Stereoselective chelate-controlled addition of Grignard reagents to unsaturated medium-ring heterocycles

Article abstract of DOI:10.1021/jo981745e

Various medium-ring heterocycles, beating a C2-substituent that contains an accessible Lewis basic heteroatom, react with Grignard reagents with high levels of regio- and stereochemical control. The substrates can be prepared in the optically pure form by the Zr-catalyzed kinetic resolution; subsequent reaction with alkylmagnesium halides leads to the formation of optically pure alkylation products. The studies outlined herein probe the influence of the length and position of the heteroatom side chain on the facility and regio- and stereoselective outcome of the allylic substitution process. A catalytic procedure for the subsequent removal of the requisite heteroatom chelating group is presented.

Full text of DOI:10.1021/jo981745e

854
J . Org. Chem. 1999, 64, 854-860
Ster eoselective Ch ela te-Con tr olled Ad d ition of Gr ign a r d Rea gen ts
to Un sa tu r a ted Med iu m -Rin g Heter ocycles
J effrey A. Adams, Nicola M. Heron, Ann-Marie Koss, and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467
Received August 25, 1998
Various medium-ring heterocycles, bearing a C2-substituent that contains an accessible Lewis basic
heteroatom, react with Grignard reagents with high levels of regio- and stereochemical control.
The substrates can be prepared in the optically pure form by the Zr-catalyzed kinetic resolution;
subsequent reaction with alkylmagnesium halides leads to the formation of optically pure alkylation
products. The studies outlined herein probe the influence of the length and position of the heteroatom
side chain on the facility and regio- and stereoselective outcome of the allylic substitution process.
A catalytic procedure for the subsequent removal of the requisite heteroatom chelating group is
presented.
Sch em e 1
In tr od u ction
Addition of alkylmetals to alkenes represents an at-
tractive and relatively unexplored method for regio- and
stereoselective C-C bond formation.1 Within this context,
and in conjunction with programs in these laboratories2
aimed at the development of metal-catalyzed alkylation
of olefins,3 we recently reported the initial results of our
studies regarding a heteroatom-assisted4 diastereoselec-
tive reaction between Grignard reagents and certain
unsaturated medium ring heterocycles.5 As illustrated in
Scheme 1, the requisite optically pure seven-membered
rings (e.g., (S)-2) may be accessed through the Zr-
catalyzed kinetic resolution.2f The enantiomerically pure
cyclic substrates thus obtained can be readily alkylated
to afford chiral acyclic products (e.g., (S)-4) with excellent
enantiopurity (>96% ee) and complete control of alkene
regio- and stereochemistry (>98% trans). In addition to
(1) For uncatalyzed examples of the addition of Grignard reagents
to olefins, see: (a) Eisch, J . J . J . Organomet. Chem. 1980, 200, 101-
117 and references therein. (b) Felkin, H.; Kaeseberg, C. Tetrahedron
Lett. 1970, 4587-4590 and references therein. (c) Richey, H. G.;
Domalski, M. S. J . Org. Chem. 1981, 46, 3780-3783 and references
therein. (d) Swiss, K. A.; Liotta, D. C.; Maryanoff, C. A. J . Am. Chem.
Soc. 1990, 112, 9393-9394 and references therein.
(2) For Zr-catalyzed diastereoselective additions: (a) Houri, A. F.;
Didiuk, M. T.; Xu, Z.; Horan, N. R.; Hoveyda, A. H. J . Am. Chem. Soc.
1993, 115, 6614-6624. (b) Morken, J . P.; Hoveyda, A. H. J . Org. Chem.
1993, 58, 4237-4244. For Zr-catalyzed enantioselective additions: (c)
Morken, J . P.; Didiuk, M. T.; Hoveyda, A. H. J . Am. Chem. Soc. 1993,
115, 6697-6698. (d) Didiuk, M. T.; J ohannes, C. W.; Morken, J . P.;
Hoveyda, A. H. J . Am. Chem. Soc. 1995, 117, 7097-7104. Zr-catalyzed
kinetic resolution through enantioselective allylic ether alkylation: (e)
Morken, J . P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J . Am.
Chem. Soc. 1994, 116, 3123-3124. (f) Visser, M. S.; Heron, N. M.;
Didiuk, M. T.; Sagal, J . F.; Hoveyda, A. H. J . Am. Chem. Soc. 1996,
118, 4291-4298. (g) Visser, M. S.; Harrity, J . P. A.; Hoveyda, A. H. J .
Am. Chem. Soc. 1996, 118, 3779-3780. (h) Harrity, J . P. A.; La, D. S.;
Cefalo, D. R.; Visser, M. S.; Hoveyda, A. H. J . Am. Chem. Soc. 1998,
120, 2343-2351.
(3) For an example of a Cu-catalyzed addition of Grignard reagents
to allylic ethers, see: (a) Gendreau, Y.; Normant, J . F. Tetrahedron
1979, 35, 1517-1521. For related Ni-catalyzed processes, see: (b)
Consiglio, G.; Piccolo, O.; Roncetti, L.; Morandini, F. Tetrahedron 1986,
42, 2043-2053. (c) Didiuk, M. T.; Morken, J . P.; Hoveyda, A. H. J .
Am. Chem. Soc. 1995, 117, 7273-7274. For an excellent recent review,
see: (d) Consiglio, G.; Waymouth, R. M. Chem. Rev. 1989, 89, 257-
276.
(4) For a review of directed reactions, see: Hoveyda, A. H.; Evans,
D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307-1370.
(5) Heron, N. M.; Adams, J . A.; Hoveyda, A. H. J . Am. Chem. Soc.
1997, 119, 6205-6206.
alcohols as the starting materials, the derived Bn, PMB,
or MEM ethers can be effectively and selectively alkyl-
ated. Although not catalytic, these allylic substitutions
complement the aforementioned Zr-catalyzed reaction, as
alkylmetals other than Et-, n-Pr, and n-BuMgCl can be
used.2d An advantage of this allylic substitution process
is that a number of useful functional groups can be
imported as part of the alkylmagnesium halide; such
functionalities may be exploited for subsequent function-
alization. The catalytic formation of unsaturated car-
bocycle (S)-5, shown in Scheme 1, through a subsequent
catalytic ring-closing metathesis,6 illustrates this point.
As shown in Scheme 1, similar strategies may be applied
to the corresponding oxocenes ((R)-6 f (R)-7). Furans and
pyrans, on the other hand, do not undergo alkylation
under these reaction conditions.
(6) For recent reviews on the utility of olefin metathesis in organic
synthesis, see: (a) Grubbs, R. H.; Miller, S. J .; Fu, G. C. Acc. Chem.
Res. 1995, 28, 446-452 and references therein. (b) Schmalz, H.-G.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1833-1836 and references
therein. (c) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl.
1997, 36, 2036-2056. (d) Furstner, A. Topics Catal. 1997, 4, 285-
299. (e) Armstrong, S. K. J . Chem. Soc., Perkin Trans 1 1998, 371-
388. (f) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413-4450.
10.1021/jo981745e CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/20/1999

Addition of Grignard Reagents to Unsaturated Heterocycles
J . Org. Chem., Vol. 64, No. 3, 1999 855
Ta ble 1. Th e In flu en ce of Sid e Ch a in Len gth on th e
Dia ster eoselective Alk yla tion Efficien cya
Ch a r t 1
Sch em e 2
In this article, we address several general key issues
related to this diastereoselective C-C bond forming
reaction. Specifically, we will describe: (1) mechanistic
aspects of the C-C bond-forming reaction, particularly
where reactivity is dependent on the nature of the
internal heteroatoms as well as the length and position-
ing of the side chain substituent; (2) stereoselective
alkylation of substrates with directing groups that can
be subsequently excised in a catalytic manner.
