One-pot synthesis of lactams using domino reactions: Combination of schmidt reaction with Sakurai and aldol reactions

Article abstract of DOI:10.1021/jo901843w

(Chemical Equation Presented) A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an azido-containing eno

Full text of DOI:10.1021/jo901843w

pubs.acs.org/joc
One-Pot Synthesis of Lactams Using Domino Reactions: Combination of
Schmidt Reaction with Sakurai and Aldol Reactions
Chan Woo Huh, Gagandeep K. Somal, Christopher E. Katz, Huaxing Pei, Yibin Zeng,
ꢀ
Justin T. Douglas, and Jeffrey Aube*
Department of Medicinal Chemistry, 1251 Wescoe Hall Drive, Malott Hall, Room 4070, University of
Kansas, Lawrence, Kansas 66045-7582
jaube@ku.edu
Received August 26, 2009
A series of domino reactions in which the intramolecular Schmidt reaction is combined with either a
Sakurai reaction, an aldol reaction, or both is reported. The Sakurai reaction of an allylsilane with an
azido-containing enone under Lewis acidic conditions followed by protonation of the resulting
titanium enolate species allowed for a subsequent intramolecular Schmidt reaction. Alternatively, the
intermediate titanium enolate could undergo an aldol reaction followed by the intramolecular
Schmidt reaction to form lactam products with multiple stereogenic centers. The stereochemical
features of the titanium enolate aldol reaction with several 3-azidoaldehyde substrates during this
domino process is discussed.
Introduction
this sequence is a Lewis acid-promoted Diels-Alder reaction
between azido-containing diene 1 and enone 2. In the second
stage, the in situ generated ketone 3 undergoes intramolecular
azide addition to form azidohydrin 4 and subsequent Schmidt
rearrangement2,3 to generate bicyclic lactam 5 in 82% yield.
Under these conditions, Schmidt rearrangement does not occur
prior to the Diels-Alder reaction because of the low reactivity
of azides toward ketones in an intermolecular setting. Other
laboratories have also begun to examine the utilization of the
Schmidt reaction in a domino reaction context.6
A logical next step was to study the combination of other
Lewis acid promoted reactions with the intramolecular
Schmidt reaction. For example, the Sakurai7,8 and aldol
reactions are typically mediated by Lewis acids similar to
those used in the intramolecular Schmidt rearrangement.
Furthermore, both the Sakurai reaction/protonation of
Domino reactions, in which two or more reactions are
carried out sequentially in one pot, have the potential of
increasing efficiency over traditional multistep processes.1
Our continuing efforts to explore the Lewis acid promoted
reaction of alkyl azides2,3 led us to consider combining that
reaction into a domino sequence with C-C bond-forming
reactions that use similar conditions. Along these lines, we
have previously reported the domino Diels-Alder/intra-
molecular Schmidt reaction and described its use in natural
product and library synthesis (Scheme 1).4,5 The first step of
(1) For reviews on domino reactions, see: (a) Nicolaou, K. C.; Edmonds,
D. J.; Bulger, P. G. Angew. Chem., Int. Ed. 2006, 45, 7134–7186. (b) Tietze,
L. F. Chem. Rev. 1996, 96, 115–136. (c) Waldmann, H. Org. Synth. 1995, 193–
202.
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(2) (a) Aube, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965–8966.
(b) Aube, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992, 57, 1635–
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1637.
(6) (a) Song, D.; Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129,
12019–12022. (b) Batchu, V. R.; Barange, D. K.; Kumar, D.; Sreekanth,
B. R.; Vyas, K.; Reddy, E. A.; Pal, M. Chem. Commun. 2007, 1966–1968. (c)
Gu, P.; Zhao, Y.-M.; Tu, Y. Q.; Ma, Y.; Zhang, F. Org. Lett. 2006, 8, 5271–
5273. (d) Reddy, P. G.; Varghese, B.; Baskaran, S. Org. Lett. 2003, 5, 583–
585.
(7) Hosomi, A.; Hashimoto, H.; Kobayashi, H.; Sakurai, H. Chem. Lett.
1979, 8, 245–248.
(8) Hosomi, A. Acc. Chem. Res. 1988, 21, 200–206.
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(3) Milligan, G. L.; Mossman, C. J.; Aube, J. J. Am. Chem. Soc. 1995, 117,
10449–10459.
(4) (a) Frankowski, K. J.; Neuenswander, B.; Aube, J. J. Comb. Chem.
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2008, 10, 721–725. (b) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.;
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Aube, J. J. Am. Chem. Soc. 2008, 130, 6018–6024. (c) Zeng, Y.; Aube, J.
J. Am. Chem. Soc. 2005, 127, 15712–15713.
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(5) Zeng, Y.; Reddy, D. S.; Hirt, E.; Aube, J. Org. Lett. 2004, 6, 4993–
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4995.
7618 J. Org. Chem. 2009, 74, 7618–7626
Published on Web 09/18/2009
DOI: 10.1021/jo901843w
r
2009 American Chemical Society

Huh et al.
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SCHEME 1
SCHEME 2
SCHEME 3
enones and the aldol reaction furnish ketones suitable for
a downstream Schmidt reaction. Herein, we describe the
development of new Sakurai/Schmidt, aldol/Schmidt, and
Sakurai/aldol/Schmidt sequences.
Result and Discussion
Domino Sakurai/Schmidt Reaction. We envisioned an
enone containing an appropriately tethered alkyl azide
would react with allyltrimethylsilane under Lewis acidic
conditions to form a ketone following protonation, thus
allowing for a subsequent intramolecular Schmidt reaction
(Scheme 2). We had previously demonstrated that trans-
enones, like that present in 6, do not allow for an intra-
molecular Schmidt reaction in 6 prior to double-bond modi-
fication.5 Reaction of 6 with allyltrimethylsilane in the
presence of TiCl4 followed by protonation of the resulting
titanium enolate 7 and subsequent intramolecular Schmidt
reaction led to a lactam 9. The best conditions involved
initial treatment of 6 with 2 equiv of TiCl4 and allyltrimethyl-
silane at -78 °C for 2 h. The reaction temperature was
brought to 0 °C over 4-5 h followed by the addition of 5
equiv of methanol. Methanol acts as the proton source for
the titanium enolate 7 to generate ketone 8 in situ. After
methanol was added, the reaction was stirred at room
temperature for an additional 45 min for the completion of
the Schmidt reaction before quenching with a saturated
solution of ammonium chloride. It seems that hydrochloric
acid, generated from the reaction between methanol and
TiCl4, is acidic enough to mediate the subsequent intramole-
cular Schmidt reaction to give lactam 9 in 46% yield.9
We also prepared and tested azide-containing cyclic enone
substrates 103 and 11 under similar conditions (Scheme 3).
