55.37%, H 7.75%; found: C 54.95%, H 7.89%.
ter t-Bu tyl (()-2-(2,2-Dim eth yl-1,3-d ioxola n -4-yl)p r op i-
on a t es (29 a n d 30). Compounds 29 and 30 were isolated
prior to purification as a mixture, the ratio (9:1) of which was
determined by GC.22
ter t-Bu t yl (()-2-(2,2-Dim et h yl-5-m et h yl-1,3-d ioxola n -
4-yl)p r op ion a tes (32 a n d 33). Compounds 32 and 33 were
isolated prior to purification as a mixture, the ratio of which
was determined by GC.23
ter t-Bu t yl (()-2-(2,2-Dim et h yl-5-m et h yl-1,3-d ioxola n -
4-yl)p r op ion a tes (35 a n d 36). Compounds 35 and 36 were
isolated prior to purification as a mixture, the ratio (>100:1)
of which was determined by GC.23
(()-(2R*,3R*)-3-Hydr oxy-2-m eth yl-δ-valer olacton e (37).
A methanolic (3.5 mL) solution containing acetal 26 (103 mg,
0.351 mmol) and p-toluenesulfonic acid monohydrate (21 mg,
0.262 mmol) was refluxed overnight. The reaction mixture
was concentrated under reduced pressure, diluted with CH2-
Cl2 (3.5 mL), and treated for 6 h with iPr2EtN (61 mL, 0.351
mmol). The reaction mixture was then concentrated under
reduced pressure, and the product was purified by flash
chromatography (CH2Cl2-acetone, 5:1) which afforded 37 (32
mg, 70%) as a colorless oil: Rf 0.28 (CH2Cl2-acetone, 10:1).
IR (neat) νmax 3450, 1720 cm-1; MS (CI, isobutane) m/e 131
1
(100%, MH+); H NMR (200 MHz, CDCl3) δ 1.32 (d, J ) 7.1
Ack n ow led gm en t. The authors would like to ac-
knowledge Bio-Me´ga Research Division/Boehringer In-
gelheim (Canada) Ltd and NSERC for financial support,
and to thank Drs. William Ogilvie and Brigitte Gue´rin
for their help in the preparation of this manuscript.
Hz, 3H), 2.00 (dddd, J ) 15.0, 5.9, 5.1, 4.0 Hz, 1H), 2.14-2.20
(21) The similarity in anti:syn ratios when tributyl deuteride was
used showed that the role of intramolecular hydrogen transfer was
negligible.
(22) The minor (syn) radical reduction product was synthesized via
a different sequence for characterization purposes: Aldol condensation
of the appropriate aldehyde with tert-butyl propionate instead of tert-
butyl 2-(phenylselenenyl)propionate, followed by in situ deprotection
of the tert-butyldimethylsilyl ether and formation of the acetal. This
sequence afforded the same products as the radical reduction but where
the syn diastereomer is favored.
(23) This minor syn radical reduction product was obtained via a
different procedure for characterization purposes. The radical reduction
was performed in CH2Cl2 at -78 °C in the presence of MgBr2‚Et2O (5
equiv). This modification gave an anti:syn ratio of 1.4:1 and 3.5:1 for
34 and 31, respectively.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for compounds 19-24, 26, 27-30, 32-36, 41, 43, 45, 46;
13C NMR spectra for compounds 17, 18, 20, 21, 32, 33, 36, 37,
and 39 (15 pages). This material is available on microfiche in
libraries, immediately follows this article in the microfilm
version of the journal, can be ordered from ACS, and can be
downloaded through the Internet; see any current masthead
page for ordering information and Internet access instructions.
J O971595S