Resu lts a n d Discu ssion
St r u ct u r a l R eq u ir em en t s for E ffect ive Alk yl-
a tion . All available data suggest that facile alkylation
occurs when both the C2 side chain and the ring system
bear Lewis basic heteroatoms that are available for
efficient metal (Mg) coordination. Thus, as depicted in
Chart 1, in contrast to substrates such as 2 (Scheme 1)
or its corresponding Bn ether, 2-substituted oxepin 8, silyl
ether 9, and cyclic amide 10 are inert to allylic substitu-
tion by alkylmagnesium halides (<2% conversion). As a
result, since there is little or no uncatalyzed alkylation,
these substrates can be resolved through the Zr-catalyzed
kinetic resolution.7
In our preliminary report,5 we proposed three possible
general pathways through which the allylic substitution
reaction could proceed (Scheme 2). The lack of reactivity
of 10 in the absence of the chiral metallocene catalyst
discredits the proposed mode of addition I (Scheme 2)8
by suggesting that association of the ring heteroatom
with a Lewis acidic metal is required (presumably to
lower the energy of the σ* orbital of the cleaving C-O
bond). The question then arises whether the positive
contribution of the side chain heteroatom is coupled with
that of the heteroatom within the ring structure. That
is, C-C bond formation and concomitant C-O rupture
might be promoted by an internal bidentate chelate
represented by II. Alternatively, the side chain oxygen
may associate with the Grignard reagent to deliver the
a
b
Conditions: 5 equiv of RMgCl, THF. Selectivity determined
by analysis of the derived (R)-MTPA ester (TBS protection,
ozonolysis, and reduction), in comparison with racemic materials
(400 MHz 19F NMR; entry 2 with 1H NMR). c Isolated yield after
silica gel chromatography.
alkylmetal, while the ring heteroatom activates the allylic
ether for reaction (mode III).
Va r ia tion s in Rea ctivity a s a F u n ction of Sid e
Ch a in P osition a n d Len gth . To address the above
questions and gain further insight into factors that allow
facile alkylations, we carried out alkylations with sub-
strates where the length and relative position of the
heteroatom-containing side chain is varied. As shown in
Table 1, oxepin (S)-2 and its derived Bn ether (S)-12
(entries 1 and 2) readily react with n-BuMgCl and
i-BuMgCl to afford (S)-11 and (R)-13 in high yield and
with excellent stereochemical control. As the examples
illustrated in entries 3 and 4 (Table 1) indicate, when
the C2 side chain is extended by one methylene unit ((R)-
14), alkylation remains efficient. With the longer side
chain, when the hydroxyl group is protected as a Bn ether
unit, reaction efficiency suffers; there is <2% reaction
with (R)-17 at 22 °C within the same length of time that
the parent alcohol ((R)-14) undergoes complete conver-
sion. Nonetheless, as shown in entry 6, under more
forcing conditions, (R)-17 reacts with n-BuMgCl to pro-
vide (S)-18 in >96% ee and 82% yield after silica gel
chromatography. The influence of the Lewis basic het-
eroatom at the C2 side chain is lost when an additional
methylene unit is incorporated: oxepin 19a or its derived
Bn ether 19b are inert to the alkylation conditions.
Zr -Ca ta lyzed Kin etic Resolu tion a n d Un ca ta -
lyzed Ad d ition . The relatively slow rate of reaction of
substrates such as 17 (entries 5 and 6, Table 1) with
(7) Relative rates were calculated by an equation reported previ-
ously: (a) Balavoine, G.; Moradpour, A.; Kagan, H. B. J . Am. Chem.
Soc. 1974, 96, 5152-5158. (b) Martin, V. S.; Woodard, S. S.; Katsuki,
T.; Yamada, Y.; Ikeda, M.; Sharpless, K. B. J . Am. Chem. Soc. 1981,
103, 6237-6240.
(8) In our initial report (ref 5), seven-membered ring substrates were
proposed to react through a pseudo-chair conformer. However, closer
inspection of models indicates that the related pseudo-boat conformers
carry less torsional strain.

856 J . Org. Chem., Vol. 64, No. 3, 1999
Adams et al.
Ta ble 2. Effect of th e P osition of th e Heter oa tom
Sch em e 3
Ch ela tin g Gr ou p on Alk yla tion Efficien cy a n d
Regioselectivitya
Grignard reagents suggests that these heterocycles might
be catalytically resolved by the Zr-catalyzed procedure
without recourse to initial masking of the side chain
heteroatom with a bulky protecting group (e.g., the TBS
unit in (S)-1 is removed to afford alkylation substrate
(S)-2 after the catalytic resolution). Indeed, as illustrated
in Scheme 3, treatment of rac-20 with 10 mol % (R)-
(EBTHI)Zr-biphen9 and 3.0 equiv of EtMgCl in THF (70
°C, 1 h) results in the recovery of (R)-20 in >99% ee after
53% conversion (krel ) 80). In contrast, the homologous
(S)-12 (or its derived PMB) cannot be resolved due to
adventitious uncatalyzed alkylation.
It is noteworthy that the catalytic resolution of rac-20
shown in Scheme 3 is carried out with three equiv
EtMgCl, in contrast to five equiv typically used in our
previous studies.2e-g This reduction in the amount of
Grignard reagent was to minimize any adventitious
uncatalyzed alkylation that may reduce the resolution
efficiency, even if it occurs in minor amounts. As the data
in Scheme 3 show, with lower amounts of EtMgCl (3.0
vs 5.0 equiv), the catalytic resolution is indeed more
efficient (krel ) 80 vs 16 for the resolution of rac-20).
However, as also illustrated in Scheme 3, this trend does
not apply to the catalytic resolution of all substrates. The
catalytic resolution of rac-1 is less efficient with lower
amounts of the Grignard reagent. It is possible that with
the slower reacting 1 (4 h vs 1 h for 20), the uncatalyzed
allylic substitution remains competitive with the metal-
catalyzed process.
Va r ia tion s in Rea ctivity a s a F u n ction of P osi-
tion in g of th e Ch ela tin g Gr ou p . To probe the influ-
ence of the position of the side chain that bears the
chelating group, substrates 21, 24, and 27 (Table 2) were
synthesized, and their reactivity under the standard
alkylation conditions was investigated. The data pre-
sented in Table 2 suggest that a two-point chelation
between a Mg and the substrate can alone promote
alkylation. Whereas silyl ether 21a is inert to the reaction
conditions, 21b and 21c afford 22 and 23 in 93 and 50%
isolated yield, respectively. The C-C bond-forming reac-
tion with C7-substituted heterocycles 21b and 21c affords
predominantly the SN2-type products 23b and 23c, in
contrast to C2-substituted substrates, where the SN2′
adducts are obtained exclusively (e.g., reaction of 2 in
Scheme 1). Similar trends in selectivity are observed in
a
b
Conditions: 5 equiv of n-BuMgCl, THF, 22 °C, 24 h. Selec-
tivity determined by analysis of the derived 400 MHz 1H NMR
spectra. c Isolated yield after silica gel chromatography; yield refers
to total yield of all product isomers.
the alkylation of the homologous alcohol 24a . However,
in contrast to benzyl ether 21c, 24b is inert to the
reaction conditions; this is presumably because the
directing effect of the tethered heteroatom is completely
abolished by the more remote positioning of the less
Lewis basic OPMB.