When azide 10 was submitted to Sakurai/Schmidt condi-
tions, lactam 14 was obtained in 75% yield (cis/trans 7:3)
with methanol and 79% yield (cis/trans > 9:1) with tert-
butyl alcohol, respectively. The improved selectivity with
bulky tert-butyl alcohol over methanol could be indicative of
an increased steric interaction with the pseudoequatorial
allyl group as shown in 13, which allows for a more favorable
attack from the alternate conformation 12.10 Azide 11
similarly led to lactam 15 in 50-66% yield but with much
lower stereoselectivity (15a/15b = 64:36). In this case, the
outcome was not affected by the nature of the proton source.
An analogous two-stage procedure in which the Sakurai-
induced enolate was quenched and equilibrated with aque-
ous saturated NH4Cl solution followed by treatment with
TFA resulted in the exclusive formation of thermodynamic
15b in overall 47% yield for the sequence. Compounds 15a
and 15b were assigned as drawn from mechanistic considera-
tions. Kinetic protonation of the enolate resulting from the
allylation reaction should afford the 2,3-cis ketone inter-
mediate affording lactam 15a following Schmidt reaction.
This was confirmed by the exclusive formation of 15b when
an equilibration step was inserted into the sequence, as this
lactam should be derived from the thermodynamically more
stable trans cyclopentanone intermediate shown.
(9) Control experiments established that related intramolecular Schmidt
reactions are not promoted by Ti(Oi-Pr)4.
(10) An analogous steric interaction between an incoming allylsilane
nucleophile and an alkyl group in the 3-position of the half-chair oxocarbe-
nium ion was discussed by Woerpel. See: Romero, J. A. C.; Tabacco, S. A.;
Woerpel, K. A. J. Am. Chem. Soc. 2000, 122, 168–169.
Domino Aldol/Schmidt reaction. We envisioned that the
aldol reaction between an enolate equivalent and an azide-
containing aldehyde would provide a Schmidt substrate
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SCHEME 4
suitable for the development of another domino reaction. To
this end, we examined various versions of aldol reactions for
silyl enol ether 16. Thus, treatment of the silyl enol ether 16
with TiCl4 in the presence of an aldehyde should enact a
Mukaiyama aldol reaction.11 In contrast, aging a solution of
16 and TiCl4 leads to titanium enolate 17 via transmetala-
tion.12 While silyl enol ether 16 is expected to react via an
open transition state, 17 should go via a closed transition
state.13 This difference could potentially give different out-
comes with regards to stereoselectivity (Scheme 4).
CH2Cl2 at -45 °C was completed in less than 1 h as
confirmed by TLC monitoring. 3-Azidoaldehyde was then
added, and the solution was warmed to 0 °C to allow the
aldol and Schmidt reactions to occur. Following workup, the
desired lactam product was obtained in 36-42% yield with
moderate to high diastereoselectivity (conditions A,
Scheme 5). Under these conditions, aldol reaction did not
occur unless the reaction mixture was warmed to 0 °C. At this
temperature, both aldol and Schmidt reactions occurred,
preventing us from isolating simple aldol products. Several
other Lewis acids were also briefly surveyed (e.g., SnCl4,
Unfortunately, these domino reactions turned out to be
synthetically impractical. The Mukaiyama aldol/Schmidt
reaction produced lactam 19 as a mixture of all four possible
diastereomers in 27% unoptimized yield. The outcome of the
titanium aldol/Schmidt reaction was slightly better with a
56% yield and diastereomeric ratio of 56:44 (major/sum of
three minor diastereomers). The structure of the major
diastereomer was confirmed by X-ray crystallography and
was shown to be derived from the anti-aldol product 20.
Although these domino aldol/Schmidt reactions were poorly
stereoselective, they provided insight into the next domino
reaction examined: the Sakurai/Aldol/Schmidt reaction.
Domino Sakurai/aldol/Schmidt Reaction. The above
experiments involving domino Schmidt reactions utilizing
aldol or Sakurai reactions led to the idea of combining
all three reaction types. Although domino Sakurai/aldol
reactions are known,7,14 no reaction combining a Sakurai
reaction, an aldol reaction, and a Schmidt reaction has been
reported.
BF3 OEt2, MeAlCl2) but led in all cases to inferior results.
3
The major product of the reaction between enone 2 and
3-azidoaldehyde 21 was 23a, arising from an anti-aldol
intermediate, in a 6.4:1 ratio. The only isolable minor
product, 23b, was the Schmidt product of the corresponding
syn-aldol intermediate. An analogous reaction of 3-azido-
nonanal (18) led to 25a in 4:1 diastereoselectivity. Again, 25a
arose from an anti-aldol intermediate, whereas minor 25b
was from a syn-aldol intermediate. Surprisingly, even with
additional stereogenic center, only two diastereomers were
1
obtained (no additional isomers were observed in the H
NMR of the crude reaction mixture). Finally, bulky alde-
hyde 22 furnished 26a as single diastereomer in 42% yield. In
all cases, strict trans selectivity was observed for the addition
across the cyclohexene double bond.
In considering ways of improving the yield of the reaction
sequence, we hypothesized that both the aldol and Schmidt
reaction steps were slow at 0 °C and could be complicated by
decomposition pathways at that temperature. Therefore, the
procedure was modified by adding an additional 2 equiv of
TiCl4 at 0 °C to facilitate the rapid completion of the Schmidt
reaction (conditions B, Scheme 5). Upon addition of TiCl4, a
moderate amount of bubbling was observed, which sug-
gested that the additional acid did in fact accelerate the
Schmidt reaction. The resulting mixture was kept at 0 °C
overnight (conditions B in Scheme 5). Using these condi-
tions, we could obtain products in higher yields (56-59%),
but the diastereoselectivity was decreased. The reaction of
aldehyde 21 still furnished two diastereomers albeit with
lower selectivity (2.6:1). With 18, we began to observe two
more minor diastereomers, which resulted in 1.8:1 selectivity
for the major relative to the sum of all minor diastereomers.