There could be two reasons for the difference in
regioselectivity in alkylations of substrates that bear a
C2 (e.g., 2) vs a C7 (e.g., 21b,c) side chain: (1) With
substrates bearing a substituent at the C2 position, SN2-
type products are not formed due to steric factors
associated with the formation of a quaternary carbon
center. (2) The SN2-type product is formed predominantly
in the reaction of 21b and 21c, because the C7 side chain
heteroatom cannot reach and thus effectively deliver the
alkylmetal reagent (assuming reactions occur via mode
III, Scheme 2). To address the latter possibility and
establish whether in the absence of two-point chelation,
a suitably situated Lewis basic site alone can deliver the
Grignard reagent and promote alkylation at the olefinic
site, we examined the reactivity of oxepins 27a and 27b
under a variety of conditions. As illustrated in Table 2
(entries 6 and 7), when the latter substrates were treated
to Grignard reagents, in all cases, <5% alkylation product
was detected.
The above-mentioned observations suggest that the
proposed mode of addition II (vs I and III, Scheme 2)
represents a more plausible model that accounts for the
required presence of accessible Lewis basic sites within
the heterocyclic structure and the C2 side chain. That
is, a two-point chelation serves to facilitate the cleavage
of the ring C-O bond through activation by the bound
Lewis acidic Mg, so that the incoming Grignard reagent
can readily add to the C-C π bond and promote the
allylic substitution. This mechanistic paradigm is sup-
ported by the fact that the less Lewis acidic dialkyl-
magnesium reagents are ineffective as alkylating agents
(<2% reaction with Et2Mg and 12 within similar reaction
periods as used with EtMgBr).
(9) Chin, B.; Buchwald, S. L. J . Org. Chem. 1996, 61, 5650-5651.
Control experiments show that binol and biphen derivatives of the
chiral Zr catalyst afford identical results in asymmetric carbomagne-
sation reactions.
The inertness of the derived pyran and furan ring
systems, in contrast to the reactivity of oxepins and
oxocins, is more difficult to explain with a reasonable

Addition of Grignard Reagents to Unsaturated Heterocycles
J . Org. Chem., Vol. 64, No. 3, 1999 857
Sch em e 4
merit mention: (1) The catalytic ring-closing metathesis
of substrates such as (S)-30 is significantly more facile
when the reaction is carried out under an atmosphere of
ethylene, presumably due to the formation of the more
active ModCH2 system.11 Thus, after the catalytic re-
moval of the directing unit, the chiral unsaturated alcohol
(S)-32, the formal (TBS protected) product of the enan-
tioselective addition of the Grignard reagent to unfunc-
tionalized heterocycle 33, is obtained. (2) The less active
(PCy3)2Cl2RudC(H)Ph12 delivers significantly lower yields
(<5% conversion).
Sch em e 5
Con clu sion s
Diastereoselective alkylation of unsaturated oxepins
and oxocenes can be promoted by an appropriately
positioned Lewis basic directing group at the C2 position.
Data summarized in Tables 1 and 2 suggest that a two-
point binding involving both the heterocycle and the side
chain heteroatom activates the allylic system to promote
addition in an SN2′ fashion (mode II, Scheme 2). Although
a chelating substituent is required for C-C bond forma-
tion, it can be easily removed by a subsequent Mo-
catalyzed process (cf. Scheme 5).
The reactivity of these medium ring heterocycles
toward Grignard reagents suggests that with an ap-
propriately designed substrate, a variety of alkylmetals
may be used to effect efficient and stereoselective C-C
bond-forming reactions. Furthermore, more general and
shorter synthesis schemes may involve the use of chiral
Lewis acids in conjunction with less nucleophilic alkyl-
metal agents (e.g., alkylzinc reagents); such plans may
also involve the utilization of a chiral metathesis cata-
lyst13 to access optically pure starting materials directly
(without the need to proceed through a silyl ether such
as 1). Research along these lines should elevate stereo-
selective addition of alkylmetals to olefins to a practical
and viable alternative that can be used in the preparation
of optically pure materials.
degree of certainty. This difference in reactivity may be
partially attributed to the overlap of the reacting π cloud
with the σ* of the cleaving C-O bond within the more
reactive conformers of the heterocycle. Such reaction-
promoting overlap may be more easily accessible with the
larger seven- and eight-membered rings.
Rem ova l of th e Ch ela tin g Gr ou p by Ca ta lytic
Rin g-Closin g Meta th esis. One of the practical short-
comings of this, or any other, heteroatom-assisted reac-
tion is that a Lewis basic site required for reaction may
not be desired in the final product. Accordingly, an
efficient method for the eventual removal of the directing
unit would be desirable. Toward this end, we examined
the ability of crotyl groups to serve as allylic substitution
promoters. As illustrated in Scheme 4, medium-ring
heterocycles that contain a crotyl unit within their C2
substituent are readily alkylated with high levels of
stereochemical control (e.g., (S)-28 f 29). It must be
noted that simple allyl units cannot be used, as they are
easily cleaved by alkylmagnesium halides (direct SN2′
addition).
The advantage of alkylation products such as 29a ,b is
that the required promoter group can then be easily
removed by catalytic ring-closing metathesis. As an
example, as depicted in Scheme 5, diastereoselective
alkylation of (S)-28 with n-BuMgCl, followed by protec-
tion of the primary alcohol, affords (S)-30 in 93% yield
and >96% ee. Subsequent treatment of (S)-30 with 5 mol
% Mo(CHCMe2Ph)(N(2,6-(i-Pr)2C6H3))(OCMe(CF3)2)2 (31),10
under 1 atm of ethylene, leads to the excision of the
directing group and formation of (S)-32 in 89% yield
(>96% ee). It is worthy of note that, unlike the majority
of reported examples, it is the released acyclic products
and not the cyclic system (2,5-dihydrofuran in this case)s
that is the product of interest.
Exp er im en ta l Section
Gen er a l. Infrared (IR) bands are characterized as broad
(br), strong (s), medium (m), and weak (w), νmax in cm-1 1H
.
NMR chemical shifts are reported in ppm from tetramethyl-
silane with the solvent resonance as the internal standard
(CHCl3: δ 7.26). Data are reported as follows: chemical shift,
integration, multiplicity (s ) singlet, d ) doublet, t ) triplet,
q ) quartet, br ) broad, m ) multiplet), coupling constants
(Hz), and assignment. 13C NMR spectra were recorded with
complete proton decoupling. Chemical shifts are reported in
ppm from tetramethylsilane with the solvent as the internal
reference (CDCl3: δ 77.0 ppm). Enantiomer ratios were
determined by GLC with either a BETA-DEX 120 (30 m ×
0.25 mm) chiral column by Supelco or an ALPHA-DEX GTA
1
(20 × 0.25 mm) chiral column by Altech Assoc. or by H NMR
(10) (a) Schrock, R. R.; Murdzek, J . S.; Bazan, G. C.; Robbins, J .;
DiMare, M.; O’Regan, M. J . Am. Chem. Soc. 1990, 112, 3875-3886.
(b) Bazan, G. C.; Schrock, R. R.; Cho, H.-N.; Gibson, V. C. Macromol-
ecules 1991, 24, 4495-4502.
(11) For a metathesis process performed under an atmosphere of
ethylene, see: Harrity, J . P. A.; La, D. S.; Cefalo, D. R.; Visser, M. S.;
Hoveyda, A. H. J . Am. Chem. Soc. 1998, 120, 2343-2351 and
references therein.
(12) Wu, Z.; Nguyen, S. T.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem.
Soc. 1995, 117, 5503-5511.
(13) (a) Alexander, J . A.; La, D. S.; Cefalo, D. R.; Hoveyda, A. H.;
Schrock, R. R. J . Am. Chem. Soc. 1998, 120, 4041-4042. (b) La, D. S.;
Alexander, J . A.; Cefalo, D. R.; Graff, D. D.; Hoveyda, A. H.; Schrock,
R. R. J . Am. Chem. Soc. 1998, 120, 9720-9721.
Several issues with regard to the metal-catalyzed
excision of the directing arm of the heterocyclic substrate

858 J . Org. Chem., Vol. 64, No. 3, 1999
Adams et al.
or 19F NMR analysis of the derived (R)-MTPA ester. Micro-
analyses were performed by Robertson Microlit Laboratories
(Madison, NJ ).
34.6, 33.8, 31.1, 30.3, 26.5. Anal. Calcd for C12H22O2: C, 72.68;
H, 11.18. Found: C, 72.55; H, 11.07.
(S)-1-(3-Hyd r oxyp r op yl)cycloh ex-2-en e ((S)-5). IR
(KBr): 3332 (br), 3011 (w), 2930 (s), 2854 (m), 1652 (w) cm-1
;
All reactions were conducted in oven (135 °C) and flame-
dried glassware under an inert atmosphere of dry argon.
Tetrahydrofuran was distilled from sodium metal/benzo-
phenone ketyl. All Grignard reagents were prepared from the
appropriate alkyl halide purchased from Aldrich, which were
distilled prior to use; Mg (turnings) were purchased from
Strem and used without further purification. (R)-(EBTHI)Zr-
binol and (R)-(EBTHI)Zr-biphen were prepared by the method
of Buchwald.14 Nonracemic (EBTHI)ZrCl2 and (EBTHI)Zr-
binol were stored under argon in a glovebox. (PCy3)2Cl2-
RudCHPh was prepared by the published methods.15
Rep r esen ta tive P r oced u r e for th e Ad d ition of Gr ig-
n a r d Rea gen ts to Cyclic Alk en es. A 5.0 mL flame-dried
flask was charged with 30.0 mg (0.23 mmol) of (S)-2, 0.10 mL
of THF, and 2.3 mL of freshly prepared 4-pentenylmagnesium
bromide (1.17 mmol). The mixture was allowed to stir at 22
°C for 20 h. Reaction was quenched by the dropwise addition
of a 1.0 mL portion of a saturated ammonium chloride solution;
the mixture was subsequently washed with 3 × 25 mL of Et2O.
Combined organic layers were dried over MgSO4, filtered, and
concentrated in vacuo to afford a pale yellow oil. Silica gel
chromatography (4:1 hexanes:EtOAc) afforded 34 mg of the
alkylation product 4 (0.17 mmol, 76% yield).
Rep r esen ta tive P r oced u r e for th e Zr -Ca ta lyzed Ki-
n etic Resolu tion . A 5.0 mL flame-dried flask with sidearm
Teflon stopcock was charged with 30.0 mg (0.114 mmol) of 9,
0.42 mL of THF, and 0.15 mL of freshly prepared EtMgCl
(0.342 mmol). The precatalyst (R)-(EBTHI)Zr-biphen was
added (6.2 mg, 1.14 × 10-2 mmol). The flask was equipped
with a flame-dried reflux condenser and lowered into a 70 °C
oil bath. The reaction was allowed to stir at 70 °C for
approximately 60 min, at which time 1H NMR analysis
indicated that the reaction had reached 55% conversion. The
reaction mixture was cooled to 0 °C in an ice bath, and excess
EtMgCl was quenched by the dropwise addition of a 1.0 mL
portion of a 1.0 M solution of aqueous HCl. The mixture was
diluted with 15 mL of distilled H2O and washed with 3 × 25
mL of Et2O. The combined organic layers were dried over
MgSO4, filtered, and concentrated in vacuo to yield a pale
yellow oil. Silica gel chromatography (9:1 hexanes:EtOAc)
afforded 12.1 mg (0.046 mmol) of recovered (R)-9 (0.046 mmol,
90% yield based on 55% conversion).
(S)-2-[(2-ter t-Bu tyld im eth ylsiloxy)m eth yl]-2,5,6,7-tet-
r a h yd r ooxep in (1). IR (KBr): 3007 (w), 2923 (m), 2845 (s),
1465 (m) cm-1; 1H NMR: δ 5.90-5.83 (1H, ddd, J ) 11.2, 5.4,
2.4 Hz), 5.67-5.62 (1H, ddt, J ) 11.3, 2.9, 1.4 Hz), 4.15-4.00
(2H, m), 3.75-3.67 (2H, m), 3.55 (1H, dd, J ) 10.2, 6.4 Hz),
2.43-2.32 (1H, m), 2.25-2.15 (1H, m), 1.92-1.72 (2H, m), 0.84
(9H, s), 0.07 (6H, s); 13C NMR: δ 133.1, 132.0, 79.2, 72.1, 66.7,
29.75, 27.8, 26.5, 19.0, -4.5, -4.6; HRCIMS C13H26O2Si
requires 226.2535, found 226.2547.
1H NMR: δ 5.68-5.64 (1H, m), 5.58-5.55 (1H, m), 3.65-3.62
(2H, t, J ) 6.8 Hz), 2.06 (1H, m), 1.96 (2H, m), 1.82-1.16 (8H,
m); 13C NMR: δ 131.8, 127.1, 63.2, 34.9, 32.3, 30.1, 29.0, 25.3,
21.4; Anal. Calcd for C9H16O: C, 77.09; H, 11.50. Found: C,
77.02; H, 11.52. HRMS C9H15O [M - H] requires 139.1123,
found 139.1123.
2-[2-(ter t-Bu t yld im et h ylsiloxy)et h yl]-2,5,6,7-t et r a h y-
d r ooxep in (9). IR (KBr): 2957 (m), 2951 (m), 2856 (m), 1654
1
(w) cm-1; H NMR: δ 5.84-5.78 (1H, ddd, J ) 11.2, 5.6, 2.4
Hz), 5.57-5.54 (1H, dt, J ) 11.2, 1.6 Hz, vinylic CH), 4.20 (1H,
m), 4.07-4.01 (1H, ddd, J ) 11.6, 6.8, 4.4 Hz), 3.78-3.63 (3H,
m), 2.38-2.34 (1H, m), 2.22-2.17 (1H, m), 1.85-1.72 (4H, m),
0.89 (9H, s, t-Bu), 0.06 (3H, s), 0.05 (3H, s); 13C NMR: δ 135.5,
132.6, 75.0, 72.2, 60.2, 40.0, 29.9, 27.7, 26.6, -4.6. Anal. Calcd
for C14H28O2Si: C, 65.57; H, 11.00. Found: C, 65.87; H, 11.14.
2-[(B e n zylo xy )m e t h yl]-2,5,6,7-t e t r a h y d r o -N -t o sy l-
a zep in (10). IR (KBr): 3032 (m), 2928 (s), 2867 (m), 1652 (w),
1597 (m) cm-1 1H NMR: δ 7.74-7.72 (2H, d, J ) 8.4 Hz),
;
7.32-7.30 (2H, m), 7.21-7.19 (3H, d, J ) 6.0 Hz), 7.16-7.14
(2H, d, J ) 8.8 Hz), 5.81-5.75 (1H, m), 5.56-5.21 (1H, m),
4.95 (1H, m), 4.46-4.43 (1H, d, J ) 12.0 Hz), 4.38-4.34 (1H,
d, J ) 12.0 Hz), 3.78-3.71 (1H, dt, J ) 14.0, 7.2 Hz), 3.23-
3.16 (1H, dt, J ) 14.4, 6.4 Hz), 3.56-3.51 (1H, dd, J ) 10.4,
8.4 Hz), 3.48-3.44 (1H, dd, J ) 10.4, 5.6 Hz), 2.36 (3H, s, Me),
2.20-2.00 (2H, m), 1.86-1.60 (2H, m); 13C NMR: δ 140.4,
131.1, 129.2, 128.3, 127.9, 127.7, 127.6, 127.3, 94.3, 72.8, 69.7,
57.0, 43.4, 27.7, 24.9, 21.5, 20.1. Anal. Calcd for C21H25NO3S:
C, 67.90; H, 6.78. Found: C, 67.73; H, 6.64.