Several 3-azidoaldehydes such as 18,15 21,16 and 2217 were
tested for the domino Sakurai/aldol/Schmidt reaction
(Scheme 5). The Sakurai reaction of allyltrimethylsilane
and 2-cyclohexen-1-one (2) mediated by 1 equiv of TiCl4 in
(11) (a) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 2,
1011–1014. (b) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem. Soc.
1974, 96, 7503–7509.
(12) Nakamura, E.; Shimada, J.-I.; Horiguchi, Y.; Kuwajima, I. Tetra-
hedron Lett. 1983, 24, 3341–3342.
(13) Ghosh, A. K.; Shevlin, M., The Development of Titanium Enolate-
based Aldol Reactions. In Modern Aldol Reactions, ed.; Mahrwald, R., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, p 63-125.
(14) Stevens, B. D.; Nelson, S. G. J. Org. Chem. 2005, 70, 4375–4379.
ꢀ
(15) Lee, H.-L.; Aube, J. Tetrahedron 2007, 63, 9007–9015.
(16) Boyer, J. H. J. Am. Chem. Soc. 1951, 73, 5248–5252.
(17) Kim, H.-O. Synth. Commun. 1998, 28, 1713–1720.
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SCHEME 5
SCHEME 6
Sterically encumbered aldehyde 22 still provided a single
diastereomer 26a as the product even with harsher conditions.
The reaction between 2 and 21 was accompanied by forma-
tion of 10% of enone species 24 as a side product. This
unexpected side product 24 could arise from β-elimination
of aldol intermediate 27 followed by a precedented Lewis
acid-promoted Cope rearrangement (Scheme 6).18 Enone
24 could in principle lead to additional side products via
nucleophilic addition, although we did not identify any
such byproducts. We anticipated that addition of excess
amount of TMSCl (5 equiv) might slow down the rate of
β-elimination of the aldol intermediate by trapping the initially
formed aldol adduct 27 as its TMS ether derivatives 29, thus
give more chance for the Schmidt reaction to occur. Although
the stereoselectivity was slightly improved (7.1:1) by adding
TMSCl, the overall yield remained the same (38%).
The structures of the three major diastereomers 23a, 25a, and
26a were confirmed by X-ray crystallography. The configura-
tion of minor diastereomer 23b was determined by oxidizing the
mixture of 23a and 23b by Dess-Martin periodinane,19 which
resulted in formation of a single ketone 30. However, the
oxidation of the mixture of 25a and 25b afforded 31 as a
mixture of two products. The structure of minor diastereomer
25b was further confirmed by NOE experiments (Scheme 7).
(18) Dauben, W. G.; Chollet, A. Tetrahedron Lett. 1981, 22, 1583–1586.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155–4156.
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SCHEME 7
SCHEME 9
SCHEME 10
SCHEME 8
aldol reaction products. However, this model fails to explain
the high anti stereoselectivity of bulky aldehyde 22
(Scheme 10). The sole formation of 26a would require the
dominating intermediacy of anti-38, which does not appear
to be greatly favored because of the steric interaction
between bulky aldehyde side chain and cyclohexene ring,
relative to the alternative syn-38, leading to 26b (not
observed). In contrast to these results, Barner observed the
inversion of stereoselectivity from anti to syn in Mukaiyama
aldol reaction of pulegone with bulky aldehydes, which is
inconsistent with the observed increase of anti-selectivity
obtained with increasing bulk from 21 to 22.21 Our results
therefore suggest that the domino Sakurai/aldol/Schmidt
reaction does not involve a Mukaiyama-type aldol reaction
and an open transition state.
The major diastereomer 23a of the domino Sakurai/aldol/
Schmidt reaction could also arise from the corresponding
titanium aldol intermediate 39a or 39b (Scheme 11). The
same anti selectivity of the aldol reaction was also observed
previously in the titanium aldol/Schmidt reaction product
lactam 19 (see Scheme 4), which strongly suggests that these
aldol reaction components involve a titanium enolate
(Scheme 9, route B). In general, the stereochemical outcome
of aldol reactions involving titanium enolates is syn regard-
less of the enolate geometry.13 Thus, (Z)-titanium enolates
have been proposed to react with aldehydes via chairlike
transition states to furnish syn-aldol products,22 whereas (E)-
titanium enolates are believed to utilize boatlike transition
states23,24 similar to 39c to also generate syn products.14,25
The analogous reaction was attempted with the homo-
logous aldehyde substrate, 4-azidobutanal (32)20 (Scheme 8).
We had previously shown that the intramolecular Schmidt
reaction involving a 7-membered azidohydrin intermediate
is possible under strong Lewis acid conditions although less
favorable than those that entail a 6-membered intermediate.3
In the present instance, the resulting aldol product from
4-azidobutanal and enone 2 under strong acidic conditions
resulted in complex mixture without any sight of the desired
Schmidt product 33. Presumably, various side reactions
prevailed before the Schmidt reaction occurred.
Reactions of 2-cyclopenten-1-one were also attempted
with 3-azidoaldehyde 18 and 21, neither of which generated
the desired domino products 34 or 35. Only the 1,4-allylated
Sakurai product of 2-cyclopenten-1-one was observed in the
crude reaction mixtures, suggesting that the aldol reaction
did not proceed in either case. As previously reported by
Kuwajima,12 the titanium enolate generated from cyclopen-
tanone was found to be unstable, possibly explaining the
absence of the desired products.
Unusual Anti-Aldol Selectivity of Domino Sakurai-
Aldol-Schmidt Reaction. To understand the anti-aldol
selectivity of the Sakurai/aldol/Schmidt reaction, we sought
a possible mechanism of this reaction. We initially consid-
ered the silyl enol ether 37 formed from TMSCl and the
titanium enolate 36 generated from the Sakurai reaction as a
potential reaction intermediate (Scheme 9, route A).
(21) Barner, B. A.; Liu, Y.; Bahman, A. Tetrahedron 1989, 45, 6101–6112.
(22) Evans, D. A.; Rieger, D. L.; Bilodeau, M. T.; Urpi, F. J. Am. Chem.
Soc. 1991, 113, 1047–1049.
(23) (a) Yamago, S.; Machii, D.; Nakamura, E. J. Org. Chem. 1991, 56,
2098–2106. (b) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1983, 24,
3343–3346.
(24) Kuwajima, I.; Nakamura, E. Acc. Chem. Res. 1985, 18, 181–187.
(25) Turos, E.; Audia, J. E.; Danishefsky, S. J. J. Am. Chem. Soc. 1989,
111, 8231–8236.
An open transition-state model for the Mukaiyama aldol
reaction could explain the observed anti selectivity of our
(20) Ma, Y. Heteroatom Chem. 2002, 13, 307–309.
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FIGURE 1. Two possible transition states for 2,2-dimethyl-3-propanal (22).
cyclohexyl moiety of the enolate would be an extremely
destabilizing factor (Figure 1).
SCHEME 11
A second possibility invokes a chelation model 39b where-
in the titanium is coordinated to both the carbonyl group
and an azide nitrogen atom. In spite of the low basicity of
sp2 nitrogen atoms, it is known that azide groups can
participate in chelation. Kihlberg proposed chelation of an
azide nitrogen with an acetal oxygen via a Lewis acidic
silicon atom and supported this idea with a 15N NMR
experiment.29 Shimizu proposed a chelated half-chair transi-
tion state to explain anti-1,3-stereoselectivities in nucleo-
philic addition to a 3-azidoimine.30,31 Thus, intermediacy
of chelate 39b could plausibly explain the observed anti-
selectivity of our aldol reaction. It is unclear if such chelation
could compensate for an unfavorable pseudodiaxial inter-
action between an R-hydrogen of the enolate reaction part-
ner and the R-methylene group of the aldehyde in the boat-
like transition state, which would instead favor alternative
boatlike transition state 39c leading to minor aldol inter-
mediate syn-40.24 However, such interactions seems to de-
pend on the situation. For example, Hoppe accounted for a
stereoselective titanium enolate addition by proposing a boat
transition state in which a methyl and tosylamine group were
both placed in 1,2-dipseudoaxial positions.28
If the transition state 39b is responsible for the stereo-
chemical outcome of the present reaction, the same type of
chelate-controlled aldol reaction of (E)-titanium enolate
with other nonazide-containing but chelatable aldehydes
such as 3-benzyloxypropionaldehyde (41) should be also
possible. We tested this hypothesis by performing an aldol
reaction of titanium enolate 17 with 3-benzyloxypropional-
dehyde (41). Titanium enolate 17 was generated by treating
cyclohexanone with TiCl4 followed by i-Pr2EtN.22 The
resulting 17 was treated with aldehyde 41 to obtain aldol
product 42 as a mixture of two diastereomers (anti/ syn=1.8:
1) in 46% yield (Scheme 12). Initial attempts at stereospecific
assignment of the NMR spectrum focused on measuring the
3J(HR-Hβ) coupling constant to assess the dihedral angle
using the Karplus curve (Stiles-House method).32 Unfor-
tunately, we could not measure 3J(HR-Hβ) by selective
We considered two possible explanations to account for
the observed anti-selectivity. The first possibility includes the
formation of a chairlike Zimmerman-Traxler transition
state26 39a instead of a boatlike transition state 39c. How-
ever, there is no clear reason why 3-azido-containing
aldehydes would prefer a chairlike transition state 39a
with (E)-titanium enolate while all of the available pre-
cedents14,23-25,27,28 suggest a boatlike transition state 39c
as being preferred under similar conditions. However, a
corresponding chairlike transition state 39a0 could plausibly
explain the high stereoselectivity observed with bulky alde-
hyde 22, which led to the exclusive formation of anti product.
In this case, alternative boat-transition state 39b0 would be
highly unlikely because unfavorable 1,2-interactions be-
tween tertiary carbon on the aldehyde and R-proton or
(29) Gustafsson, T.; Schou, M.; Almqvist, F.; Kihlberg, J. J. Org. Chem.
2004, 69, 8694–8701.
(30) Shimizu, M.; Yamauchi, C.; Ogawa, T. Chem. Lett. 2004, 33, 606–
607.
(31) In another paper, the authors of ref 30 reported the Lewis acid
promoted allylation of 3-azidoaldehyde but did not invoke azide-aldehyde
chelation for that example. However, chelation seems unlikely under their
reported conditions (excess water and protic acid). See: Shimizu, M.; Nishi,
T. Synlett 2004, 889–891.
(26) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79, 1920–
1923.
ꢀ
(27) (a) Ahrach, M.; Schneider, R.; Gerardin, P.; Loubinoux, B. Tetra-
hedron 1998, 54, 15215–15226. (b) Tanabe, Y.; Matsumoto, N.; Higashi, T.;
Misaki, T.; Itoh, T.; Yamamoto, M.; Mitarai, K.; Nishii, Y. Tetrahedron
2002, 58, 8269–8280.
(32) (a) Kitamura, M.; Nakano, K.; Miki, T.; Okada, M.; Noyori, R.
J. Am. Chem. Soc. 2001, 123, 8939–8950. (b) House, H. O.; Crumrine, D. S.;
Teranishi, A. Y.; Olmstead, H. D. J. Am. Chem. Soc. 1973, 95, 3310–3324. (c)
Stiles, M.; Winkler, R. R.; Chang, Y.-L.; Traynor, L. J. Am. Chem. Soc. 1964,
86, 3337–3342.
€
€
(28) Bruggemann, M.; Frohlich, R.; Wibbeling, B.; Holst, C.; Hoppe, D.
Tetrahedron 2002, 58, 321–340.
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SCHEME 12
SCHEME 13
Evans nonchelating dipole interaction model.36 However,
both analyses predict the formation of 1,3-anti products. To
the best of our knowledge, this aldol reaction with aldehyde 18
is a very rare example of 1,3-syn asymmetric induction.37
However, the origin of this 1,3-syn selectivity is unclear in this
point and the subject of further investigation in our laboratory.
Experimental Section
General Procedures. All reaction solvents were purified before
use. Tetrahydrofuran, dichloromethane, and diethyl ether were
purified by passing through a solvent column composed of
activated A-1 alumina. Unless indicated otherwise, all reactions
were conducted under an atmosphere of nitrogen or argon using
flame-dried glassware. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a commercial 400 MHz
instrument. Carbon-13 nuclear magnetic resonance (13C NMR)
spectra were recorded at 100 MHz. The proton signal for
residual nondeuterated solvent (δ 7.2638 for CHCl3) was used
homonuclear decoupling because of overlapping of the
peaks and the complex splitting patterns in the decoupled
1
1D H spectrum. Alternatively, the E-COSY experiment33
was recorded and analyzed for 42. However, the presence of
multiple passive coupling led to complex cross-peak pat-
terns, which did not yield conclusive 3J(HR-Hβ) values.