(S)-(E)-1-Hyd r oxy-4-bu tylh ep -2-en -7-ol ((S)-11). IR
(KBr): 3328 (br), 2954 (w), 2928 (m), 2869 (m), 1656 cm-1; 1H
NMR: δ 5.60-5.54 (1H, dt, J ) 15.4, 6.0 Hz), 5.41-5.35 (1H,
dd, J ) 15.4, 9.0 Hz), 4.08-4.06 (2H, d, J ) 5.6 Hz), 3.62-
3.53 (2H, m), 2.00-1.85 (1H, m), 1.56-1.11 (10H, m), 0.87-
0.83 (3H, t, J ) 7.0 Hz); 13C NMR: δ 137.9, 129.8, 64.3, 63.6,
42.9, 35.6, 31.8, 31.1, 30.1, 23.5, 14.7; HRMS C11H22O2 requires
186.1618, found 186.1602.
(S)-2-[(Ben zyloxy)m eth yl]-2,5,6,7-tetr ah ydr ooxepin ((S)-
12). IR (KBr): 3018 (m), 2930 (s), 2860 (s), 1652 (w) cm-1; 1H
NMR: δ 7.33-7.25 (5H, m), 5.90-5.83 (1H, ddt, J ) 11.2, 5.4,
2.4 Hz), 5.57-5.53 (1H, dtd, J ) 11.3, 3.1, 1.7 Hz), 4.62-4.60
(1H, d, J ) 12.2 Hz), 4.56-4.53 (1H, d, J ) 12.3 Hz), 4.13-
4.07 (1H, ddd, J ) 11.6, 6.8, 4.3 Hz), 3.75-3.69 (1H, ddd, J )
11.6, 7.1, 4.8 Hz), 3.55-3.51 (1H, dd, J ) 10.0, 7.2 Hz), 3.46-
3.43 (1H, dd, J ) 10.1, 4.6 Hz), 2.42-2.35 (1H, m), 2.23-2.14
(1H, m), 1.88-1.70 (2H, m); 13C NMR: δ 138.9, 133.8, 131.6,
128.9, 128.4, 128.2, 77.4, 74.1, 73.6, 72.3, 27.9, 27.8; HRMS
C
14H18O2 requires 218.1303, found 218.1306.
(R)-E-1-(Ben zyloxy)-4-isobu tylh ep -2-en -7-ol ((R)-13). IR
(KBr): 3394 (br), 2950 (s), 2923 (s), 2864 (s), 1650 (w) cm-1
;
1H NMR: δ 7.38-7.20 (5H, m), 5.59-5.52 (1H, dt, J ) 15.6,
6.0 Hz), 5.43-5.37 (1H, dd, J ) 15.6, 8.8 Hz), 4.49 (2H, s,
PhCH2O), 3.99-3.98 (2H, d, J ) 6.0 Hz), 4.94-4.90 (1H, dd,
J ) 10.4, 2.4 Hz), 4.50 (2H, s), 3.99-3.98 (2H, d, J ) 6.0 Hz),
3.61-3.58 (2H, t, J ) 6.8 Hz), 2.09-2.01 (1H, m) 1.62-1.15
(7H, m) 0.87-0.86 (3H, d, J ) 6.8 Hz), 0.85-0.83 (3H, d, J )
6.4 Hz); 13C NMR: δ 139.6, 139.1, 129.0, 128.5, 128.2, 127.0,
72.4, 71.5, 63.7, 45.3, 40.9, 32.2, 31.2, 26.0, 24.2, 22.5; HRMS
(S)-2-(Hyd r oxym eth yl)-2,5,6,7-tetr a h yd r ooxep in ((S)-
1
2). IR (KBr): 3408 (br), 2930 (s), 2860 (s), 1652 (w) cm-1; H
NMR: δ 5.95-5.90 (1H, ddt, J ) 11.1, 5.4, 2.4 Hz), 5.48-5.42
(1H, ddt, J ) 11.2, 3.1, 1.3 Hz), 4.20-4.10 (1H, m), 3.78-3.75
(1H, dd, J ) 7.0, 4.2 Hz), 3.75-3.72 (1H, dd, J ) 7.6, 4.2 Hz),
3.64-3.55 (2H, m), 2.45-2.20 (2H, m), 1.95-1.73 (2H, m); 13
C
NMR: δ 134.5, 130.5, 79.3, 72.5, 66.2, 29.8, 27.9. Anal. Calcd
C
18H28O requires 276.2089, found 276.2088.
for C7H12O2: C, 65.60; H, 9.44. Found: C, 65.35; H, 9.44.
(R)-2-(H yd r oxyet h yl)-2,5,6,7-t et r a h yd r ooxep in ((R)-
(S)-(E)-1-(Hyd r oxym eth yl)-4-(3-h yd r oxyp r op yl)n on a -
2,8-d ien e ((S)-4). IR (KBr): 3345 (br), 2936 (s), 2854 (s), 1671
(w), 1646 (m) cm-1; 1H NMR: δ 5.83-5.74 (1H, ddt, J ) 16.8,
10.0, 6.8 Hz), 5.64-5.57 (1H, dt, J ) 16.4, 6.8 Hz), 5.44-5.38
(1H, dd, J ) 15.2, 8.8 Hz), 5.01-4.91 (2H, m), 4.10 (2H, t, J )
5.2 Hz), 3.63-3.61 (2H, m), 2.06-1.92 (3H, m), 1.58-1.18 (8H,
m); 13C NMR: δ 138.9, 136.9, 129.3, 114.4, 63.6, 62.9, 42.2,
14). IR (KBr): 3376 (br), 3018 (s), 2860 (s), 2930 (w), 2835
1
(w), 1652 (s) cm-1; H NMR: δ 5.86-5.79 (1H, m), 5.52-5.48
(1H, m), 4.31 (1H, m, HOCH2CH2CHO), 4.09-4.04 (1H, m),
3.88-3.67 (3H, m), 2.40-2.30 (1H, m), 2.23-2.14 (1H, m),
1.90-1.75 (4H, m); 13C NMR: δ 133.7, 132.2, 78.4, 71.5, 61.1,
37.9, 28.9, 26.8. Anal. Calcd for C8H14O2: C, 67.57; H, 9.92.
Found: C, 67.28; H, 10.20.
(S)-(E)-1-Hyd r oxy-5-bu tyloct-3-en -8-ol ((S)-15). IR
(KBr): 3339 (br), 2961 (s), 2930 (s), 2860(s), 1652 (w) cm-1
;
(14) Grossman, R. B.; Davis, W. M.; Buchwald, S. L. J . Am. Chem.
Soc. 1991, 113, 2321-2322 and references therein.
(15) Schwab, P.; Grubbs, R. H.; Ziller, J . W. J . Am. Chem. Soc. 1996,
118, 100-110.