These complications motivated us to use NOE-based
approach to assign the diastereomers through interproton
distances. The initial slope of the NOE buildup curves
1
as an internal reference for H NMR spectra. For 13C NMR
spectra, chemical shifts are reported relative to the δ 77.0
resonance of CDCl3. Coupling constants are reported in hertz.
1-(3-Allylpyrrolidin-1-yl)ethanone (9). To a solution of 65 (68
mg, 0.49 mmol) in CH2Cl2 (0.3 M with respect to 6) at -78 °C
were added titanium tetrachloride (2 equiv) and allyltrimethyl-
silane (2 equiv). The solution was stirred at -78 °C for 3 h and
allowed to warm to 0 °C over 5 h. MeOH (5 equiv) was added,
and the solution was stirred at room temperature for 45 min.
The reaction mixture was quenched by the addition of a
saturated solution of ammonium chloride and extracted with
CH2Cl2. The organic layer was washed with brine and aqueous
saturated NaHCO3 solution. On evaporation and purification
of the organic layer by chromatography, the oily product 9 was
obtained as a mixture of rotamers (35 mg, 47%): IR (neat) 3460,
1610, 1610 cm-1; HRMS-ESI (m/z) [M þ Hþ] calcd for
C9H16NOþ 154.1232, found 154.1380; major rotamer 1H
NMR (400 MHz, CDCl3) δ 1.59-1.69 (m, 1H), 1.92-2.40 (m,
4H), 2.02, (s, 3H), 2.96-3.11 (m, 1H), 3.28-3.45 (m, 1H),
3.46-3.75 (m, 2H), 4.95-5.15 (m, 2H), 5.67-5.86 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 22.2, 31.6, 37.2, 38.9, 47.0, 52.3,
measured via
a GOESY (gradient enhanced NOE
spectroscopy) experiment34 enabled us to assign the major
product as anti-42 (for details, see the Supporting
Information). The moderate level of diastereoselectivity
from the titanium aldol reaction between cyclohexanone
and 42 showed that chelation control is still possible even
with an unfavorable 1,2-diaxial-like interaction in the pro-
posed boat transition state analogous to 39b. This experi-
ment also provides indirect evidence that our 3-azido-
aldehyde substrates could react with the titanium enolate
of cyclohexanone via chelated boat transition state 39b.
Unusual 1,3-Syn-Selectivity in the Aldol Reaction of 3-Azi-
dononanal (18). Another unexpected stereochemical out-
come was observed in the reaction between 3-azidononanal
18 and enone 2. Specifically, the aldol products 43a and 43b
were formed with unusually high 1,3-syn-stereoselectivity,
which was the sole relative stereochemistry observed in both
products isolated from this reaction (Scheme 13).
116.4, 136.0, 169.3; minor rotamer (diagnostic peaks only): 13
C
NMR (100 MHz, CDCl3) δ 22.4, 30.2, 37.2, 37.4, 45.1, 50.2,
116.6, 136.1, 169.3.
(9R*,9aS*)-9-Allylhexahydro-1H-pyrrolo[1,2-a]azepin-5(6H)-
one (14). To a solution of azido enone 10 (58 mg, 0.32 mmol) in
CH2Cl2 (1 mL) at -78 °C were added TiCl4 (0.12 mg,
0.65 mmol) and allyltrimethylsilane (0.10 mL, 0.65 mmol).
There are two widely accepted models for 1,3-asymmetric
induction in the nucleophilic addition to β-heteroatom-sub-
stituted aldehydes. Those are the Reetz chelation model35 and
(36) Evans, D. A.; Duffy, J. L.; Dart, M. J. Tetrahedron Lett. 1994, 35,
8537–8540.
(33) Griesinger, C.; Soerensen, O. W.; Ernst, R. R. J. Am. Chem. Soc.
2002, 107, 6394–6396.
(34) Stonehouse, J.; Adell, P.; Keeler, J.; Shaka, A. J. J. Am. Chem. Soc.
2002, 116, 6037–6038.
(35) Reetz, M. T.; Jung, A. J. Am. Chem. Soc. 1983, 105, 4833–4835.
(37) For an example of 1,3-syn-stereoselective aldol reaction under non-
chelating conditions, see: Boxer, M. B.; Yamamoto, H. J. Am. Chem. Soc.
2005, 128, 48–49.
(38) Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62,
7512–7515.
7624 J. Org. Chem. Vol. 74, No. 20, 2009

Huh et al.
JOCFeatured Article
The solution was stirred at -78 °C for 3 h and allowed to come
to 0 °C over 5 h. t-BuOH (0.15 mL, 1.6 mmol) was added, and
the solution was stirred at room temperature for 45 min. The
reaction mixture was then quenched by the addition of a
saturated solution of ammonium chloride and extracted with
CH2Cl2. The organic layer was washed with brine and aqueous
saturated sodium bicarbonate solution. Upon evaporation and
purification of the organic layer by chromatography (SiO2, 5%
MeOH in CH2Cl2), a mixture of two diastereomeric products 14
was obtained as an oil (49 mg, 79%, dr >9:1): HRMS (ESI) m/z
calcd for C12H20NO [M þ Hþ] 194.1545, found 194.1570. Major
diastereomer 14a: oil; IR (neat) 2940, 1630 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.40-2.69 (m, 13H), 3.16-3.29 (m, 1H),
3.80-3.92 (m, 1H), 3.98-4.09 (m, 1H), 4.99-5.14 (m, 2H),
5.64-5.80 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 17.5, 23.7,
28.9, 31.6, 32.4, 37.9, 40.0, 47.5, 61.4, 116.6, 136.7, 173.9. Minor
diastereomer 14b: oil; IR (neat) 2920, 1630 cm-1; 1H NMR (400
MHz, CDCl3) δ 1.12-2.67 (m, 13H), 3.21-3.36(m, 1H),
3.48-3.61 (m, 1H), 3.80-3.95 (m, 1H), 5.02-5.15 (m, 2H),
5.64-5.84 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.9, 23.1,
28.9, 32.5, 34.6, 37.6, 42.2, 62.9, 62.6, 117.1, 135.6, 174.7.
(8R*,8aS*)-8-Allylhexahydroindolizin-5(1H)-one (15a) and
(8R*,8aR*)-8-Allylhexahydroindolizin-5(1H)-one (15b). To a
solution of azido enone 11 (144 mg, 0.87 mmol) in CH2Cl2
(3 mL) at -78 °C were added titanium tetrachloride (0.24 mL,
1.75 mmol) and allyltrimethylsilane (0.28 mL, 1.75 mmol). The
solution was stirred at -78 °C for 3 h and allowed to come to
0 °C over 5 h. tert-Butyl alcohol (0.41 mL, 4.4 mmol) was added,
and the solution was stirred at room temperature for 45 min.
The reaction mixture was quenched by the addition of a
saturated solution of ammonium chloride and extracted with
CH2Cl2. The organic layer was washed with brine and aqueous
saturated sodium bicarbonate solution. On evaporation and
purification of the organic layer by chromatography (SiO2, 5%
MeOH in CH2Cl2), a mixture of two diastereomeric products 15
was afforded as an oil (78 mg, 50%, dr = 64:36). Major
diastereomer 15a: oil; IR (neat) 2940, 1610, 1410 cm-1; HRMS
(ESI) m/z calcd for C11H18NO [M þ Hþ] 180.1388, found
mL, 1.0 mmol) in 5 mL of CH2Cl2 was added cyclohexenylo-
xytrimethylsilane (16) dropwise at ambient temperature. The
resulting mixture was stirred for 2 min and then cooled to
-45 °C (acetonitrile-dry ice bath). A solution of 3-azidono-
nanal (18, 210 mg, 1.1 mmol) in 0.6 mL of CH2Cl2 was added
slowly to the in situ generated titanium enolate solution. The
reaction mixture was stirred at -45 °C for 10 min and rt for 24 h.
After being quenched with 20 mL of aqueous saturated NH4Cl
solution, the organic layer was extracted with CH2Cl2 (20 mL ꢀ
3), and the combined extracts were dried over Na2SO4, filtered,
and concentrated to afford crude product. The crude product
was purified by column chromatography (SiO2, 5%
MeOH-CH2Cl2) to afford 19 (135 mg, 53%) as a mixture of
four diastereomers (major/sum of all minors = 56:44). From
further purification with column chromatography and recrys-
tallization from THF, a pure major diastereomer could be
obtained: mp 122-124 °C; IR (thin layer) 1618 cm-1; HRMS-
ESI (m/z) [M þ Hþ] calcd for C15H27NO2 254.2115, found
254.2097. Major diastereomer: mp 122-124 °C; 1H NMR (400
MHz, CDCl3) δ 0.82-0.87 (m, 3H), 1.10-1.34 (m, 10H),
1.43-1.58 (m, 2H), 1.80-1.89 (m, 3H), 1.95 (ddd, J = 12.4,
6.4, 1.6 Hz, 1H), 1.99-2.04 (m, 1H), 2.05-2.10 (m, 1H),
2.43-2.46 (m, 2H), 3.76 (dd, J=10.8, 7.2 Hz, 1H), 3.96-4.01
(m, 1H), 4.47 (dt, J=10.4, 6.8 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.0, 22.6, 23.5, 26.4, 27.0, 29.0, 29.2, 31.8, 33.8, 35.0,
38.1, 55.2, 61.7, 70.5, 174.4. Minor diastereomers (diagnostic
peaks correspond to the 3.76 ppm peak of the major
1
diastereomer): H NMR (400 MHz, CDCl3) 3.72 (d, J=10.4
Hz, 1H, first minor diastereomer), 3.40 (dd, J=10.4, 6.4 Hz, 1H,
second minor diastereomer), 3.18-3.22 (m, 1H, third minor
diastereomer).
General Conditions A for Domino Sakurai/Aldol/Schmidt
Reaction for Azido-Containing Aldehyde Substrates. To a solu-
tion of enone (1.0 mmol) in 5 mL of CH2Cl2 was added TiCl4
(0.11 mL, 1.0 mmol) followed by allytrimethylsilane (0.22 mL,
1.4 mmol) dropwise at -45 °C under a nitrogen atmosphere.
The resulting deep red solution was stirred for 1 h at -45 °C. To
this reaction solution was added slowly the azidoaldehyde (1.6
mmol) dissolved in 1 mL of CH2Cl2 over a 3 min period. After
being stirred at -45 °C for 10 min, the reaction flask was
disconnected from nitrogen source, wrapped with parafilm,
and kept in a 0 °C refrigerator for 24 h without stirring. The
flask was brought out to place in an ice bath. Upon stirring, the
reaction was quenched with aqueous saturated NH4Cl solution
(50 mL), and the aqueous layer was extracted three times with
CH2Cl2 (3 ꢀ 50 mL). The combined CH2Cl2 solution was dried
over Na2SO4, filtered, and concentrated. The resulting crude
material was purified by column chromatography (SiO2, 10%
MeOH/CH2Cl2) to afford the corresponding lactam products.
General Conditions B for Domino Sakurai/Aldol/Schmidt
Reaction. The same procedure as A was followed up to the
point where the reaction flask was placed in a 0 °C refrigerator.
Then, the reaction flask was kept for only 6 h in the refrigerator
instead of 24 h. Upon stirring at 0 °C under nitrogen atmo-
sphere, an additional 2 equiv of TiCl4 (0.22 mL, 0.2 mmol) was
added, which resulted in gentle bubbling. After the bubbling
subsided, the reaction flask was again kept in a 0 °C refrigerator
for 18 h. The workup procedure was initiated by quenching with
aqueous saturated NH4Cl and was thereafter identical to the
general procedure A.
1
180.1360; H NMR (400 MHz, CDCl3) δ 1.60-2.08 (m, 7H),
2.09-2.63 (m, 4H), 3.45-3.63 (m, 2H), 3.64-3.77 (m, 1H),
5.06-5.18 (m, 2H), 5.69-5.84 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.2, 24.1, 26.2, 28.7, 29.5, 32.9, 45.5, 62.3, 117.1,
135.6 170.5. Minor diastereomer 15b: oil; IR (neat) 2920, 1610,
1410 cm-1; HRMS (ESI) m/z calcd for C11H18NO [M þ H]þ
180.1388, found 180.1369; 1H NMR (400 MHz, CDCl3) δ
1.36-2.68 (m, 11H), 3.06-3.24 (m, 1H), 3.44-3.70 (m, 2H),
5.03-5.22 (m, 2H), 5.69-5.88 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 22.1, 26.3, 30.5, 32.1, 36.9, 39.8, 45.6, 63.8, 117.5,
134.9, 170.5.