1H NMR: δ 5.37-5.30 (1H, dt, J ) 15.6, 6.4 Hz), 5.28-5.22
(1H, dd, J ) 15.2, 8.4 Hz), 3.63-3.59 (4H, m), 2.29-2.24 (2H,
dt, J ) 6.4, 6.0 Hz), 1.96-1.89 (1H, m), 1.60-1.16 (10H, m),

Addition of Grignard Reagents to Unsaturated Heterocycles
Sch em e 6
J . Org. Chem., Vol. 64, No. 3, 1999 859
0.86 (3H, t, J ) 7.2 Hz, CH3); 13C NMR: δ 138.4, 125.9, 63.0,
2-[(p -Me t h oxyb e n zyloxy)e t h yl]-2,5,6,7-t e t r a h yd r o-
oxep in (20). IR (KBr): 3024 (br), 2942 (s), 2841 (s), 1620 (m)
62.1, 42.8, 36.0, 35.1, 31.2, 30.5, 29.5, 22.7, 14.1. HRMS calcd
1
C
12H24O2 (M+1) requires 201.1854, found 201.1855.
cm-1; H NMR: δ 7.27-7.25 (2H, d, J ) 8.8 Hz), 6.88-6.86
(R)-E-1-H yd r oxy-5-isob u t yloct -3-en -8-ol ((S)-16). IR
(2H, d, J ) 8.8 Hz), 5.85-5.79 (1H, ddt, J ) 11.2, 2.8, 1.6 Hz),
5.69-5.65 (1H, m), 4.27-4.21 (1H, d, J ) 11.2 Hz), 4.40-4.36
(1H, d, J ) 11.6 Hz), 4.24-4.17 (1H, m), 4.04-3.98 (1H, ddd,
J ) 12, 7.2, 5.2 Hz), 3.79 (3H, s), 3.68-3.51 (3H, m), 2.40-
2.12 (2H, m), 1.86-1.75 (4H, m); 13C NMR: δ 159.8, 135.2,
132.7, 131.4, 129.9, 114.4, 75.3, 73.3, 72.1, 67.2, 55.9, 37.1, 29.8,
27.6. Anal. Calcd for C11H18O2: C, 72.96; H, 8.74. Found: C,
73.08; H, 8.72. HRMS calcd C16H23O3 requires 263.1647, found
263.1648.
(KBr): 3320 (br), 2948 (s), 2923 (s), 2867(s), 1652 (w) cm-1
;
1H NMR: δ 5.38-5.31 (1H, dt, J ) 15.2, 6.8 Hz), 5.26-5.20
(1H, dd, J ) 15.2, 8.8 Hz), 3.64-3.60 (4H, m), 2.29-2.25 (2H,
dt, J ) 6.8, 6.4 Hz), 2.09-2.00 (1H, m), 1.60-1.10 (8H, m),
0.87-0.85 (3H, d, J ) 6.8 Hz), 0.84-0.82 (3H, d, J ) 6.8 Hz);
13C NMR: δ 138.8, 126.6, 63.5, 62.7, 45.5, 41.2, 36.6, 32.2, 31.0,
25.9, 24.2, 22.4. HRMS calcd C12H24O2 (M + 1) requires
201.1854, found 201.1860.
P r oof of Absolu te Ster eoch em istr y for Alk yla tion of
(R)-14 w ith n -P r MgCl (not shown in Table 1). The stereo-
chemical identity of the product of addition of n-PrMgCl to
(R)-14 was determined as illustrated in Scheme 6. Analysis
of the 400 MHz 19F NMR of the derived (R)-MTPA esters
supports the correlation.
2-[(ter t-Bu t yld im et h ylsiloxy)m et h yl]-2,3,4,7-t et r a h y-
d r ooxep in (21a ). IR (KBr): 3018 (w), 2930 (br), 2854 (s), 1658
1
(w) cm-1; H NMR: δ 5.84-5.78 (1H, m), 5.67-5.62 (1H, m),
4.34-4.02 (2H, m), 3.69-3.60 (2H, m), 3.52-3.47 (1H, m),
2.42-2.09 (2H, m), 1.97-1.60 (2H, m), 0.89 (9H, s), 0.05 (6H,
s); 13C NMR: δ 132.4, 130.5, 82.2, 68.2, 66.5, 30.9, 26.6, 26.3,
19.1, -4.5, -4.6. HRMS calcd C11H22O2 (M + 1) requires
243.1780, found 243.1770.
(R)-2-[(Ben zyloxy)eth yl]-2,5,6,7-tetr a h yd r ooxep in ((R)-
17). IR (KBr): 3005 (br), 2936 (s), 2835 (s), 1658 (w), 1507
1
(m) cm-1; H NMR: δ 7.35-7.27 (5H, m), 5.84-5.78 (1H, m),
2-(Hyd r oxym eth yl)-2,3,4,7-tetr a h yd r ooxep in (21b). IR
5.57-5.54 (1H, m), 4.55-4.48 (2H, dd, J ) 16.1, 12.0 Hz), 4.23
(1H, m), 4.04-3.98 (1H, m), 3.68-3.54 (3H, m), 2.41-2.30 (1H,
m), 2.26-2.15 (1H, m), 1.88-1.70 (4H, m); 13C NMR: δ 134.5,
132.1, 128.3, 127.6, 127.5, 126.7, 74.6, 72.9, 71.5, 66.9, 36.5,
29.1, 26.9. Anal. Calcd for C15H20O2: C, 77.55; H,8.68. Found:
C, 77.68; H, 8.89.
(KBr): 3420 (br), 2930 (s), 2854 (s), 1658 (w), 1463 (m) cm-1
;
1H NMR: δ 5.86-5.80 (1H, m), 5.70-5.65 (1H, m), 4.39-4.34
(1H, dd, J ) 15.6, 4.8 Hz), 4.12-4.06 (1H, m), 3.71-3.65 (1H,
m), 3.57-3.48 (2H, m), 2.45-4.10 (2H, m), 1.57-1.48 (2H, m);
13C NMR: δ 132.4, 130.3, 82.5, 68.6, 66.4, 30.9, 26.5. HRMS
calcd C7H12O2 requires 128.0837, found 128.0838.
(S)-(E)-1-(Ben zyloxy)-5-b u t yloct -3-en -8-ol (a cet a t e of
2-[(Ben zyloxy)m eth yl]-2,3,4,7-tetr a h yd r ooxep in (21c).
IR (KBr): 3383 (br), 3024 (s), 2930 (m), 2854 (m), 1671 (w)
cm-1; 1H NMR: δ 7.35-7.26 (5H, m), 5.86-5.78 (1H, m), 5.70-
5.63 (1H, m), 4.64-4.52 (2H, dd, J ) 28.8, 16.4 Hz), 4.39-
4.32 (1H, dd, J ) 21.6, 6.4 Hz), 4.14-4.07 (1H, m), 3.88-3.80
(1H, m), 3.59-3.38 (2H, m), 2.42-2.10 (2H, m), 1.97-1.60 (2H,
m); 13C NMR: δ 138.9, 132.3, 130.5, 129.0, 128.4, 128.2, 80.5,
74.0, 73.7, 68.2, 31.4, 26.3; HRMS calcd C14H18O2 requires
218.1306, found 218.1307.
(Z)-5-Un d ecen e-1,2-d iol (23b). IR (KBr): 3376 (m), 2962
(m), 2920 (s), 2860 (m), 1655 (w) cm-1; 1H NMR: δ 5.48-5.33
(2H, m), 3.75-3.69 (2H, m), 3.66-3.62 (1H, m), 2.19-1.95 (4H,
m), 1.49-1.24 (8H, m), 0.89-0.85 (3H, t, J ) 6.8 Hz); 13C
NMR: δ 131.7, 129.3, 72.6, 67.5, 33.7, 32.2, 30.0, 29.3, 27.9,
24.0, 14.8. Anal. Calcd for the diacylated derivative: requires
(S)-18). IR (KBr): 2961 (m), 2923 (m), 2854 (w), 1765 (s) cm-1
;
1H NMR: δ 7.34-7.26 (5H, m), 5.41-5.34 (1H, dt, J ) 15.2,
6.4), 5.21-5.15 (1H, dd, J ) 15.6, 8.8 Hz), 4.51 (2H, s), 4.03-
3.99 (2H, t, J ) 6.4 Hz), 3.51-3.47 (2H, t, J ) 6.8 Hz), 2.35-
2.30 (2H, app. q, J ) 6.8 Hz), 2.03 (3H, s), 1.90-1.86 (1H, m),
1.63-1.13 (10H, m), 0.88-0.84 (3H, t, J ) 7.2 Hz, CH2CH3);
13C NMR: δ 171.9, 139.2, 137.2, 129.0, 128.3, 128.2, 127.3,
73.5, 71.5, 71.0, 43.3, 35.8, 33.8, 32.1, 30.1, 27.1, 23.4, 21.7,
14.8.