(8R*,8aR*)-8-Allylhexahydroindolizin-5(1H)-one (15b). To a
solution of azidoenone 11 (144 mg, 0.87 mmol) in CH2Cl2
(3 mL) at -78 °C were added titanium tetrachloride (0.24 mL,
1.75 mmol) and allyltrimethylsilane (0.28 mL, 1.75 mmol). The
solution was stirred at -78 °C for 2 h before quenching with
aqueous saturated NH4Cl solution. The biphasic mixture was
warmed to rt. The organic layer was extracted with 50 mL ether
and washed with aqueous saturated NaHCO3 solution and
brine. The solution was dried over Na2SO4, filtered, and con-
centrated. The resulting crude residue was dissolved in 0.9 mL of
trifluoroacetic acid. The resulting mixture was stirred at rt for
30 min. The reaction mixture was diluted with 50 mL of ether
and quenched carefully with aqueous saturated NaHCO3. The
organic layer was separated, washed with brine, dried (Na2SO4),
filtered, and concentrated. The crude oil residue was purified by
column chromatography (SiO2, 5% MeOH in CH2Cl2) to afford
15b as an oil (74 mg, 47%).
(1S*,9R*,9aS*)-9-Allyl-1-hydroxyhexahydro-1H-pyrrolo-
[1,2-a]azepin-5(6H)-one (23a). Compound 23 was prepared from
2-cyclohexen-1-one (12, 0.10 mL, 0.10 mmol) and 3-azidopro-
pionaldehyde (21, 160 mg, 1.6 mmol) using either general
conditions A or general conditions B. After column purification,
79 mg of 23a/b was obtained as a solid mixture of two diaster-
eomers (ratio=6.4:1) by following conditions A or 123 mg of
23a/b as an oily mixture of three diastereomers (ratio=2.6:1) by
(1S*,3S*,9aS*)-3-Hexyl-1-hydroxyhexahydro-1H-pyrrolo-
[1,2-a]azepin-5(6H)-one (19). To a stirred solution of TiCl4 (0.11
J. Org. Chem. Vol. 74, No. 20, 2009 7625

Huh et al.
JOCFeatured Article
following the conditions B. The structure of the major diaster-
eomer 23a was determined by X-ray crystallography after
recrystallization from MeOH/EtOAc: mp 171-172°; IR (neat)
3250, 1610 cm-1; HRMS calcd for C12H20NO2 [M þ Hþ]
a solid single diastereomer by following general conditions
A or 133 mg (56%) of 26a as a solid single product by follow-
ing general conditions B. The structure of the 26a was
determined by X-ray crystallography after recrystallization
from tetrahydrofuran: mp 154-155 °C; IR (thin layer) 3282
(br), 2916, 1606 cm-1; HRMS calcd for C14H24 NO2 [M þ Hþ]
238.1807, found 238.1792; 1H NMR (400 MHz, CDCl3) δ 0.92
(s, 3H), 1.08 (s, 3H), 1.32 (tdd, J = 14.0, 10.8, 3.2 Hz, 1H),
1.45-1.56 (m, 1H), 1.74-1.82 (m, 1H), 1.85-1.92 (m, 1H),
1.99-2.08 (m, 2H), 2.28 (ddd, J = 14.8, 12.0, 2.8 Hz, 1H),
2.38-2.44 (m, 1H), 2.57 (dd, J=6.0 Hz, 14,4 Hz, 1H), 3.23 (d,
J=11.2 Hz, 1H), 3.62 (dd, J=9.6, 4.0 Hz, 1H), 3.67 (d, J=11.2
Hz, 1H), 3.83 (t, J=4.4 Hz, 1H), 5.04-5.09 (m, 2H), 5.75-5.85
(m, 2H); 13C NMR (100 MHz, CDCl3) δ 19.9, 21.5, 24.4, 34.3,
36.7, 37.3, 38.0, 39.4, 56.4, 65.6, 79.5, 116.4, 136.5, 175.0.
(S*)-2-((S*)-3-(Benzyloxy)-1-hydroxypropyl)cyclohexanone
(anti-42) and (S*)-2-((R*)-3-(Benzyloxy)-1-hydroxypropyl)cy-
clohexanone (syn-42). The Evans protocol for titanium aldol
reaction was followed.24 To a solution of cyclohexanone (0.35
mL, 3.4 mmol) in CH2Cl2 (17 mL) was added TiCl4 (0.40 mL,
3.6 mmol) as a neat solution dropwise at -78 °C. Three minutes
later, i-Pr2EtN (0.68 mL, 3.9 mmol) was added to the resulting
pale yellow solution which resulted in a gradual color change to
dark red. The reaction mixture was then stirred at -78 °C for 1 h
to ensure the formation of the titanium enolate. A solution of 3-
benzyloxypropionaldehyde (41, 0.46 g, 2.8 mmol) in CH2Cl2
(2.8 mL) was then added slowly over 5 min. After the addition of
aldehyde, the reaction mixture was stirred at -78 °C for 2 h
before quenching with aqueous saturated NH4Cl solution
(20 mL). After being warmed to rt, the reaction mixture was
diluted with 50 mL of ether. The organic layer was separated and
washed successively with aqueous saturated NaHCO3 solution
(30 mL) and brine (30 mL) and then dried over Na2SO4, filtered,
and concentrated to afford crude mixture. NMR analysis on the
resulting crude mixture showed a diastereomeric ratio of 1.8:1.
The resulting crude mixture was purified by column chroma-
tography (SiO2, 33% EtOAc in hexanes) to afford 42 (316 mg,
46%) as an inseparable mixture of two diastereomers: IR (thin
layer) 3507, 2932, 2859, 1702, 1451, 1100 cm-1; HRMS calcd for
1
210.1494, found 210.1508. Major diastereomer 23a: H NMR
(400 MHz, CDCl3) δ 1.31-1.44 (m, 1H), 1.45-1.62 (m,
1H), 1.73-1.82 (m, 2H), 1.84-1.96 (m, 3H), 2.10 (dt, J=15.2,
8.0 Hz, 1H) 2.33-2.25 (m, 1H), 2.47-2.41 (m, 1H), 2.54 (ddd,
J=14.4, 6.8, 2.4 Hz, 1H), 3.41 (dd, J=9.6, 4.0 Hz, 1H) 3.51 (td,
J=11.2, 6.0 Hz, 1H), 3.94 (ddd, J=11.6, 8.0, 2.0 Hz, 1H), 4.53
(dd, J=dd, J=6.0, 4.0 Hz, 1H) 5.08-5.02 (m, 2H), 5.86-5.72
(m, 1H); 13C NMR (100 MHz, CDCl3) δ 21.2, 32.1, 33.6, 36.7,
37.3, 38.0, 45.3, 66.6, 72.7, 116.7, 136.4, 174.6. Minor diaster-
eomer 23b: 1H NMR (400 MHz, CDCl3, diagnostic peaks only
from the mixture) 3.69 (ddd, J =12.0, 9.2, 7.2 Hz, 1H), 4.41 (m,
1H) ppm.