2-(Hyd r oxyp r op yl)-2,5,6,7-tetr a h yd r ooxep in (19a ). IR
(KBr): 3389 (br), 3024 (w), 2923 (m), 2860 (m), 1652 (w) cm-1
;
1H NMR: δ 5.83-5.77 (1H, m), 5.53-5.50 (1H, m), 4.08-4.02
(2H, m), 3.70-3.62 (3H, m), 2.53 (1H, br s, OH), 2.40-2.10
(2H, m), 1.85-1.67 (4H, m); 13C NMR: δ 134.1, 131.9, 77.9,
71.3, 62.7, 33.1, 28.9, 26.8, 76.7. Anal. Calcd for C9H16O2: C,
69.19; H,10.32. Found: C, 68.84; H, 10.57.
C
15H26O4: C, 66.62; H, 9.70. Found: C, 66.68; H, 9.53.
(Z)-1-(Ben zyloxy)-5-u n d ecen -2-ol (23c). IR (KBr): 3446
2-[(Ben zyloxy)p r op yl]-2,5,6,7-tetr a h yd r ooxep in (19b).
(m), 2923 (s), 2860 (m), 1652 (w) cm-1; 1H NMR: δ 7.36-7.30
(5H, m), 5.42-5.30 (2H, m), 4.55 (2H, s), 3.86-3.80 (1H, m),
3.52-3.49 (1H, dd, J ) 9.6, 3.2 Hz), 3.36-3.32 (1H, dd, J )
9.6, 8.0 Hz), 2.35 (1H, m, OH), 2.19-2.11 (2H, m), 2.05-1.99
(2H, dt, J ) 13.6, 6.8 Hz), 0.89-0.86 (3H, t, J ) 6.4 Hz); 13C
NMR: δ 138.7, 131.4, 129.5, 129.1, 128.4, 75.2, 73.9, 70.6, 33.7,
32.1, 30.0, 27.8, 23.9, 23.2, 14.8; HRMS calcd C18H28O2 (-H2O)
requires 258.1983, found 258.1980.
IR (KBr): 3024 (br), 2930 (m), 2867 (m), 1652 (w) cm-1 1H
;
NMR: δ 7.35-7.27 (5H, m), 5.83-5.77 (1H, m), 5.56-5.52 (1H,
m), 4.50 (2H, s), 4.07-4.00 (2H, m), 3.68-3.62 (1H, ddd, J )
11.6, 7.2, 4.4 Hz), 3.52-3.47 (2H, m), 2.38-2.16 (2H, m), 1.84-
1.60 (6H, m); 13C NMR: δ 138.6, 134.6, 131.8, 128.3, 127.6,
127.4, 77.6, 72.3, 71.3, 70.2, 32.9, 29.1, 26.9, 25.8. Anal. Calcd
for C16H22O2: C, 78.01; H, 9.00. Found: C, 78.00; H, 8.85.

860 J . Org. Chem., Vol. 64, No. 3, 1999
Adams et al.
2-(Hyd r oxyeth yl)-2,3,4,7-tetr a h yd r ooxep in (24a ). IR
Hz), 3.88-3.86 (2H, d, J ) 6.0 Hz), 3.59 (2H, t, J ) 6.4 Hz),
2.11-2.02 (1H, m), 1.70 (3H, d, J ) 6.4 Hz), 1.66-1.18 (8H,
m), 0.84 (3H, d, J ) 6.4 Hz), 0.82 (3H, d, J ) 6.4 Hz); 13C
NMR: δ 138.5, 129.5, 127.6, 126.5, 70.6, 70.5, 63.1, 44.6, 40.1,
31.5, 30.5, 25.3, 23.5, 21.8, 17.7; HRMS C15H28O2 (M + H)
requires 241.2167, found 241.2163. Anal. Calcd for C15H28O2:
C, 74.95; H, 11.74. Found: C, 75.28; H, 12.04.
1
(KBr): 3389 (br), 2942 (s), 1665 (w) cm-1; H NMR: δ 5.87-
5.81 (1H, m), 5.70-5.64 (1H, m), 4.31-4.26 (1H, dd, J ) 16.0,
5.2 Hz), 4.10-4.03 (1H, m), 3.88-3.74 (3H, m,), 2.40-2.10 (2H,
m), 1.91-1.81 (2H, m), 1.67-1.59 (2H, m); 13C NMR: δ 132.9,
130.3, 82.6, 67.7, 62.3, 38.6, 34.9, 26.5; Anal. Calcd for
C8H14O2: C, 67.57; H, 9.92. Found: C, 67.24; H, 9.98; HRMS
calcd C8H14O2 requires 142.0994, found 142.0993.
(S)-(E)-1-(Bu t-2-en yloxy)-4-(3-pen tyn yl)h ep-2-en e 7-(ter t-
Bu tyld im eth ylsilyl eth er ) (29b). IR (KBr): 3408 (br), 3024
2-[(p -Me t h oxyb e n zyloxy)e t h yl]-2,3,4,7-t e t r a h yd r o-
oxep in (24b). IR (KBr): 3024 (m), 2942 (br), 2841 (m), 1620
1
(w), 2923 (s), 2854 (s), 1677 (w) cm-1; H NMR: δ 5.73-5.50
1
(m) cm-1; H NMR: δ 7.27-7.25 (2H, d, J ) 8.8 Hz), 6.89-
(3H, m), 5.40-5.32 (1H, m), 3.92-3.91 (2H, d, J ) 6.0 Hz),
3.88-3.86 (2H, d, J ) 6.4 Hz), 3.58-3.55 (2H, t, J ) 6.4 Hz),
2.11-2.00 (3H, m), 3.59 (2H, t, J ) 6.4 Hz), 2.11-2.02 (1H,
m), 1.77-1.75 (3H, t, J ) 2.4 Hz), 1.71-1.70 (2H, d, J ) 6.4
Hz), 1.56-1.24 (6H, m), 0.88 (9H, s), 0.03 (6H, s); 13C NMR:
δ 137.4, 137.3, 129.4, 127.6, 127.4, 79.1, 75.4, 70.6, 70.5, 70.4,
64.9, 63.2, 41.4, 34.3, 30.9, 30.4, 25.9, 18.3, 17.7, 16.6, 3.4, -5.3;
HRMS C22H40SiO2 (M + H) requires 365.2875, found 365.2877.
(S)-(E)-1-(Bu t-2-en yloxy)-4-n -bu tylh ep -2-en -7-ol (30). IR
6.86 (2H, d, J ) 8.8 Hz), 5.85-5.79 (1H, m), 5.69-5.65 (1H,
m), 4.40 (2H, s), 4.27-4.21 (1H, dd, J ) 16.0, 4.0 Hz), 4.03-
3.97 (1H, m), 3.80 (3H, s, OMe), 3.78-3.76 (1H, m), 3.62-3.47
(2H, m), 2.40-2.10 (2H, m), 1.92-1.54 (4H, m); 13C NMR: δ
159.7, 132.4, 131.3, 130.7, 129.9, 114.3, 78.7, 73.3, 67.6, 67.5,
55.9, 36.9, 34.9, 26.5; HRMS calcd C16H22O3 (M - H) requires
261.1491, found 261.1493.
(Z)-6-Dod ecen e-1,3-d iol (26a ). IR (KBr): 3346 (br), 2932
1
(m), 2857 (m), 1651 (w) cm-1; H NMR: δ 5.41-5.33 (2H, m,
1
(KBr): 3389 (br), 2923 (s), 2860 (s), 1665 (w) cm-1; H NMR:
3.91-3.79 (3H, m), 2.19-2.09 (2H, m), 2.05-2.00 (2H, m),
1.71-1.35 (10H, m), 0.89-0.86 (3H, t, J ) 6.8 Hz); 13C NMR:
δ 131.6, 129.5, 72.8, 62.5, 38.9, 38.3, 32.2, 30.0, 27.9, 24.1, 23.2,
14.7. Anal. Calcd for the diacylated derivative: C16H28O4: C,
67.57; H, 9.92. Found C, 67.65; H, 9.70.
δ 5.73-5.62 (1H, m), 5.61-5.54 (1H, m), 5.53-5.43 (1H, m),
5.43-5.36 (1H, m), 3.91-3.90 (2H, d, J ) 6.0 Hz), 3.88-3.86
(2H, d, J ) 6.0 Hz), 3.59 (2H, t, J ) 6.4 Hz), 1.96 (1H, m),
1.70 (3H, d, J ) 6.4 Hz), 1.65-1.17 (10H, m), 0.86 (3H, t, J )
6.8 Hz); 13C NMR: δ 138.5, 129.5, 127.6, 126.5, 70.6, 70.4, 63.1,
42.3, 34.8, 31.1, 30.5, 29.4, 22.7, 17.7, 14.1; HRMS C15H28O2
(M + H) requires 241.2167, found 241.2168. Anal. Calcd for
4-(Hyd r oxym eth yl)-2,5,6,7-tetr a h yd r ooxep in (27a ). IR
1
(KBr): 3408 (br), 2930 (s), 2860 (s), 1658 (w) cm-1; H NMR:
δ 5.78-5.73 (1H, dtd, J ) 11.6, 4.0, 2.4 Hz), 5.70-5.67 (1H, d,
J ) 11.4 Hz), 4.18-4.14 (1H, m), 4.03-3.97 (1H, dt, J ) 12.4,
5.6 Hz), 3.78-3.74 (1H, dd, J ) 8.8, 4.4 Hz), 3.75-3.71 (1H,
dd, J ) 8.8, 4.8 Hz), 3.67-3.59 (2H, m), 1.97-1.90 (1H, m),
1.84-1.75 (1H, m); 13C NMR: δ 133.5, 131.5, 70.8, 68.9, 67.0,
41.6, 32.7; HRMS calcd C7H12O2 (M - H) requires 127.0378
found 127.0755.
C
15H28O2: C, 74.95; H, 11.74. Found: C, 74.92; H, 12.04.
Rep r esen ta tive P r oced u r e for th e Mo-Ca ta lyzed Re-
m ova l of th e Ch ela tin g Gr ou p . A 5.0 mL flame-dried flask
was taken into the glovebox and charged with 2 mg of the Mo
catalyst 31 (2.6 × 10-3 mmol). To this was added a solution of
diene (S)-30 in benzene (8.5 mg, 0.025 mmol, 0.05 M). The
mixture was removed from the glovebox, sealed under an
atmosphere of ethylene, and stirred at 22 °C for 3 h. Reaction
was quenched by the addition of anhydrous MeOH (0.5 mL),
volatiles were removed in vacuo, and the remaining dark
brown residue purified by silica gel chromatography (hexanes)
to afford 6.1 mg of (S)-32 (2.2 × 10-4 mmol, 89% yield).
(S)-4-Eth en ylocta n -1-ol (32). IR (KBr): 2930 (s), 2860 (s),
1652 (w) cm-1; 1H NMR: δ 5.56-5.47 (1H, ddd, J ) 19.2, 10.4,
8.8 Hz), 4.97-4.90 (2H, m), 3.59-3.56 (2H, t, J ) 6.4 Hz),
1.93-1.91 (1H, m), 1.65-1.17 (10H, m), 0.88 (12H, m), 0.04
(6H, s); 13C NMR: δ 144.1, 114.7, 64.1, 44.5, 35.4, 31.7, 31.2,
30.1, 26.7, 23.5, 20.8, 14.8, -4.6; HRMS C16H34OSi (M - H)
requires 269.2301, found 269.2309.
4-[(p -Met h oxyb en zyloxy)m et h yl]-2,5,6,7-t et r a h yd r o-
oxep in (27b). IR (KBr): 3011 (w), 2930 (m), 2848 (s), 1608
1
(m) cm-1; H NMR: δ 7.27-7.25 (2H, d, J ) 8.8 Hz), 6.89-
6.87 (2H, d, J ) 8.4 Hz), 5.73-5.65 (2H, m, vinylic CH), 4.64
(2H, s), 4.15-4.13 (2H, m), 3.99-3.94 (1H, dt, J ) 11.6, 4.8
Hz), 3.80 (3H, s, OMe), 3.75-3.69 (1H, ddd, J ) 11.6, 9.2, 4.0
Hz), 3.45-3.36 (2H, m), 2.78-2.76 (1H, m), 1.91-1.85 (1H,
m), 1.81-1.72 (1H, m); 13C NMR: δ 159.8, 134.4, 131.1, 130.9,
129.9, 114.4, 74.2, 73.4, 71.2, 68.9, 55.9, 39.4, 32.9. Anal. Calcd
for C15H20O3: C, 72.54; H, 8.12. Found: C, 72.69; H, 8.14.
HRMS calcd C15H20O3 requires 248.1412, found 248.1407.
(S )-2-[(B u t -2-e n y lo x y )m e t h y l]-2,5,6,7-t e t r a h y d r o -
oxep in (28). IR (KBr): 3024 (m), 2930 (s), 2854 (s), 1677 (w),
1652 (w) cm-1; 1H NMR: δ 5.85-5.79 (1H, m), 5.69-5.49 (3H,
m), 4.20-4.18 (1H, m), 4.08-4.02 (1H, m), 3.96-3.86 (1H, m),
3.70-3.64 (2H, m), 3.49-3.33 (2H, m), 2.39-2.24 (1H, m),
2.10-2.04 (1H, m, allylic CH), 1.81-1.62 (2H, m), 1.65-1.64
(3H, d, J ) 6.4 Hz), 1.61-1.59 (3H, d, J ) 6.8 Hz); 13C NMR:
δ 133.9, 131.7, 130.5, 128.2, 77.4, 73.4, 72.8, 72.4, 29.7, 27.8,
18.5. Anal. Calcd for C11H18O2: C, 72.48; H, 9.96. Found: C,
72.62; H, 10.01.
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM-47480) and the National
Science Foundation (CHE-9632278) for support of this
research.
Su p p or tin g In for m a tion Ava ila ble: Spectral data for
determination of product enantiopurities (4 pages). This
material is available free of charge via the Internet at
http://pubs.acs.org.
(R)-(E)-1-(Bu t-2-en yloxy)-4-isobu tylh ep -2-en -7-ol (29a ).
IR (KBr): 3389 (br), 3011 (w), 2955 (s), 2867 (m), 1671 (w)
cm-1; 1H NMR: δ 5.74-5.63 (1H, m), 5.61-5.56 (1H, m), 5.53-
5.46 (1H, m), 5.40-5.33 (1H, m), 3.91-3.90 (2H, d, J ) 6.4
J O981745E