2-(1-Azidohex-5-en-3-yl)cyclohex-2-enone (24). Isolated as a
side product from the reaction described above, following
conditions A: IR (neat) 2924, 2096, 1674, 1456 cm-1; HRMS
calcd for C12H18NO [M - N2 þ Hþ] 192.1383, found 192.1369.
1H NMR (400 MHz, CDCl3) δ 1.71-1.81 (m, 2H), 1.93-2.00
(m, 2H), 2.15-2.27 (m, 2H), 2.37-2.44 (m, 4H), 2.76 (apparent
quint, J=7.2 Hz, 1H) 3.17 (t, J=7.2 Hz, 2H), 4.93-4.95 (m, 1H),
4.97 (dd, J=1.2, 1.2 Hz, 1H), 5.58-5.69 (m, 1H) 6.69 (t, J=4.4
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 22.8, 26.1, 32.4, 36.1,
38.6, 38.8, 49.7, 116.4, 136.4, 140.7, 145.7, 198.9.
(1S*,3S*,9R*,9aS*)-9-Allyl-3-hexyl-1-hydroxyhexahydro-
1H-pyrrolo[1,2-a]azepin-5(6H)-one (25a). Prepared from 2-cy-
clohexen-1-one (12, 0.10 mL, 0.10 mmol) and 3-azidononanal
(18, 290 mg, 1.6 mmol) using either general conditions A or
general conditions B. After purification with column chroma-
tography, 101 mg (34%) of 25a/b was obtained as a solid
mixture of two diastereomers (ratio=4.2:1) by following the
general conditions A or 173 mg (59%) of 25a/b as a solid mixture
of four diastereomers (ratio between major and sum of all other
minor diastereomer=1.8:1) by following the general conditions
B. The structure of the major diastereomer 25a was determined
by X-ray crystallography after recrystallization from MeOH/
EtOAc: mp 96-98 °C; IR (neat) 1614 cm-1; HRMS calcd for
C18H32NO2 [M þ Hþ] 294.2428, found 294.2426. Major dia-
stereomer 25a: 1H NMR (400 MHz, CDCl3) δ 0.88 (t, J=6.8 Hz,
3H), 1.25 (m, 9H), 1.49-1.58 (m, 2H), 1.66-1.72 (m, 2H), 1.76
(dt, J=13.2, 6.0 Hz, 1H), 1.88-1.97 (m, 2H), 2.00-2.12 (m, 2H),
2.31-2.50 (m, 3H), 3.40 (dd, J=8.8, 5.2 Hz, 1H) 4.13 (m, 1H),
4.42 (dd, J=10.8, 5.2 Hz, 1H), 5.02 (d, J=10.8 Hz, 1H), 5.05 (d,
J = 17.2 Hz, 1H), 5.72-5.81 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 18.3, 22.6, 25.7, 28.1, 29.2, 31.9, 33.6, 34.0, 34.8,
36.3, 37.0, 55.8, 65.5, 71.3, 116.7, 136.5, 173.3. Minor diaster-
eomer 25b: 1H NMR (400 MHz, CDCl3) 0.86 (t, J=6.8 Hz, 3H),
1.33 (m, 9 H), 1.37-1.57 (m, 3H), 1.79-1.97 (m, 5H), 2.03-2.11
(m, 1H), 2.34-2.46 (m, 3H), 3.35 (dd, J=9.6, 4.4 Hz), 4.20 (m,
1H), 4.43 (dd, J = 10.8, 6.4 Hz, 1H), 5.04-5.11 (m, 2H),
5.76-5.83 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 14.0, 21.8,
22.6, 26.3, 29.3, 31.8, 34.3, 34.5, 36.9, 37.1, 37.5, 41.9, 56.2, 70.3,
74.6, 116.9, 136.4, 173.8.
1
C16H22NaO3 [M þ Hþ] 285.1461, found 285.1440; H NMR
(400 MHz, CDCl3) δ 1.36-1.86 (m, 7H), 1.95-2.02 (m, 1H),
2.04-2.11 (m, 1H), 2.18-2.38 (m, 3H), 2.94 (d, J=3.6 Hz, 0.3H,
syn-42), 3.49 (d, J=4.0 Hz, 0.7H, anti-42), 3.57-3.60 (m, 0.6H,
syn-42), 3.62 (t, J=6.4 Hz, 1.4H, anti-42), 3.91 (dddd, J=9.2,
6.8, 4.0, 2.8 Hz, 0.7H, anti-42), 4.19 (dddd, J=9.2, 3.6, 3.6, 3.6
Hz, 0.3H, syn-42), 4.44 (s, 0.6H, syn-42), 4.45 (s, 1.4H, anti-42),
7.19-7.29 (m, 5H) ppm.
Acknowledgment. We thank the National Institutes of
Health (GM-49093) for support of this work. We also thank
Dr. David Vander Valde and Sarah Ann Neuenswander for
NMR analysis and Dr. Victor Day for X-ray crystallogra-
phy.
Supporting Information Available: Experimental details and
characterization data for substrates 10 and 11 and their syn-
thetic intermediates, 1H/13C NMR spectra for new compounds,
and X-ray data for compounds 19 (major), 23a, 25a, and 26a
(CIF). This material is available free of charge via the Internet at
http://pubs.acs.org.
(1S*,9R*,9aS*)-9-Allyl-1-hydroxy-2,2-dimethylhexahydro-
1H-pyrrolo[1,2-a]azepin-5(6H)-one (26a). Prepared from 2-cy-
clohexen-1-one (2, 0.10 mL, 0.10 mmol) and 3-azido-2,2-
dimethylpropanal (22, 290 mg, 1.6 mmol) using either general
conditions A or general conditions B. After purification with
column chromatography, 100 mg (42%) of 26a was obtained as
7626 J. Org. Chem. Vol. 74, No. 20, 2009